Review Article

Introduction

Lichtenstein tension-free mesh repair has been the standard practice in open inguinal hernia repair for many years. The procedure involves suture fixation of the mesh via an anterior approach to the inguinal canal. It is hypothesised that this invasive fixation contributes to the development chronic postoperative inguinal pain (CPIP), a condition which can cause significant morbidity.

A sound repair should restore the groin anatomy whilst minimising recurrence and not adversely affecting the patient quality of life. Considering the large number of these operations performed each year, reducing complications such as chronic postoperative pain will have a significant impact on healthcare resources.

The introduction of anatomical self-adhesive meshes such as Parietx ProGrip^TM addresses this concern in theory by obviating the need for mesh fixation. This mesh is a macro porous polyester mesh that utilizes polylactic acid micro grips (PLA) to aid placement within 60 seconds¹ without the need for additional fixation. The manufacturer does suggest, however, that additional fixation is left to the discretion of the operating surgeon.

We conducted a review of the literature to evaluate the reported outcomes of using this mesh in open inguinal hernia repair.

Methods

We conducted a PUBMED/MEDLINE search using the search words “Self-adhesive mesh”, “Lichtenstein repair”, “Open inguinal hernia repair” and “Self-gripping mesh” .We looked primarily at the outcomes of postoperative pain and recurrence. The result highlighted five well-structured meta-analyses and several RCTs and retrospective reviews.

Results

In a retrospective review of 211 patients who underwent open inguinal hernia repair with self-adhesive mesh, Tarchi P et al reported a recurrence rate of 0.5% at 1 year and 2.4% at 2 years. They incidence of chronic pain was less than 3%. There were no cases of seroma, testicular complications or mesh infection at 1, 2 and 3-year follow-up. The report highlighted the shorter operative duration with no effect on recurrence rates as a point in favour of self-adhesive mesh. The authors acknowledged the limitation of the study design and the need for randomised trials to address the issue.⁸ A few other small non-randomised trials draw similar conlusions.⁹

A randomised blinded trial from the Danish Multicentre DANGRIP Study Group allocated 163 vs 171 patients to self-adhesive and suture fixation respectively. There were no significant differences between the groups in postoperative complications (33.7 versus 40.4 %; P = 0·215), rate of recurrent hernia within 1 year (1.2 % in both groups) or quality of life. The 12 month prevalence of moderate or severe symptoms was 17.4 and 20.2% respectively (P = 0.573).

The study concluded that the avoidance of suture fixation using a self-gripping mesh was not accompanied by a reduction in chronic symptoms after inguinal hernia repair. ⁵

The FinnMesh trial is a randomised multicentre trial from Finland that Compared glue fixation, self-gripping mesh, and suture fixation of mesh. 625 patients were randomised to cyanoacrylate glue (Histoacryl, n = 216), self-gripping mesh (Parietex ProGrip, n = 202), or conventional non absorbable sutures (Prolene 2-0, n = 207) There was no significant differences postoperatively in pain response or need for analgesics between the study groups at 1 year follow up. The mean operative duration was lower in the self-adhesive mesh group.⁶

The HIPPO trial is a randomised double-blinded trial of 165 patients. The reported hernia recurrence rate after 24 months was 2.4% for the ProGrip mesh and 1.8% for the sutured mesh (P = 0.213).

The incidence of CPIP was 7.3% at 3 months declining to 4.6% at 24 months and did not differ between both groups. ⁷ The mean duration of surgery was significant shorter with the ProGrip mesh (44 vs 53 minutes, P < 0.001).

In a systematic review of 7 studies comparing self-gripping versus sutured mesh for inguinal hernia repair totalling 1353 patients, Zhang C et al found no difference in recurrence (risk difference -0.02 [95% confidence interval -0.07 to 0.03], P = 0.40) or chronic pain (risk difference -0.00 [95% confidence interval -0.01 to 0.01], P = 0.57). ² This review found no difference in wound infection, hematoma, and seroma formation. Self-adhesive mesh was again associated with a shorter mean operative duration. In its conclusion, the authors surmised that both mesh types are comparable in outcome but further long term analysis might be needed.

Pandanaboyana S published a meta-analysis of 5 RCTs and 1170 patients, that also found no significant difference in recurrence or chronic pain. Wound infection was lower in the self-gripping mesh group compared to sutured mesh but this was not statistically significant (risk ratio (RR) 0.57, 95% confidence interval 0.30-1.06, P = 0.08). The duration of operation was significantly shorter with self-gripping mesh compared to sutured mesh with a mean difference of -5.48 min [-9.31, -1.64] Z = 2.80 (P = 0.005).³

In another meta-analysis, Li J et al included 5 RCTs and 2 prospective comparative studies and 1353 patients. Statistically, there was no difference in the incidence of chronic pain [odds ratio = 0.74, 95% confidence interval (CI) (0.51-1.08)]. There was no statistical difference in the incidence of acute postoperative pain [odds ratio = 1.32, 95% CI (0.68-2.55)], hematoma or seroma [odds ratio = 0.89, 95% CI (0. 56-1.41)], wound infection [risk difference = -0.01, 95% CI (-0.02 to 0.01)], and recurrence [risk difference = 0.00, 95% CI (-0.01 to 0.01)]. The self-gripping mesh group was associated with a shorter operating time (1-9 minutes).¹⁰

In Ismail A et al’s meta-analysis of 12 randomized controlled trials and 5 cohort studies, 3722 patients were included in the final analysis. The two groups, using self-gripping mesh or sutured mesh fixation, did not differ significantly in terms of recurrence rate (odds ratio = 0.66, 95% confidence interval 0.18-2.44; P = 0.54) or postoperative chronic groin pain (odds ratio = 0.75, 95% confidence interval 0.54-1.05; P = 0.09). The operative time was less in the self-gripping mesh group (mean difference = -7.85, 95% confidence interval -9.94 to -5.76; P < .0001). There were comparable risks between self-gripping mesh and sutured mesh fixation groups in terms of postoperative infection (odds ratio = 0.81, 95% confidence interval 0.53-1.23; P = 0.32), postoperative hematoma (odds ratio = 0.97, 95% confidence interval 0.7-1.36; P = 0.9), and urinary retention (odds ratio = 0.66, 95% confidence interval 0.18-2.44; P =0.54).¹¹

A more recent meta-analysis including 10 RCTs and 2541 patients also draws similar conclusions, with no significant difference in the incidence of chronic pain (odds ratio = 0.93; 95% confidence interval, 0.74-1.18), recurrence (odds ratio = 1.34; 95% confidence interval, 0.82-2.19), or foreign body sensation (odds ratio = 0.82; 95% confidence interval, 0.65-1.03).⁴ The mean operating time was significantly shorter (odds ratio = -7.58; 95% confidence interval, -9.58 to -5.58) in the self-gripping mesh group which is consistent with the reported literature.

Discussion

Open inguinal hernia repair is a routinely performed operation and chronic postoperative inguinal pain is a significant cause of morbidity that can impact negatively on patients’ quality of life. Eliminating the need for suture fixation seems theoretically a step in the right direction.

The published literature, however, seems to arrive at similar conclusions. Whilst using self-adhesive mesh results in a shorter operative duration and seemingly does not affect the outcome negatively otherwise, there is no evidence that it reduces postoperative chronic pain and therefore should not be advocated on this merit. A shortened operative time coupled with a non-inferior outcome does seem like a more reasonable evidence-based argument for its proponents.

The decision of which mesh fixation technique to use can be left to the discretion of the operating surgeon. Further long-term follow up data is required to arrive at more definitive conclusions as the mean follow up duration in the reviewed studies ranged from 4 months to 3 years. The cost implications involved in the choice of mesh used should also be taken into account in future studies.

Schizophrenia (SCZ) is a chronic relapsing and remitting disorder with a lifetime prevalence of 4 per 1000 persons.¹Positive symptoms include delusions and hallucinations. Negative symptoms are characterised by deficits in normal behaviour, which are categorised into five domains: blunted affect, alogia, social withdrawal, anhedonia, and avolition. In clinical practice, when monotherapy fails multiple augmentation strategies – such as another antipsychotic, mood-stabilisers, benzodiazepines, lithium, electroconvulsive therapy, and repetitive trans-cranial magnetic stimulation – have been used to improve the clinical state of these patients, but evidence relating to the use of these interventions is lacking.²None of the regulatory bodies has openly endorsed polytherapy with antipsychotics.

The introduction of chlorpromazine in the 1950s revolutionised psychiatry, and the coming of slow-release, slow-acting forms (depot medication) contributed to the closure of asylums and paved the way to community psychiatry. Second-generation antipsychotics ameliorated the situation for a number of psychotic patients, but some remained resistant to all forms of psychopharmacology. In 1958, clozapine was formulated and marketed commercially in 1972. ³ The arrival of clozapine facilitated the rescue of some schizophrenia sufferers for a short time, but the drug disappeared from the scene because of initial untoward incidents. ^4,5 The observation that clozapine has the potential to control the motor symptoms of tardive dyskinesia and to treat the psychotic symptoms of patients already diagnosed with tardive dyskinesia, led to its reintroduction, but with restrictions. ^6,7,8 Clozapine is recommended for use only after a trial of two other antipsychotics. Combining depot antipsychotics with oral drugs of a different class has been the practice ever since the introduction of depot medications, and this practice has come to have general clinical acceptance.

Treatment resistance

Historically, it was observed that a specific group of chlorpromazine users remained symptomatic. They were considered to be refractory to phenothiazines. The availability of clozapine led to a better definition of treatment resistance. ‘Response to treatment’ means a reduction in the severity of symptoms, while ‘remission’ implies an absence of symptoms for a considerable period. ‘Recovery’ signifies absence of the disease for a long period.⁹‘Treatment resistant schizophrenia’ (TRS) is the term used for persistence of psychotic symptoms despite a certain number of adequate treatments. Since the introduction of first-generation antipsychotics, clinicians have been cognizant of TRS and operational definitions have been used such as those developed by Kane et al. ¹⁰ Sometimes, treatment has been based on algorithms such as the Texas Medication Algorithm Project (TMAP).

According to the most common definition of TRS, if patients present with persistent, moderate to severe, positive disorganization or negative symptoms together with poor social and work function over a prolonged period of time after at least 2 adequate trials of neuroleptic drugs, they may meet the criteria of having TRS. ¹¹ A common agreement is that adequate drug treatment requires a duration of 4 to 10 weeks, a dosage equivalent to 1000 mg/d of chlorpromazine, and trials of 2 to 3 different classes of antipsychotic drugs. ¹² The current treatment guidelines recommend 2 or more treatment trials of atypical antipsychotics at adequate dosages. Adequate response to treatment has been defined as at least a 20% reduction in symptoms as measured by rating scales. Typical antipsychotics can also be used for 4 to 6 weeks to screen for TRS.

Resistance to treatment and poor outcome are different from genuine TRS. Resistance to treatment may be defined as a state in which the patient has access to medication, but the effectiveness of the treatment is suboptimal. TRS may be conceptualised as a state in which medication has reached target receptors but does not seem to be effective. Chronicity has often been misconstrued with treatment-resistance. Schizophrenia is a chronic disorder that progresses to various levels of clinical deterioration without sustained remission or full recovery. Poor-outcome SCZ applies to 50% of patients, and TRS comprises a subset of such patients. In these, cognitive impairment, negative symptoms and mood symptoms are independent of positive symptoms, resulting in poor-outcome SCZ.

It is generally accepted that 30% of SCZ sufferers have TRS. Many people with SCZ do not achieve a satisfactory treatment response to their initial antipsychotic drug treatment. They may manifest a poor response to therapy because of intolerance to medication, poor adherence and inappropriate dosing, as well as true resistance of their illness to antipsychotic drug therapy. Assessing treatment resistance is a priority in the management of TRS. ¹³ TRS has to be closely evaluated before a comprehensive management plan is developed (Table 1). From a multidimensional point of view, TRS is dependent on manifold factors, such as longer duration, several episodes, gender, early onset, poor pre-morbid personality, family history, substance misuse, presence of soft neurological signs and a long untreated period.¹⁴ Genes are thought to be involved in the development of TRS; reliable genetic prediction of which patients will be TRS would have serious clinical implications. Structural neuroimaging techniques have revealed that TRS patients do not differ importantly than those responsive SCZ in terms of brain abnormalities.¹⁵

When clozapine fails or rejected

Clozapine may be the preferred drug for TRS – effectively the gold standard – but its side effects put off many patients to the extent that some of them refuse clozapine therapy. It is a unique atypical antipsychotic and there is robust evidence supporting its use in people with TRS. Though clozapine often represents the best hope for recovery, it is associated with severe and enduring adverse reactions that may delay its prescription and increase morbidity and mortality. The major side effects are a) agranulocytosis; b) metabolic side effects; c) myocarditis; d) seizures; e) severe constipation with gastrointestinal complications such as intestinal obstruction, bowel perforation, paralytics ileus and toxic megacolon; and f) sialorrhea. These side effects hinder the popular use of clozapine in TRS. It is a life-saving drug, but without extra care it may itself shorten the life span. Side effects are more common with higher doses. It has been estimated that between 10 and 60% of patients resistant or intolerant with other antipsychotic drugs respond to clozapine.

The side effects mentioned above are inevitably an impediment to its common use. When standard doses (300mg to 5oomg) do not produce the desired effects or patients develop unwanted effects, combining clozapine with other antipsychotics is a common practice for TRS. To mention a few antipsychotics, amisulpride and aripiprazole are atypical antipsychotics ordinarily used in combination with clozapine. The anti-salivatory effect of amisulpride and the alerting effect of aripiprazole are added advantages of such a combination, and these drugs are fairly weight neutral – in contrast to clozapine. Clozapine, representing a second generation of so-called atypical antipsychotic drugs, has shown positive effects in desperate cases of TRS. Furthermore, two epidemiological studies have shown that clozapine has the lowest mortality rate among antipsychotics.

Nevertheless, even supported by the literature as the best-known antipsychotic in terms of efficacy and rates of response, a sizeable number of patients remain resistant to clozapine therapy and continue as symptomatic and dysfunctional. It has been estimated that 40–70% of patients on clozapine may not respond satisfactorily to it.¹⁶ When patients do not respond to clozapine, they are categorised as super-refractory, but the very concept of super-refractory state is debatable. They do not differ from the refractory cases in terms of demographical factors but have high score of positive symptoms. It may be simply explainable that the aetiological mechanism of the illness of such patients may be different from the clozapine responders and that makes them unresponsive to clozapine. There are no operational definitions for super-refractory schizophrenia. According to the schizophrenia algorithm of the International Psychopharmacology Algorithm Project (www.jpap.org), persistence of psychotic symptoms after a trial with adequate doses of clozapine(300-900mg/day) for at least six months is designated as super-refractory cases. ¹⁷

Many predictors of clozapine response have been suggested without any firm ground. These include severe clinical symptoms, higher levels of functioning before the onset of schizophrenia, low levels of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid, reduced metabolism in the prefrontal cortex, reduced volume of the caudate, and the improvement of P50 gating at the 500-ms prepulse interval. ¹⁸ However, none of these factors is consistent or specific as a predictor of clozapine response. More genetic and brain imaging studies are warranted with such patients. In these cases, augmenting strategies are necessary, and some have been in use: typical and atypical antipsychotics, mood stabilizers, antidepressants and electroconvulsive therapy. Some studies have favoured ECT, but no definitive conclusion has been drawn. So also, half of clozapine patients discontinue taking the medication on their own accord. In a retrospectively studied sample of patients who discontinued clozapine, the majority terminated the treatment as a result of their own decision or because of non-compliance with medical procedures such as blood sampling.¹⁹

There are currently no evidence-based pharmacotherapies for the TRS patients who do not respond to clozapine ^20,21 or those who terminate clozapine therapy due to adversative reactions. ²² In the nutshell, clinicians should be prepared to try different alternative treatment options for TRS and super-refractory cases. Thus, combination therapy may become a choice as pre-clozapine therapy or post-clozapine therapy. Clozapine is not a drug that could normally be imposed on patients, but it has to be earned by the patient.

Combination therapy

The range of antipsychotic medications available is wide, with variable effectiveness, and there are also differing profiles for typical and atypical agents, adding to a confusing array of terminologies and dilemmas regarding what the best drug for service users is.²³ Combination therapy involves the addition of a second antipsychotic to the therapy regimen. It is different from adjunctive therapy, in which a second agent is employed to reverse an emergent side effect or to obtain a complementary clinical effect. Augmentation involves the use of a non-antipsychotic along with the antipsychotic already in use. Combination therapy and augmentation therapy are sometimes used interchangeably. In general, ‘combination’ refers to the use of more than one type of disease-specific treatment to treat a particular illness.

A change from one antipsychotic to another in same class seldom produces any additional benefit, whereas switching to an antipsychotic with a different mechanism of action has proved to produce a more impressive response rate. Combination becomes desirable when the drug already in use produces some favourable effect, but that is not sufficient to control the symptoms. It is imperative to distinguish between partial response and no response when considering a change in medication. Past antipsychotic drug response, adverse effect profile differences, concomitant medical disorders and concurrent drug therapy are factors to be considered when choosing between switching and combination or augmentation approaches. A switch is indicated when there is no response to the drug and combination therapy; augmentation is recommended for partial response. Another antipsychotic combination may become necessary as an option for TRS patients who cannot be treated with clozapine for various reasons. It is common practice in such situations to add a second antipsychotic, in combination with the original one.

Clinical team do not have to be disheartened or disillusioned when clozapine therapy fails due to non-response or clozapine intolerance, and also when augmentation and combination therapies do not bring about the desired outcome. Switching back to atypical drugs once again may turn out to be effective in some cases and clozapine is not to be considered as the last resort. A multicentre open label 18-week trial evaluated a switch to olanzapine in 48 clozapine resistant or intolerant patients. ²⁴ Switching to olanzapine 5-25 mg per day resulted in a mean drop in total scores on the Positive and Negative Syndrome Scale (PANNS) and Brief Psychiatric Rating Scale (BPRS) of 17.7 (14.2%) and 9.8 points (20.2%) respectively.

Cautions

Monotherapy is the most desirable form of treatment for SCZ. There is no good objective evidence to support dual antipsychotic therapy except in combination with clozapine. The evidence base supporting such combinations consists mostly of small open-label studies and case series.²⁵ Combination therapy should be considered only when several attempts at monotherapy, including one atypical antipsychotic, fail. It is assumed that two different treatments together may have a different mechanism of action and therapeutic response from that of either drug alone. Studies have been conducted to determine whether treatment with antipsychotic combinations is effective for SCZ and whether such treatment is safe for the same illness. The results of trial studies are based on very low or low-quality results, and research that provides high-quality evidence is needed before firm conclusions may be drawn. The results so far show that there may be some clinical benefit in combination therapy in that more people receiving a combination of antipsychotics showed an improvement in symptoms. For other important outcomes – such as relapse, hospitalisation, adverse events and discontinuing treatment – no clear differences between the two treatment options were observed. Currently, most evidence regarding the use of antipsychotic combinations comes from short-term trials; the assessment of long-term efficacy and safety is limited. There is some very low-quality evidence that a combination of antipsychotics may improve the clinical response.

There are published case reports of serious side effects, such as a higher prevalence of extrapyramidal symptoms (EPS), metabolic side effects, paralytic ileus, grand mal seizures and prolonged QTc in association with a combination of antipsychotics.²⁶Combining three antipsychotics may be extremely dangerous; studies have revealed that such a procedure substantially increases mortality.²⁷A negative case control study exists.²⁸ It should be usual practice to document the rationale for combined antipsychotic use in individual cases in clinical records, along with a clear account of benefits and disadvantages, including side effects.

Newer combinations and augmentation strategies are supported only by case reports and open trial data. Along with advantages, a number of potential concerns regarding antipsychotic combinations have been identified (Table 2) and specific clinical cautions have to be implemented in combination therapy (Table 3). Yet, fixed combinations of drugs are common in medicine and at one time were common in psychiatry. An example is small doses of an antipsychotic in combination with an antidepressant for treating major depression; this lost popularity because of side effects. Also, SNRI-NaSSA combination therapy (e.g. California Rocket Fuel) is prevalently used for treatment-resistant depression.

Olanzapine–amisulpride combination

In spite of the objections put forward against combination therapy, there are isolated case studies favouring the olanzapine–amisulpride combination. Zink et al. (2004) performed a retrospective study, aiming at the systematic evaluation of patients on combined olanzapine and amisulpride. The open study designed as a retrospective chart review of Zink et al. concludes that the olanzapine–amisulpride combination for TRS is encouraging, but requires further evaluation in prospective and randomised studies.²⁹They point out that a reduction of the daily dose of both drugs helped to minimise the side effects of these drugs – such as weight gain and EPS – resulting in better compliance. They did not notice any additional side effects or undesirable drug interactions.

Within the heterogeneous group of atypical antipsychotics, the thienobenzodiazepine derivative olanzapine has a receptor profile that is quite similar to that of clozapine, indicated by having a greater affinity for serotonergic 5-HT_2A receptors than for dopaminergic D₂ receptors. The positive and negative symptoms of schizophrenic psychoses usually respond well to this drug. In contrast to clozapine, olanzapine does not induce major agranulocytosis but may, in a significant number of cases, lead to troublesome side effects including significant weight gain, type ii diabetes, sedation, anticholinergic effects and transient increases in liver enzymes. Assertive weight management from the start of treatment is recommended. Weight should be monitored and also waist circumference measurements made. In addition, blood lipids should be assessed routinely. A suggested schedule for these investigations would be at 3, 6, and 12-month intervals, and biannually thereafter.³⁰The pharmacology of antipsychotics is not the only factor that determines their effect on weight. Olanzapine has also been shown to elevate prolactin significantly in some patients.³¹ As indicated earlier, Olanzapine can succeed in some cases even where clozapine fails.²⁴

Amisulpride is an atypical antipsychotic of the benzamide class. It blocks D2 and D3 receptors (presynaptic in low doses, postsynaptic in higher). Unlike other atypical or typical antipsychotics, it has low affinity for serotonin, α-adrenergic, histaminergic, muscarinic and sigma receptors including D1, D4 and D5 receptors. It can lead to dose-related EPS that are significantly less than those of typical antipsychotics such as haloperidol and comparable to risperidone.³²It is recognised that amisulpride is only sparingly metabolised by liver enzymes, and thus it is not known to participate in many drug interactions.³³ Amisulpride may elevate prolactin, which may cause sexual dysfunction, osteoporosis, amenorrhoea, gynaecomastia or galactorrhoea. It is a weight-neutral compound and may ameliorate negative symptoms.³⁴ Both olanzapine and amisulpiride are not associated with QTc prolongation.

One advantage of the combination of these drugs is that when olanzapine and amisulpride are combined, they may be given at a lower dose, which will spare the patients from the main unwanted side effects of the individual drugs: the over-sedation and weight gain of olanzapine; and the hyperprolactinemia of amisulpride, resulting in sexual side effects of a particularly undesirable extent. Our limited studies have found that this combination was well tolerated by TRS patients and its efficaciousness was similar to that of clozapine, but without any major side effects. Patients have been fully compliant. The combination of these drugs is managed by slowly introducing them one at a time and has been transformative in many cases. More studies of the olanzapine–amisulpride combination are needed in order to report on such outcomes as relapse, remission, social functioning, service utilisation, cost-effectiveness, satisfaction with care, and quality of life.

Table 1. Assessing Treatment Resistance

Table 2. Advantages and disadvantages

Table 3 Physical cautions with combination

Summary

Combination therapies are the second choice when monotherapy fails. Clozapine is the first choice in severe cases of TRS, but there are super-refractory cases of TRS where clozapine fails. At least in isolated cases, the combination of olanzapine and amisulpride (Ami-olan combination) is worth considering for TRS patients who are reluctant to go on to clozapine therapy or in instances when clozapine failed, or patents dropped out. Combination therapies are normally avoided, but clinicians’ helplessness and patients’ despair justifies such measures in hard-to-treat cases of TRS. Only time will tell whether this combination will become an important part of clinical practice in future or will be ruled out as just another dual antipsychotic therapy.

The aetiology of SCZ remains obscure. The symptoms of different psychotic disorders are not clearly demarcated and there are no physiological parameters on which to make a firm diagnosis. In such a situation, the treatment of TRS has to be tailored on an individual basis. Even though it is normally well calculated, it may be somewhat hit and miss. Finding the right combination of antipsychotics or augmenting agents when the clinician is stranded and torn between monotherapy and polypharmacy is a gargantuan task. Clinical judgement along with patient preference must take over when treatment algorithms fall short. Given the data on polytherapy with antipsychotics that is available, it is hard to make any firm recommendation regarding its efficacy and safety of its use. Clinicians should be reminded that they should try monotherapy in adequate dosages before considering combinations.

For the management of TRS, comprehensive treatment strategies that integrate pharmacological, psychological, and psychosocial approaches are highly relevant and for that to happen, TRS should be clearly recognised. NICE offers very little guidance on clozapine resistant cases of SCZ. Combination of antipsychotics is not a panacea or a permanent solution for TRS. More investigation of schizophrenic illness is the only way forward. In comparison with other medical conditions (eg,HIV), research into it is making little progress. As it stands now, deconstructing clozapine’s unique pharmacology may offer ‘light at the end of the tunnel’ for patients who are clozapine intolerant or non-responders.

Introduction

Hyperglycaemia is a condition in which an excessive amount of glucose circulates in the blood plasma. The origin of the term is Greek: hyper-, meaning excessive; -glyc-, meaning sweet; and -aemia, meaning "of the blood". Hyperglycaemia, or high blood glucose, is a serious health problem for those with diabetes. Normal fasting glucose is <100 mg/dl, impaired fasting glucose is 100–125 mg/dl, and diabetes mellitus is defined as a fasting glucose >126 mg/dl ¹. Several values above normal are indicated before making a diagnosis of impaired fasting glucose or diabetes. Two types of hyperglycaemia can be seen in diabetic patients, they are, fasting hyperglycaemia defined as a blood sugar greater than 126 mg/dl after fasting for at least 8 hours and postprandial or after-meal hyperglycaemia defined as a blood sugar usually greater than 180 mg/dl. In people without diabetes postprandial or post-meal sugars rarely go over 140 mg/dl but occasionally, after a large meal, a 1-2 hour post-meal glucose level can reach 180 mg/dl.

Consistently elevated high post-meal glucose levels can be an indicator that a person is at high risk for developing type 2 diabetes. Stress hyperglycaemia also called as stress diabetes or diabetes of injury is a medical term referring to transient elevation of the blood glucose due to the stress of illness. It usually resolves spontaneously, but must be distinguished from various forms of diabetes mellitus. It is often discovered when routine blood chemistry measurements in an ill patient reveal an elevated blood glucose. Blood glucose can be assessed either by a bedside ‘fingerstick’ glucose meter or plasma glucose as performed in a laboratory. The glucose is typically in the range of 140-300 mg/dl but occasionally can exceed 500 mg/dl especially if amplified by drugs or intravenous glucose. The blood glucose usually returns to normal within hours unless predisposing drugs and intravenous glucose are continued.

Stress hyperglycaemia is especially common in patients with hypertonic dehydration and those with elevated catecholamine levels. Steroid diabetes is a specific and prolonged form of stress hyperglycaemia. In some people, stress hyperglycaemia may indicate a reduced insulin secretory capacity or a reduced sensitivity, and is sometimes the first clue to incipient diabetes (do you mean insipidus diabetes). Because of this, it is occasionally appropriate to perform diabetes screening tests after recovery from an illness in which significant stress hyperglycaemia occurred ^{Table 1}.

Table 1: Aetiology of Hyperglycaemia

Prevalence and risk of hyperglycemia

Acute hyperglycaemia is common in patients with ST- elevation myocardial infarction (STEMI) even in the absence of a history of type 2 diabetes mellitus (DM). Hyperglycaemia is encountered in up to 50% of all STEMI patients, whereas previously diagnosed DM is present in only 20% to 25% of STEMI patients ² .The prevalence of type 2 DM or impaired glucose tolerance may be as high as 65% in myocardial infarction patients without prior DM when oral glucose tolerance testing is performed ³. Elevated plasma glucose and glycated haemoglobin levels on admission are independent prognosticators of both in-hospital and long-term outcome regardless of diabetic status ^{4, 5}. For every 18-mg/dl increase in glucose level, there is a 4% increase in mortality in nondiabetic subjects ⁶. When admission glucose level exceeds 200 mg/dl, mortality is similar in non-DM and DM subjects with myocardial infarction (MI). Admission glucose has been identified as a major independent predictor of both in-hospital congestive heart failure and mortality in STEMI ⁷.

Fasting glucose the day after admission appears to be a better predictor of early mortality than glucose level on admission ⁸. Patients with both an elevated admission glucose and an elevated fasting glucose the next day have a 3-fold increase in mortality. Similarly, failure of an elevated glucose level to fall within 24 hours of admission is associated with excess mortality in STEMI patients without DM ⁹. The presence and degree of hyperglycaemia may not correlate with infarct size, as is commonly thought ⁶. Counter regulatory hormones like catecholamine, growth hormone, glucagons and cortisol are released in proportion to the degree of cardiovascular stress and may cause hyperglycemia and an elevation of free fatty acids, both of which lead to an increase in hepatic gluconeogenesis and a decrease in insulin-mediated peripheral glucose disposal.

Pathogenesis of hyperglycaemia

When acute coronary artery occlusion leads to symptoms, aid this is not always the case, there is stimulation of postganglionic sympathetic nerve endings with release of norepinephrine, and of the adrenal medulla with release of epinephrine. Both catecholamines are present in high concentrations in plasma and urine during the first 24-48 hours after the onset of symptoms. The concentrations of these catecholamines in plasma reach high levels within the first few hours after the onset of symptoms and later appear to be related to the severity of the infarct. Norepinephrine acts through beta-adrenergic receptors, to activate the adenylcyclase system in adipose tissue causing conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (AMP) and cyclic AMP activates a lipolytic system leading to hydrolysis of stored triglycerides to diglycerides, free fatty acids (FFA) and also glycerol. While some reesterification of FFA occurs, the net effect is release of FFA and glycerol into the circulation. In acute myocardial infarction, plasma FFA concentrations are elevated within 4 hours of the onset of symptoms. The highest values are found on the first day, and by the sixth day normal values are usually reached.

Glycerol levels are also elevated. There is a close relationship between blood catecholamine and FFA values in myocardial infarction. Epinephrine has a weak effect on adipose tissue lipolysis but its main action at this time is to stimulate glycogenolysis in liver and muscle with elevation of blood glucose levels. Epinephrine also suppresses beta cell activity in the pancreas with a decrease in insulin secretion leading to further elevation of blood glucose. Thus, hyperglycaemia occurs after acute myocardial infarction, and more than half of these patients have an abnormal glucose tolerance test during the first 72 hours of the attack. Reduction of insulin secretion has been demonstrated in patients after acute myocardial infarction following an intravenous glucose load and an intravenous Tolbutamide test. The degree of failure in these responses has been positively correlated with the severity of the illness and with the presence of cardiogenic shock.

Cortisol secretion and plasma growth hormone levels are increased during the first 24 hours after the onset of acute myocardial infarction. As the clinical condition improves, the degree of glucose intolerance diminishes and insulin secretion increases. In the second week plasma insulin levels are above normal, and at this stage the anabolic effect of insulin in enhancing the transport of amino acids into cells and their incorporation into protein is important for repair of the injured myocardium. Cortisol stimulates the breakdown of protein for gluconeogenic purposes and also the key gluconeogenic enzymes, but it is doubtful whether these actions operate until the acute period has passed ¹⁰, ^{Figure 1}.

Figure 1

Cardiovascular effects of hyperglycaemia

Acute hyperglycaemia is associated with numerous adverse effects that contribute to a poor outcome in STEMI. Acute hyperglycaemia rapidly suppresses flow-mediated vasodilatation, likely through increased production of oxygen derived free radicals ¹¹. Hyperglycaemia increases intranuclear nuclear factor-B binding and activates proinflammatory transcription factors, which increase the expression of matrix metalloproteinase, tissue factor, and plasminogen activator inhibitor-1. The degree of oxidative stress correlates most closely with acute, not chronic, glucose fluctuations ¹².

Increased oxidative stress interferes with nitric oxide mediated vasodilatation and reduces coronary blood flow at the micro vascular level. In STEMI subjects, acute hyperglycaemia is associated with reduced TIMI grade 3 flow before intervention compared with euglycemia and is the most important predictor of the absence of coronary perfusion ¹³. Similarly, diabetic subjects have reduced myocardial blush grades and diminished ST-segment resolution after successful coronary intervention in STEMI, consistent with diminished micro vascular perfusion ¹⁴.

Acute hyperglycaemia is associated with impaired microcirculatory function as manifest by “no reflow” on myocardial contrast echocardiography after percutaneous coronary intervention ¹⁵. Pre-existing HbA1c levels and diabetes status do not differ between subsets with and without no reflow, suggesting that acute, not chronic, hyperglycaemia is the dominant factor. Finally, the well-known adverse effects of hyperglycaemia on platelet function, fibrinolysis, coagulation, and ischaemic preconditioning likely contribute to the adverse effects of acute hyperglycaemia in STEMI. Hyperglycaemia is a reflection of relative insulinopenia, which is associated with increased lipolysis and free fatty acid generation, as well as diminished myocardial glucose uptake and a decrease in glycolytic substrate for myocardial energy needs in STEMI. Myocardial ischemia results in an increased rate of glycogenolysis and glucose uptake via translocation of GLUT-4 receptors to the sarcolemmal ¹⁶. Because glucose oxidation requires less oxygen than free fatty acid oxidation per molecule of ATP produced, myocardial energetics are more efficient during the increased dependence on glucose oxidation with ischaemia.

With relative insulinopenia, however, the ischaemic myocardium is forced to use free fatty acids instead of glucose as an energy source because myocardial glucose uptake is acutely impaired. Thus, a metabolic crisis may ensue as the hypoxic myocardium becomes less energy efficient in the setting of hyperglycaemia and insulin resistance. Acute hyperglycaemia may precipitate an osmotic diuresis. The resulting volume depletion may interfere with the frank starling mechanism for the failing left ventricle in which increased end diastolic volume leads to increased stroke volume thus decreasing the cardiac output ¹⁷, ^{Table 2}.

Table 2: Acute Cardiovascular Effects of Hyperglycaemia

Conclusion

An essential diagnostic feature of diabetes is increased blood glucose concentration and the principal aim of diabetes treatment is normalisation of blood glucose. Hyperglycaemia can also occur when normal hormonal control of blood glucose concentration is disturbed by the stress associated with acute myocardial infarction.

The blood glucose is raised in the immediate period following acute myocardial infarction irrespective of diabetes status. In this review article the current understanding of the significance of hyperglycaemia occurring as a result of acute myocardial infarction is discussed.

A significant part of the review is directed to the discussion of epidemiological prevalence that confirms an association between hyperglycaemia and mortality following myocardial infarction.

It remains clear and undisputed that there is association between hyperglycaemia and increased mortality following acute myocardial infarction. Review of various articles ranging from experimental and clinical studies have demonstrated several mechanisms by which hyperglycaemia could adversely affect outcome of myocardial infarction. The final part of the review concluded that if treatment is aimed at normalising blood glucose improves outcome of acute myocardial infarction patients who present with hyperglycaemia.

Introduction

Depression is a clinical syndrome. The International Classification of Diseases (ICD) diagnostic classification systems describe three core symptoms of depression; low mood, anhedonia and reduced energy levels¹. Other symptoms include impaired concentration, loss of confidence, suicidal ideation, disturbances in sleep and changes in appetite. Symptoms must have been present for at least a period of two weeks for a diagnosis of depression to be made. Major depression refers to the presence of all three core symptoms and, in accordance with ICD criteria, at least the presence of a further five other symptoms¹. See Table 1 for severity criteria of a depressive episode according to ICD criteria.

Table 1: Severity criteria of a depressive episode according to ICD-10¹

Depressive symptoms, which can be clinically significant, can be present in the absence of a major depressive episode. Depressive symptoms are those that do not fulfil diagnostic criteria for a diagnosis of depression to be made. Depressive symptoms can be collectively referred to as sub-threshold depression, sub-syndromal depression or minor depression².

It has been proposed that there are two types of depression; early-onset and late-onset depression. Late-onset depression refers to a new diagnosis in individuals aged 65 years of age or older. Over half of all cases of depression in older adults are newly arising (i.e. the individual has never experienced depression before) and thus late-onset type depression. Late-onset type depression is associated more with structural brain changes, vascular risk factors and cognitive deficits. It has been suggested that late-onset depression could be prodromal to dementia³.

The Kings Fund has estimated that by 2032 the proportion of older adults aged 65-84 years old will have increased by 39% whereas the proportion over the age of 85 years will have increased by 106%⁴. This increase in population will consequently see the incidence and prevalence of depression rise. By 2020 it is estimated that depression will be the second leading cause of disability in the world regardless of age⁵. Recognising, and so diagnosing, depression in older adults will become more important because of a greater demand on existing healthcare services and provisions, due to physical health consequences, impact upon healthcare utilisation and greater economic healthcare costs.

Presentation of depression in older adults

The presentation of depression in older adults is markedly different to that in younger adults. The most significant and fundamental difference in presentation in older adults is that depression can be present with the absence of an affect component, i.e. subjective feelings of low mood or sadness are not experienced^3,6-9. The absence of an affective component is referred to as ‘depression without sadness’^8-9. It is common instead for older adults to report a lack of feeling or emotion when depressed^8-9.

Anhedonia is also less prevalent in this population. However, reduced energy levels and fatigue are frequently reported^8-9.

Compared to younger adults, psychological symptoms of depression occur more frequently and are more prevalent in older adults¹⁰. Such psychological symptoms include feelings of guilt, poor motivation, low interest levels, anxiety related symptoms and suicidal ideation. The presence of irritability and agitation are key features as well⁷. Hallucinations and delusions are also more common in older adults, particularly nihilistic delusions (i.e. a person believing their body is dead or a part of their body is not working properly or rotting).

Cognitive deficits are characteristic of depression in older adults^7,11 and are described as ‘substantial and disabling’¹². Such deficits mainly concern executive function^13-14. Pseudodementia is a phenomenon seen in older adults¹⁵. The term refers to cognitive impairment secondary to a psychiatric condition, most commonly depression¹⁶. Pseudodementia has become synonymous with depression. Pseudodementia can be mistaken for an organic dementia and so older adults who are depressed can present primarily to mental health services with memory problems. Pseudodementia is classically associated with ‘don’t know’ answers, whereas older adults with a true dementia will often respond with incorrect answers¹⁷.

‘Depression-executive dysfunction syndrome’ is a more specific and descriptive term to describe the cognitive deficits found in older adults with depression¹⁴. It is associated with psychomotor retardation, which can be a core feature of depression in this population^7,14,18. Psychomotor retardation describes a slowing of movement and mental activity¹⁹. Like pure cognitive deficits, psychomotor retardation contributes significantly to functional impairment¹⁹. Both executive dysfunction and psychomotor retardation have been found to be related to underlying structural changes in the frontal lobes^{14, 20-21}. Psychomotor retardation is further related to white matter changes in the motor system, which leads to impaired motor planning²¹. There is conflicting evidence of whether the presence of psychomotor retardation is related to depression severity^18-19.

Somatisation and hypochondriasis are associated with depression in older adults and increasing age in general^22-23. Somatisation is often overlooked in older adults by healthcare professional who actively search to attribute such symptoms to a physical cause. Somatisation is more common in those who have physical comorbidities. Somatisation in older adults is associated with structural brain changes and cognitive deficits²⁴.

Depression in older adults is associated with functional impairment cognitively, physically and socially^7,12,25. Such functional impairment is linked to loss of independent function and increased rates of disability²⁶. Withdrawal from normal social and leisure activities can be marked^7,25. Social avoidance reduces interaction with others and is often a maintaining factor for depression²⁵.

Self-neglect is a classical feature of depression⁷, with the presence of depressive symptoms in older adults being predictive of it²⁷. Behavioural disturbances can be a common mode of presentation, especially for older adults living in institutionalised care ^6-7. Behavioural disturbances include incontinence, food refusal, screaming, falling and violence towards others⁷.

Diagnostic difficulties

Depression in older adults has been a condition that has constantly been under-recognised. Several issues account for this. Firstly, phenomenological differences are present. Many have argued that phenomenological issues contribute heavily to diagnostic difficulties²⁸; both the DSM and ICD classification systems do not have specific diagnostic criteria for depression in older adults. Potentially invalid diagnostic criteria for depression in older adults could result in fundamental difficulties in understanding, with consequent impact on both clinical practice and research.

Diagnostic difficulties are also encountered because depression in older adults can present with vague symptoms, which do not correspond to the classical triad of low mood, low energy levels and anhedonia, which can all be cardinal symptoms in a younger population. Reports of fatigue, poor sleep and reduced appetite can be attributed to a host of causes other than depression and therefore it is no surprise that a diagnosis of depression is overlooked and goes undetected by healthcare professionals²⁹.

The absence of an affective component (i.e. low mood) can lead to healthcare professionals disregarding the potential for the presence of depression and consequently not exploring for other symptoms.

Furthermore, symptoms of depression, especially somatic ones, are often attributed to physical illnesses. Depressive somatic symptoms often lead to a diagnosis of depression being over looked; such symptoms ‘mask’ the clinical diagnosis of depression and hence the term ‘masked depression’³⁰. Depressive somatic symptoms – e.g. low energy levels, insomnia, poor appetite and weight loss - are often attributed to physical illness and/or frailty by both the individual and healthcare professional^{7-8, 31}.

Further complicating diagnostic difficulties and under-recognition is the fact that older adults are less likely to report any symptoms associated with mental health problems and ask for help in the first place^7,10,32; explanations for this include older adults being less emotionally open, having a sense of being a burden or nuisance, and believing symptoms are a normal part of ageing or secondary to physical illness^7,10,29,33.Older adults also have a reluctance to report mental health problems due to their perception of associated stigma; many older adults hold the view the mental health problems are shameful, represents personal failure and leads to a loss of autonomy⁷.

There is an overlap between symptoms of depression and symptoms of dementia. It is quite common for older adults with dementia to initially present with depressive symptoms. Depression has a high incidence in those with dementia, especially those with vascular dementia. Depression is particularly difficult to diagnose in dementia due to communication difficulties; diagnosis is often based on observed behaviours^8,33.

Depression and comorbidity in older adults

In those with pre-existing physical health problems, depression is associated with deterioration, impaired recovery and overall worse outcomes³⁴. For example, the relative risk of increased morbidity related to coronary heart disease is 3.3 in comparison to individuals without depression³⁵. Mykletun et al. established that a diagnosis of depression in older adults increased mortality by 70%³⁶. Several causative routes account for poor physical illness outcomes. Older adults with depression are less likely to report worsening health. Depressive symptomatology indirectly affects physical illness through reduced motivation (often secondary to feelings of helplessness and hopelessness) and engagement with management. Poor compliance with management advice, notably adherence to medications is observed³⁷. Feelings of hopelessness, helplessness and negativity will contribute to the failure to seek medical attention in the first place or report worsening health when seen by a healthcare professional.

Depression affects biological pathways directly, which impairs physical recovery. Such biological effects include pro-inflammatory factors, metabolic factors, impact upon the hypothalamic-pituitary axis and autonomic nervous system changes³⁸.

Older adults who are depressed are more likely to have existing physical health conditions and more likely to develop physical health conditions¹⁵. Depression is particularly associated with specific physical illnesses; cardiovascular disease and diabetes mellitus. A study by Win et al. found that cardiovascular mortality is higher in older adults with depression because of physical inactivity; the study established that physical inactivity was accountable for a 25% increased risk in cardiovascular disease³⁹. The relationships between depression and cardiovascular disease and depression and diabetes have been described as “bidirectional”³⁸.

Higher incidents of cardiovascular disease and diabetes mellitus are seen in people with depression regardless of age. A study by Brown et al. found that older adults with depression had a 1.46 relative risk increase for developing coronary heart disease compared to those without depression⁴⁰. The hypothalamic-pituitary axis dysfunction found in depression leads to increased levels of cortisol, which in turn, increases visceral fat. Increased visceral fat is associated with increased insulin resistance, promoting diabetes mellitus, and increased cardiovascular pathology³⁸.

Depression is a risk factor for the subsequent development of dementia; this is especially so if an older adult has no previous history of depression (i.e. depression is late-onset)¹³.

Healthcare utilisation and economic impacts

Older adults are less likely to report depressive symptoms to healthcare professionals explaining the under-utilisation of mental health services for depression^32,41. Despite older adults under-utilising mental health services they over utilise other healthcare services^26,41. For example, those presenting with non-specific medical complaints or somatisation have been found to have an increase use of healthcare services. Non-specific medical complaints and somatisation lead to an unnecessary use of resources, such as unnecessary consultations with healthcare professionals and investigations⁴¹. Increase in service utilisation means an increase in the associated economic cost of depression in older adults^41-43.

Healthcare costs of older adults with a comorbid physical illness and depression are far greater than those without depression – findings in diabetes mellitus are a good example⁴³. The majority of the increased healthcare costs are associated with the chronic physical disease and not the care and treatment of the depression⁴⁴. Poor compliance with physical illness management is associated with missed appointments and a greater number of hospital admissions, which both have financial implications.

Aetiology and associations of depression in older adults

Late-onset type depression in older adults has been associated with the term ‘vascular depression’^45-47. Studies have found a significant higher rate and severity of white matter hyperintensities on MRI imaging in older adults with depression compared to those without depression^46,48,50. White matter hyperintensities represent damage to the nerve cells; such damage is a result of hypo-perfusion of the cells secondary to small blood vessel damage⁴⁹. White hyperintensities are associated with vascular risk factors (e.g. age, hypertension, hypercholesterolaemia, obesity, diabetes mellitus, smoking) and are linked to cerebrovascular disease, such as stroke, vascular dementia. A relationship has been found between psychosocial stress and consequent development of vascular risk factors, which further supports the hypothesis of ‘vascular depression’⁴⁶. Clinically, ‘depression-executive dysfunction syndrome’ and psychomotor retardation are associated with vascular changes⁴⁸.

In older adults with depression, white matter hyperintensities are associated with structural changes to corticostriatal circuits and subsequent executive functional deficits. Loss of motivation or interest and cognitive impairment in depression are hallmark features of structural brain changes associated with the frontal lobes, which in turn are associated with a vascular pathology²⁰. A study by Hickie et al. established that white matter hyperintensities in older adults with depression are associated with greater neurological impairment and poorer response to antidepressant treatment⁵⁰. It is not fully understood why vascular depression responds less well to antidepressants; poor response has been linked directly to vascular factors but has also been associated with deficits in executive function^46-47.

The relationship between cerebrovascular disease and depression is described as ‘bi-directional’^45,51; depression has been found to cause cardiovascular disease and vice versa⁵¹. Baldwin et al. direct the reader to the presence of post-stroke depression and the occurrence of depression in vascular dementia⁴⁵.

Younger and older adults share a number of fundamental risk factors for depression; such as female gender, personal history and family history⁷. Older adults have additional risk factors related to ageing, which are not just physiological in nature.

Age related changes:

Age related changes occurring in the endocrine, cardiovascular, neurological, inflammatory and immune systems have been directly linked to depression in older adults³.

The normal ageing process sees changes to sleep architecture and circadian rhythms with resultant changes to sleep patterns⁵². Thus sleep disturbances are common in older adults and positively correlated to advancing age⁵²; over a quarter of adults over the age of 80 years report insomnia, and research has well-established that this is a risk factor for depression^53-54. A meta-analysis by Cole et al. found sleep disturbances to be a significant risk factor for the development of depression in older adults⁵³.

Sensory impairment:

Sensory impairments, whether secondary to the ageing or a disease process, are risk factors^53,55. Research has found that hearing and vision impairments are linked to depression⁵⁶. A sensory impairment can lead to social isolation and withdrawal, which, in turn, are further risk factors for depression.

Physical illness:

Physical illness, regardless of age, is a risk factor for depression. Older adults are more likely to have physical illnesses and so in turn are more at risk of depression. See Table 2. Physical illness is associated with sensory impairments, reduced mobility, impairment in activities of daily living and impaired social function, all of which can lead to depression. Physical illnesses associated with chronicity, pain and disability pose the greatest risk for the subsequent development of depression^7,53,55. Physical illness affecting particular systems of the body, such as the cardiovascular, cerebrovascular and neurological, are more likely to cause depression³. Essentially, however, any serious or chronic illness can lead to the development of depression. It should be noted that a large proportion of older adults have physical illness but do not experience depression symptoms, therefore other factors must be at play^5,57.

Treatments of physical illness are directly linked to aetiology in depression, for example, certain medications are known to cause depression; cardiovascular drugs (e.g. Propranolol, thiazide diuretics), anti-Parkinson drugs (e.g. levodopa), anti-inflammatories (e.g. NSAIDs), antibiotics (e.g. Penicillin, Nitrofurantoin), stimulants (e.g. caffeine, cocaine, amphetamines), antipsychotics (e.g. Haloperidol), anti-anxiolytics (e.g. benzodiazepines), hormones (e.g. corticosteroids), and anticonvulsants (e.g. Phenytoin, Carbamazepine)^7,29. Polypharmacy is present in many older adults further increasing the risk of depression. Pharmacokinetic and pharmacodynamic age related changes also contribute to an increased risk of medication induced depression in older adults.

Table 2: Table of physical illnesses associated with depression^3,7

Dementia:

Dementia is common in old age and those with dementia are at higher risk of developing depression compared to those who do not have it⁵⁸. 20-30% of older adults with Alzheimer’s disease have depression⁵⁹. Depression is a risk factor for the subsequent onset of dementia.

Psychosocial:

When compared to younger adults, older adults are at a greater risk of developing depression due to the increased likelihood of experiencing particular psychosocial stressors, in particular adverse life events. Stressors include lack of social support, social isolation, loneliness and financial hardship. Financial hardship and functional impairment often sees older adults downsizing in property. Deteriorating physical health often sees older adults no longer being able to manage living independently at home necessitating a move into institutional living. Bereavement, especially spousal, and the associated role change that follows this are risk factors for depression³.

Sub-threshold depression:

Sub-threshold depression is an established risk factor for major depression.

Prevalence and epidemiology

The prevalence of depression in older adults in England and Wales was found to be 8.7% in 2007; however, if those with dementia are included this figure rises to 9.7%⁶⁰. A meta-analysis by Luppa et al. established a 7.2% point prevalence of major depression and a 17.1% point prevalence of depressive disorder in older adults⁶¹. The projected lifetime risk of an older adult developing major depression by the age of 75 years old is 23%⁶².

Sub-threshold depression is 2-3 times more prevalent than major depression in older adults^26,63. These depressive symptoms are often clinically relevant^26,29. 8-10% of older adults per year with sub-threshold depressive symptoms go onto develop a major depressive episode⁶³.

Incidence and prevalence are greater in women; 10.4% of women over the age of 65 years have depression compared to 6.5% of men⁶⁰. Older women are more likely to experience recurrent episodes of depression compared to older men⁶². The gender gap in incidence and prevalence becomes narrower with increasing age³. It should be acknowledged however that women are more likely to present to healthcare services and seek help in comparison to men^64-65.

The prevalence of major depression in older adults varies by setting⁶⁶. Highest rates are seen in long-term institutional care and inpatient hospital settings⁶⁷. Table 3 summaries prevalence rates of major depression by setting.

Table 3: Prevalence rate of major depression by setting ^{7, 67}

Prognosis of depression in older adults

Depression in older adults is associated with a slower rate of recovery⁹, worse clinical outcomes compared to younger adults³ and is associated with higher relapse rates⁶⁸. Worse prognosis in older adults correlates with advancing age, physical comorbidities and functional impairment⁷⁰. The structural brain changes associated with depression in older adults are linked, as discussed, to poorer treatment response.

Morbidity and mortality associated with depression can be described as primary or secondary; primary morbidity and mortality arises directly from the depressive illness; whereas secondary morbidity and mortality arises from physical health problems, which are secondary to depression.

Outcomes from sub-threshold depression are on par with those of major depression; however sub-threshold depression which develops into major depression is associated with worse outcomes².

Proportionally more people over the age of 65 years commit suicide compared to younger people⁷¹. Depression is the leading cause of suicide in older adults^29,71; one study reports that 75% of older adults who killed themselves were depressed⁷².

The vast majority of older adults who commit suicide have had contact with a health professional within the preceding month⁹; this figure has been quoted as high as 70%³. This further supports and suggests the fact the depression is under-detected. Unlike younger adults, older adults are less likely to report suicidal ideation and can experience suicidal ideation without feeling low in mood^3,7. Older adults have few suicide attempts, compared to younger adults, because their suicide methods are more lethal¹³.

Introduction

Bed bugs belong to the family Cimicidae and there are two species involved in the modern resurgence; the Common bed bug, Cimex lectularius and the Tropical bed bug, Cimex hemipterus. They are wingless insects with an oval-flat shape that allows them to hide in narrow cracks and crevices. The adults are dark brown, 4-5mm long, becoming to around 10mm when fully blood-engorged. There are five smaller juvenile stages (nymphs) that are similar in appearance, although lighter in colour. All nymphs require a blood meal to moult to the next stage, and both adults also bloodfeed for nutrition, and egg development in the case of the female. Bed bugs are solely haematophagous ectoparasites. After feeding they return to a harbourage and do not remain on the host. The main hosts are humans, but pets, bats, and birds may act as secondary hosts.

Epidemiology

In the past, bed bugs were particularly an affliction of the poor. However, in the early part of the modern resurgence it was the tourist areas and the hospitality sector that were initially impacted.^1-3 Today, bed bugs have conquered quite diverse locations, ranging from hospitals, hotels and homes, to trains, cruise ships, and even airplanes. Most commonly, bed bugs travel in comfort as stowaways in luggage, although they can be transferred via furnishing and other belongings, as well by spreading to adjoining properties. Unfortunately, exact figures on the occurrence of bed bugs are unknown, as there are no mandatory reporting requirements. Additionally, due to the stigma associated with bed bugs, many infestations are simply not reported.

During the day, the largely nocturnal bed bugs will crawl deep into crevices of bed frames and mattresses (Fig.1), or behind wallpaper, and floor moldings. Here they tend to lay their eggs, often several hundred during the female lifetime. Live bed bugs, shed nymphal skins, and dark excrement spots indicate an active infestation. At night they are attracted by carbon dioxide, heat and other host odours to a victim, from which they may take a blood meal every 3-5 days. The adult bugs can survive long periods of starvation, up to five months at 22^oC or even longer at cooler temperatures. When a host is found, they insert their mouthparts into the skin, blood feeding for 5-10 minutes. When bed bugs are in large numbers, often lines of bites occur on the unfortunate victim and this sign is almost a sure indication of the presence of the insect. The bites tend to occur along the arms and legs, down the back and across the shoulders.^4,5

There has been long speculation whether bed bugs can transmit diseases, and in fact more than 40 different pathogens have been implicated. This has included Hepatitis B and C viruses, Human Immunodeficiency Virus (HIV), and Coxiella burnetii (Q fever). Recently, research has indicated that bed bugs are capable of transmitting the agent of Chagas Disease, Trypanosoma cruzi,in the laboratory. However, to date there is not one piece of evidence that bed bugs have transmitted any pathogen to humans.^4,6

Clinical Features

During the act of feeding, saliva is injected which contains a variety of anticoagulants as well as other proteins whose function has yet to be determined. Contrary to popular belief, there is no evidence that bed bugs inject an anaesthetic. One protein, Nitrophorin, is involved in the transport of nitric oxide into the wound. This results in local vasodilation that increases blood supply to the feeding insect. The same protein can also induce a sensitivity to the bite.⁶

The diagnosis of Cimicosis is via the clinical appearance of the bite reaction and confirmation of an actual bed bug infestation (Table 1).^3,5 The most commonly affected body parts are those that are left uncovered during sleep (Fig. 2,3,4), notably the arms, shoulders and legs. In young children, the face and even the eyelids can be bitten. Rarely, however, armpits are bitten, which are often preferred by other insects and ticks (Table 2).

Figure 1: Typical appearance of bed bugs

Figure 2: Bites on the back, note the lines of bites common in moderate to large infestations

Figure 3: Bed bug bites on the arm, typical formation

Figure 4: Bed bug bites on the torso and arm

Figure 5: Bullae due to bed bug bites

Figure 6: Bed bugs, their droppings and eggs underneath a mattress

The degree of the bite reaction often depends on the level of prior exposure. With low level sensitization, individuals may develop a 1-2 cm wheal, with a small central haemorrhagic point. This haemorrhagic point can be recognized easily by diascopy. In contrast, a highly sensitized person will react immediately and may develop a wheal up to 15cm across (6 inches). If many bed bugs are present, an urticarial rash may develop as a result of the large number of bites and subsequent trauma to the area from scratching. On rare occasions, vesicles and bullae (Fig. 5) may form on the arms and legs. In the course of Cimicosis, papules that are extremely itchy may develop and can persist for several days to weeks. Due to the strong pruritus eczematous lesions, bacterial infections may occur, although this is extremely rare. There are case reports of systemic reactions such as anaphylaxis and asthma, although these are uncommon.

Through repeated exposure, some individuals may develop a tolerance to the bites. The clinical symptoms are then largely inapparent with small punctures at the bite site. Small blood spots are then the only clues that an infestation may be present.

Differential Diagnosis

Since reactions to stings and bites of various arthropods are non-specific, bed bug bites are commonly misdiagnosed. Single bites, notably that of other insects such as mosquitoes, fleas and biting midges may appear very similar morphologically (Table 2).

Consideration of where the bites are on the body can assist in the differential diagnosis. For bed bugs, lines of bites are very common in moderate to large infestations and this clinical picture is virtually unique amongst blood sucking arthropods. For the most part, the identification of the actual pest is required to confirm the diagnosis. Histologically, bed bug bites resemble perivascular eosinophilic infiltrates through the superficial and deep dermis, with minimal spongiosis.

Other possible diagnostic confounders can be various allergic reactions and other medical conditions such as urticaria, chickenpox, prurigo subacuta, and erythema multiforme.^7,8 These do not show a central haemorrhagic point in the lesion which allows a correct diagnosis. However, in young children the diagnosis can sometimes be difficult. 

Treatment

The treatment of Cimicosis is symptomatic. Local lesions can be treated with antipruritics e.g. Polidocanol 2-4% in Lotio alba (aqueous lotion) and topical antiseptic. Spirit of menthol may also be helpful. Local treatment with antihistamines is controversial. In severe reactions topical glucocorticoids such as Betamethasone may be required. In severe itching, the use of oral antihistamines is recommended. With infected bites, antibiotic therapy may be required. Uncomplicated bed bug bites tend to stop itching within 1-2 weeks, although temporary scarring from the bite may remain for several months.

Management

Treatment of patients with bed bug bites ultimately comes down to removing the source of the irritant, namely the eradication of the active infestation. Bed bugs have a typical pungent odor. This can be used to detect bed bugs through specially trained sniffer dogs that can rapidly locate the insects.⁹ Due to insecticide resistance, bed bugs are very difficult to control with traditional insecticides alone, and non-chemical means of eradication must be employed to reduce the overall insect biomass. Bed bug control should be undertaken by professionals trained in bed bug management, and the process may take some weeks to achieve.

Prevention

When travelling (1) always inspect the bed and surrounds for bed bugs hiding beneath the mattress and/or in seams of the bedding. Also, look for blood stains or small black dots (Figure 6, Table 1). (2) If present, request another room. (3) Always keep your luggage on the desktop or the luggage rack. A good preventative is to seal luggage in plastic or garbage bags during travelling, even when in transit. (4) When returning home, all clothing should be washed in at temperatures exceeding 60°C or frozen for one week with delicate fabrics. If there is no choice, then repellents containing N, N-Diethyl-meta-toluamide (DEET) should reduce the biting rate, but will not completely prevent all bed bug bites.^10,11

Bed bugs can enter homes via an array of additional ways, particularly from objects bought second hand at flea markets or thrift stores, for example wooden frames, vintage clothes, furniture and the like. These should be heat-treated for a minimum of 10-20 minutes to kill bugs and their eggs.

Schizophrenia sufferers feel like abstract entities with non-animated bodies, often experiencing auditory verbal hallucinations (AVH) due to morbid “objectification” of inner dialogue.¹ From the patient’s perspective, AVHs are a subjective–objective phenomenon. AVH is a non-consensual, dynamic and psychologically charged experience and the voices often echo significant emotions. Derogatory voices are common representations of unconscious self-hatred that cannot stand up to the external world’s logic. Thus, patients need help to incorporate it. Auditory hallucinations may be arising because of an interaction between biological predisposition, perceptual and cognitive factors. According to an integrated model of auditory hallucination (AHs) suggested by Waters et al,² AHs arise from an interaction between abnormal neural activation patterns that generate salient auditory signals and top-down mechanisms that include signal detection errors, executive and inhibition deficits, a tapestry of expectations and memories. Recently, neuro-quantologists have proposed that AVHs may be an objectification of parallel thinking/quantum thinking.³ Parallel thinking is a source for thought insertion. There may be different variables of AVHs. Experiencing AVH has serious impact on the quality of life of the affected individual, and is a significant factor in prevalence of suicides among schizophrenic patients.⁴

Incidence

One in four schizophrenia sufferers experiences persistent AVH .⁵ AVHs are experienced by approximately 53% of schizophrenia sufferers ⁶ and are present in 28% of major affective disorders (Goodwin& Jamison, . ⁷ Evidence indicates that each patient responds differently to the voices, according to his/her evaluation of them (Table 1), which influences the degree of interventions. Specific dimensions of AVHs can give hints to the future likelihood of treatment resistance. Although the percentages differ in various studies, it is assumed that about 30% of patients have command hallucinations and they are seen as the ultimate betrayal of the mind. ⁸ Often, the content of such messages is negative; thus, commanding AVHs are more distressing than commenting ones. Schizophrenia predisposes them to a greater risk of suicides and homicides. Command hallucinations are more prevalent among forensic patients and contribute to their forensic status.

Table1. Patients’ Response to AVH

The multi-factorial polygenic model of schizophrenic disorders has received great support and signifies that genetic factors play a bigger role than environmental factors in familial transmission of these disorders. Relevant studies provide little support for the mechanism of single major locus inheritance. A mechanism involving two, three, or four loci cannot be ruled out even though there is no compelling support for such models.⁹ It has also been proposed that a single gene may be even responsible for hallucinatory experiences ¹⁰ implying that those who have not inherited such a gene may not experience auditory hallucinations, but still could experience other characteristic symptoms of schizophrenia. One may also hypothesise that an individual who has inherited such a “hallucinatory gene” but not all the schizophrenia genes could hear non-clinical voices without having other schizophrenic symptoms. It is also arguable that those who carry such a specific gene are more vulnerable to experience hallucinations when they abuse psychoactive substances and could get misdiagnosed as having schizophrenia, but hallucinations may cease to occur once they abstain from illicit drug abuse.

Measurements for Assessment

AVH is a subjective experience and is hard to measure objectively. Several rating scales are now available for an efficient evaluation of different aspects of voice activities. Some are general and a number of them are specifically designed. Using rating scales facilitates better engagement with patients and helps in reinforcing the message that patients and the distress they experience are carefully considered.

Beliefs About Voice Questions (BAVQ) is an assessment scale useful in measuring the key beliefs about the voices.¹¹ It is typically used in conjunction with the Cognitive Assessment Schedule (CAS).¹² Voice Compliance Scale (VCS) is an observer rated scale aimed exclusively at measuring the frequency of command hallucinations and the level of obedience or confrontation with each recognized command.¹³ Voice Power Differential Scale (VPD) is another measure that can be applied to rate the perceived relative power differential between the voice and voice experience. ¹⁴ On the other hand, Omniscience Scale (OS) is intended to quantify the voice hearer’s beliefs about their voices’ knowledge regarding the bio data. ¹⁵ Another measure presently in use is Risk of Acting on Commands Scale (RACS), designed to assess the level of risk of acting on commands and the amount of associated distress. ¹⁶

The Bonn Scale (BSABS) is used for the assessment of basic symptoms, ¹⁷while the Schizophrenia Proneness Instrument (SPI-A) ¹⁸and the Examination of Anomalous Self Experience (EASE) ¹⁹ are useful aids in identifying minimal changes in subjective experience and for longitudinal monitoring (Table 2). In the extensively used Positive and Negative Syndrome Scale (PANSS), the hallucination item is one of seven in the positive subscale, which also includes delusions, conceptual disorganization, excitement, grandiosity, suspiciousness, and hostility. Given such a great number of scales in use, there is an obvious risk that differential anti-hallucinatory efficacy among antipsychotic drugs may be obscured by means of sum scores for the whole sample in clinical trials.

Table 2. Measurement scales

Treatments

Although many forms of treatments aiming to eliminate AVH or improve quality of life are available, use of medication seems to be the most prevalent. Besides drug treatment, non-invasive physical treatments, such as TMS and different forms of psychological interventions, have recently evolved. Drug therapies are aimed at symptom eradication, whereas psychological therapies tend to foster healing, recovery and personal growth. Rather than being specifically anti-hallucinatory, typically, neuroleptics offer a generalised calming effect and patients are given some “breathing space” to work through their voices. Usage of non-pharmacological tools is needed in the long-term management of refractory cases. Presently, intervention strategies for AVH are based on different models of hallucinations, but regrettably no clear models have been established.

Pharmacotherapy

The current understanding of AVH and the neural mechanisms involved is limited, and knowledge on how CNS drugs, such as antipsychotics, influence the subjective experience and neurophysiology of hallucinations is inadequate. Consequently, using pharmacotherapy in the management of AVH remains very challenging. ²⁰ Despite multiple trials of different combination and adjunctive therapies to an antipsychotic regime, AVH can remain drug resistant. It is also important to note that all antipsychotics are potentially anti-hallucinatory, even though these effects are usually modest. Moreover, given that, even when medications are effective, concordance can be an issue, antipsychotics should be used prudently and weighed up against effectiveness and side effects (Table 3). There are no clear guidelines for the drug treatment of AVH and comparisons of the efficacy of antipsychotics for AVHs are few. Clinical drug trials very rarely focus on single symptom scores, such as hallucinations, and tend to report group mean changes of overall psychopathology, or at best the positive subscale scores.

Evidences show that AVHs persist in spite of treatment in 32% of chronic patients ²¹ and 56% of acutely ill patients.²² Trifluperazine was popular as an anti-hallucinatory drug before the advent of atypical antipsychotic drugs. Clozapine is currently favoured for intractable AVHs and is beneficial in 30–60% of unresponsive patients.

Antipsychotic co-treatment is an option for clozapine augmentation. Olanzapine and risperidone may be alternative drugs in first episode psychosis. However, it is being debated whether clozapine should be used in such cases.

Table 3. Drug Treatment

Clozapine

Use of clozapine is suggested only after two other antipsychotics have been tried. It works better with continued usage and clinicians have to be patient in its upward titration. At six months, improvement in Global Assessment of Functioning score is significantly higher for clozapine in comparison to other antipsychotic drugs.²³ However, when prescribing clozapine, cautions and contraindications must be noted (Table 4).

While higher doses of clozapine may not have more anti-hallucinatory effect, they still carry the risk of inducing the potential side-effects of this highly efficacious drug (Table 5). The most dreaded haematological side-effects are usually manifested within six months. For that reason, during clozapine therapy, patient has to be closely monitored, bearing in mind its limitations in achieving the anti-hallucinatory effects. If higher doses do not have the desired effect, clozapine dose should be titrated downwards to a point of its maximum anti-hallucinatory effect in a particular patient. Such an endeavour can prevent the emergence of serious side-effects, resulting in a complete failure of the therapy. The dose can also be adjusted to a safer level in cases where the psychological interventions are found to be successful. Clozapine can be effective even in lower doses, such as 200 mg/day. Only in the presence of command hallucinations, higher doses should be prescribed to patients whose other positive symptoms are well under control.

Prophylaxis with an antiepileptic drugs, such as lamotrigine or sodium valproate, or similar should be commenced before titrating the dose above 600 mg daily. Close monitoring and active treatment of metabolic dysregulation should be initiated concurrent with clozapine therapy. In clozapine therapy, weighing up safety and superior antipsychotic efficacy and educating the patients on “clozapine lifestyle” is immensely important, as it helps in treating refractory cases of AVH. Thirty percent of patients treated with clozapine may remain unresponsive and clinicians have to lower their expectations to the level of achievement without being cynical. Isolated cases of clozapine-induced joint visual and auditory hallucinations have been reported. ²⁴ In spite of Clozaril treatment having the highest anti-hallucinatory effect, a good percentage of AVH sufferers remain symptomatic and are classed as super-refractory.⁸ According to Gonzales (2006), ²⁵ 50% of patients receiving antipsychotics achieve full remission, while 25% hear voices occasionally and 25% are unresponsive.

Table 4. Cautions & Contraindications of Clozapine

Table 5. Benefits and risks of Clozapine

Benzodiazepines are often abused by voice hearers aiming to reduce their anxiety. Such patients might benefit by the addition of antidepressant, as this could enhance their mental resources to cope with the voices, even though they have no anti-hallucinatory effects per se. Mood stabilisers are sometimes used to augment the efficacy of antipsychotics without any clinical validation. Despite multiple trials of different adjuvant therapies to an antipsychotic regimen, there have been few promising results. Still, in practice, clinicians may get frustrated, as they struggle to provide symptomatic relief to the voice hearers at any cost. Recently allopurinol, an anti-gout agent has been used as an adjunctive therapy and based on three randomized controlled trials, the result has been encouraging. ²⁶

Psychological Interventions

Persistent AVHs alone may not warrant pointless alteration of medication, as non-pharmacological interventions may achieve some control. When clinicians are not cognizant of non-pharmacological therapies, AVH patients that do not respond to antipsychotics alone may be mislabelled as having refractory AVH. In fact, they are only unresponsive to drug treatment, and could potentially respond to an integrated approach. Similarly, patients with treatment-refractory AVH are often over-diagnosed as suffering from hard to treat schizophrenia, even when other positive symptoms have been ameliorated.

There exists a false dichotomy between physical and psychological treatment approaches to AVH. In practice, both treatment modalities have to be modified in a personalised form. After all, psychiatry was originally known as psychological medicine. Presently, even though different forms of non-pharmacological interventions are available for drug-resistant AVH, some have questionable effects. ^27,28,29 (Table 6).

Table 6. Psychological Interventions

CBT therapists predicate that AVHs are a manifestation of the morbid objectification of inner dialogue (thinking in words),and accordingly verbalised thoughts are the raw material for AVHs.Verbal thinking differs from external speech in many respects and has several distinct features. CBT therapists believe that cognitive dysfunctions underlie AVH and they target them with cognitive remediation strategies. Those experiencing voices commonly think that they are caused by a powerful external agency, and are controlling and potentially harmful. Psychological factors, such as meta-cognitive biases, beliefs, and attributions concerning the origins and intent of voices, also play critical modulatory role in shaping the experience of AVH. Teaching patients to recognize the source of the voices alone has yielded beneficial effects.

Specific techniques have been designed to modify the frequency of AVHs and restore a sense of control over them. Earlier methods involved behavioural approaches based upon addressing hypothesized antecedents and reinforcers of voices and explored a variety of specific interventions such as relaxation training, graded exposure to voice triggers, manipulation of environmental possibilities and even aversion therapy. ³⁰ These behavioural techniques were eventually expanded on by the application of cognitive methods. The primary aim of psychological therapy is to change the belief that voices are omnipotent and uncontrollable and to suppress the associated attributes of false identity, wrong intentions, and urges to harm oneself and others. They encourage patients to challenge irrational interpretations and modify maladaptive behaviour, diverting attention from voices with distraction techniques (Table 7).

Reality testing and behavioural experiments are one form of CBT intervention, based on the view that behavioural changes can prompt cognitive changes. Attention switching can also be used to challenge the belief that hallucinations are uncontrollable. Command AVHs are more prevalent among the forensic population and are more distressing than the commenting ones. The risk of the sufferer acting on them is high when voices are perceived as omnipotent and uncontrollable. CBT has been proven beneficial in tackling command hallucinations. Lack of insight and formal thought disorder may not necessarily disqualify CBT for AVH; nonetheless, negative symptoms may pose a barrier to this form of psychological intervention. The current model of CBT for psychosis has been criticized, suggesting that it is simply an extension of general CBT concepts without taking into account the specificities of psychosis. ³¹ Patients with higher intelligence, who have the ability to grasp abstract concepts, might gain greater benefits from CBT. ³²

Table 7. Goals of CBT

Combining psycho-education and supportive psychotherapy has been found to enhance the functioning and self-esteem of voice hearers, providing a therapeutic structure. In the increasingly popular self-help voice-hearing groups, the ethos of recovery is understanding, accepting and integrating the sufferer’s turmoil. Acceptance and non-judgemental support of people with similar experiences has helped many patients cope with the condition. In response, the number of books on AVH, aiming to educate the sufferers and carers, has grown considerably.

Newer Psychological Interventions

Attention Training Technique (ATT) focuses on negating psychological distress through cognitive and meta-cognitive modification. ^33,34 Patients focus on up to five neutral sounds, such as a dripping tap, before switching their attention between different sounds. They then practise listening to all the sounds simultaneously. After a few weeks, they focus on neutral sounds and then on the AVH. Once this process is mastered, they switch attention between voices and other sounds, before being asked to divide their attention among them. This exercise continues for several weeks, whereby the aim is to replace the self-regulatory process with new processing configurations.

Acceptance and commitment therapy (ACT) is aimed at achieving psychological flexibility. It incorporates mindfulness and acceptance, considering AVH as a private experience and asserting that patients experience distress only when they try to deafen the voices. . By reducing struggle with voices and engagement with them, key responses such as arousal, attention and activation of brain areas are hypothesised to be reduced. ³⁵ The ideas behind ACT are consistent with the emphasis on the recovery movement of finding a way to live a valued life despite the ongoing problems. To this effect, unique and effective coping strategies are offered, whereby patients are given the insights that parts of the self are behind the voices. Thus, accepting them means sending a loving message of compassion, acceptance and respect to oneself Two randomised control studies have yielded promising results. ^36,37ACT follows a set manualised structure, rather than relying upon the complex and lengthy process of belief modification: therapy can be much briefer and potentially practiced by a wider range of clinicians and cost effective. ³⁸

There are verbal and non-verbal routes to emotions. As CBT uses the former in voice therapy, it is less effective when patients are negatively involved with the voices. On the other hand, Competitive Memory Training (COMET) uses the non-verbal route. Generally COMET sessions involve four stages.³⁹ A. identification of aspects of negative self-esteem reinforced by the voice; B. retrieval and re-living of memories associated with positive self-esteem; C. positive self-esteem is brought to compete with the content of the voices to weaken associations between voice content and negative self-valuation; and D. learning to disengage from the voices and to accept the voices as psychic phenomenon.

The significant past comes back to the conscious mind in AVH, as life experiences charged with emotion make a compelling impression on the brain. The observation that voices are knowledgeable about patients suggests that auditory hallucinations are linked to memory. In other words, negative experiences from memories evoke emotions, which should be deactivated. Distancing and decentring techniques could help patients to interpret voices as false mental events. As a result, incompatible memories could become tools to modify the power of voices—they are deactivated by new learning. Thus, when voices torment hearers, telling them that they are failures, a competing memory of such success as passing a significant examination is introduced. Posture, facial expression, imagination, self-verbalisation and music are all procedures included in the COMET protocol.⁴⁰

Compassionate mind training (CMT) is used to encourage better resilience to unpleasant commenting voices.CMT involves practicing exercises which promote self-compassion and compassion towards others. It is targeted to activate brain systems involved in social and self-soothing that amend threat systems active when experiencing unfriendly voices. ⁴¹

Mindfulness is paying attention in a particular way – on purpose, in the present moment and non-judgementally. Clinical literature cautions against use of meditation in psychosis, but the effectiveness of mindfulness-based approaches for people with psychosis has been demonstrated in controlled clinical settings. ⁴²and in the community. ⁴³ Abba et al. ⁴⁴ argue that effectiveness of mindfulness is a three-stage process: a. Becoming knowledgeable and developing more awareness of psychotic experiences and observing the thoughts and emotions that follow them. B. Permitting psychosis to come and go without reacting in order to cultivate understanding that distress is produced by the meanings one attaches to thoughts and sensations. C. Becoming autonomous by accepting psychosis and the self by acknowledging that the sensations only form part of the experience, and are not a definition of the self.

Neuroimaging studies are beginning to explain the neural mechanisms of how mindfulness might be working clinically. Structural changes have been observed in the anterior cingulate cortex, which is an area of the brain associated with emotional regulation. ⁴⁵ . There is evidence to suggest that mindfulness practice is correlated to reduced brain activity in the default mode network. ⁴⁶

Limited improvements with mono-therapy have prompted the development of multi-modular approaches. Hallucination-focused Integrative Therapy (HIT) is geared towards integrating CBT with neuroleptics, coping strategies, psycho-education, motivational intervention, rehabilitation and family treatment.⁴⁷ Extant studies indicate that integrated treatment is more effective than TAU (treatment as usual).

The continuum model of psychosis and ordinary mental events has incited the development of normalisation of the voice hearing experience.⁴⁸ Most psychiatric symptoms occur in normal people—just as breathlessness and palpitations occur while exercising—but are potential clinical symptoms. It is the frequency and duration that determine the borderline. According to the cognitive model, an internal mental event receives external attribution. Through normalisation, the external attribution can be reversed.

Although drug treatment may be the most practical way of managing AVH, refractory cases pose formidable challenges and it must be emphasized that psychological treatments are not counterproductive if applied skilfully. Clinicians who espouse the view that psychosis is a medical condition dismiss the usefulness of psychological interventions. The counter argument would be that a patient with a medical condition, such as stroke, benefits from physiotherapy, occupational therapy and psychological approaches.⁴⁹

Repetitive Trans-cranial Magnetic Stimulation

There are several ongoing trials in which the aim is to treat refractory AVH (Table 4). Repetitive transcranial magnetic stimulation (rTMS) is thought to alter neural activity over language cortical areas. Several studies on rTMS have shown improvement in the frequency and severity of AVHs, albeit without offering any strong conclusive evidence for its efficacy .⁵⁰ Moderate rates of AVH attenuation following rTMS have been noted in three meta analyses. Given that remarkable improvements in isolated cases have also been claimed, this suggests that rTMS may be appropriate mode of therapy for some patients.

Available data suggest that .rTMS selectively alters neurobiological factors that determine the frequency of AVH. However, a recent meta-analysis indicated that the effect of rTMS may be short-lived (less than one month).⁵¹ Studies seem to indicate that rTMS may be effective in reducing the frequency of AVHs, with little effect on their other topographical aspects.^50,52 Sham stimulation has also led to improvements in a number of AVH parameters. Compared to bilateral stimulation, rTMS of left tempero-parietal region appears more effective in reducing the AVH frequency . ⁵³ To reduce the distress associated with AVH and help patients to cope with hallucinatory predilection, rTMS could be combined with CBT. The side-effect profile is much cleaner for this biological approach when compared to medications. Still, like any other anti-hallucinatory treatments, neuro-stimulation technique does not guarantee long-term elimination of AVH. Electroconvulsive therapy (ECT) is considered a last resort for treatment resistant psychosis. Although several studies showed clinical improvement, a specific reduction in hallucinations severity has never been demonstrated.

Avatar Therapy

Computer-assisted voice therapy is a budding form of computerised psychological treatment that is currently undergoing trials.²⁸ In this novel therapy, persecutory voices are directly depowered with the aid of a computerised dummy of the alleged persecutor through voice dialogue. Analytically-oriented therapists can even converse with “voices” and such committed clinicians will find computerised voice therapy as another helpful tool. It is hard to ascertain whether the benefits of the avatar therapy were due to the specific technique involved or simply the increased attention and care, and Leff’s team acknowledged the limitations of their work.⁵⁴

Sound Therapy

Another important development in voice therapy is the use of tinnitus control instrument (TCI)—a form of sound therapy—in treating refractory AVH. Similar to AVH, subjective tinnitus is defined as the false perception of sound in the absence of acoustic stimuli. Even though their definitions are similar, the origin and underlying causes of these two conditions differ. Tinnitus is characterised by a simple sound—a monotone—and is non-verbal. In tinnitus, the brain is believed to interpret an internally generated electromagnetic signal as an acoustic sound or sounds.

Kaneko, Oda, and Goto²⁹ reported successful intervention in two cases of refractory AVH with sound therapy, using tinnitus control instrument (TCI) alongside antipsychotic medications. They posited that, in sound therapy, the auditory system is directly helping the limbic nervous system and the neuro-mechanism for AVH is sensitive to sound therapy .⁵⁵ They concluded that low-level auditory stimulation might be hindering the progression of voices and brain might be getting a breathing space to initiate self-healing process.

Future Directions

Hallucinogenic drugs, anti-hallucination medications and neuroimaging studies may lead to a better understanding of AVH. Animal models of hallucinations and pharmacogenetics might help to find more efficacious anti-hallucinatory drugs. AVHs themselves may have a genetic origin.¹⁰ Thus, not all patients that develop schizophrenia would experience AVHs. Such a finding might help shed more light on the genetics-linked mechanism and remedial measures of hallucinations in schizophrenia. Because the biological substrates facilitating drug effects on hallucinations remain largely unidentified, future studies with translational designs should address this important issue to find a more targeted drug treatment of psychosis.⁵⁶

If a derivative of clozapine without the haematological side-effects is formulated in the future, it might be an important milestone in the treatment of refractory AVHs and schizophrenia because clozapine has the most potent anti-hallucinatory effect. Such a novel drug could become the first line of treatment for schizophrenia, as it would address many of schizophrenic symptoms at their onset. This is crucial, as symptoms and habits become stronger and more resistant the more frequently they occur. Fatty acid amide derivatives of clozapine, such as DHA-clozapine, are found to have better pharmacological properties and enhanced safety. However, such claims are awaiting substantiation in clinical trials.⁵⁷ Thus, more attention needs to be directed into this potentially rewarding research arena. It is, however, very likely that, even after a better pharmacological cure is found for AVHs, a few symptoms might linger on for long periods. With this view, efficient non-pharmacological remedies have to be designed to deal with such residual symptoms.

Discussion

Medications help reduce the psychic pain, and protect the dignity of patients, as well as prevent suicides and homicides. From the patient’s perspective, the calming and relaxing effects of pharmacological therapies are a priority for relief from the distress due to AVH. Among the antipsychotics, clozapine has the maximum anti-hallucinatory effect and it is a shame that it cannot be used as a first line treatment choice. Treatment of AVH should be individualistic and clinicians should be prepared to apply several clinical and non-clinical approaches in concert to address them.

More research into the aetiology and mechanism of AVH is warranted in order to find effective treatment strategies. There is no shortage of theories about the mechanism of AVH, but there is no consensus among the investigators. It is unlikely that AVH is a pure neuro-chemical experience or a biological glitch, and this is where the currently available drug treatments fail. The distinction between primary and secondary symptoms was lost with the triumph of biological psychiatry in the last century. Thus, some authors presently claim that AVHs may even be a secondary symptom or a neuroquantological manifestation of an underlying biological disorder. We should not minimise the importance of eliminating symptoms when such symptoms are incapacitating, as in the case of hallucinatory experiences.

The present recovery model that emphasises and supports the patient’s potential for recovery involving hope, supportive relationship, empowerment, social inclusion, coping skills and meaning cannot be achieved without the help of psychological interventions. In this respect, CBT is a useful tool in the rehabilitation of psychotic patients with residual AVH. Jauhar et al.⁵⁸ argued that the effectiveness of CBT in schizophrenia is influenced by failure to consider sources of bias. Consequently, the benefits are more apparent than real, prompting the question of whether CBT has been oversold.⁴⁹ The verdict of Maudsley debate on the issue has been that CBT has not been oversold, but rather has a great impact on symptom reduction and enhancing concordance and insight. Perhaps the most informative trial so far accomplished has been the work on cognitive therapy for command hallucinations, which has proven the benefit of specific model development, and which productively, combined measurement of process and a targeted outcome.⁵⁹

There is ample evidence suggesting that a combination of family and psychological interventions, alongside pharmacotherapy, can be the most effective way of dealing with refractory AVH.⁶⁰ The inner dialogue hypothesis of AVH held by CBT therapists has its opponents.⁶¹ Patients respond to the voices they experience by utilising inner speech. Some observations with corresponding features weaken the inner-dialogue hypothesis. David and Lucas have demonstrated in a single case study that short-term maintenance of phonological representation (inner dialogue) may co-exist with AVHs – they are not synonymous experiences. The cost-effectiveness of psychological interventions is poorly studied, despite being highly relevant for policy decisions in healthcare.

Computerised voice therapy works better with technically minded, highly intelligent patients. In contrast, individuals of low to average intelligence may require a primarily behavioural approach, with limited efforts to understand concepts, such as automatic thinking and schema. Unlike sound therapy through music playing instruments (iPad, iPod, iPhone, etc.), TCI causes no disruption to daily functioning and can be used continuously. Computerised voice therapy and sound therapy warrant standardised case trials. When it comes to treating AVHs, optimizing compliance, reducing the burden of symptoms, and improving control, quality of life and social functioning should be the therapeutic goals.⁶² Neuroquantological views of AVHs⁶³ explain the limitations of pharmacotherapy and the usefulness of psychological interventions.

INTRODUCTION

During my placement in Psychiatry at the Brooker Centre, Runcorn, UK, I have come into contact with a wide array of psychiatric disorders, none more so than borderline personality disorder (BPD). It is undoubtedly one of the most prevalent problems in the area which the Brooker Centre serves. I can recall an example of a patient with BPD who had been quite unwell for a prolonged period of time and had struggled with affective instability. This patient had been quite successfully treated with Lithium therapy, has exhibited stability and is happy on the current treatment. There is a pattern of pharmacological treatment in BPD patients despite the fact that guidelines suggest otherwise…

Personality disorders are defined as ‘an enduring pattern of inner experience and behaviour that deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adulthood, is stable over time, and leads to distress or impairment’ . Personality disorders are representative of long-term functioning and are not considered in terms of episodes of illness ¹.

The Diagnostic and Statistical Manual of Mental Disorders, 5^th edition (DSM-5), groups the various personality disorders into three clusters based on their descriptive similarities.

Cluster A includes the Paranoid, Schizoid, and Schizotypal personality disorders which are categorised as ‘odd/eccentric’;

Cluster B includes the Antisocial, Borderline, Histrionic, and Narcissistic personality disorders which are categorised as ‘dramatic/emotional/erratic’;

Cluster Cincludes the Avoidant, Dependent, and Obsessive-compulsive personality disorders which are categorised as ‘anxious/fearful’ ².

The International Classification of Diseases, 10^th edition (ICD-10), specifies the condition of emotionally unstable personality disorder which has two subtypes: The impulsive type and the borderline type. The borderline type in essence overlaps with the DSM-5 definition ³.

It has proven difficult to provide robust clinical recommendations with regards to the treatment of personality disorder. This is, in part, due to the fact that study populations are diverse but also compounded by the use of different assessment criteria. Furthermore, it is important to consider that personality disorders often present with a great deal of psychiatric comorbidity. Of the personality disorders, particular attention has been paid to borderline personality disorder (BPD) as the symptom clusters which it involves have been shown to improve considerably with treatment ⁴.

Figure 1: Diagnostic Criteria for Borderline Personality Disorder according to DSM-5 ²:

Borderline personality disorder is characterised by a pervasive instability in mood, interpersonal relationships, self-image and behaviour. The condition was first recognised in the United States by Adolf Stern in 1938. He described that these are a group of patients who neither fit into psychotic or psychoneurotic group, which gave rise to the term ‘borderline’. BPD is often diagnostically comorbid with depression and anxiety, eating disorders (notably bulimia), post-traumatic stress disorder, substance misuse and bipolar affective disorder. Furthermore, psychotic disorders have also been found to overlap. Due to this extent of comorbidity it is rare to see a patient who has a pure BPD ⁵.

The pharmacological treatments of BPD are tailored according to the symptom clusters that present. These include impulsivity, affective instability, transient stress-related psychotic symptoms and suicidal & self-injurious behaviours ^5,6.

Recommended Psychological and Pharmacological treatment, 2009 National Institute for Health and Clinical Excellence (NICE) guidelines on Borderline Personality Disorder ^{5, 7}:

Psychological

NICE guidelines state that when offering psychology for BPD or for the individual symptoms of the disorder, brief psychological interventions (i.e. less than a 3 month period) should not be used. It states that the frequency of psychotherapy sessions should be adapted to the patient’s needs and ‘context of living’ and suggests that twice-weekly session may be considered. The guidelines also specify that for women with BPD for whom recurrent self-harm is a priority, a comprehensive dialectical behaviour therapy programme should be considered. NICE recommends that when psychological treatment is provided in BPD, the effects should be monitored using a broad range of outcomes. These should include personal functioning, drug and alcohol use, self-harm, depression and the symptoms of BPD.

Pharmacological

The NICE guidance states that drug treatment should not be used specifically for BPD or for the individual symptoms or behaviour associated with the disorder (e.g. repeated self-harm, marked emotional instability, risk taking behaviour and transient psychotic symptoms). It goes on to suggest that antipsychotics should not be used for the medium- and long term treatment of BPD. However, with regards to the management of comorbidities, it specifies that drug treatment may be considered and that in each case, the NICE guidelines for each comorbid condition must be referred to. Antidepressants, mood stabilisers and antipsychotics are commonly used in clinical practice. The guidelines mention that short-term use of sedative medication may be considered in a crisis. ‘Short-term’ denotes treatment lasting no longer than one week.

With regards to drug treatment during a period of crisis, NICE recommends that there should be a consensus among prescribers and other involved professionals about the proposed drug treatment and also that a primary prescriber should be identified. There should be an appreciation of the likely risks of prescribing, including alcohol and illicit drug use. NICE emphasises that the psychological role of prescribing (both from the patient’s and prescriber’s perspective) should be taken into account, and the impact that such prescribing decisions may have on the therapeutic relationship and overall care plan. NICE recommends that a single drug be used and that polypharmacy is to be avoided as much as possible.

In a crisis NICE recommends prescribing ‘a drug that has a low side-effect profile, low addictive properties, minimum potential for misuse and relative safety in overdose.’ The minimum effective dose is favourable, prescribing fewer tablets more frequently if there is a significant risk of overdose and also agreeing with patient on the symptoms that are being targeted. NICE suggests that following a crisis, a plan should be made to stop drug treatment that was started during a crisis. If this is not possible, a regular review of the effectiveness, side effects, misuse and dependency of the drug is advised. BPD patients can often have concomitant insomnia and for this, NICE details basic advice regarding sleep hygiene and forwards on to the guidance on the use of zaleplon, zolpidem and zopiclone for the short-term pharmacological management of insomnia.

AIMS AND OBJECTIVES

This report will review the current guidelines specifically regarding the management of borderline personality disorder and explore the literature according to the research recommendations that are set by NICE. The report is to focus on the two aspects of the management of BPD – The psychological/psychosocial aspect and the pharmacological aspect.

CURRENT NICE GUIDELINES ON PSYCHOLOGICAL AND PHARMACOLOGICAL TREATMENT OF BPD ⁷:

Psychology

Mentalisation-based therapy and dialectical behavioural therapy are proposed in the setting of a ‘well structured, high quality community based service’ e.g. a day hospital setting or a community mental health team. NICE suggests that these techniques should be compared with ‘high-quality community care delivered by general mental health service without the psychological intervention for people with BPD’ in order to measure efficacy. For outpatients, cognitive analytic therapy, cognitive behavioural therapy, schema-focussed therapy and transference focussed therapy are suggested and are catered to those with less severe BPD (i.e. fewer comorbidities, higher level of social functioning, greater ability to depend on self-management methods). Randomised controlled trials reporting medium term outcomes (e.g. quality of life, psychosocial functioning, employment outcomes and BPD symptomatology) of a minimum of 18 months are recommended

Pharmacology

Mood stabilisers are proposed as it is detailed that emotional instability is a key feature in BPD. In particular, topiramate and lamotrigine are mentioned as they have been shown to produce encouraging results in small-scale studies. A randomised placebo-controlled trial with medium to long-term follow up is recommended.

ANALYSIS

Psychology: Dialectical Behaviour Therapy (DBT)

Dialectics can be defined as the art of investigating the relative truth of opinions, principles, and guidelines ⁸. Dialectical in DBT refers to a means of arriving at the truth by examination of the argument i.e. the ‘thesis’ and ‘antithesis’ and resolving the two into a rational synthesis. DBT was introduced in 1991 by Marsha Linehan (a psychology researcher) and colleagues tailored as a treatment for BPD. In this, patients are supported in understanding their own emotional experiences and are taught new skills for dealing with their stresses. A combination of individual and group sessions are used. More adaptive responses and effective problem-solving techniques are integrated to improve functioning and quality of life as well as improving morbidity and mortality ^{9, 10}.

A study published in 2015 by M. Linehan et al detailed a randomized clinical trial that set out to compare

1) Standard DBT (DBT group skills training + DBT individual therapy) with

2) A treatment that evaluated DBT group skills training with manual case management (i.e. with the removal of DBT individual therapy) and

3) A treatment that removed DBT skills training by providing only DBT individual therapy with an activities group and prohibited individual therapists from teaching DBT skills.

All 3 versions of the treatment were found to be comparably effective at reducing suicide attempts, suicidal ideation, medical severity of intentional self-harm, use of crisis services owing to suicidality and improving reasons for living ¹¹.

Psychology: Mentalization based therapy

Mentalization is ‘the process by which we make sense of each other and ourselves, implicitly and explicitly, in terms of subjective states and mental processes.’ It is a social construct suggesting that we are attentive to the mental states of those we are with, physically or psychologically ¹². Mentalization based treatment is a psychosocial treatment for BPD in which therapists monitor attachment and mentalizing capacity, and use interventions that aim to reinstate or maintain the capacity of patients to mentalize ¹³.

A longitudinal study, published in 2008, involving an eight-year follow-up of patients treated for BPD evaluated the effect of mentalization-based treatment (MBT) with partial hospitalization compared with treatment as usual. Five years after discharge from MBT, the MBT group exhibited clinical and statistical superiority to treatment as usual measured on suicidality, diagnostic status, service use, medication use, global function and vocational status ¹⁴. A more recent review article, published in 2015, emphasises the consideration of disruptions in three closely related domains in individuals with BPD. These are ‘in attachment relationships, in different polarities of mentalizing, and in the quality of epistemic vigilance and trust’. It is suggested that this approach allows seemingly paradoxical features of BPD patients appear more coherent. It is supposed that this approach provides a clear focus for the therapist enabling them to monitor the therapeutic process in terms of imminent mentalizing impairments and epistemic mistrust due to activation of the attachment system.

The article goes on to assert that the effectiveness of MBT in BPD may be elucidated due to the fact that it ‘enables the therapist to maintain and foster a mentalizing stance, even–and perhaps particularly–under high arousal conditions that are so characteristic of work with these patients’ ¹⁵.

Psychology: Cognitive analytic therapy (CAT)

CAT is a brief focal therapy that is informed by cognitive therapy, psychodynamic psychotherapy and elements of cognitive psychology. It was originally developed by Anthony Ryle tailored towards the needs of the NHS ¹⁶. It is based on a collaborative therapeutic position which sets out to create narrative and diagrammatic reformulations with patients concerning their difficulties. The theory centres on descriptions of sequences of linked external, mental and behavioural events. At first, the emphasis was on how such procedural sequences prevented revision of dysfunctional ways of living. More recently, this has been extended to understanding the origins of reciprocal role procedures in early life and their repetition in current relationships and self-management ¹⁷.

One study detailed a randomised controlled trial which aimed to investigate the effectiveness of time-limited CAT for participants with personality disorder. The study found that participants receiving CAT exhibited reduced symptoms and showed considerable improvement compared with the control group who showed signs of deterioration during the treatment period. They concluded that CAT is superior to treatment as usual in improving outcomes associated with personality disorder ¹⁸.

Psychology: Cognitive behavioural therapy (CBT) and Schema-focussed therapy

CBT is a time-limited, problem focussed psychotherapy that has been applied to a wide range of psychiatric disorders. The development of this technique was born out of the observation that patients referred for psychotherapy often would hold ingrained, negatively skewed assumptions of themselves, their future and their environment. The therapy is based on the notion that disorder is caused not by life events, but by the view the patient adopts of events. The therapy focusses on current problems and helps to develop new skills to provide symptom relief and sustain recovery ^{9, 19}.

Initially CBT was predominantly insight-orientated, using introspection to bring about change. Beck et al began to integrate a range of behavioural techniques to improve the impact on dysfunctional controlling belief systems (schemas). The goal of treatment is not to replace the dysfunctional schemas; it aims to modify beliefs and develop new ones allowing the patient to cope more effectively in challenging situations ^{20, 21}.

A 2013 review article that set to explore schema-focussed therapy concluded that schema-therapy is based on a ‘cohesive theoretical model’ and that there seems to be sufficient evidence supporting its validity. Regarding effectiveness, it goes on to indicate that one should be encouraged by the results of studies, however it points out that due to the small number of ‘methodologically-good efficacy studies’ it is difficult to be certain. The article claims that when evaluated against other psychotherapeutic treatments, specifically DBT and MBT, schema-therapy requires more investigation ²². A pilot study (2013) set out to monitor the effects of group schema-based CBT on global symptomatic distress in young adults with personality disorders or features of personality disorder. Their findings provide preliminary evidence that schema-based CBT might be an effective treatment ²³.

Furthermore, there is a multicentre randomized controlled trial being conducted with the aim of investigating schema-focussed therapy versus treatment as usual in BPD, which has a closing date of 1^st February 2016 ²⁴.

Psychology: Transference focussed therapy (TFT)

The classic use of the term transference originates in psychoanalysis and comprises “the redirection of feelings and desires and especially of those unconsciously retained from childhood toward a new object” ²⁵. Transference-focussed psychotherapy is an evidence-based manualised treatment using a psychodynamic approach with a focus on object relations theory ²⁶. TFT aims to ‘facilitate the reactivation, under controlled circumstances, of the dissociated internalised object relations in the transference relationship to observe the nature of the patient’s split polarised internal representations, and then, through a multistep interpretive process, work to integrate them into a fuller, richer, and more nuanced identity ²⁷.

Yeomans et al produced an article in 2013 consisting of vignettes to illustrate the techniques used in TFT with the view to evaluate its use in treating BPD. Their findings supported the validity of TFT in treating BPD patients who specifically had difficulty with relationships.

They distilled TFT down to three important components ²⁸:

1) The treatment contracting/setting the frame

2) Managing one’s affective response

3) The interpretative process

Pharmacology

A Cochrane intervention review assessing the effects of drug treatments in BPD, included twenty-eight randomised control trials, published in the period 1979-2009 (20 of 28 trials dating from 2000 or later), involving a total of 1742 participants ²⁹.

Figure 2: The pharmacological agents that were tested included the following:

The authors arrived at the conclusion that pharmacotherapy in BPD ‘is not based on good evidence from trials’. The review found that there is support for the use of Second-generation antipsychotics (in improving cognitive-perceptual symptoms and affective dysregulation); Mood stabilisers (in diminishing affective-dysregulation and impulsive-aggressive symptoms); and Omega-3 fatty acids.

However, these claims were made based on single study effects and therefore require replication. No drug was found to significantly affect the symptom clusters, specific to BPD, including avoidance of abandonment, chronic feelings of emptiness, identity disturbance, and dissociation.

One noteworthy finding was that Olanzapine was associated with an increase in self-harming behaviour. Furthermore, the review states that ‘special attention’ is needed in BPD when prescribing tricyclic antidepressants (due to toxic effects in overdose) and hypnotics & sedatives (due to there being potential for misuse or dependence). Another problem that was highlighted was that in comorbid eating disorders the use of Olanzapine can contribute to weight gain and Topiramate can produce weight loss.

The review goes on to elucidate that there is not any evidence from randomised controlled trials that any drug reduces the severity of BPD and that it consists of ‘distinct pathology facets’. They recommend that the pharmacotherapy of BPD should be targeted at ‘defined symptoms’ and that polypharmacy is not supported by the latest evidence and should be avoided as much as possible.

The authors end by reaffirming that the evidence is not robust and that the studies may not satisfactorily reflect certain characteristics of the clinical environment. They propose that further research is needed in order to produce reliable recommendations. They detail the complications that arise from the ‘polythetic nature’ of BPD i.e. each patient is likely to experience different aspects of the disorder. There lacks a consensus among researchers about a common battery of outcome variables and measures. They comment that there is a fragmentary view on drug effects and that it is unknown as to how the alteration of one symptom affects another.

Comorbidity

Comorbidity is a foremost concern in the interpretation of data concerning personality disorders ³⁰. A majority of individuals diagnosed with one personality disorder often meet criteria for at least one other personality disorder ³⁰. A large proportion of patients with personality disorder have one axis I ³¹ disorder comorbidly, mostly depression, anxiety and alcohol and substance use disorders ³². [Axis I is a reference to the multi-axial classification system used in the Diagnostic and Statistical Manual of Mental Disorders that was removed in the latest version, DSM-5 ²

It is important to consider therefore that, an improvement in the symptom clusters in personality disorders might be an improvement in comorbid axis I disorder symptoms. It is reported that the rates of depression are very high in BPD ³³ and that the response to antidepressants in depressed individuals with comorbid personality disorders appears lower than in those without comorbid personality disorder ³².

The most recent guidance on the treatment of BPD from the National Health and Medical Research Council of Australia (NHMRC), which reviewed the literature and integrated a series of meta-analyses, details that pharmacotherapy does appear to be effective in altering the nature and course of BPD and that evidence does not warrant the use of pharmacotherapy as a sole or first-line treatment for BPD ³⁴.

DISCUSSION

All of the aforementioned psychotherapy techniques are shown to produce promising results when applied to the treatment of BPD, with some standing out, such as DBT and MBT, due to the presence of a relatively robust evidence base. With such a wide variety of different approaches that all show some propensity for successful treatment of BPD it is clear that these approaches must be taken more seriously in clinical practice. These treatments have been shown to considerably improve symptomatic outcomes however there is a shortcoming in that they have failed to significantly improve social functioning. Each of the therapies follow distinct theories, however, when each treatment modality is applied to BPD, similar effects are seen. This is intriguing and should be explored further.

An analysis of these therapies revealed some common features which are now suggested as core requirements for all effective psychotherapeutic treatments:

Figure 3: Five common characteristics of evidence-based treatments for BPD ^{35, 36}.

An update to the aforementioned Cochrane review ²⁹ was published in 2013. The update focussed on the psychotherapies that are available for the treatment of BPD and included a total of 1804 participants spread over 28 studies. The psychotherapies discussed were divided into ‘comprehensive’ if they substantially involved an individual psychotherapy element or as ‘non-comprehensive’ if they did not. The comprehensive therapies included dialectical behaviour therapy, mentalization-based therapy (delivered in either a partial hospitalisation or outpatient setting), transference-focussed therapy, cognitive behavioural therapy, dynamic deconstructive psychotherapy, interpersonal psychotherapy and interpersonal therapy for BPD. These were assessed against a control condition and also with some direct comparisons against each other. Non-comprehensive psychotherapies included DBT-group skills training, emotion regulation group therapy, schema-focussed group therapy, systems training for emotional predictability and problem solving for borderline personality disorder (STEPPS), STEPPS plus individual therapy, manual assisted cognitive treatment, and psychoeducation ³⁷.

The authors concluded that both comprehensive and non-comprehensive therapies indicated beneficial effects for the core pathology of BPD and associated general psychopathology. The authors identified that dialectical behaviour therapy had been studied the most comprehensively followed by mentalization-based therapy, transference-focussed therapy, schema-focussed therapy and STEPPS. However, the authors do state that none of the treatments presented a very robust evidence base and that there are concerns over the quality of individual studies ³⁷.

In terms of pharmacotherapy, the NICE and NHMRC guidelines agree with the 2006 Cochrane interventional review among others ^{38, 39} that there is some evidence that some second-generation antipsychotics (aripriprazole and olanzapine) and some mood stabilisers (topiramate, lamotrigine and valproate) could improve BPD symptoms in the short term. However, for some of these agents, it is necessary to balance risks against benefits as they have considerable long-term risks (e.g. with antipsychotics, extrapyramidal side effects such as tardive dyskinesia can persist even after withdrawal of the drug ⁴⁰). Such risks are not a problem in psychological treatments and it is probable that this influences guidelines. In practice, off-label use of psychotropics is widespread, despite the fact that the NICE guidance negates their use. It is arguable that clinicians should preferentially use pharmacological treatments that have the strongest evidence base (i.e. antipsychotics and mood stabilisers) and refrain from using agents with the least evidence (i.e. antidepressants and benzodiazepines).

CONCLUSION

Specialist treatments, in particular DBT and MBT substantiate the use of psychotherapy in BPD and these findings support the validity of the NICE guidance. However, the array of such treatments must be amalgamated with the view to provide a comprehensive, multi-faceted treatment approach. Each treatment must be broken down in order to outline the components that are particularly useful in BPD with the view to understand the condition in greater depth and to provide more focussed therapies.

The 2013 Cochrane review ³⁷ highlights that further psychotherapies are available and have been shown to successfully treat BPD core pathology, however, as it is clearly stated the evidence base lacks robustness and there is a need for further studies that can replicate results. The therapies that have been included in this Cochrane review that have not been covered in the guidelines (e.g. STEPPS) may prove to be superior to those put forward by NICE, and I recommend that these be explored thoroughly when the guidelines are due for update.

While the NICE guidance emphasises that the use of psychotropics is reasonable in the management of comorbidities, it worth noting that to understand BPD, it is necessary to explore both the underlying aberrant psychological processes and biological processes that manifest in the disorder. This will enable the use of more specific pharmacological therapies in targeting the symptoms of BPD in the future.

Summary points

• The non-vitamin K antagonist oral anticoagulants have demonstrated favourable benefit–risk profiles in large phase III trials, and these findings have been supported by real-world studies involving unselected patients representative of those encountered in routine clinical practice and including those deemed ‘challenging-to-treat’
• Accurate detection of atrial fibrillation and assessment of stroke and bleeding risk is crucial in identifying patients who should receive anticoagulation
• Elderly populations represent a significant proportion of patients seen in general practice, and advanced age should not be regarded as a contraindication to treatment; acetylsalicylic acid is not considered an effective treatment option to reduce the risk of stroke in patients with non-valvular atrial fibrillation (except for those declining oral anticoagulation), particularly in fragile elderly patients, for whom this drug was historically prescribed
• The frequency of follow-up visits, in particular to check compliance, should be tailored according to patients’ clinical characteristics and needs, but there is no requirement for routine coagulation monitoring, unlike vitamin K antagonists

Atrial fibrillation: a clinical and economic burden to society

Atrial fibrillation (AF) is the most frequently encountered sustained cardiac arrhythmia, with a prevalence of about 1.5–2% in the general population^1,2. Its incidence is predicted to rise sharply over the coming years as a consequence of the ageing population and increased life expectancy in those with ischaemic and other structural heart disease². In addition to being associated with significantly increased rates of mortality³, AF is also associated with significantly increased rates of heart failure, which is both a common cause and consequence of AF and greatly worsens the prognosis⁴. However, it is stroke that is the most devastating consequence of AF, with an average fivefold increased risk⁵.

AF-related strokes are often more severe than other strokes^6,7because the clots that embolise from the left atrium or left atrial appendage are often much larger⁸than from other sources of emboli. These clots usually lodge in large cerebral vessels, commonly the middle cerebral artery, resulting in huge neurological and functional deficits and increased mortality compared with other stroke types. Moreover, the strokes suffered by patients with AF are more likely to lead to extended hospital care than strokes in patients without AF, thus impacting on patients’ quality of life⁷.

Current evidence suggests that, in the UK, AF has a causative role in almost 20% of all strokes⁹. This is likely to represent a significant underestimate given that long term electrocardiogram (ECG) monitoring in patients who would previously have been diagnosed as having cryptogenic stroke has demonstrated a significant AF burden in these patients¹⁰.

With improved AF detection and stroke prevention, it is estimated that approximately 8000 strokes could be avoided and 2100 lives saved every year in the UK, resulting in substantial healthcare savings of £96 million^11,12.

A key objective of this short review is to provide primary care clinicians with the confidence to manage patients with AF in need of anticoagulation, including the safe and appropriate use of the non-vitamin K antagonist oral anticoagulants (NOACs) apixaban, dabigatran, rivaroxaban (approved in the EU, US and several other countries worldwide) and edoxaban (approved in the EU, US and Japan).^13-20The focus will be on how to accurately identify, risk-stratify and counsel patients on the risks and benefits associated with the different treatment options.

Who to treat. Accurate detection and assessment of stroke and bleeding risk

Many patients with AF are asymptomatic, particularly the elderly, less active patients who may not notice the reduction in cardiac performance associated with AF. Unfortunately, it remains the case that AF is undetected in up to 45% of patients²¹, and stroke is very often the first presentation of AF.

Both the National Institute for Health and Care Excellence (NICE) and the European Society of Cardiology (ESC) guidelines recommend opportunistic screening in patients aged ≥65 years by manual pulse palpation followed by ECG in patients found to have an irregular pulse^1,22. Opportunistic screening (manual pulse palpation) was shown to be as effective as systematic screening (ECG) in detecting new cases²³, and this simple strategy should be used to screen at-risk patient groups as often as possible. Hypertension and increasing age are the two leading risk factors for developing AF, but other high-risk groups include patients with obstructive sleep apnoea, morbid obesity or a history of ischaemic heart disease^24-26. In the context of proactive AF detection, many initiatives have been launched worldwide to encourage primary care clinicians to integrate manual pulse checks into their routine practice. The Know Your Pulse campaign was launched by the AF Association and Arrhythmia Alliance during Heart Rhythm Week in 2009 and was quickly endorsed by the Department of Health in the UK and by many other countries. This initiative has assisted in diminishing some of the gaps in AF detection²¹.

The most frequently used tools to evaluate stroke risk in patients with non-valvular AF (AF that is not associated with rheumatic valvular disease or prosthetic heart valves) are the CHADS₂²⁷ and CHA₂DS₂-VASc²⁸scores, with recent guidelines favouring the use of the latter and emphasising the need to effectively identify ‘truly low-risk’ patients¹. The CHA2DS2-VASc score is superior to CHADS₂ in identifying these truly low-risk patients, who should not be routinely offered anticoagulation¹. Patients with any form of AF (i.e. paroxysmal, persistent or permanent), and regardless of whether they are symptomatic, should be risk stratified in this way. The risk of stroke should also be assessed using CHA₂DS₂-VASc in patients with atrial flutter and probably for the majority of patients who have been successfully cardioverted in the past²². Unless the initial underlying cause has been removed (e.g. corrected hyperthyroidism) and there is no significant underlying structural heart disease, the risk of patients suffering from a recurrence of AF following ‘successful’ cardioversion remains high²⁹. The ESC guidelines recommend that anticoagulation should be offered to patients with a CHA₂DS₂-VASc score ≥1 based on assessment of risk of bleeding complications and the patient’s clinical features and preferences¹.

The new Quality and Outcomes Framework (QOF) for 2015–2016 now recommends the use of CHA₂DS₂-VASc for risk stratification and no longer recommends antiplatelet agents as a therapeutic option for stroke prevention in patients with non-valvular AF³⁰; this should result in significantly more patients receiving anticoagulation for this indication. The changes to QOF 2015–2016 compared with 2014–2015 are summarised in Table 1³⁰.

Table 1. Summary of changes to UK the Quality and Outcomes Framework (QOF) 2015–2016³⁰

Key: AF = atrial fibrillation; CHADS₂ = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, Stroke (doubled); CHA₂DS₂-VASc = Congestive heart failure or left ventricular dysfunction Hypertension, Age ≥75 years (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age 65–74 years, Sex category (female); NICE = National Institute for Health and Care Excellence

The Guidance on Risk Assessment and Stroke Prevention in Atrial Fibrillation (GRASP-AF) clinical audit software detection tool is now very widely used in primary care to improve clinical outcomes in the AF population by identifying patients likely to benefit from anticoagulation. GRASP-AF systematically scans general practice software systems and calculates CHADS₂ and CHA₂DS₂-VASc scores in patients who are coded as having AF, thus enabling physicians to identify high-risk patients who are not adequately treated for stroke prevention³¹. Identification of AF patients who are poorly controlled on warfarin (defined as having a time in therapeutic range <65% or a labile international normalised ratio [INR], e.g. one INR value >8 or two INR values <1.5 or >5 within the past 6 months)²² is crucial because these patients are more likely to experience major bleeding or stroke. These patients should be reviewed and, if possible, the cause for the poor warfarin control should be identified. The Warfarin Patient Safety Audit tool is another software tool that has been developed to help identify patients with poor warfarin control³².

Primary care clinicians are being urged to objectively assess the bleeding risk of AF patients who are receiving, or about to receive, anticoagulation^1,22,32. HAS-BLED is the bleeding assessment scheme advocated by both NICE and the ESC^1,22, this has been validated in several independent cohorts and was shown to correlate well with the risk of major bleeding, in particular intracranial bleeding¹. The key aspect of HAS-BLED is that, unlike CHADS₂ and CHA₂DS₂-VASc, it consists of risk factors that are modifiable. It should, therefore, not be a tool to influence the decision of whether to anticoagulate, but instead to identify ways to reduce the risk of bleeding in patients receiving an anticoagulant; for example, optimising blood pressure control, stopping unnecessary antiplatelet or anti-inflammatory agents and reducing alcohol consumption can all significantly reduce HAS-BLED scores and bleeding risk¹. In addition, it needs to be emphasised that the absolute number of patients with AF experiencing a serious bleeding event while receiving anticoagulant therapy is low (~2–3%/year in the XANTUS, PMSS and Dresden NOAC Registry real-world studies) , with prospective real-world studies indicating that most bleeding events can be managed conservatively^33-35. Whilst concerns have been raised about not having a reversal agent to counter the anticoagulant action of NOACs in patients who experience serious bleeding, the low incidence of major bleeding in real-world and phase III studies and its conservative management in most cases demonstrate that such agents would not be required routinely. Despite these low rates of major bleeding, reversal agents have been developed and successfully completed phase III studies and undergone approval in some markets, including idarucizumab in the UK^36,37. Notably, high-risk patients with AF were shown to be more willing to endure bleeding events in order to avoid a stroke and its consequences³⁸, thus reinforcing the message that “we can replace blood but we cannot replace brain tissue”.

Adequate anticoagulation therapy should follow appropriate patient identification

Identifying the right treatment option for patients with AF is likely to improve clinical outcomes. Involving patients in the decision-making process and rationale, and ensuring they understand the net benefit–risk of treatment options, is likely to lead to better compliance and improved clinical outcomes. The ESC guidelines consider patients with valvular AF (patients with AF in the presence of either rheumatic mitral stenosis [very rare now in the UK] or prosthetic heart valves) to be at high risk, and these patients should be anticoagulated with a VKA regardless of the presence of any other risk factors¹. Warfarin is very effective at reducing the risk of stroke compared with acetylsalicylic acid (ASA)^39,40, but an unpredictable dose–response relationship and multiple drug and food interactions can be problematic for some patients, and many patients remain sub-optimally treated⁴¹. ASA is also not considered an effective treatment option to reduce the risk of stroke in patients with non-valvular AF especially in frail, elderly patients in whom ASA was historically prescribed. The GARFIELD-AF registry (10,614 patients enrolled in the first cohort) revealed that real-world anticoagulant prescribing in AF populations deviates substantially from guideline recommendations: 40.7% of patients with a CHA₂DS₂-VASc score ≥2 did not receive anticoagulant therapy, and a further 38.7% with a score of 0 received anticoagulant therapy. At diagnosis, 55.8% of patients overall were given a VKA, just over one quarter (25.3%) received an antiplatelet drug alone, and ~4.5% received a NOAC²⁴. Inappropriate prescribing was further confirmed by data from UK general practices (n=1857, representing a practice population of 13.1 million registered patients) using the GRASP-AF tool. Only 55% of patients with high-risk AF (CHADS₂ ≥2) were receiving oral anticoagulation (OAC) therapy, whereas a further 34% of patients with no known contraindication did not receive OAC therapy⁴².

The NOACs have altered the landscape in terms of stroke prevention management by increasing the available options for patients. These agents exhibit some important practical advantages over traditional therapy (e.g. no requirement for routine anticoagulation monitoring, simple fixed dosing oral regimens, fast onset of action, fewer drug reactions and no food interactions), leading to their increased uptake in primary care.

Key patient groups who are likely to benefit from the NOACs include patients poorly controlled on VKAs, those predicted to require medications that interact with VKAs (e.g. patients who require frequent antibiotics), those without severe renal impairment or those with a prior ischaemic stroke while receiving a VKA with an adequate INR. These agents could also be a good choice for patients living a considerable distance from their local hospital or surgery and commuters. The NICE guidelines state that primary care clinicians should consider clinical features and patient preference before deciding on the most appropriate option for patients²². In addition, cost may be important in some settings. All of the NOACs have demonstrated cost-effectiveness versus warfarin, and although cost models vary by country, there is little doubt that these agents provide cost-effectiveness largely through the number of adverse events avoided and their associated costs⁴³.

Choice of anticoagulant: which to choose?

The demonstration of a favourable benefit–risk profile (stroke prevention vs bleeding events) in large phase III studies involving over 70,000 patients has resulted in the regulatory approval of apixaban, dabigatran, edoxaban and rivaroxaban^44-47for the prevention of stroke and systemic embolism in patients with non-valvular AF and one or more risk factors.

Overall, NOACs have demonstrated an improved benefit compared with warfarin, with lower rates of intracranial haemorrhage (for all NOACs) and similar or superior efficacy for stroke prevention^44-48. Statistically significant relative risk reductions (RRRs) in the incidence of fatal bleeding events were seen with low-dose dabigatran (110 mg twice daily [bd]; RRR=42%), both tested doses of edoxaban (30 mg once daily [od] and 60 mg od; RRR=65% and 45%, respectively) and rivaroxaban (20 mg od; RRR=50%)^46,47,49; rates of fatal bleeding were also lower in patients treated with apixaban compared with warfarin (34 patients vs 55 patients, respectively)⁴⁴. These data are promising, especially considering the current lack of a specific antidote for any of the NOACs, and it is likely that the very short half-life of these drugs play an important role in mitigating the bleeding risk.

Owing to a lack of head-to-head comparisons between the NOACs in phase III clinical trials, patient characteristics, drug compliance, tolerability issues and cost may be important considerations¹. In addition, subanalyses of phase III trial data for rivaroxaban, apixaban and dabigatran indicate that the challenging-to-treat patient groups often encountered by primary care clinicians can be treated effectively and safely with the NOACs (Table 2). A recent meta-analysis showed a similar treatment effect for almost all subgroups encountered in clinical practice; NOACs appeared to be at least as effective as VKAs in reducing the risk of stroke and systemic embolism and no more hazardous in relation to the risk of major bleeding events, irrespective of patient co-morbidities⁵⁰.

Table 2.Novel oral anticoagulants studied in key patient subgroups*

*No subgroup analyses have been presented for edoxaban Key: AF = atrial fibrillation; ARISTOTLE = Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation; CAD = coronary artery disease; CHADS₂= Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, Stroke (doubled); MI = myocardial infarction; PAD = peripheral artery disease; PK/PD = pharmacodynamics/pharmacokinetics; RE-LY = Randomized Evaluation of Long-term anticoagulation therapy; ROCKET AF = Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation; VKA = vitamin K antagonist

Because patient selection in clinical trials is based on strict inclusion/exclusion criteria, patient populations in such studies are not always representative of patients routinely seen in real-world practice. In addition, bleeding events may be managed differently in clinical trials versus routine clinical practice. Real-world data are, therefore, needed to help validate drug safety and effectiveness in unselected patient populations. Following phase III clinical trials and the widespread approval of the NOACs in stroke prevention in patients with non-valvular AF, real-world experience has been steadily accumulating. The current real-world data for rivaroxaban, apixaban and dabigatran have been very reassuring and bridge the evidence gap between clinical studies and real-world experience^33-35,51-57.

The lack of routine coagulation monitoring with NOACs does not remove the necessity for regular follow-up. Instead, the frequency of visits can be tailored according to patients’ clinical characteristics and needs. NOACs are all partially eliminated by the kidneys; therefore, regular monitoring of renal function is important either to use a lower recommended dose of these drugs or to avoid them. For example, renal function should be monitored every 6 months in patients who have stage III chronic kidney disease (creatinine clearance [CrCl] 30–60 ml/min)⁵⁸. Apixaban, rivaroxaban and edoxaban are not recommended in patients with CrCl <15 ml/min, and dabigatran is contraindicated in patients with CrCl <30 ml/min^13,15,17,19. Reduced-dose regimens of NOACs are recommended for patients at higher risk of bleeding events, including those with reduced renal function. For example, a reduced apixaban dose of 2.5 mg bd is indicated in patients with at least two of the following characteristics: age ≥80 years, body weight ≤60 kg or serum creatinine ≥1.5 mg/dl (133 μmol/l); a reduced rivaroxaban dose of 15 mg od is indicated in patients with CrCl 15‒49 ml/min⁵⁸; edoxaban is recommended at a reduced dose of 30 mg od in patients with CrCl 15‒50 ml/min and contraindicated in patients with CrCl >95 ml/min⁵⁸; and a reduced dose of 110 mg bd dabigatran should be considered in patients with CrCl 30‒50 ml/min who are at a high risk of bleeding⁵⁸. Follow-up visits should also systematically document patient compliance, thromboembolic and bleeding events, side-effects, co-medications and blood test results⁵⁸.

Conclusions

The NOACs have demonstrated favourable benefit–risk profiles in large phase III trials, and these findings have been supported by real-world studies involving unselected patients, including those deemed challenging to treat. The NOACs also address many of the limitations associated with VKA use, thus assisting with their integration into clinical practice for stroke prevention in patients with non-valvular AF. In addition, the results from subgroup analyses should provide primary care clinicians with the confidence to manage stroke-prevention strategies in a wide variety of patients with AF.

Introduction

A clearer understanding of the aetio-pathogenesis of schizophrenia would ultimately lead to effective treatment strategies and provide the impetus for elucidation. The autoimmune hypothesis promulgates that it is the auto-antibodies that are responsible for schizophrenia and, according to the viral hypothesis, it may be the body’s abnormal response to a slow viral infection or the undefeated viral antigens causing the schizophrenia pathology. The autoimmune and viral hypotheses are interlinked, as autoimmune disorders can be triggered by microbial infection. Viral aetiology is less convincing than the autoimmune model, but from a treatment perspective, the former is more promising than the latter. To gain a detailed understanding of aetiological models of a subset of schizophrenia, herein the author has reported on a review of the literature relating to the immunity- and viral-based aetiological models of schizophrenia. Genetic vulnerability has been highlighted in the schizophrenia literature alongside environmental factors. The veracity and contestability of the immunity- and viral-based aetiological hypothesis of schizophrenia merits further investigation.

Schizophrenic Syndromes

A prerequisite for incorporating autoimmune and viral aetiology into a scientific discussion would be acceptance of the heterogeneous hypothesis of schizophrenias; they may be a cluster of entities with different aetiologies and the end-stage of different disease processes. ¹ Autoimmune or viral aetiology may account for one subgroup.

Schizophrenia has diverse signs and symptoms, and a long history of controversy. Nosologists designate it as polythetic, whereas most other mental illnesses are monothetic, seemingly affecting only one brain system. ² In the second half of the twentieth century, the psychosocial model gave way to evidence that it is a brain disorder. Schizophrenia has a long history of controversies and there has been much contention over the aetiology, psychopathology, nomenclature, and diagnostic criteria. Schizophrenia is currently seen as a neurodevelopmental encephalopathy, in which the cognitive deficits are produced due to the errors during the normal development of the brain ³ or a neuro-degenerative disorder and the cognitive deficits are derived from a degenerative process that goes on unalterably. Modern neuroimaging techniques and an intensification of studies of necropsy tissue have been responsible for this shift. Researchers seem to agree that a neurodevelopmental or degenerative assault precedes the symptoms by several decades.

The aetiology of the cognitive deficits is unidentified and several potential factors, genetic and epigenetic, are envisaged. Environmental factors—including infectious agents and disturbance in utero through malnutrition—account for a few cases. Autoimmunity and viral theories would fit in with the neuro-developmental and neurodegenerative hypotheses. Proponents of viral aetiology view viruses as acting alongside susceptible genes to initiate a trajectory that manifests as psychotic symptoms.

Lessons from Autoimmunity

Disorders of an autoimmune nature are known to occur with increasing frequency in patients with another autoimmune disease. This is somewhat like the coexistence of multiple psychosomatic disorders in a person; as per Halliday’s psychosomatic formula, association of other psychosomatic afflictions justifies the diagnosis of a new psychosomatic condition. ⁴ It is well recognised that the central nervous system (CNS) may be directly affected by autoimmune processes, as in the case of multiple sclerosis (MS) and autoimmune limbic encephalitis. A physical autoimmune disease, such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome are also associated with psychiatric morbidity. Paediatric autoimmune neuropsychiatry disorder is a post-infection (group A Beta-haemolytic streptococcal infection) autoimmune disorder characterised by abrupt onset of obsessive compulsive disorder (OCD) and Tourette’s syndrome, brought about by molecular mimicry. ⁵ Nicholson et al observed that 20% of OCD patients were positive for anti-basal antibodies, considered to be part of a post-streptococcal autoimmune reaction. ⁶

Autoimmunity is a misdirected response occurring when the immune system attacks the body; it is the loss of tolerance to self-antigens. Immunological tolerance to one’s own tissue is probably normally acquired during foetal life, helping to prevent the occurrence of the autoimmune process (see Table1). Some clones of cells that can produce auto-antibodies (forbidden clones) are thought to be produced throughout life, and are suppressed by large amounts of self-antigens or antigen-specific T cells. Auto-antibodies are produced for a wide variety of antigens; some are organ-specific and others are non-organ-specific. Some microorganisms or drugs may trigger changes in individuals who are genetically vulnerable to autoimmunity.

Table 1- Mechanisms preventing and causing autoimmunity

A human disease may be considered of autoimmune origin on the basis of knowledge from molecular biology and hybridoma technology, ⁷ along with the Witebsky postulations. It is established by the presence of auto-antibodies and T cells that react with host antigens. Approximately 25% of patients with an autoimmune disease (AD) tend to build up additional auto-antibodies. Strausburg et al (1996) explained several hypotheses for the virally-triggered autoimmune mechanism (see Table 2). ⁸ Allergy is the consequence of a strong response to a harmless substance, but ADs are caused when the destructive potential of the immune system is misdirected to oneself. ADs share common effect or mechanisms with hypersensitivity reactions and can be classified into three main types corresponding to the type ii, type iii, and type IV categories of hypersensitivity reactions (see Table 3)

Table 2 - Virally triggered autoimmune mechanisms

Table 3 - Classification of Autoimmune disorders

Shared Aetiology

ADs are characterised by shared threads in terms of their propensity to co-exist in a patient or direct relatives. Two major autoimmune clusters have been recognised via, thyrogastric—mostly organ-specific—diseases and lupus-associated—mainly multi systems—diseases. ⁹ Some ADs are distributed within either cluster and there are also overlaps within each cluster. These patterns of concurrence depend predominantly on genetic determinants.

Poly-autoimmunity is the term proposed for the association of multiple autoimmune disorders in a single patient and such co-occurrences indicate a common origin of the disease. ¹⁰ Adriana et al, by grouping diverse ADs in the same patient, demonstrated that they are true associations as part of autoimmune tautology rather than chance findings.

Co-Occurrence of ADs

Theories for autoimmune aspects of schizophrenia raise the concept of early infection by microorganisms with antigens so analogous to CNS tissue that resulting antibodies act against the brain.Some data suggest that an autoimmune process precedes schizophrenia, non-affective psychosis, and bipolar disorder, ¹¹ but do not establish whether this is affected by viral attack, as viral footprints may be hard to detect, especially in the target organ, once the autoimmune process has begun. Psychosis is reported in 25% of SLE cases.

A Danish study revealed that schizophrenia is associated with a large range of ADs. ¹² The researchers found that a history of any AD in the patient is allied with a 45% increase in the incidence of schizophrenia. Specifically, nine ADs have a higher prevalence rate among patients and 12 ADs have a higher prevalence rate among their parents than among comparison groups. In comparison with the control group, Thyrotoxicosis, Celiac disease, Acquired haemolytic anaemia, interstitial cystitis, and Sjogren’s syndrome had a higher prevalence rate among schizophrenia sufferers and their family members.

Three of the Ads—namely, celiac disease, thyrotoxicosis, and acquired haemolytic anaemia—have been previously associated with schizophrenia. Celiac disease involves an immune reaction to wheat gluten. This could be due to increased permeability of the intestine, raising the level of antigen exposure, resulting in increased risk of an autoimmune response to brain components or it may be that gluten proteins are broken down into psychoactive peptides. Eaton et al opined that the association of schizophrenia and ADs could be due to common genetic causes, perhaps related to the HLA or other genes, and some cases of schizophrenia may be consequential to the production of autoantibodies that disrupt the brain function.

Researchers for a Taiwan study identified a greater variety of ADs in schizophrenic patients than anticipated and recommended further research. ¹³ Chen et al. found that 15 ADs are significantly associated with the schizophrenia group. Their studies also confirmed an earlier observation of a negative relationship between schizophrenia and rheumatoid arthritis (RA). It has been observed in a small sample study that mothers of schizophrenia patients have a lower risk for RA.¹⁴

Rheumatoid Connection

The negative correlation between schizophrenia and RA is puzzling. ¹⁵ Such dissociation was interpreted as the effect of antipsychotic medication. Similarly, the metabolic changes associated with one disease may inhibit another.¹⁶ Genes predisposing a person to have one disorder may have a protective influence against another and, in that way, the negative rheumatoid connection with schizophrenia is consistent with an autoimmune model.

RA has a genetic predisposition partly mediated by major histocompatibility complex (MHC) alleles and triggered by infection. Similarly, schizophrenia has genetic and environmental associations and has been cautiously connected with MHC genes other than those perhaps involved in RA. In addition to gene products accountable for antigen presentation, the MHC gene complex holds a multitude of genes-controlling aspects of immune response. Hypothetically, depending on the set of genes an individual has inherited at the MHC complex, a viral assault will lead the immune system to an immune cascade toward the development of RA, or along a genetically-predetermined path with a network of cytokines and immune mediators and directed against CNS components, resulting in schizophrenia. ¹⁷

The negative rheumatoid connection may be attributable to two mutually-exclusive alleles of the same gene. Such associations may lead to novel treatment strategies; sickle cell anaemia patients are thought to be less affected by malaria. Of note, the combined research of Karolinska Institute in Sweden and John Hopkins’s University School of Medicine in the United States have recently discovered the genes and the specific deoxyribonucleic acid (DNA) sequences that regulate them plot together to the progress of RA; rheumatology may be inching close to an early detection method and effective treatments. Such a development could hopefully happen in the schizophrenia research.

Commonalities

Even though ADs superficially seem different, the vast majority of them share several similarities. Like ADs, schizophrenia, as such, is neither infectious nor congenital. Schizophrenia and ADs have well-established genetic propensities, and a combination of genes, rather than a single gene, is thought to be responsible for their manifestations. Both schizophrenia and ADs can be triggered by environmental toxins and they have a remitting and relapsing course. Worsening of symptoms is observed when patients are exposed to stress and both conditions have a peak increase in late adolescence or early adulthood. These similarities argue in favour of an autoimmune aetiological model of schizophrenia. ¹⁸

Apparently, there is an interesting epidemiological dissimilarity between ADs and schizophrenia. The incidence of ADs is on the increase in developed countries, whereas schizophrenia has a consistent incidence of 1% globally. According to the hygiene hypothesis of ADs, the widespread practice of hygiene, vaccination, and antibiotic therapy in rich countries have disabled children’s immune systems to deal with proper infections and are more geared to charge with one’s own tissues in highly-destructive ways. ¹⁹ The incidence between the sexes was thought to be almost similar in the case of schizophrenia, but a recent study shows that for every three males with schizophrenia, there are two females with the disease. ²⁰ ADs are slightly higher among the female population.

Immune Modulation of Clozapine

Antipsychotics may have an immunosuppressant effect; plasma levels of IL-6, soluble IL-6R and transferrin-receptor (TfR) were significantly lower after antipsychotic drug treatment. Activation of cell-mediated immunity may occur in schizophrenia; neuroleptic agents may modulate this through suppression of IL-6 or IL-6R-related mechanisms. ²¹ The antipsychotic effect may involve a counter-effect on the brain-mediated immune system.

Clozapine, the gold standard for refractory schizophrenia, is a dibenzodiazepine and lowers D2 receptor occupancy and is also a 5-hydroxytryptamine antagonist. Studies indicate that among the atypical antipsychotics, clozapine seems to have an immunosuppressant effect along with neuro-modulatory effect. It has been suggested that clozapine may diminish antibody synthesis in hematopoietic cells and also argued that a possible immunosuppressive action may contribute to its superior antipsychotic efficacy. ²² The long-term immunosuppressive effects of antipsychotics may inhibit putative autoimmune responses against neurological sites and could, thus, act synergistically with the direct antagonistic action on brain receptors for the evident improvement of psychotic symptoms. ²³ It is also conjectured that the increase of soluble IL-2 receptor levels in Clozapine-treated patients indicates an immunosuppressant mechanism. ²⁴

Haloperidol may also be a neuro-immune-modulating drug. A study of in-vitro effects of clozapine and haloperidol on cytokine production by human whole blood suggested that both drugs, at concentrations within their therapeutic range, may exert immunosuppressive effects through an enhanced production of IL-1 receptor antagonists. ²⁵

It is well recognised that unlike other antipsychotics, clozapine works better over time, as immune modulation may take longer than neuro modulation. In addition to the neuro modulation, antipsychotics may be working on the principles of immune modulation, as well. If a derivative of clozapine, without its haematological and metabolic side effects is discovered, such a drug would become the first line of choice among the antipsychotics, and that could be a significant event in schizophrenia research. The immunosuppressant effects of clozapine seem to have public health awareness that patients on clozapine are advised to have the winter flue jab. Elderly patients on antipsychotic medications are more prone to get pulmonary infections, indicating that such drugs have a delicate immunosuppressant property.

Autoimmune-Neuropsychiatric Disorder?

If schizophrenia is an AD, a higher rate of other ADs may be expected among schizophrenics. Most studies confirm that it is tied to irregularities affecting multiple levels of the immune axis.There are multiple interlinked causative factors in the aetiology of schizophrenia. There are suggestions that the neuro-behavioural changes follow an abnormal response to microbial invasion, but that does not necessarily lead to an autoimmune process. The literature deciphering the role of viruses in neurotransmitter abnormalities linking neurodevelopment assaults and the neuropsychological manifestations of schizophrenia is unhelpful. For those who adhere to the autoimmune model of schizophrenia, the simplest suggestion would be that the pathogenesis of the subset of schizophrenia studied may be caused by antibodies in the plasma and CSF that react with brain proteins, resulting in a neuro-autoimmune process.

Lessons from Viral Infections

The concept that certain psychiatric disorders are the neuro-behavioural sequel of the body’s immune response to viral infections was prevalent in the early part of the 20^th century. That was an outcome of research conducted into rabies in the late 1880s, which revealed the affinity of viruses for the nervous system. Research into tertiary syphilis also provided evidence of an infectious aetiology for specific psychiatric disorders. Investigation of the encephalitis lethargica pandemic (1919 - 1928) contributed to recognition of viral causation on account of similarities apparent between the psychotic symptoms associated with encephalitis lethargica and the clinical presentation of schizophrenia. ²⁶

Post-influenza depression, depression following mononucleosis, and hallucination associated with herpes encephalitis are well recognised. Menninger, who studied post-influenza psychosis, promulgated the first acceptable viral hypothesis for schizophrenia. ²⁷ In the mid-twentieth century, psychodynamic studies began to encompass the origins of schizophrenia and viral aetiology lost its novelty. Dementias associated with Acquired Immune Deficiency Syndrome (AIDS) have reawakened interest in the correlation between virology and psychiatric disorders, and different authors have revisited these hypotheses in the last three decades. ^28-36

The immune response to influenza and other viruses involves cell-mediated immunity and cytokine activity, which tend to turn tryptophan into kynurenic instead of serotonin. The outcome of this deviation is mood disturbance. It is the body’s immune response that blocks the conversion of tryptophan into serotonin, thereby resulting in post-influenza depression. It is arguable that there may be other psychiatric disorders consequential to a slow immune response of the body to viral infections. The possibility of viral oncogenesis was originally ridiculed, but now there is some evidence to support the view that viruses are responsible, at some stage, for approximately 20% of human malignant diseases. ³¹

In theory, a virus could induce schizophrenic symptoms or depression by stimulating antibodies that cross-react with brain tissue, without necessarily gaining entry into the brain. At different developmental stages, the immune response may become less efficient and viral agents may become potentiated, leading to neuropsychiatric conditions. The supposedly inflammation-mediated brain diseases occur at different stages—for instance, schizophrenia in late adolescence or early adulthood, and Alzheimer’s typically at an advanced age. It is well established that the human immunodeficiency virus (HIV) may lead to a form of AIDS dementia, and other common viruses that infiltrate the neurons may cause other types of dementia. HIV/AIDS and Borna Disease Virus (BDV) in animals help to bring the infection-based model of schizophrenia to the realm of scientific imagination

Viruses can influence the human genome. After becoming effective, viral sequences are integrated into the genome of brain cells. These sequences are not thought to be inheritable, but may cause mutations that interfere with brain functions and contribute to the development of psychiatric disorders. ³⁷ It may be arguable that the combination of the body’s sustained immune response and the constant release of antigens of a hypothetical slow virus (schizovirus) may account for the neuro-behavioural alterations. In the following paragraphs, the author discusses how viral pathogens and other potential contributors could interact and lead to schizophrenic psychopathology.

Immune Responses

Neuro-developmental theories of schizophrenia fit the hypothesis that viral insult occurs early in sufferers, not proximally to a psychotic episode. The interaction between host and virus is affected by coordinated activity of the immune system and the brain. There is evidence that schizophrenia is accompanied by mutations in the immune system. Innate immunity is the first defence against microbes; infection results in invasion by live microorganisms and their toxic products, stimulating an inflammatory response. Neuronal functions are disrupted by pathogens and the brain’s inflammatory responses. Non-cytolytic viruses may affect neurones without causing cyto-architectural alteration, but disturbing neurotransmitter production and weakening hormones involved in neurodevelopment. ³⁸ In schizophrenia, immune infiltration is absent, as are vital inclusion bodies and minimal gliosis. There is subtle disruption of neuronal function and brain development, but no significant loss of neuronal cells. Thus, the schizophrenia subset may have a viral aetiological origin, bringing about anomalous, specific immune responses, an autoimmune basis, or both. What triggers the autoimmune process is uncertain, but microbial triggers are a strong possibility.

Immune dysfunctions including lymphocytic abnormalities, protein abnormalities, auto-antibodies, and cytokines have been suggested in seriously-ill patients ³⁹. One study showed significantly higher plasma levels of interleukin-6 (IL-6) in schizophrenics, and soluble IL-6R and soluble IL-2R were significantly high in mania. ⁴⁰ A few early investigators claimed to have microscopically visualised virus-like particles in the cerebrospinal fluid (CSF) of patients or in chicken embryos inoculated with CSF. Studies of viral antibodies, viral antigens, viral genomes, the cytopathic effect of specimens on cell cultures, and animal transmission experiments are other avenues for exploring the viral infection hypothesis.

The subset of schizophrenics in question may have a highly-sensitive surveillance system, but a less-discerning immune mechanism than the general population. It could be the over-reaction of the immune system to the microbial adversary that may eventually lead to the schizophrenia pathogenesis. The fault may lie in the surveillance system, as well as in the body’s anomalous response to the microbial invasion. ¹⁷ In general, innate and acquired immune mechanisms interact and cooperate, but any derangement can lead to deviant immune responses that may result in neuropsychiatric abnormalities.

From an evolutionary perspective, innate immunity is less evolved and the mammalian brain is endowed with a complex immune response system, implying that the neurobehavioral aberrations of schizophrenia could be more linked with deviant and vigorous specific immune responses. ¹⁷ It is possible that the proposed subset of schizophrenia may have either an autoimmune basis or a viral aetiological origin, bringing about anomalous, specific immune responses, or both. It has been argued that a gene family involved in the specific immune system and autoimmunity is involved in schizophrenia. ⁴¹ The genome-wide association studies (GWAS) have been disappointing in schizophrenia, whereas the major histocompatability complex (MHC) region continues to be the best replicated.

Epidemiological Findings

Epidemiological studies offer useful supporting evidence for viral aetiology (see Table 4). Epidemiological studies characterised by certain broad patterns of incidence and distribution of schizophrenia offer evidence to suspend the scepticism of the viral causal hypothesis. In a study of adults at risk of exposure in utero to the 1957 influenza A2 epidemic in Helsinki, those at risk during the second trimester had significantly more hospitalisations for schizophrenia than those potentially exposed during the other trimesters or immediate years. ⁴² Researchers for nine subsequent epidemiological studies scrutinised the risk of schizophrenia after possible intrauterine exposure to influenza in Europe and the USA; these identified a small majority claiming to find an association.⁴³ Falsifying the influenza link with the origin of schizophrenia does not altogether make the viral aetiology null and void. There could still be an unknown virus (schizo-virus) as the causative agent. The Hepatitis C virus came to medical attention only 15 years ago. At least these epidemiological studies illustrated that viruses can help set the stage for schizophrenia as a long-term sequel

Table 4 - Suggested Evidences for Viral aetiology

A worldwide average of 1% prevalence of “core schizophrenia” is generally accepted, ⁴⁴ even though such a concept of universal distribution and gender equality has opposition. ⁴⁵ However, there is evidence to assume that there may not be gross variations in this global prevalence. Cross-culturally stable rates, despite decreased fecundity in affected individuals, support an external biological aetiology. These point toward biologically-interlinked and multifactorial causation including an evolutionary genetic factor, as a single biological factor would be insufficient. The preservation of susceptibility genes for schizophrenia in the human gene pool is an evolutionary enigma; gene carriers or first-degree relatives may have some compensatory evolutionary advantage. ⁴⁶ In a multifactorial aetiological model of schizophrenia, infectious theories are contestable. ¹⁷

Such a consistent prevalence, if true, could also be argued in favour of a biologically-inter-linked and multi-factorial causation of schizophrenia, as it is obvious that a single biological factor would be insufficient to maintain a delicate and consistent global prevalence of a disease. Many viruses are relatively constantly distributed, while genetic diseases present distinct geographical clustering due to inbreeding. One may hypothesise that where viral loading is high, genetic input may be less and vice versa. The consistent global incidence points toward universal microbes, a readily-available environmental factor, or, more specifically, a “schizovirus.” The interaction of vulnerable host genes with a virus could yield epidemiology like that of schizophrenia.

Birth patterns rank highly among epidemiological observations in schizophrenia. ⁴⁷ Many more schizophrenics are born in winter and spring than in summer and fall. ⁴⁸ Infectious aetiology is a plausible explanation, as many viruses show a surge in the same months and viral aetiology is a more convincing explanation of the consistency in question. While gene coding for particular proteins is inherited, environmental and developmental factors are undoubtedly implicated in modulating genes’ expression.

Exposure to prenatal infections and other obstetric complications are neuro-developmental assaults that increase vulnerability to schizophrenia. ^49-52 In obstetrics, infection in the mother generates antibodies transmitted to the foetus, producing auto-antibodies that upset neural development and increase the schizophrenia risk. ⁵³

Schizo-Virus or any Microbe?

It is not certain whether it is body’s abnormal response to any virus and other microbes or a specific unknown virus that results in “schizophrenic reactions.” It is even unclear that the unbeatable antigens of this hypothetical virus alone are capable of inducing the neuro-behavioural changes associated with schizophrenia. The hepatitis C virus came to medical attention only 15 years ago. The rotavirus was isolated in 1973 and the HIV virus was isolated in 1983. Non-detection of a pathogen does not exclude its role in the pathogenesis. If a specific virus is responsible for schizophrenia, it should have been with human society for a very long time, as the illness has been reported from the beginning of recorded human history. Some people may have a genetic vulnerability to the hypothetical schizovirus; inheritability would lie in contracting the specific virus. Poliomyelitis has a concordant rate of 36% among monozygotic twins; the rest are attributed to environmental factors. The majority of children exposed to the polio virus may not develop poliomyelitis and a genetic propensity may be required for the viral manifestation. It is even reported that 10% of the world population rarely catch influenza, in spite of its yearly mutation.

Cardiac disease due to endocarditis (caused by an autoimmune process affecting many parts of the body), a sequel to acute rheumatic fever, is an analogy to demonstrate how, theoretically, a microbial infection may lead to impaired neurodevelopment and psychiatric disorders in a different scenario. Endocarditis is triggered by a reaction to streptococcal bacteria, not a bacterial infection. It may begin a chronic process, leading to valvular cardiac disease. Generally, rheumatic heart diseases are diagnosed 10 - 20 years following rheumatic fever. Similarly, schizophrenia could be an autoimmune complication of a subtle microbial infection; finding and countering the antigenic triggers of ADs may lead to an effective cure.

HIV/AIDS

Patients with HIV are at risk for developing psychiatric symptoms and disorders similar to those seen in the general population, as well as those that are direct effects of HIV. HIV is a neurotropic and lymphotropic virus that causes immune suppression and allows the entry of opportunistic pathogens with an affinity for the CNS. There is some evidence that HIV may trigger a psychotic episode and contribute to first-onset schizophrenia. ⁵⁴ Serious CNS complications occur late in the course of HIV infection, when the immunity function has diminished considerably. The viral load is closely associated with the degree of cognitive impairment. HIV-associated dementia (AIDS dementia complex) is defined as acquired cognitive abnormality in two or more domains and is associated with functional impairment and acquired motor or behavioural abnormality in the absence of other aetiology. It is estimated that 30% to 60% of patients experience some CNS complications during the course of their illness and 90% reveal neuropathological abnormalities at autopsy.

Pearce argued that HIV-related encephalitis could engender a scenario for a viral aetiology of schizophrenia. ¹⁷ HIV produces symptoms after being latent for several years. HIV was not identified as the aetiological agent of AIDS until the conditions for viral replication in lymphoid cell lines were identified. Prior to the evolution of PCR serology techniques, it was debatable whether the virus was in circulation at all. This indicates that the absence of a demonstrable virus does not mean the absence of a subtle virus-induced disease process. No virus, as such, is currently detectable in the schizophrenia disease process. Even in the absence of opportunistic infections, HIV infection of the brain causes severe neuro-behavioural syndromes, such as AIDS dementia, without infecting neurons, but by complex interaction with host molecules and non-neuronal cells. All these suggest that a rare or unknown infectious agent is involved; it would not be identified unless it was specifically tested for.

The finding that the neurophysiological and psychological stress of HIV infection can aggravate an underlying psychotic illness implies that viruses, without being a direct causative agent in psychotic episodes, can unmask pre-existing psychiatric vulnerabilities, acting on the brain physiology through unknown pathways. A curious aspect of HIV-related psychosis is that it responds to anti-psychotic treatment and to anti-retroviral drugs. Several anti-psychotic drugs have been shown to have antiviral properties, both in vitro ⁵⁵ and in vivo. ⁵⁶ The deduction is that a virus could initiate events resulting in psychosis, and anti-psychotic drugs can interrupt that sequence. All these features of HIV infections are consistent with the idea that a virus can cause neurobehavioral abnormalities after several years.

Borna Disease Virus

It has been recognised that Borna disease virus (BDV) could cause neuropsychiatric complications including neurological, behavioural, and mood alterations in animals. ⁵⁷ A ribonucleic acid (RNA) virus from the family Bornaviridae, it is a neurotropic virus with an affinity to a variety of hosts, particularly hoofed animals, and can cause persistent infection of the CNS. Such an infection may be either latent or chronic and slow, but BDV presents with the latent type, characterised by a lack of viral particles. It may resemble the alleged pathogens in non-affective psychosis. The severity of clinical symptoms depends on the immune response of the host.BDV can directly influence the CNS through the binding of viral proteins with neurotransmitter receptors and indirectly through immune response and inflammatory reactions.

Depending on the host’s age and the integrity of the immune response, an infection may be asymptomatic or involve a broad spectrum of behavioural disorders. The severity of clinical symptoms depends on the immune response of the host.^{58, 59} Unusual features of BDV biology include nuclear localisation of replication and transcription, varied strategies for the regulation of gene expression, and interaction with signalling pathways, resulting in subtle neuropathology.⁶⁰ BDV can directly influence the CNS through the binding of viral proteins with neurotransmitter receptors and indirectly through immune response and inflammatory reactions. The issue of human BVD infection has been recently questioned by American researchers who reported an absence of association of psychiatric illness with antibodies to BDV or with nucleic acids in serially-collected serum and white blood cell samples from 396 participants. ⁶¹ However, BDV in animals helps to bring the infection-based model of schizophrenia to the realm of the scientific imagination.

Neurotransmitters

It is an overstatement to say that schizophrenia is a neurotransmitter disease, although it is well established that it incorporates a derangement of dopamine activity. Some viruses have been shown to alter dopamine metabolism. ⁶² The literature deciphering the role of viruses in bringing about neurotransmitter abnormalities linking neurodevelopment assaults and the neuropsychological manifestations of schizophrenia is unhelpful. ⁶³ It has been reported that in rodents, BDV could crash neurotransmitter systems, including dopamine, neuropeptides, and glutamate. ⁶⁴ How viruses alter neurotransmitters is a central issue. Communication between the immune system and the brain is crucial to defend against viral infection; this is mediated through neurotransmitters. Viruses are bound to tamper with the intrinsic communication system as part of their cellular offensive. Some viruses have been shown to alter dopamine metabolism. ⁶⁵

Genetics

The undisputed genetic factor in schizophrenia may be posited to discount the viral hypothesis. However, genetic factors do not exclude environmental contributions. Monozygotic twins have a concordance rate of only 48%. Brief reactive psychosis due to acute sequels to viral infection, though regarded as unrelated to schizophrenia, may still be schizophrenic reactions and they do not progress to schizophrenia only because the sufferers are not genetically predisposed to schizophrenia. Genetic predilection may be attributable to genes that determine idiosyncratic differences in immune responsiveness to common viral pathogens.

Susceptibility and immune response to infectious agents are known to be subject of genetic control and may involve multiple interacting susceptibility genes. ⁶⁶ The genetic component of schizophrenia may engross multiple interacting susceptibility genes. These together or singularly may moderate the virus, and the virus and gene product may act at different points. Many cases would have a genetic foundation and it may be extremely rare to develop schizophrenia independently of a genetic anomaly. A small subset of patients may have a purely genetic form. Research should also be directed at identifying risk genes and why they assert themselves and cause the disease. Any future research which sheds more light on some people are affected more readily than others would bring researchers closer to more effective treatments and early intervention (see Table 5).

Table 5 - Future Directions

Summary

There are multiple interlinked causative factors in schizophrenia and viral infection may be only a trigger. Viral infections may be the cause of vigorous immune responses or triggering an autoimmune process that lead to neuro-behavioural aberrations and a subset of schizophrenia would emerge as viro-immuno-neuropsychiatric disorder or autoimmuno-neuro-psychiatric disorder. If such a subset of schizophrenia contains an autoimmune component, either triggered by infectious agents or due to unidentified intrinsic factors, the disease process would be determined by genetic vulnerability. There is not sufficient evidence established to identify viruses as being implicated in the aetiology of schizophrenia, but researchers have reason to anticipate further laboratory studies, as newer, more sensitive laboratory technologies are evolving. A viral or autoimmune model of schizophrenia may illuminate its pathogenesis, but not necessarily the diversity of psychiatric symptomatology. In the last few decades, schizophrenia research has been focussed on neurotransmitter derangements and neuro-developmental anomalies. The cause of a tsunami is not in the sea water, but due to the tectonic shifts under the sea bed; the aetiology of schizophrenia may be similarly due to immune alterations.

Pellagra psychosis due to niacin deficiency was hidden under the schizophrenia umbrella. ⁶⁷ There may be other psychotic disorders grouped under schizophrenia, and they may have a pure biological aetiology—chemical or infectious—but with genetic vulnerability. No one can be sure whether it is the toxic chemical of the pathogens or the immune response of the host, or both, that may lead to the psychopathology. Searching for this hypothetical virus is a challenging task, but if researchers found it, the benefits would be enormous. A viral aetiology of certain types of schizophrenia, if demonstrable, could affect radical changes in treatment and management. In fact, the hypothesis of viral aetiology is more promising than any other biological hypothesis, as it gives a message of potential drug cure. In this contest, it is interesting to note that the antigenic similarity between components of the streptococcus and cardiac tissue resulted in rheumatic heart diseases, but with the advent of penicillin, this disease has virtually disappeared. Only time will determine the validity and therapeutic prospects of the viral and autoimmune aetiology of schizophrenia.

Davison opined that as evidence accumulates about the autoimmune basis of at least a subset of psychiatric disorders, clinicians should keep abreast of immune-neuropsychiatric research. ⁶⁸ Psychiatry must constantly expand to meet the growing needs with the emergence of novel ideas in other medical specialities and it is high time to introduce a new terminology—“Psycho-immunovirology”—to study the viral aetiological mechanisms involved in psychiatric disorders like schizophrenia. Neuro-virology and psycho-immuno-virology could develop as an interdisciplinary field which represents a melding of virology, psychiatry, the neurosciences and immunology.

Introduction

What is medical pain? One answer would be a poorly defined concept which suffers the ignominy of poor management.

A quick internet search for the term brings up several hits to clinics offering the services of medical practitioners with pain specialty training. Definitions of ‘medical pain’ however, as opposed to those of its more easily construed post-surgical cousin, are both sparse and elusive in the learned literature. One potential candidate is provided by the International Association for the Study of Pain (IASP), whose professional presence on the web offers both a respectable description of pain syndromes of medical aetiologies as well as a taxonomical guide thereto¹.

With a struggle to even define the concept, is it any wonder that medical patients with pain complaints continue to score reprehensible figures on studies into pain incidence and effective relief? This is far from a new phenomenon, with the British Journal of Anaesthesia (BJA) reporting a staggering 52% of medical inpatients in one study (N=1594) of a UK district general hospital to be in pain on the medical ward, with 20% and 12% of those in pain rating this complaint as severe and unbearable respectively². What is particularly distressing about these statistics is the fact that data collection in the same study occurred over five days; more than ample time for complaints to be reported or recognised and appropriate relief strategies implemented. Barriers clearly exist to the provision of adequate medical pain relief, with practice shown to fall below standards recommended by the Royal College of Anaesthetists.³ A sketchy definition is perhaps one such barrier, but what other challenges exist to management of medical pain?

Predictability & On-Call Skills

In contrast to the anticipated pain following an elective surgical procedure, medical pain is less predictable in onset and consequently more the realm of an on-call physician than a specialist pain management team.  One unambiguous fact when equating specialist pain rounds and the on-call services of a more junior recruit is that the former clearly benefit from greater levels of experience, even allowing for acquisition of specialist training. The latter inevitably rely more heavily on the knowledge base afforded them by theoretical education, which sadly tends to be rather scant in undergraduate medical programmes.

The lack of early teaching of junior staff on the subject represents one barrier to pain management in general, with formal teaching on the subject of medical pain management a particular shortcoming in several international medical curricula. This fact is supported by the findings of a cross-sectional study in one Sydney hospital utilising a multinational population of medical interns and residents⁴, indicating some 56.2% of responders felt education on pain management to be inadequate. Up to 68.8% of responders were willing to receive additional lectures on opiate use to increase their knowledge base in this regard, suggesting a definite dearth of dedicated teaching.

In recognition of similar sentiments, a dedicated junior doctor-targeted postgraduate pain curriculum was suggested in 2011 by the Faculty of Pain Medicine (FPM) of the Australia & New Zealand College of Anaesthetists (ANZCA)⁵. This not only recognises the need for effective pain management skills at an early career stage, but also proposes a core set of competencies and assessments thereof for application to early postgraduate physicians’ skill sets.

A Surgical Predilection?

Skills of junior on-call medics aside, the provision of committed specialist pain services undoubtedly represents one of the major advancements in acute pain patient care. And yet, the needs of medical patients have often been overlooked in favour of acute surgical pain relief, and presumably continue to be so in the face of a lack of convincing evidence to the contrary. One study published in 2008 reporting data from over 220 United Kingdom National Health Service (NHS) hospitals revealed a paltry 16% incidence of routine acute pain service in medical wards⁶. The same study revealed that 82.2% of clinical leads in acute pain services actually recognise this problem of inadequate pain control on medical wards. With this stark admission from front line algologists in mind, why do elderly and general medical patients consistently appear to produce disconcertingly poor results in pain studies?

Perhaps the lack of adequate medical pain services in the light of a frank admission to a predilection for surgical patients reflects inadequate training, staffing or application of resources as a barrier to effective management of medical pain.

Community Confounders

Limitations of secondary care pain services aside, the primary care setting also exhibits a confounding factor for professional provision of medical pain management – the propensity for patients to easily self-medicate their complaints with non-prescription remedies. The immemorial complaint of headache in the community provides a convenient example of the potential for patients to self-manage their pain symptom. In doing so however, they simultaneously skirt the legion of adverse drug reactions, drug interactions and other implications including paradoxical rebound pain which may complicate management later on in the professional setting. Data published following a recent review of literature sources⁷ indicate codeine-based compound analgesics to be the most popular over-the-counter medications dispensed across several international populations. This telling fact may be suggestive of a trend in non-professional pain management which impedes effective management according to professional standards. Assuming a relative deficit of surgical to medical pain patients in the community, this may represent a unique challenge to providers of medical pain services.

Chronicity

One further important consideration to be made in medical pain is its potential for chronicity, with prevalence of leading pain disorders including lower back pain and chronic migraine indicated at 10.2%⁸ and 1-3%⁹ respectively in recent studies. The former in particular has exhibited an explosive trend in prevalence over recent years, with a more than 2.5-fold increase since 1992 in relative prevalence observed in one 2006 American study of households state-wide (N=5357)⁸.

Implicit in the chronicity of pain complaints exist a number of secondary disorders which can prove troublesome for effective engagement of pain management services. The European Journal of Pain quotes a large transnational study of chronic pain patients (N=46,394)¹⁰ as finding 21% of patients to have been diagnosed with depression because of their pain. Interestingly while almost half of subjects were self-administering over-the-counter analgesics and only 2% were being seen by a pain specialist, an astonishing 40% reported inadequate pain relief –an almost anticipated outcome of the ‘do it yourself’ approach to pain management in chronic, refractory cases? This may be less relevant in surgical pain experiences which intuitively represent a more acute event in a more controlled environment, and therefore may be more amenable to effective management than a drawn out pain experience over several years!

Fear of Pain

Chronicity of pain in turn evokes a largely self-explanatory phenomenon known as fear of pain, which can present a potentially sizeable obstacle to management of patients. High levels of fear of pain and also movement as a provocative agent thereof have been described in 38.6% of fibromyalgia syndrome patients (N=233)¹¹, with this heightened fear of a painful experience linked to increased disability, depressed mood and most importantly pain severity. This latter component alludes to one of the more insurmountable barriers to management of chronic medical pain – the impasse resulting from a vicious circle of pain, fear and infinite vice versas.

The fear of pain may in turn be compounded by a fear of narcotic analgesic therapy on both the part of the patient and the prescribing physician, with this being an issue in non-cancer pain as well as malignant disease. The fear of commencing and continuing long term opiates is traditionally said to be particularly prevalent in the primary care setting¹². Fear can arise in view of a number of reasons, including the potential for addiction and major side effects as well as the notion that opiate drugs represent a terminal stage in a disease process. Mention of opiates has been linked to accusations of ‘hidden diagnoses’ on the part of the physician, where patients suspect malignant pathology has been concealed from them by their care provider out of a deep-rooted belief that opiate analgesia is merited solely by cancerous conditions¹³. Whether this signifies an already fragile patient-doctor relationship or a contribution to the deterioration thereof, the connotation for effective management of medical pain remains a significant one. Repeated careful review of patients on long term opiate therapy for chronic non-cancer pain must be emphasised however, with up to 19% of chronic pain patients found to have some form of addictive disorder in a 2001 paper on the subject¹⁴ courtesy of the BJA.

Conclusion

In summary, patients requiring relief of medical pain issues are clearly disadvantaged by the presence of numerous hurdles to effective management of their complaints. The literature base in this regard is conspicuous by its absence, with practices in medical pain management being poorly evidence-based as a result. This represents a major potential target for investigative studies and research into potential trends and best practices. Exploration of effective methods for implementation of improved education for newer staff and also resource allocation for more experienced practitioners would also be of benefit to the standard of care in medical pain.

Introduction:

Dengue made its debut as early as 1780, when Benjamin Rush described the condition as “break bone fever”. This hitherto unfamiliar infection has now grown to demand the attention of all public health care providers. It is a mosquito borne, fast emerging, viral infection manifesting in four serotypes ^(1). Approximately 2.5 billion people, living mainly in urban areas of tropical and subtropical regions, are estimated to be at risk of acquiring dengue infection ⁽²⁾. While dengue is endemic in more than 100 countries, most cases are reported from Southeast Asia and the western Pacific regions. Around 50 million cases and 24,000 deaths are estimated to occur in these 100 endemic countries. This includes hospitalisation of nearly half a million cases of dengue haemorrhagic fever (DHF), of which 90% are children. Treated (DHF)/dengue shock syndrome (DSS) is associated with a 1% mortality rate while mortality rate among untreated cases escalates to 20%^(3,4).

India is one of the seven identified countries in the Southeast Asia region regularly reporting incidence of DF/DHF outbreaks. The first confirmed report of dengue infection in India dates back to 1940s, and since then more and more new states have been reporting the disease which mostly strikes in epidemic proportions often inflicting heavy morbidity and mortality, in both urban and rural environments^.(5)

The various manifestations of dengue may not have a distinct line of demarcation: apart from the classic features, reports of rare presentations have recently become more frequent ^(6,7). During recent outbreaks in India, the clinical manifestations which were shown by the patients were slightly different from those in previous years^(8).. There have been many reports of difficulties in the use of the previous classification, which were summarised in a systematic literature review ⁽⁹⁾. Difficulties in applying the criteria for dengue haemorrhagic fever in the clinical situation, together with the increase in clinically severe dengue cases which did not fulfil the strict criteria, led to the request for the classification to be reconsidered .Hence, WHO revised the dengue case classification into dengue (with or without warning signs), and severe dengue ⁽¹⁰⁾.The present study was done to analyse the clinical features, complications, cost incurred and outcome of cases admitted to a tertiary care teaching hospital in Bangalore.

Methodology:

A record based descriptive study was conducted in paediatric patients admitted with signs and symptoms suggestive of dengue fever to KIMS hospital Bangalore, during the period between January 2012 to December 2012. SD BioLine kit was used for testing with NS1 antigen\ IgM\ IgG. The medical records were perused for collecting data about these cases using a pre-designed proforma. Data was analysed for the clinical presentations, outcome and direct cost incurred in respect to hospital charges and laboratory investigations.

Results:

Out of 1230 cases admitted with clinical signs and symptoms suggestive of dengue syndrome 757 (61.5%) cases were found to be NS1 antigen\ IgM\ IgG positive for dengue. Among the 757 positive cases, males were 499 (65.9%) and females 258 (34.1%). The majority of the cases were in the school going age group and this consisted of 310 cases (41%) and adolescent children which accounted for 249 cases (33%), the median age being 8 years of age. The least number of cases were seen in infants which accounted for 45 cases (6%).

Table 1. Sex distribution

The majority, 88.5% of cases presented as dengue fever without warning signs, 6.34% with dengue fever with warning signs and 5.15% with severe dengue. Of the cases with warning signs 92.3% of cases had fever, 42.5% cases had vomiting and 38.2% cases had abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority (87%) presented with petechiae followed by haematemesis (9%) and epistaxis (4%). Rashes were seen in 4% and arthralgia in 13% of cases. Pleural effusion was seen in 21% of cases and ascites was seen in 16% of cases. Complications in the form of acute respiratory distress syndrome (ARDS) was seen in 12.06% cases, 6% cases showed neurological manifestations in the form of encephalopathy and 1.3% cases had renal failure.

Table 2. Severity of dengue

Table 3. Presenting complaints

Fig 1 presenting complaints.

Haemoglobin level of > 12gm% was found in 73.4% cases, 9-12gm% in 23.4%, 6-9gm% in 2.1% and <6 gm% in 1.1% of cases. Platelet count of < 20,000 was found in 21.5% of cases, 20-50 thousand in 39.5% , 50,000 to 1.5 lakh in 36% of cases and >1.5 lakh was found in 3% of cases. Majority (65.5%) of cases were NS1 Ag positive alone or with IgM/ IgG/ or both positive.

Remaining were positive for either of the antibodies.13.7% cases werepositive for all the three i.e. Ag, IgM,& IgG. The mortality rate was found to be 8.6%

Figure 2: outcome

Cost incurred which includes direct cost (transporting patient to the hospital, diagnostic testing and laboratory investigations, medications, hospitalisation, food) was found to been average of Rs.12,611=00. The indirect cost loss of wages of patient &attendants) was found to be an average of Rs.3, 109=00. The hidden cost (out of pocket expenses) was found to be an average of Rs.50=00. The cost of treatment of other co-morbid conditions was found to be an average of Rs.2, 275=00. The total cost of treating dengue syndrome was 18,045=00

Discussion:

In the present study it was found that males were commonly affected and the most common age group was between 5 to 15 yrs of age. Similar results were reported in a study by Faridi et al, 76% of all cases of DHF /DSS were aged 6 years or more^[11].

In the present study, the most common presenting symptoms was fever followed by vomiting and abdominal pain which is similar to study done by Kumar A et al showed fever in 99.2% followed by myalgia (64.6%), vomiting (47.6%), headache (47.6%) and abdominal pain (37.5%) ⁽¹²⁾.

In the present study, the most common bleeding manifestation was haematemesis and epistaxis. In a study by Ratageri et al, common bleeding manifestations were gastrointestinal bleeding (22%) and petechiae (18%) ^[13]. The gastrointestinal tract was reported as the commonest site of bleeding (61%) in a study by Ahmed et al ^[14].

In the present study majority of cases had platelet count between 20,000 to 50,000/mm3.In a study by Kamath et al, platelet counts less than 50,000/mm were noted in 62.3% ^[15]. In our study complicated cases showed ARDS and neurological manifestations in the form of encephalopathy. Almost all the cases which expired were found to have ARDS. Dengue associated ARDS is associated with a high mortality ^[16]. Dengue infection is found to cause neurological manifestation ranging from non-specific symptoms to encephalitis and rarely Guillain-Barre Syndrome ^[17]. In our study the mortality rate was found to be 8.6% , in the study by Anju et al overall mortality seen was 6% ^[18], compared to 3% by Ahmed et al ^[14].

Conclusion:

The seropositivity for dengue was 61.5% with NS1 antigen\ IgM\ IgG. Males were commonly affected and most vulnerable age group was found to be 5-15 year olds. The median age was 8 years. 88.5% of cases presented as dengue fever without warning signs, the remaining being dengue with warning signs and severe dengue. Fever was the most common symptom seen followed by vomiting and abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority presented with petechiae followed by haematemesis. The mortality rate was 8.6%. Acute Respiratory Distress Syndrom (ARDS) and multiple organ dysfunction syndrome (MODS) was found to be the most dreadful complications with high rates of mortality .

In this study it was found that cost incurred which includes direct cost (transporting patient to the hospital, diagnostic testing and lab investigations, medications, hospitalisation, food) was found to bean average of Rs. 12,611=00. Thus dengue syndrome also causes significant economic burden on the patients.

In the recent few years, the world has seen varied clinical presentation of the dengue fever in different epidemics, even in the same regions and even with the period of time. Where some known features are still manifesting, few atypical features are noted from several parts of the world. A continuous seroepidemiological surveillance and timely interventions are needed to indentify the cases, so that its complications, outbreak and mortality can be minimised.

Moreover community awareness, early diagnosis and management and vector control measures need to be strengthened, especially during peri-monsoon period, in order to curb the increasing number of dengue cases.

Introduction

Oesophageal cancer (OC) is the eighth most common cancer affecting an estimated 481,000 people worldwide with a rapidly rising incidence. Due to the poor prognosis of patients with these cancers it is the sixth leading cause of cancer related mortality with 406,000 deaths.^1,2 Although the overall 5-year survival has increased from 4% in the 1970s³ to currently ranging between 15 to 20%⁴, it remains a challenge to treat as clinical presentation is often late and diagnosis is made at advanced stages. Incidence and mortality rates for OCs are two fold higher in males compared to females, however this ratio rises to up to 5-10:1 for oesophageal adenocarcinomas. Cohort studies have shown that the incidence of OC increases with age; the average of onset is between 65 to 70 years. ¹⁴ This article seeks to discuss the epidemiology, diagnosis and staging, prevention and current trends in the management of OC.

Methods

We searched PubMed/MEDLINE, EMBASE and Cochrane Library and Central Register of Controlled Trials (CENTRAL) databases up to November 2014. Our search strategy used a combination of MeSH, textwords, and appropriate words variants of “oesophagus”, “cancer”, “epidemiology”, “adenocarcinoma”, or “squamous cell carcinoma”, and “staging”, “transhiatal oesophagectomy”, “transthoracic oesophagectomy”, “chemotherapy”, “radiotherapy”. This was supplemented with selected systematic reviews, evidence based guidelines and consensus statements.

Epidemiology

There have been major changes in the epidemiology of OC over the last thirty years. The two key histological types of OC are adenocarcinoma and squamous cell carcinoma (SCC) and they differ significantly in their fundamental patterns of incidence and aetiological factors. Oesophageal SCC comprises the majority of cases worldwide and represents 90% of all OCs in most Eastern countries. However the incidence of adenocarcinoma has risen rapidly over the last three decades and it is now the predominant histological type in Western Europe, USA and Australia, particularly amongst white males.^{5, 6} There are other rare histological types, which include lymphoma, leiomyosarcoma, melanoma, rhabdomyosarcoma and small cell carcinoma.⁷ OC accounts for almost 3% of all cancers in the UK and is the ninth most common malignancy in the UK. There were 8,173 new cases in 2008; incidence rates have increased over the last thirty years in the UK and are now one of the highest in Europe.⁸ Incidence rates of OC differ markedly by geographical locations and between ethnic groups; overall, rates are twice as high in less developed regions compared with more-developed regions and the highest rates occur in Asia. In this region, especially in Iran, Turkey, Kazakhstan and China, a very high incidence of oesophageal SCC exists with greater than 100 cases per 100,000 population annually. A similar trend is also seen in South Africa.^9-12 In contrast, the rate of rise in incidence of oesophageal adenocarcinoma in more-developed countries has exceeded that of oesophageal SCC, which has remained the same or decreased. Oesophageal adenocarcinoma now comprises approximately 50% of all OCs in these countries. ¹³

Who gets oesophageal cancer?

The aetiology of OC is multifactorial, with interactions between environmental risk exposures and genetic factors. These can be divided between the two different histological types of OC.

Pathology of oesophageal tumours

Oesophageal tumours are classified as epithelial and non epithelial. Epithelial tumours include papilloma, intraepithelial neoplasia, carcinoma and carcinoid tumours. Non epithelial tumours include leiomyoma, lipoma and gastrointestinal stromal tumours (Table 1).

Table 1: WHO histological classification of oesophageal tumours

Oesophageal adenocarcinoma

Established risk factors for oesophageal adenocarcinoma (Fig. 1) include gastro-oesophageal reflux disease, Barrett’s oesophagus, obesity, male sex, tobacco smoking and a low intake of fruit and vegetables.^{15, 16} There is evidence to suggest that previous infection with Helicobacter Pylori and the use of non-steroidal anti-inflammatory drugs may decrease the risk of OC. ¹⁷

Fig. 1: Adenocarcinoma of the oesophagus (from Lewin et al. Gastrointestinal pathology and its clinical implications)

Barrett’s oesophagus (Fig. 2) occurs when there is metaplastic change in the lining of the oesophagus from normal stratified squamous mucosa to single layered columnar glandular mucosa with variable degrees of goblet cell differentiation.¹⁸ This transition usually occurs in the context of chronic gastro-oesophageal reflux disease, which causes exposure of the epithelium to refluxate. Gastro-oesophageal reflux disease is a major contributory factor and 5% of people with reflux disease develop Barrett’s oesophagus. The estimated prevalence of Barrett’s oesophagus is just under 2% amongst adults in the West and the annual incidence is approximately 0.1%. However, there is evidence to suggest that the rate of diagnosis is increasing by 2% annually.¹⁹ There has been a rise in the incidence of gastro-oesophageal reflux disease, which may be explained by a number of factors. The rise in the prevalence of obesity, specifically central and intra-abdominal obesity has been found to have a link with oesophageal adenocarcinoma. This can be explained by the fact that an increase in adiposity will cause a rise in intra-abdominal pressure thereby increasing reflux that may be asymptomatic. However, studies also suggest that obesity is a strong independent risk factor for oesophageal adenocarcinoma regardless of gastro-oesophageal reflux symptoms implying an underlying link. ^{20, 21} Another factor that may contribute to the rise in reflux disease is the increased use of drugs that relax the lower oesophageal sphincter. There is evidence to suggest that individuals with previous H. Pylori infections are less likely to develop oesophageal adenocarcinoma.²² This might be explained by the gastric atrophy that results from this infection, which will reduce the acidity and quantity of gastric secretions and thus decreasing the chances of gastro-oesophageal reflux. However, the prevalence of H. Pylori infections is decreasing in the Western population, which may contribute to the rising incidence of oesophageal adenocarcinoma. Gastro-oesophageal junction (GOJ) adenocarcinoma was classified by Siewert and Stein into three types. Type I arises from 1 to 5 cm proximal to the GOJ (tumours of the distal oesophagus), type II arises from 1 cm proximal to 2 cm distal to the GOJ (true cardiacarcinoma), and type III arises from 2 to 5 cm distal to the GOJ (subcardial gastric carcinoma). ⁶¹

Fig. 2: Barrett’s oesophagus (adapted from WHO classification of oesophageal tumours)

Oesophageal squamous cell carcinoma

The major risk factors for the development of oesophageal SCC (Fig. 3,4) are tobacco use and alcohol consumption; particularly a combination of both.^{23, 24} Nitrosamine exposure in tobacco smoking and the alcohol metabolite aldehyde, which is a known carcinogen, are probably the underlying reasons for these two risk factors. The high incidence of oesophageal SCC in Northern China, Iran and areas of Southern Africa may be related to a diet rich in nitrosamines and deficient in trace elements and vitamins A & C.

Other risk factors for oesophageal SCC in the Western world include low socioeconomic status, poor oral hygiene, achalasia, history of thoracic radiation, caustic injury, hereditary tylosis and Plummer-Vinson Syndrome.²⁵

Fig. 3: Squamous cell carcinoma of the oesophagus

Fig. 4: Microscopic picture of squamous cell carcinoma (adapted from WHO classification of oesophageal tumours)

How does oesophageal cancer present clinically?

Patients presenting with symptoms of OC almost invariably have advanced disease. The most common presenting symptom is progressive dysphagia with 74% of patients reporting difficulty swallowing.²⁶ This is graded according to the following: ²⁷

• Grade 1: Able to swallow most foods
• Grade 2: Able to swallow soft foods only
• Grade 3: Able to swallow liquids only
• Grade 4: Unable to swallow anything

17% of patients will also report pain on swallowing food and liquids (odynophagia). ²⁶ Typically, patients with oesophageal adenocarcinoma will be white males with a background of gastro-oesophageal reflux disease who have developed dysphagia. On the other hand, patients with oesophageal SCC will present with dysphagia, associated with weight loss and a history of smoking and increased alcohol intake may exist.

Other less common symptoms include dyspnoea, cough, hoarseness, acute haemorrhage and pain which may be retrosternal, back or right upper abdominal. These will usually represent the existence of metastatic disease.

Physical examination is often normal; positive clinical findings may include cachexia, lymphadenopathy and hepatomegaly in the presence of metastases.

How is oesophageal cancer diagnosed?

It is essential to have a low threshold if cancers are to be detected at an early, treatable stage. National Institute for Health and Clinical Excellence (NICE) guidelines state that a patient presenting with symptoms suggestive of upper gastrointestinal cancer should be referred to a team specialising in the management of these cancers. Specifically; patients of any age presenting with dyspepsia in association with alarm symptoms should be urgently referred for endoscopy or to a specialist. The classical ‘alarm’ symptoms associated with OC includes dysphagia, vomiting, anorexia, weight loss and symptoms associated with gastro-intestinal blood loss. Patients aged 55 or more with persistent, recent onset, and unexplained dyspepsia should be referred urgently for an endoscopy.

Diagnosis is usually made by oesophago-gastro-duodenoscopy where multiple biopsy samples must be taken from any mucosal abnormality to exclude early tumours. Suspicious lesions including oesophageal strictures may require repeated biopsies if initial results are negative.

Once diagnosis is made patients should be urgently referred to an Upper Gastro-intestinal team at a specialist centre for investigations to stage disease and further management.

Staging oesophageal cancers

It is essential to accurately stage disease to exclude patients with widespread metastatic disease for whom surgery will not be curative and to identify subgroups of patients who will require neo-adjuvant therapies. Whilst it is difficult to completely eliminate the possibility of ‘open and shut’ cases where tumours are found to be inoperable at the time of surgery; it is important to develop a staging strategy with investigations and procedures that help to minimise this risk. The TNM (Tumour, Node, Metastasis) staging system is used to classify the depth of tumour invasion into or through the oesophageal wall, the status of regional lymph nodes and metastases to distant sites. The TNM7 categories are shown in Tables 2 and the current stage groupings is shown in Table 3. ²⁸

Table 2: TNM7 staging system

Table 3: Stage classification for oesophageal cancer in the 2010 TNM7 staging system

Initial staging assessment includes Computed Tomography (CT) (Fig. 5) of the thorax, abdomen and pelvis and its major role will be in evaluating the T stage to detect local tumour invasion into adjacent structures and determining the presence or absence of metastatic disease. However CT will not be able to determine the depth of tumour invasion. Endoscopic ultrasound (EUS) (Fig. 6) is the main modality used to stage the primary tumour and primarily aids in distinguishing T1 lesions from T2-4 lesions. This method has an accuracy ranging from between 73% to 89% in tumour staging.²⁹ Accurately distinguishing tumour stage will affect treatment as T1 lesions may be treated with endoscopic therapy or with oesophagectomy whereas T2-4 lesions may require neo-adjuvant chemo-radiotherapy prior to surgery. EUS is also used for evaluation of regional lymph nodes however although sensitivity is approximately 80%, the specificity is lower at approximately 70%. ³⁰ It is best to perform a EUS-guided lymph node biopsy for confirmation of involvement.

Fig. 5: CT scan shows irregular wall thickening of the esophagus and enlarged metastatic lymph node.

Fig. 6: Endoscopic ultrasound (EUS) of oesophagus showing T3 tumour

FDG-PET (¹⁸F-fluoroudeoxyglucose PET) (Fig. 7) is a key modality for the detection of distant metastatic disease in OC.^{31, 32} PET may reveal previously occult distant metastases in nodal and non-nodal sites with a sensitivity of 67% and high specificity of 97%. ³³ It can also reveal metastases to bone, which may not be detected using conventional methods. An investigation has shown PET to be the only modality that predicted intended curative resection and it may also be used to prevent unnecessary surgical explorations.³⁴ The use of PET has been shown in a study to change the management of patients from curative to palliative due to detection of previously unknown metastases.³⁵ It has also been used in a prospective study to assess response early after neo-adjuvant chemotherapy to determine the need for urgent surgery or further chemotherapy. The usage of CT and PET in combination has become increasingly available and is useful in selective cases.³⁶

Fig. 7: FDG PET/CT image demonstrating increased uptake at the distal oesophagus and coeliac lymph node in oesophageal cancer case

Minimally invasive surgery is also used as a method to stage OC in many specialist centres.³⁷ A staging laparoscopy can visualise the primary tumour, identify metastases such as hepatic and regional nodal and can accurately detect intraperitoneal dissemination of disease, which may not have been appreciated on other radiological staging investigations. Samples of peritoneal ascites or washings for cytology can also be obtained at this stage if present.

Endoscopic mucosal resection (EMR) can provide accurate histological staging for high grade dysplasia and intramucosal carcinomas. ³⁸ In many cases EMR alone can be a therapeutic intervention depending on the depth of invasion on the specimen.

Treatment

The management of OCs requires a multi-disciplinary team approach involving surgeons, oncologists, radiologists, pathologists, specialist nurses, dietitians and specialists from other specialties if required. Patients considered for surgery or chemo-radiotherapy will require a fitness assessment. In addition to pulmonary function tests, ECG and echocardiogram, cardio-pulmonary exercise testing (CPEX/CPET) is now being increasingly used to assess fitness for major surgery.

OCs can be managed with surgery, chemotherapy or radiotherapy, a combination of the three or palliation in many cases. Disease that is locally advanced without signs of distant metastases is treated with an intention to cure and this will involve a multimodal approach. Metastatic, disseminated and recurrent disease will be treated with palliative intent with chemotherapy to increase survival or measures such as radiotherapy or stent placement for symptomatic relief.

Surgical

Surgical resection can be part of a multimodal approach or alone and is the main option for curative treatment. There are a number of surgical procedures that can be used however it is important to ensure removal of macroscopic and microscopic tumour in association with dissection of lymph nodes with either method as these are vital prognostic factors following surgery.

Open oesophagectomy (OO):

Options for resection include trans-hiatal oesophagectomy and transthoracic approaches and the choice of approach will depend on the location of the tumour, access to lymph nodes and surgeon preference. An Ivor Lewis oesophagectomy (also known as Lewis-Tanner oesophagectomy) involves abdominal mobilization of the stomach and right thoracic approach for resection of the oesophagus. The three-stage modified McKeown oesophagectomy involves a laparotomy, right thoracotomy and neck anastomosis. A resection margin 8-10 cm proximally and 7 cm distally is recommended to achieve an R0 resection (recommendation class IIB, level of evidence C). The next step is to construct a conduit for the anastomosis and this can be achieved by using a gastric tube, large or small bowel. A gastric tube is preferred due to the following factors; ease of use, tension free and longest term conduit survival (recommendation class IIA, level of evidence C). The anastomosis can be performed in the chest or the neck. This relies on multiple factors such as ease of the anastomosis, tension on the repair, ability to diagnose and treat complications and the oncological status. Circular staplers or hand sewn technique usually used with no significant differences in the outcomes. A drainage procedure such as pyloroplasty is recommended to avoid delayed gastric emptying (recommendation class I, level of evidence B). ⁶²

Radical oesophagectomy using either approach has a perioperative mortality of 5-10% and morbidity of 30-40%. ³⁹ Lymph node dissection plays an important role owing to the extensive submucosal lymphatic drainage of the oesophagus. This has meant that nearly 80% of patients undergoing surgery have positive lymph nodes and prognostically this is of importance.^{40, 41} However, there has been controversy with regards to the extent of lymph node dissection required. For optimal staging 10 lymph nodes for T1 and 20-30 lymph nodes for T2 and T3 tumours should be harvested. ⁶² In order to perform a curative resection for carcinoma of the middle and lower third of the oesophagus it is recommended to dissect the abdominal and mediastinal lymph nodes. Three-field lymphadenectomy in the abdomen, chest and neck, is performed in Japan for oesophageal SCC.⁴² Proponents of radical lymphadenectomy argue that it does allow optimal staging, improves loco-regional disease free survival improving the quality of life for these patients.

Minimally invasive oesophagectomy (MIO):

Minimally invasive approaches, which involve laparoscopic mobilisation of the stomach, thoracoscopic mobilisation of the oesophagus and hybrid or robotic approaches, are increasing in many specialist centres. Benefits of this approach include shorter recovery times, decreased post-operative pain and reduced cardiopulmonary complications without jeopardising the oncological outcomes. Luketich et al. reported a mortality rate of 1.7%, leak 5% and empyema 6% following MIO. ⁶³Several randomised controlled trials (RCTs) and comparative studies were conducted to investigate the efficacy and outcomes of MIO. A study by Li et al was conducted on 407 patients underwent MIO and OO found that the overall incidence of complications was lower in the MIO patients. The incidence of pulmonary complications was 20.7% in contrast to 39.7% in the OO group. However, there was no difference in the overall survival among the groups. Another comparative retrospective study by Mu et al. didn’t reveal any difference in the morbidity, anastomotic leak rate, pulmonary complications and length of stay between the approaches and the authors concluded that both techniques are equivalent. ^{63, 64}

Neo-adjuvant chemotherapy

This aims to improve operability; achieving this by shrinking the tumour prior to surgery, down-staging the disease as well as treating occult metastatic disease. Response to treatment can be assessed prior to surgery with repeat radiological investigations. It is now common for patients in the UK with locally advanced disease to undergo neo-adjuvant chemotherapy followed by resection. This is based on the results of a multi-centre study conducted by the Medical Research Council (OEO2), which showed a 9% improvement in two-year survival in patients given 2 cycles of Cisplatin and 5-Fluorouracil chemotherapy compared to those who were not. Five-year survival with surgery alone was 17%, compared with 23% with neoadjuvant chemotherapy.⁴³ The MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial randomized patients to chemotherapy with surgery or to surgery alone and it was found that patients in the chemotherapy group (who received Epirubicin, Cisplatin and infused 5-Fluorouracil, ‘ECF’) had a significant improvement in progression-free survival and a 13% increase in 5-year survival.⁴⁵

In a meta-analysis of neoadjuvant chemotherapy, there was an overall all-cause absolute survival benefit of 7% at 2 years with the addition of chemotherapy. When analysed by subtype, chemotherapy had no significant effect on mortality for patients with squamous cell carcinoma; however, there was a significant survival benefit for patients with oesophageal adenocarcinoma (HR 0.78; p=0.014). ⁴⁷

As a result of this evidence, neoadjuvant chemotherapy is a standard of care for patients with operable mid and lower oesophageal and GOJ adenocarcinoma. The ongoing MRC OEO5 trial is evaluating optimal neoadjuvant chemotherapy regimens: 4 cycles of chemotherapy with ‘ECX’ (Epirubicin, Cisplatin and Capecitabine) compared to two cycles Cisplatin and 5-Fluorouracil, as in OEO2.⁴⁴

Patients who are deemed suitable for surgical management of mid or distal oesophageal (including GOJ) adenocarcinomas are referred to the GI oncology team to assess fitness for chemotherapy. Many of the criteria assessed are similar to those in the pre-operative assessment, particularly performance status and medical comorbidities. Significant history of renal disease or cardiovascular disease, especially ischaemic heart disease would be a relative contraindication to systemic chemotherapy. Toxicities from chemotherapy are wide-ranging and include gastrointestinal upset, hair loss, skin rash, neurotoxicity, renal toxicity, bone marrow suppression (with risk of neutropaenic sepsis, thrombocytopaenia, and anaemia), cardiovascular toxicity, and chemotherapy-related fatigue. In the MAGIC trial, three cycles of epirubicin, cisplatin and capecitabine (ECX) chemotherapy were given both before and after surgery, and approximately one quarter of patients had CTCAE grade 3 or 4 neutropaenia. ⁴⁵

The REAL 2 trial ⁴⁸ was a 2x2 factorial non-inferiority comparison of cisplatin versus oxaliplatin and 5-fluorouracil (5-FU) versus oral capectiabine in patients with oesophageal, gastro-oesophageal junction and gastric tumours. Treatment was given as triplet chemotherapy: epirubicin plus platinum agent (cisplatin or oxaliplatin) plus 5-FU or capecitabine. The trial results showed that oxaliplatin was at least as effective as cisplatin, and oral capectibine was at least as effective as intravenous 5-fluorouracil. There was less grade 3 and 4 neutropaenia with oxaliplatin versus cisplatin, but this was offset by an increase in neuropathy and diarrhoea. As a result of this trial, EOX chemotherapy can be used as an alternative to ECX in both the neoadjuvant and metastatic settings (Table 4).

Table 4: Efficacies of major combination chemotherapy drugs

Neo-adjuvant chemo-radiotherapy

In contrast to the UK, patients in the USA commonly receive neo-adjuvant chemo-radiotherapy (CRT) for locally advanced oesophageal carcinoma. There is evidence that preoperative CRT is superior to surgery alone. A meta-analysis of ten randomised controlled trials showed a hazard ratio for all-cause mortality of 0.81 (95% CI 0.70 to 0.93; p=0.002). This corresponded to a 13% absolute survival benefit at 2 years.⁴⁷ In the subgroup analysis of the Dutch CRT trial (which used paclitaxel and carboplatin combination chemotherapy), the beneficial effect was more pronounced in patients with squamous cell carcinoma (HR 0.34; 95% CI 0.17 to 0.65) compared to adenocarcinoma (HR 0.82; 95% CI 0.58 to 1.16).⁴⁹

There has been no direct head-to-head comparison of neoadjuvant chemotherapy and neoadjuvant CRT in the context of a phase III randomised control trial. Concerns regarding the added morbidity of CRT have meant that chemotherapy alone is the standard neoadjuvant treatment of choice in the UK. However, the role of neoadjuvant CRT is currently being reassessed in the Neo-SCOPE trial.

Definitive chemo-radiotherapy (CRT)

According to current UK consensus guidelines, CRT is the definitive treatment of choice for localised squamous cell carcinoma of the proximal oesophagus. ⁵⁰ Localised squamous cell carcinoma of the middle or lower oesophagus may be treated with CRT alone, or CRT plus surgery. ⁵⁰

In a pivotal study, US Intergroup RTOG-8501 randomised 121 patients with squamous cell carcinoma or adenocarcinoma to receive CRT (cisplatin and 5-Fluorouracil with 50 Gray in 25 fractions), or radiotherapy alone (64 Gray in 32 fractions). This trial ⁴⁶, together with a subsequent systematic review ⁵⁵, demonstrated a survival superiority of CRT over radiotherapy alone (1-year mortality odds ratio 0.61; 95% CI 0.31 to 0.89; p<0.001). This was at the expense of increased toxicity.

This and similar studies ^56-57 have demonstrated a remarkably consistent median survival of 14-18 months and 2 year overall survival of 30-40% with CRT.

CRT practice in the UK is somewhat varied, but within the authors’ multidisciplinary team Cisplatin and 5-Fluorouracil chemotherapy is given in weeks 1 and 5 of a five-and-a-half week course of radiotherapy. The radiation dose used is 50.4 Gray in 28 daily fractions, treating Mondays to Fridays. An alternative radiation dose-fractionation which is supported by the Royal College of Radiologists guidelines is 50 Gray in 25 daily fractions. ⁵⁸

There are few trials directly comparing surgery alone with CRT. A study of 80 patients with squamous cell carcinoma randomised to surgery or CRT failed to show superiority of either strategy in terms of early disease free survival or overall survival. ⁵¹ Adding surgery to CRT can improve local control rates compared with CRT alone, but combined-modality therapy has not been shown to improve survival. It predictably also leads to significantly more treatment-related morbidity.⁵²

The French FFCD 9102 trial recruited 444 patients with potentially resectable OC (90% squamous cell carcinoma) to receive induction CRT. Those patients who showed evidence of response to CRT were then randomised to further CRT or surgery. Median overall survival was 19.3 months in the CRT alone arm, and 17.7 months in those randomised to surgery. The trial met its endpoint of non-inferiority for 2 year overall survival. Again, toxicity was shown to be significantly higher in patients who received both CRT and surgery.⁵³

Although definitive CRT is a current recommended standard of care for localised squamous cell carcinoma of the oesophagus, there is insufficient evidence to to support either a surgical or non-surgical approach ⁵⁰. Surgery should be considered in patients who have histologically-confirmed residual disease at the end of CRT.

For patients deemed unsuitable for surgery with localised adenocarcinoma of the oesophagus, CRT is a valid option for treatment. An American case series of 25 patients with a median age of 77 years showed that CRT using two cycles of mitomycin-C and 5-fluorouracil in combination with radiation (dose 50.4Gy in 28 daily fractions) was effective and tolerable. 68% of these patients had no evidence of residual disease on post-treatment endoscopy. This small series of patients had a two year overall survival of 64%, with a median overall survival of 35 months.⁵⁴

Salvage surgery after definitive CRT

Local recurrence occurs within the first year in 10-30% of patients treated with definitive CRT.⁵⁰ Salvage curative oesophagectomy may be considered within a multidisciplinary team setting. Repeat staging investigations including a CT-PET and EUS are required before a final decision for salvage surgery is made. Survival benefit is limited, and such surgery is associated with an increased in-hospital mortality rate and increased morbidity.⁵⁹ Informing patients of the potential high risks and poor outcomes is an integral part of the decision-making process for salvage surgery.

Palliation

The majority of patients diagnosed with OC are never treated with curative intent as a result of advanced disease or their physical fitness and comorbidities not allowing for radical treatment. It also includes patients who have developed recurrent or metastatic disease following resection. For this group of patients, there are a number of palliative treatments available for relief of symptoms, prolonging and maximising their quality of life. Once again, a multidisciplinary, holistic approach is required to provide the best treatment.

Treatments to provide symptomatic relief such as dysphagia can include intraluminal brachytherapy, endoscopic stenting using self-expanding metal stents or repeated endoscopic dilatations. Dysphagia can also be palliated by chemotherapy or external beam radiotherapy. Laser-thermal Nd-YAG endoluminal tumour destruction and photodynamic therapy can also be administered however this requires a number of treatments and may be more suitable for short exophytic tumours. It is essential to manage pain and nutrition and feeding options through a gastrostomy, jejunostomy or even intravenously can be provided to ensure adequate nutritional status. In addition to providing symptomatic relief it is important to also ensure that these patients receive social and psychological support by identifying and addressing the needs of the patients as well as their carers.

Palliative radiotherapy can be offered to patients with symptomatic primary oesophageal tumours in the context of metastatic or inoperable disease. Palliative dose and fractionation options are varied, but include 27 Gray in 6 fractions treating twice a week for 3 weeks; 30 Gray in 10 fractions treating daily for 2 weeks; 20 Gray in 5 fractions treating daily for 1 week.⁵⁸ The aim of such radiation treatment is to palliate dysphagia. This effect is not immediate, and therefore patients with significant dysphagia are better served initially by endoscopic stenting.

Chemotherapy has been shown to be effective in improving symptoms and overall survival. Patients with good performance status are offered combination chemotherapy. This can be with EOX, as per the MAGIC trial, ⁴⁵or with Cisplatin and 5-Fluorouracil, with or without the addition of Epirubicin (CF or ECF). 5-Fluorouracil can be substituted for oral Capecitabine (i.e. CX or ECX) without any adverse effects on outcomes.⁴⁵

When choosing palliative systemic chemotherapy for patients with incurable OC, the primary aim should be about maximising quality of life. Improvements in outcome with more intensive chemotherapy regimens, such as docetaxel, cisplatin and 5-Fluorouracil, have been shown to be offset by significantly more toxicity.⁶⁰ As a result, Docetaxel containing regimens are not approved in the UK for this indication.⁵⁰

Conclusions

The incidence of oesophageal carcinoma is increasing and despite advances in management and treatment the overall prognosis remains poor. It is essential to recognize and diagnose early, to have a clear pathway for subsequent investigations to ensure accurate staging. This will allow appropriate therapy to be administered to ensure the best possible outcomes are achieved. Treatment of OC is still a challenge however recent advances in surgery, endoscopic treatments and new therapeutic agents will hopefully improve prognosis.

Description of the disorder

Autism Spectrum Disorders (ASD) is the umbrella term increasingly used to describe the set of pervasive developmental disorders that included the diagnosis of Autism, Asperger’s Syndrome, and Pervasive Developmental Disorder Not Otherwise Specified under DSM IV. These are a group of disorders characterised by pervasive difficulties in a combination of the key areas of social communication interaction, and restrictive repetitive behaviours or activities ^{1, 2}. The Diagnostic and Statistical Manual of Mental Disorders (the DSM-5), released by the American Psychiatric Association, officially eliminated many familiar autism spectrum diagnoses and now incorporated them into the single diagnosis of autism spectrum disorder. In DSM-IV, Asperger Syndrome was diagnostically differentiated from Autism by the lack of a significant language delay and intellectual functioning within the normal range.

The epidemiology of ASD is approximately estimated 30 in 10,000, although with increasing awareness of the disorder, this has led to greater rates of diagnosis, more recent estimates suggest the rate may be as high as 60 in 10,000 ³. ASD may be as common as 1 in every 68 children according to the United States Centre for Disease Control ⁴.

Difficulties with an understanding of prevalence possibly related to early studies relying on clinically identified cases rather than community-based surveys, which may have resulted in cases not in treatment were being missed, and possibly only the most severe cases being recorded. Previous estimates may also have been incorrect due to previous narrower case definitions. As sampling methods have improved and better diagnostic instruments are used more cases have been identified and there has been a better delineation of ASD from other psychotic disorders. As more children with ASD are identified, there will be a likely rise in the number of families and children seeking treatment.

Comorbidities

There are very high levels of co-morbid psychiatric difficulties amongst this population with estimates ranging from 7-15%. Anxiety related concerns are among the most common presenting problems for school age children and adolescents with ASD ⁵. Several studies have examined the prevalence of anxiety within the ASD population. A review by white et al ⁶ of 11 such studies reported a prevalence to range from 11-84%. This large range in the prevalence may be accounted for by difference in methods used to measure anxiety, differences in definitions and in diagnostic subtypes.

Studies have also looked at prevalence rates of anxiety within the ASD population to other populations. Compared to groups of typically developing children, those with autism had a higher occurrence of anxiety ^{7, 8}. Comparison with other groups considered to be at risk
(children with conduct disorders and learning disabilities) children with ASD were more likely to be diagnosed with an anxiety disorder and/or have more intense anxiety symptoms ^9,10.

A formal diagnosis of anxiety disorder in this group is hard for therapists due to overlap between comorbid anxiety and the core symptoms of ASD makes. Several anxiety disorders in DSM- IV and ICD 10 have autism as an exclusion criterion, implying that an anxious procession style is a feature of ASD.

The development of anxiety among children with ASD may relate to their cognitive impairment as they may lack the cognitive flexibility to generate strategies to adapt to varying circumstances and may experience distress over even trivial changes in the environment. The information processing style in children with ASD termed ‘weak central coherence’ is similar to non ASD anxious children whereby they selectively attend to threatening cues which results in the misinterpretation of ambiguous situations as threatening ^11,12. As a consequence these cognitive deficits can result in a repertoire of social and communication difficulties resulting in children experiencing severe difficulties in social relationships which may in turn lead to the development of anxiety ¹³. If a child or adolescent has a co-occurring anxiety disorder, this could further negatively impact on the overall social impairment associated with ASD. This can impact on the child or adolescents ability to participate in activities at school, at home and within the community. Children with significant anxiety symptoms are at risk for serious educational difficulties, later unemployment, substance abuse and other psychiatric problems ¹⁴.

Some of the most frequently reported anxiety disorders and symptoms seen in children with Autistic Spectrum disorders are simple phobia, generalised anxiety disorder, separation anxiety disorder, obsessive-compulsive disorder and social phobia.

Treatment with Cognitive Behavioural Therapy

Pharmacological and psychosocial treatment have been the most common approaches to the treatment of anxiety in children with ASD but no single anxiety treatment has emerged to attain well established or probably efficacious empirically supported treatment status for children with an autistic spectrum disorder. Evidence for pharmacological intervention is limited. Also the effects of medication only appear to last as long as the medication is used, with relapse once regime is ceased.

The recommended treatment of choice by NICE guidelines for mood and anxiety disorders is cognitive behavioural therapy (CBT) and the primary psychosocial treatments have used CBT.

Despite the fact that CBT has been shown to be an effective empirically supported treatment for typical children, there continues to be differing views as to whether or not it can be used effectively with other populations. Some of the difficulties associated with treating children with ASD are due to suggestions from research that children with ASD have difficulty in identifying emotions and cognitions both in themselves and others. As CBT relies on the child’s ability to infer their own emotional states and thoughts in order to shift their cognitive style and in turn their anxious behaviour, standard CBT treatments need modification to address the difficulties associated with this.

Although there is recognition of the high comorbidity of anxiety with ASD, there have also been suggestions to the use of strict behavioural analysis ¹⁵ and an argument against using a cognitive component to treat this population. Lindsay ¹⁶ provides a different view, arguing children with ASD can benefit from the use of a cognitive component.

Various modifications have been proposed on the approach of CBT in this population. Some of the models have suggested adjustment of the developmental level to reflect the child’s ability, the use of coping model instead of curative model, the involvement of caretakers, and extending treatment both by the number of sessions and by overall session duration ¹⁷. Attwood ¹⁸ has recommended the use of role-plays and visuals, the involvement of special interests of the young person, the adjustment of material according to the developmental level and the incorporation of a social skills module due to the vast deficits associated with ASD. Anderson and Morris ¹⁹ recommend a more directive approach to treatment and the use of specifically in vivo practice to aid in the generalisation of skills. Each of these variations may contribute differently to the adaptation of CBT to meet the specific needs of the child being treated; however, the most appropriate pattern of practical and functional strategies is yet to be determined.

Chorpita and Daleiden ²⁰ in their review of evidence based treatment for children and adolescents noted the most commonly used techniques to treat anxiety in typically developing children. These include exposure, relaxation, cognitive restructuring and modelling in that order. The most commonly used techniques to treat ASD include communication skills training, modelling, social skills training, goal setting and parent psycho-education.

CBT generally consists of six components which include assessment of the nature and degree of the disorder, affective education, cognitive restructuring, stress management, self-reflection and a schedule of activities to practice new cognitive skills. It is important to ensure that the young person has the same definition and interpretation of words, and affective education can help increase their vocabulary of emotional expression.

Attwood ²¹ has described several intervention components which can be added to CBT. Some of the suggestions include; a) Increasing the use of visual aids. b) Associating emotions with tangible objects. c) An emphasis on coping strategies that do not require the use of abstract language for instance the use of relaxation. d) Use of alternative communication modes. e) Embedding the use of preservative interests into CBT sessions. f) Increasing the focus on teaching social skills.

Attwood also developed the concept of an emotional toolbox and focused on working with the young person in identifying different tools to ‘fix’ problems that occur as a consequence of negative emotions including anger, anxiety and sadness. The ‘tools’ are further divided into those that constructively release or reduce energy and those that improve thinking. The therapist generally works together with the young person to draw a variety of tools and activities which encourage constructive emotions repair.

Cognitive restructuring aims to enable the young person to correct distorted conceptualisations and dysfunctional beliefs. It involves challenging the current thinking with logical evidence and ensuring rationalisation and cognitive control of their emotions. Young people with ASD can make false assumptions of their circumstances and intentions of others due to impaired or delayed theory of mind abilities. These young people also tend to make literal interpretations and are less able to seek alternative explanations or responses.

Summary of Case Reports, Case Series, and Randomised Control Trials

Method

Studies that used CBT with the aim of reducing anxiety symptoms in young people with an ASD diagnosis were looked at.

Search Procedures

A search was carried out in electronic bases: Psychinfo and Medline. The publication year was not restricted but the search was limited to English- language peer reviewed journals. Over the databases, the terms ‘Asperger’, ‘Autism’, or ‘developmental disability’, plus ‘anxiety’ or ‘CBT’ and the search was limited to children and adolescents.

Review of Case series and reports

There have been five case studies that used CBT in treatment of anxiety as well as one case report that used CBT in treatment of OCD in children with ASD.

The first case study by Reaven and Hepburn (2003)²² reported a 7 year old girl with Asperger syndrome who markedly responded to a 6 month modified CBT treatment which was primarily tailored for her OCD. Afterwards, Greig and MacKay (2005) ²³, Sze and Wood (2007) ²⁴ and (2008) ²⁵, Reaven et al (2009) ²⁶, and White et al (2009) ²⁷ reported further successful outcomes of using modified CBT for treatment of Anxiety in children with ASD. See table 1 for a summary of published case reports and series of studies.

Table 1: A Summary of Published Case Reports and Series of studies using CBT for anxiety symptoms in young people with an ASD diagnosis

CY-BOCS children’s Yale-Brown Obsessive Compulsive Scare, SAD- Separation Anxiety Disorder, OCD- Obsessive Compulsive Disorder, GAD- Generalised Anxiety Disorder, HFA – High Functioning Autism, ADIS – Anxiety Disorder Interview Schedule, CGI – Clinical Global Scale, MASC – Multidimensional Anxiety Scale for Children, CBCL – Child Behavioural Checklist, SSRS –Social Skills Rating System, VABS – Vineland Adaptive Behaviour Scales, SWQ – Social Questionnaire, MCIT – Multi- Component Integrated Treatment, PARS – Paediatric Anxiety Rating Scale, RCMSA- Revised Children’s Manifest Anxiety Scale, SRS- Social Responsiveness Scale, CASI-Anx - Child and Adolescent Symptom Inventory-4 ASD Anxiety Scale

Review of Randomised Control Trials

There have been eight studies that have met criteria for a randomised controlled trial that identified CBT as a treatment for anxiety in children with ASD. See table 2 for published randomised controlled trials.

Table 2: Published randomised controlled trials of cbt

Sofronoff, Atwood, and Hinton (2005) ²⁸ evaluated the impact of a six week cognitive-behavioural intervention for anxiety in 71 school children aged between 10 to 12 with Asperger’s Syndrome. The authors also looked at the potential impact of parent involvement on outcome. The diagnosis of Asperger’s Syndrome was confirmed by semi-structured telephone interview and anxiety symptoms were based on parent report in the initial telephone interview. Children were randomly assigned to one of three groups: child based intervention, combined child and parent intervention or a waiting list group. The intervention focused on teaching the children strategies to manage feelings and expanding emotional knowledge and was delivered weekly in a group format. The focus was on teaching the children strategies to effectively manage feelings and expanding emotional knowledge. Parents served as co-therapists in the combined parent-child intervention as they were trained in all aspects of the intervention.

Using the Spence Child Anxiety Scale-Parent report, children in the combined parent-child intervention reported fewer symptoms of anxiety post–treatment and at a six week follow up than children in the child-only intervention. A child report measure (James and the Maths Test) was used to identify the number of strategies the child could identify for coping with anxiety. Compared to children on the waiting list, children who received either intervention were able to develop more coping strategies. Those in the combined intervention generated significantly more coping strategies at endpoint compared to those in the child only intervention.

Parental involvement is an important aspect of treatment of young people with ASD in ensuring better generalisation and therapy outcome. Authors of this study found that children whose parents were involved in treatment were significantly more improved at follow up than those whose parents were not involved. There are different models of parents involvement and include either only direct participation in each session or with a separate parent only component or both. It seems that regardless of which approach is used parent involvement increases the sustainability and success rate of CBT. Involvement of parents helps to improve their understanding of exposure and practice and helping the young person to learn how to master the skills on their own.

Limitations of this study include the reliance on the parent report of anxiety symptoms and both Asperger’s Syndrome and anxiety symptoms were not formally diagnosed. Parents who were involved in the delivery of treatment may have had a more vested interest in their children’s progress with higher expectations for improvement affecting outcome measure reports. However, no independent (blinded) ratings of anxiety were gathered.

Chalfant, Rapee, and Carroll (2006) ²⁹ evaluated a 12 week group delivered cognitive –behavioural treatment for anxiety in 47 school children aged between 8 to 13 with ASD and no intellectual disability. The intervention was adapted from the ‘Cool Kids’ program (Lyneham et al, 2003), a 12 week group based activity for treatment of childhood anxiety. Cognitive strategies were simplified in the intervention, with a greater focus on visual aids, structured worksheets and homework and exposure and the programme was extended over a 6 month period of time.

The authors randomly assigned participants to either the CBT (n=28) or waiting list (n=19) before beginning of each treatment group. Those under waiting list condition were offered treatment after approximately 7 months, when the waiting list period ended. Multi-modal and Multi-person assessment of anxiety were used. At pre-treatment, over 75% of the sample met criteria for more than one anxiety disorder.

Structured diagnostic measures used in the study included the ADIS (Albano& Silverman, 1996), Spence Children’s Anxiety Scale (Spence, 1998), The Revised Children’s Manifest Anxiety Scale (Reynolds & Richmond, 1978), and Children’s Automatic Thoughts Scale (Schniering& Rapee, 2002). Parent report measures included the SDQ-Parent Report (Goodman, 1997), and SCAS-Parent Report (Spence, 1998).

At post treatment, 71.4% of the treated children (n=28) no longer met criteria for an anxiety disorder compared to 0% in the wait list condition (n=19). It was also found that children in the CBT condition were largely able to identify their automatic thoughts indicating some theory of mind ability and had a significant reduction in automatic thoughts, in comparison to the wait list condition.

Limitations of this study include the small sample size so the data may not be reflective of the wider population with high functioning autism and anxiety. Also the lack of confirmation of the diagnosis of ASD by the investigating clinicians reduced the validity of the participant’s diagnostic status. Participants were accepted based on previous evaluations completed within the community setting.

There was no time spent with the waiting list group to help ensure that the benefits of treatment could be attributed to the treatment alone and not to time spent with the therapist. Also the issue of the waiting list group being aware of the treatment programme and knowledge of future treatment may have attenuated the response of those on the waiting list. Clinicians who implemented the CBT groups and collected the relevant pre-and post-treatment data were not blind to the study’s aims.

Wood et al (2009) ³⁰ used a standard CBT program augmented with multiple treatment components as a randomised controlled trial for 40 children aged between 7 to 11. It was designed to accommodate the social and adaptive skill deficit of children with ASD that could pose barriers to anxiety reduction. They also used a family based intervention program adapted for use with children with ASD. Enhancements included addressing of poor social skills, adaptive skill deficits, circumscribed interests and stereotypes, poor attention and motivation, common co-morbidities as well as school based problems. During modules, children were given social coaching by the therapist, parents and available school providers on appropriate ways to enter interactions and maintain conversation with peers.

Children were randomly assigned to 16 sessions of CBT (n=17) or a 3 month wait list (n=23). Independent evaluators blind to treatment condition, were involved in structured diagnostic interviews. Parents and children completed anxiety symptom checklists at baseline and post treatment/ post waitlist.

The Clinical Global Impressions Improvement Scale (CGI) criteria showed that 78.5% of the CBT group showed positive treatment response at post treatment as compared to only 8.7% of the waitlist group.

Children randomised to CBT had primary outcomes comparable to those of typically developing children receiving CBT for anxiety disorder, which were remission of all anxiety disorders for over half the children in immediate treatment at post treatment and follow up and a high rate of positive treatment response on the CGI. However child- reported anxiety did not yield a significant treatment effect.

Limitations of this study include the small sample size which precluded tests of moderation. The study was also undertaken by researchers who developed the intervention and would need independent replication to validate the intervention.

Also using measures not designed for children with ASD had major impact on the outcomes. The child report of Multidimensional Anxiety Scale for Children (MASC) scores did not yield a significant effect for treatment group largely due to a decrease in MASC scores from pre to post treatment for children in both groups. This may have been due to the MASC being not particularly effective in this population and children’s scores at baseline were relatively low on average. Parental scores showed less of a change from pre to post treatment in the waiting list group. The MASC does not specifically measure OCD and GAD symptoms and as there was a wide range of anxiety symptoms, the type of change that some children may have experienced may not have been properly assessed.

Sung et al (2011) ³¹ compared the effects of a 16-week cognitive-behavioural therapy program and a Social Recreational (SR) program for 70 children with ASD aged between 9 to16. 36 of them were randomised to CBT and 34 to Social Recreational program. Children in both programs showed significantly lower levels of generalized anxiety and total anxiety symptoms at 6-month follow-up on SCAS-C. They suggest factors such as regular sessions in a structured setting, consistent therapists, social exposure and the use of autism-friendly strategies are important components of an effective framework in the management of anxiety in children and adolescents with ASD.

Reaven et al (2012) ³² used a modified CBT intervention for anxiety in 50 children aged between 7 to 14 with high-functioning ASD and anxiety, who were randomized to group CBT (n=24) or treatment-as-usual (TAU) (n=26) for 12 weeks. Independent clinical evaluators blind to condition, completed structured ADIS-P pre- and post-intervention condition. They found a significant difference between CBT and TAU group.

47 children completed either the CBT or TAU condition. They also had 3 and 6 month follow-ups. Results indicated markedly better outcomes for the CBT group. Clinician Severity Ratings, diagnostic status, and clinician ratings of global improvement showed significant differences by group. In the intent-to-treat sample, the CBT group, 10 of 20 children (50%) had a clinically meaningful positive treatment response, compared to 2 of 23 children (8.7%) in the TAU group. Initial results from this randomized, designed treatment study suggest that a group CBT intervention specifically developed for children with ASD may be effective in decreasing anxiety.

Limitations of this study include small sample size, lack of an attention control group, use of outcome measures normed with typically developing children, and no use of teacher or child measures. TAU remained variable, and the study did not mention the situation of the children in TAU as were or weren’t receiving any treatment.

White et al (2012) ³³ combined treatment approaches, and evaluated the feasibility and preliminary outcomes of the Multimodal Anxiety and Social Skills Intervention (MASSI) program in 30 adolescents aged between 12 to 17 with ASD and anxiety symptoms of moderate to greater severity who were randomised to CBT (n=15) or Wait list group (n=15). A 16 % improvement in ASD related social impairment (within-group effect size = 1.18) was observed on a parent-reported scale. Although anxiety symptoms declined by 26 %, the change was not statistically significant. These findings suggest MASSI as a feasible treatment program and further evaluation is warranted. High subject adherence and therapist fidelity demonstrate the treatment was acceptable to families.

Storch et al (2013) ³⁴ examined the efficacy of the Behavioural Interventions for Anxiety in Children with Autism (BIACA), a modular cognitive behavioural therapy protocol, relative to treatment as usual (TAU) among 45 children with ASD aged between 7 to 11. Children with clinically significant anxiety (including OCD), and no intellectual disability, were randomised to receive 16 sessions of weekly CBT (n=22, 2 drop out) or TAU (n=21). After screening, assessments were conducted at baseline, post-treatment, and 3-month follow up for only CBT group which was not blind. The raters were blind to treatment condition. They did also use both child- and parent-report versions of ADIS. Children receiving CBT showed substantial improvement relative to TAU on primary anxiety outcomes. Of 24 children randomised to the CBT group, 18 (75 %) were treatment responders, versus only 3 of 21 children (14%) in the TAU group. Treatment gains were generally maintained at 3-month follow up for CBT responders. They concluded that relative to usual care, CBT adapted for anxious youth with high-functioning ASD demonstrates large effects in reducing anxiety symptoms.

The limitations of this study include that only about 75% of the TAU children were in fact getting treatment of any kind at all, as 25% of their TAU weren’t getting anything. Also TAU group was extremely variable, therefore the control group were getting a variety of treatments, or none, making comparisons with the children who received CBT difficult.

McNally et al (2013) ³⁵ used a modified version of the Coping Cat Program in reducing anxiety in children with ASD. They randomly assigned 22 children with ASD aged between 8 to14, with clinically significant anxiety and no intellectual disability, to 16 sessions of the Coping Cat cognitive-behavioural therapy (CBT) program or a 16-week wait list group.

They used ADIS-parent at pre-treatment and post-treatment phases, and they also video-recorded therapy sessions to check for treatment fidelity. Children in the CBT condition evidenced significantly larger reductions in anxiety than those in the waitlist. Treatment gains were largely maintained at two-month follow-up. Results provide preliminary evidence that a modified version of the Coping Cat program may be a feasible and effective program for reducing clinically significant levels of anxiety in children with high-functioning ASD.

The limitations of this study include small sample size which recommended statistical and effect size to be interpreted with caution, and also the outcome measures were largely based on parent- ADIS reports by parents who were not blind to the treatment. Also, examining treatment response was limited to the primary author who delivered all of the treatment. Similarly, with waiting list as a comparison, there was a danger of getting placebo effects with the intervention arm, especially with parent-report measures, as most parents were very keen to get any help at all for their children.

Discussion and future perspective

It is clear from the 8 randomised controlled studies that young people on the autistic spectrum benefit from some form of CBT when modified as part of a therapeutic package. Unfortunately it is not clear what specific aspect of the therapy is making the difference. Cognitive Behavioural Therapy has many components to it as well as the actual cognitive, i.e. ‘thinking’ part and behavioural part. Which bit of the therapy is making a difference to the anxiety? Is it the cognitive reframing, the relaxation, the exposure, the parental involvement, or simply the therapeutic relationship with a therapist? As with CBT studies which are delivered as part of a package, positive results are often obtained when there is no control group or when compared to a waiting list.

Other limitation to research papers cited above include fairly small sample sizes, and outcome measures that are normed with a non ASD cohort.

Only 2 studies had non waiting list comparison ^{32, 34}. These studies did show significant clinical improvement in anxiety levels. These studies have shown that CBT can be effective if modified for the ASD population. Many clinics often fail to pick up associated anxiety difficulties in the ASD cohort and if present, often are under the impression that CBT would not work in this population due to misunderstanding and ill informed prejudices about the ASD population. As there is such a high comorbidity with anxiety disorders, young people on the autistic spectrum should be offered effective interventions such as CBT. Research should focus on modifications of the CBT package to enable better engagement and better understanding of the CBT constructs.

Practice Points

• Children with high-functioning Autism Spectrum Disorder (ASD) are at high risk for developing significant anxiety
• Anxiety can adversely impact on functioning across school, home and community environments
• Cognitive Behavioural Therapy (CBT) is frequently used with success for children with anxiety symptoms
• Standard CBT treatments need modification to address the anxiety difficulties associated with ASD
• Modified CBT interventions for anxiety in children with ASD have also yielded promising results