'Plus ca change' : Back to the future

Malcolm P Weller

Psychiatric conditions tend to cluster together so that if a person suffers from one neurotic psychiatric disorder that person is significantly more likely to simultaneously suffer from another, so called comorbidity, and sufferers from psychiatric disorders are more likely to suffer psychiatrically again in the future in comparison to a random population.

The situation in respect of post traumatic stress disorder (PTSD) might be expected to be somewhat different because, atypically, in this disorder we presume that we know the aetiology and it is a necessary diagnostic criterion that a person has been exposed to an unusually threatening event. Nevertheless, there is recent evidence that the likelihood of recurrence of PTSD is high, despite the low frequency of catastrophic precipitating events. The various symptomatic manifestations, upon which specific psychiatric diagnoses are based, may be surface phenomena of a unifying underlying predisposition with common biological substrates. This would accord with the fact that antidepressants are effective not only in psychotic depression, melancholic type depression and non-melancholic depression but confer a wide spectrum of additional therapeutic benefits, including benefit in panic disorder, phobic disorders, obsessive compulsive disorder and PTSD.

Alternative or aggravating factors are that people who suffer from a neurotic disorder or disorders tend both to complain more and to attract adversities. These issues will be discussed in relation to the psychological concepts of neuroticism and recent biological factors.

Recurrence of disorders

Depression

Once initiated depression tends to recur (DSM - IV), in his review, Judd¹ found that about 80% of persons experiencing a major depressive episode will have at least 1 more such episode during their lifetime, with the rate of recurrence being even higher if minor episodes are included. The review by Judd¹ is close to the more recent estimate of Andrews² that over the 10 years following a depressive episode, 75% of patients experience a recurrence². Depression resulting as a reaction to stress (in which environmental demands are perceived as exceeding resources) is particularly likely to pursue a chronic and relapsing course^3;4.

Anxiety Disorders

Anxiety is often an appropriate emotion which should lead to behaviour which reduces the anxiety rather than a disordered state of frozen inactivity or maladaptive actions which exacerbate the anxiety.  Anxiety disorders are known to be familial and heritable⁵ and tend to be persistent. They can be associated with depression or be the prelude to depression⁶. The severity of symptoms may vary with time and be less problematic in calm, uneventful circumstances but panic disorder with or without agoraphobia often remains a chronic condition^7;8.

PTSD

The definition of PTSD stands in contrast to adjustment disorder. In DSM IV an adjustment disorder is characterised by a disproportionate reaction to the stressor and therefore probably indicative of prior psychiatric vulnerability. This interpretation is reinforced in ICD 10; Individual predisposition or vulnerability plays a greater role in the risk of occurrence and the shaping of the manifestations of adjustment disorders than it does in the other conditions in F43 (Acute Stress Reaction). However, the notion that certain experiences can trigger a disproportionate reaction in some people by virtue of some perhaps occult vulnerability exhibiting a much greater susceptibility, a disproportionate effect, was commented on in the second World War for conditions which we would now diagnose as PTSD (e.g.⁹). An early Israeli study of soldiers exposed to combat traumas¹⁰ suggested that prior combat stress reactions was a marker for subsequent similar problems rather than part of a process of aggregation of stress.

The majority of people will experience one or more traumatic events in their lifetimes, with estimates ranging from 51% to 90%11;12. Despite the shared nature of the experience, after natural disasters such as earthquakes, volcanic eruptions, tsunamis and of combat, only a minority of the population exposed to similar stressful experiences suffer from PTSD. Those who succumb are likely to have experienced prior psychiatric problems^13;14;15. Prior psychiatric problems, less education, high neuroticism, extroversion, and certain ethnic grouping are associated with the development of PTSD ^{16;14;15;17;18;19;20;21;22}. In the Blanchard et al¹⁷ study, prior depression was associated with Post Traumatic Stress Disorder following a motor vehicle accident to a highly significant extent, (P<0.004).

Risk factors

Pervasive factors which reconciles the various studies is the finding that temperamental characteristics, detected very soon after birth, proved to endure and to predict later behaviour and adjustment²³. The personality dimension of adult neuroticism renders an individual vulnerable to neurotic disorders but there are elements of double counting. However, it is stable trait when corrected for age²⁴. Those who are psychiatrically vulnerable are likely to succumb to the impact of significant life events, particularly if they have demonstrated that they have already done so in the past, which situation could be interpreted to indicate that they have less resilience to stress. Provocation tests are used in medicine, such as the glucose tolerance test for unmasking diabetes and the dexamethasone suppression test for testing for possible pituitary autonomous or semiautonomous malfunction in Cushing's syndrome. In an analogous fashion, it could be assumed that a latent psychiatric vulnerability would be revealed by psychosocial stress.

The propensity to experience traumatic events has cultural, educational and personality roots. Among young American adults, those with less education, blacks, and those with high extroversion scores (with a propensity for sensation seeking) are more likely than others to be exposed to traumatic events and are thus at greater risk for PTSD¹⁶. Age, gender, race, and socioeconomic status are relevant parameters, with youth, female sex and low socioeconomic status being markers for an increased likelihood of developing PTSD^25;26;27;28. The level of social support and individual self-esteem, have also been implicated in the onset and course of PTSD across cultures^29;30;31. This literature is suggestive of prior psychiatric, social and socio-economic pressures being conducive to PTSD and would inferentially support prior PTSD as being a marker, amongst other psychiatric markers, of psychiatric vulnerability arising from a variety of factors. A very recently published study from Naomi Breslau and her team, who have conducted a series of influential studies, brings additional and more direct evidence that prior PTSD is in fact a vulnerability marker, rather than the consequence of cumulative stress for the eruption of subsequent PTSD³². In this study, a sample of 1200 persons was randomly selected in 1989 from all 21-to 30-year-old members of a large health maintenance organization and were repeatedly assessed over a 10 year follow-up. The conditional risk of PTSD during the follow-up periods was found to be significantly higher among trauma-exposed persons who had experienced previous PTSD, relative to those with no prior trauma (odds ratio, 3.01; 95% confidence interval, 1.52-5.97). The estimates were only marginally revised after adjustment for sex, race, education, and pre-existing major depression and anxiety disorders. In contrast, the conditional risk of PTSD during follow-up among trauma-exposed persons who had experienced prior traumatic events but not PTSD was not significantly increased, relative to trauma-exposed persons with no prior trauma. The difference between the 2 estimates was significant (P = 0.005). The authors concluded that prior trauma increases the risk of PTSD after a subsequent trauma only among persons who developed PTSD in response to the prior trauma. The findings suggest that pre-existing susceptibility to a pathological response to stressors may account for the PTSD response to the prior trauma and the subsequent trauma.

One can only speculate as to why the individual developed PTSD in the first place. It has been argued on the basis of the Israeli combat data¹⁰ and natural disasters^16;13;14;15 that the first episode of PTSD is likely to be a manifestation of psychiatric vulnerability rather than a manifestation of exposure to universally intolerable stress. These studies, particularly the most recent of Breslau and her team, have medico-legal implications which accord with the U.K. legal concepts of "nervous shock" and "eggshell personality" (Malcolm v Broadhurst [1970] 3 All ER 508).

In a similar fashion, Hammen et al³³ found that non depressed persons were relatively resistant to the onset of depression, even when exposed to high- impact stressful events, whereas those who were symptomatic continued to have both more depression and more high-impact events over time. This may be partially a recording bias, because depressed people may better remember adversities and problems but there may be a further reason. In our competitive society, there seems to be some magnet-like effect of depressed people inducing others to assert their dominance and, metaphorically, to kick them while they are down, probably because of inadvertent signals of loss of self esteem and being an incapacitated adversary³⁴. The converse is also true, with well-being decreasing life events vulnerability³⁵. Brown Harris and Eales³⁶ have illustrated the various implications of this interaction, particularly as to anxiety in the early and residual phases of depression. Recent biological evidence has shown a strong interconnection between the personality trait of neuroticism and depression. Neuroticism is associated with characteristics of serotonin receptors^37;38 and the weight of evidence is that the short variant of the serotonin transporter gene is associated with depression^39;40;41, although there is a contradictory study⁴².

Comorbidity

Between 48.6% and 51% of patients with a DSM-IIIR/DSM-IV diagnosis of major depression had at least one concomitant ('comorbid') anxiety disorder and only 26% to 34.8% had no comorbid mental disorder^43;44. Comorbid depression occurred in 44.5% of PTSD patients at 1 month and in 43.2% at 4 months in 211 trauma survivors and was associated with greater symptom severity and lower levels of functioning¹³. In an Australian study, 21% of people fulfilling DSM-IV criteria for any mental disorder met the criteria for three or more comorbid disorders⁴⁵. In a recent large-scale epidemiological study of 9,282 English-speaking respondents 18 years and older the researchers found that almost a quarter (23%) had 3 or more diagnoses, a situation which correlates with severity⁴⁶. Using data from community surveys, many researchers have noted that if the range of psychiatric symptoms properly dictates 2 or more diagnoses, this is associated with greater symptom severity^{47;48;49;50;51}, poorer outcome^47;50 and poorer treatment response⁵², more functional impairment^47,48;53 and increased use of medical service^54;55;56;57 (see Wittchen⁵⁸ for theoretical discussion of comobidity). Earlier, Kessler⁵⁹ and Angst⁶⁰ had noted that people who had more than one diagnosis at some time used services more often. Later work in a study of 10,641 adults showed a strong relationship between the number of disorders and disability and distress, with the combination of affective and anxiety disorders associated with four-fifths of the disability and service utilization⁴⁵.

Ubiquity of stress

Certain stresses are inevitable, such as bereavement and one expects a period of readjustment. Despite the fact that stresses rain down upon us^61;11;12;62 it is still the majority of the population who are not given a formal psychiatric diagnosis. A genetically determined constitution or an adverse childhood could well determine resilience and susceptibility to their impact. Complicating a model of exclusive social inculcation, childhood adversity is generally the product of parental behaviour by persons of shared genetic constitution.

Social Factors

The interaction between adversity and vulnerability, and the moderating effects of social integration and support are well known. Writing in the late 70s, a major research programme by Brown and Harris concluded: attention to a persons environment may turn out to be at least as effective as physical treatment." Clinically significant anxiety is much commoner amongst single people⁶³. The situation is interactive in both directions. Psychiatric symptoms are likely to cause adverse social consequences and to be aggravated by these consequences, and multiple symptoms are more likely to have even greater adverse social resonances^{64;65;66;67;68;69;70;71}.

A unifying model

The child is father of the man and half of all lifetime psychiatric cases start by age 14, and three fourths by age 24 ^46a, later-onset disorders occur in large part as temporally secondary comorbid conditions^46b and the effect of aging on brain function may explain some of the late onset depressions^{72;73;74;75;76}.

Linkage between the various neurotic disorders (i.e., anxiety, depressive, phobic, and obsessional neurosis) and the centrality of the neurotic disposition pervading all used to be commonly assumed. The subdivision in the DSM classificatory systems beginning with the third edition created a more rigid subdivision, which has been criticised adversely (e.g.⁷⁷).

The personality factor of neuroticism is a pervasive risk factor for a variety of psychiatric illnesses (e.g.^24;16;45). The temperamental characteristics may be no more than a forme fruste of illness which is highlighted by stress. People have varying coping capacities which are a product of their temperament and childhood experiences but the interaction, with adaptive and maladaptive responses, has even greater explanatory power. Parenting style and adequacy has been emphasised by the psychoanalytical movement and includes parental adjustment as interwoven with child rearing practices as well as with shared genetic propensities. On the other hand, enduring temperamental characteristics have been exhibited extremely early in life^23;78;79 and are likely to be biologically determined and to introduce interactional biases in the developmental trajectory.

There are 3 models of the impact on mental health of adult trauma:

1. Repeated traumas, sometimes beginning in childhood produce a cumulative destructive effect and increasing sensitisation to further traumas (e.g.⁸⁰).

2. Repeated small traumas produce a "stress inoculation" increasing resilience, in a manner analogous to the term battle hardened.

3. Prior psychiatric problems, perhaps surprisingly including PTSD, are markers of psychiatric vulnerability and predictors of subsequent psychiatric problems, including a further episode or episodes of PTSD.

The models do not conflict with one another but the recent study of Breslau et al³² provides empirical data emphasising the third possibility.

Treatment

Neurotic psychiatric disorders have a common underlying predisposing cause which can be modified by SSRIs and CBT. Claims are made for the effectiveness of exploring and reconciling childhood experiences and relationships and short-term psychodynamic psychotherapy has also proved to be an effective treatment (e.g.⁸¹). Depression is often mixed with anxiety or develops from anxiety. Anxiety disorders are by far the most common mental disorders but the proportion of serious cases is lower than for other classes of disorder. Mood disorders are the next most common with a higher proportion of serious cases⁴⁶. Cognitive factors, especially the way people interpret or think about stressful events, are considered to play a pivotal role in the aetiology of anxiety⁸² and negative thoughts are frequently found in individuals with anxiety⁸³. Anxiety is associated with a tendency to overestimate the association between a feared cue and personal harm^84;85;86. Prominent negative thoughts in anxiety are underpinned by a sense of uncontrollability, feelings of helplessness and a perception that the sufferer is unable to predict, control, or obtain desired results⁸².

An amplifying factor in demands upon treatment is that high neuroticism contributes to patients' over-reporting of mood symptoms and help seeking, e.g.⁸⁷. Appropriate treatment of neurotic disorders includes educating sufferers to identify and examine their negative thoughts, and to see if they can re-construe them in a more realistic and constructive way. Such cognitive behavioural therapy both promotes recovery and also guards against recurrence. In accord with biological findings regarding variance of the serotonin receptor, these twin advantages can also be obtained from continuing pharmacological treatments (e.g.^{88;67;89;90;91;92;93}). The effect is amplified if the two approaches are applied in combination^94;95;96;97.

References

1. Judd LL. Pleomorphic expressions of unipolar depressive disease: summary of the 1996 CINP President's Workshop. J Affect Disord. 1997; 45:109-116.

2. Andrews G. Should depression be managed as a chronic disease? Br Med J. 2001; 322:419-421.

3. Thornicroft G. and Sartorius N. The course and outcome of depression in different cultures: 10-year follow-up of the WHO Collaborative study on the assessment of depressive disorders. Psychol. Med. 1993; 3: 1023-1032.

4. Coryell W; Zimmerman M; Pfohl B. Short-term prognosis in primary and secondary major depression. J AFFECT DISORD. 1985; 9/3 265-270.

5. Smoller JW, Tsuang M. Panic and phobic anxiety: defining phenotypes for genetic studies. Am J Psychiatry. 1998; 155(9):1152-1162.

6. Lesser I.M., Rubin R.T., Pecknold J.C., et al. Secondary depression in panic disorder and agoraphobia, I: frequency, severity and response to treatment. Arch Gen Psychiatry. 1988; 45:437-443.

7. Bakker, A; Van Balkom, A; Spinhoven, P; Van Dyck, R. Follow-Up on the Treatment of Panic Disorder With or Without Agoraphobia: A Quantitative Review. J of Nerv and ment. Dis. 1998; 186(7) 414-419.

8. Rosenbaum JF, Pollack MH, Pollock RA. Clinical issues in the long-term treatment of panic disorder. J Clin Psychiatry. 1996; 57 (Suppl 10):44-48.

9. Symonds, Air Vice-Marshal Sir Charles P and Wing Commander Denis J Williams. Clinical and statistical study of neuroses precipitated by flying duties. Chap. 10 in Air Ministry Air Publication 3139, HMSO, London 1947.

10. Solomon Z, Mikulincer M, Jakob BR. Exposure to recurrent combat stress: combat stress reactions among Israeli soldiers in the Lebanon War. Psychol Med. 1987; 17(2):433-440.

11. Breslau N, Kessler R, Chilcoat HD, Schultz LR, Davis GC, Andreski P. Trauma and posttraumatic stress disorder in the community: The 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry. 1998; 55:626632.

12. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995a; 52:1048-1060.

13. Shalev, A Y.; Freedman, S; Peri, T; Brandes, D; Sahar, T; Orr, S P.; Pitman, R K. Prospective Study of Posttraumatic Stress Disorder and Depression Following Trauma. Am J Psychiatry. 1998; Volume 155(5).May 630-637.

14. Sutherland, A G; Alexander, D A; Hutchison, James D. The Mind Does Matter: Psychological and Physical Recovery After Musculoskeletal Trauma. Journal of Trauma-Injury Infection & Critical Care. 2006; 61(6):1408-1414, December.

15. Zatzick DF, Kang SM, Muller HG, et al. Predicting posttraumatic distress in hospitalized trauma survivors with acute injuries. Am J Psychiatry. 2002; 159:941946.

16. Breslau N, Davis G C and Andreski P. Risk factors for PTSD-related traumatic events: a prospective analysis. Am J Psychiatry. 1995; 152:529-535

17. Blanchard, Edward B; Hickling, Edward J; Taylor, Ann E; Loos, W. Psychiatric morbidity associated with motor vehicle accidents. Journal of Nervous & Mental Disease. 1995; Vol 183(8) 495- 504.

18. North CS; Smith EM; Spitznagel EL. Post-traumatic stress disorder in survivors of a mass shooting. American J. Psychiatry. 1994; 151: 82-88.

19. Breslau N. Davis GC. Peterson EL. Schultz L. Psychiatric sequelae of posttraumatic stress disorder in women. Arch Gen Psychiatry. 1997; 54(1):81-7.

20. Blanchard E B and Hickling, E J. After The Crash: Assessment and Treatment of Motor Vehicle Accident Survivors, American Psychological Association (APA). 1997.

21. McFarlane A.C. The aetiology of post-traumatic morbidity: Predisposing, precipitating and perpetuating factors. British Journal of Psychiatry. 1989; 254: 221-228.

22. Tennant C; Streimer JH; Temperly H. Memories of Vietnam: Post-traumatic stress disorders in Australian veterans. Aust New Zealand J Psychiatry. 1990; 24: 29-36.

23. Thomas, A., Chess, S., and Birch, H.G. Temperament and behavior disorders in children. University of London Press. 1968.

24. Angst J. Course and prognosis of mood disorders 4.5.6, part of Chapter 4.5, 2000, - Mood disorders in: New Oxford Textbook of Psychiatry (1st Edition) Editors: Gelder, Michael G., Lopez-Ibor, Juan J., Andreasen, Nancy Publisher: Oxford University Press. 2000.

25. Brewin CR, Andrews B, Valentine JD. Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol. 2000; 68:748-766.

26. Bromet EJ, Dew MA. Review of psychiatric epidemiologic research on disasters. Epidemiol Rev. 1995; 17:113-119.

27. Norris FH, Friedman MJ, Watson PJ, Byrne CM, Diaz E, Kaniasty K. 60,000 Disaster victims speak, part I: An empirical review of the empirical literature, 1981-2001. Psychiatry. 2002; 65:207-239.

28. Rubonis AV, Bickman L. Psychological impairment in the wake of disaster: The disaster-psychopathology relationship. Psychol Bull. 1991; 109:384-399.

29. Adams RE, Boscarino JA. Stress and well-being in the aftermath of the World Trade Center attack: The continuing effects of a community-wide disaster. J Commun Psychol. 2005; 33:175-190.

30. Boscarino JA. Post-traumatic stress and associated disorders among Vietnam veterans: The significance of combat exposure and social support. J Trauma Stress. 1995; 8:317-336.

31. Breslau N, Peterson EL, Schultz LR, Lucia VC. Estimating post-traumatic stress disorder in the community: Lifetime perspective and the impact of typical traumatic events. Psychol Med. 2004; 34:889-898.

32. Breslau N; Peterson E L; Schultz L R. A Second Look at Prior Trauma and the Posttraumatic Stress Disorder Effects of Subsequent Trauma: A Prospective Epidemiological Study. Arch Gen Psychiatry. 2008; 65(4):431-437.

33. Hammen C, Mayol A, deMayo R, Marks T. Initial symptom levels and the life-event-depression relationship. J Abnorm Psychol. 1986; 95:114-122.

34. Weller M P I and R. Priest R. Ethology In: The Scientific Basis of Psychiatry, Second edition, ed. M.P.I. Weller and M. Eysenck, W.B. Saunders, London, Philadelphia, Toronto etc. 1992.

35. Ryff CD, Singer B. The contours of positive human health. Psychol Inquiry. 1998; 9:1-28.

36. Brown GW, Harris TO, Eales MJ. Aetiology of anxiety and depressive disorders in an inner city population, 2: comorbidity and adversity. Psychol Med. 1993; 23:155-165.

37. Frokjaer V.G., Mortensen E.L., Nielsen F.A., et al. Frontolimbic serotoninc 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder. Biol. Psychiatry. 2008; 63: 569-576.

38. Takano A., Arakawa R., Hayashi M, Takahashi, H, Ito H, Suhara T. Relationship between enrutocisim personality trait and serotoninc transporter binding. Biol Psychiatry. 2007; Sep 15; 62(6): 588-92. Epub 2007 Mar 6.

39. Gonda, X, Rihmer, Z and Zsombok, T et al. The 5HTTLPR polymorphism of the serotonin transporter gene is associated with affective temperaments as measured by TEMPS-A, J. Affect. Disord. 2006; 91: 125-131.

40. Rihmer, Z, Gonda, X and Akiskal, K K et al. Affective temperament: a mediating variable between environment and clinical depression?, Arch. Gen. Psychiatry. 2007; 64: 1096-1097.

41. Schmitz, A, Hennig, J and Kuepper, Y et al., The association between neuroticism and the serotonin transporter polymorphism depends on structural differences between personality measures, Pers. Individ. Differ. 2007; 42:789-799.

42. Willis-Owen S.A.G. Turri. M.G, Munfa M.R., P.G. Surtees PG, N.W.J. Wainwright NW J , R.D. Brixey R D and J. Flintj, The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association, Biol. Psychiatry. 2005; 58: 451-456.

43. Kessler, R. C., McGonagle, K. A., Zhao, S., et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Archives of General Psychiatry. 1994; 51: 8-19.

44. Wittchen, H.-U., Nelson, C. B. & Lachner, G. Prevalence of mental disorders and psychosocial impairments in adolescents and young adults. Psychological Medicine. 1998; 28: 109-126.

45. Andrews, G., Slade, T. & Issakidis, C. Deconstructing current comorbidity: data from the Australian National Survey of Mental Health and Well-Being. British Journal of Psychiatry. 2002; 181: 306-314.

46a. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age- of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry.2005; 62:593-602

46b. Kessler R C, Chiu W T , Demler O, Walters E E. Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication Arch Gen Psychiatry. 2005; 62:617-627.

46. Clancy J., Noyes R., Hoenk P.R., et al. Secondary depression and anxiety neurosis. J.Nerv Ment Dis. 1978; 166:846-850.

47. Van Valkenburg C, Akiskal HS, Puzantian V, Rosenthal T. Anxious depression: clinical, family history and naturalistic outcome: comparisons with panic and major depressive disorders. J of Affective Disorders. 1984; 6: 67-82.

48. Vollrath, M. & Angst, J. Outcome of panic and depression in a seven-year follow-up: results of the Zurich study. Acta Psychiatrica Scandinavica. 1989; 80: 591-596.

49. Noyes, R., Reich, J., Christansen, J., et al. Outcome of panic disorder. Relationship to diagnostic subtypes and comorbidity. Archives of General Psychiatry. 1990; 447: 809-818.

50. Roy-Byrne, P., Vitaliano, P., Cowley, D., et al. Coping in panic and major depressive disorder. Relative effects of symptom severity and diagnostic comorbidity. Journal of Nervous and Mental Disease. 1992; 180: 179-183.

51. Keller, M. B., Lavori, P. W., Lewis, C. E. & Klerman, G. L. Predictors of relapse in major depressive disorder. Journal of the American Medical Association. 1983; 250: 3299-3304.

52. Roy-Byrne PP, Stang P, Wittchen HU, Ustun B, Walters EE. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course and help- seeking. Br J Psychiatry. 2000,Mar; 176: 229-35.

53. Sturt, E. Hierarchical patterns in the distribution of psychiatric symptoms. Psychological Medicine. 1981; 11: 783-794.

54. Boyd, J. H., Burke, J. D., Gruenberg, E., et al. Exclusion criteria of DSM-III: a study of co-occurrence of hierarchy-free syndromes. Archives of General Psychiatry. 1984; 41: 983-989.

55. Andrews, G. Comorbidity and the general neurotic syndrome. British Journal of Psychiatry. 1996; 168 (suppl. 30): 76-84.

56. Kessler, R. C., Nelson, C. B., McGonagle, K. A., et al. Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey. British Journal of Psychiatry. 1996; 168 (suppl. 30): 17-30.

57. Wittchen, H. U.Critical issues in the evaluation of comorbidity of psychiatric disorders. British Journal of Psychiatry. 1996; 168 (suppl. 30): 9-16.

58. Kessler, R. C. Epidemiology of psychiatric comorbidity. In Textbook in Psychiatric Epidemiology (eds M. T. Tsuang, M. Tohen & G. E. P. Zahner). 1995b: 179-198. New York: Wiley-Liss.

59. Angst J. Comorbidity of mood disorders: a longitudinal prospective study. Br J Psychiatry. 1996; Suppl Jun;(30):31-7.

60. Kendler KS, Kessler RC, Walters EE, et al. Stressful life events, genetic liability, and onset of an episode of major depression in women. Am J Psychiatry. 1995; 152:833-42.

61. Farmer AE, McGuffin P. Humiliation, loss and other types of life events and difficulties: a comparison of depressed subjects, healthy controls and their siblings. Psychological Medicine. 2003; 7: 1169-1175.

62. Reiger,D.A., Narrow, W.E. and Rae,D.S. The epidemiology of anxiety disorders: the epidemiology catchment area experience. J.Psychiat.Res. 1990; 24, Suppl.2: 3014.

63. Brown G W, Harris T. Social origins of depression. Tavistock Publications London. 1978.

64. Kedward H. The outcome of neurotic illness in the community. Social Psychiatry. 1969; 4: 1-4.

65. Figley C.R. Traumatic stress: the role of the family and social support system. In, Trauma and its Wake. The study of Post Traumatic Stress Disorder (ed. C.R. Figley), pp 39-56, Brunner/Mazel, New York. 1985.

66. Frank, E., Kupfer, D. J., Perel, J. M., et al. Three-year outcomes for maintenance therapies in recurrent depression. Archives of General Psychiatry. 1990; 47: 1093-1099.

67. Dalgard OS. Social support, negative life events and mental health. British Journal of Psychiatry. 1995; 166: 29-34.

68. King LA. King DW. Fairbank JA. Keane TM. Adams GA. Resilience-recovery factors in post-traumatic stress disorder among female and male Vietnam veterans: hardiness, postwar social support, and additional stressful life events. Journal of Personality & Social Psychology. 1998; 74(2):420-34.

69. George, L. K., Blazer, D. G., Hughes, D. C. & Fowler, N. Social support and the outcome of major depression. British Journal of Psychiatry. 1989; 154, 478-485.

70. Surtees, P. G. Social support, residual adversity and depressive outcome. Social Psychiatry. 1980; 15: 71-80.

71. Lockwood KA, Alexopoulos GS, van Gorp WG: Executive dysfunction in geriatric depression. Am J Psychiatry. 2002; 159:11191126.

72. Sanders M, Lyness JM, Eberly S, King DA, Caine ED: Cerebrovascular risk factors, executive dysfunction, and depression in older primary care patients. Am J Geriatr Psychiatry. 2006; 14:145152.

73. Alexopoulos GS, Meyers BS, Young RC, Kalayam B, Kakuma T, Gabrielle M, Sirey JA, Hull J: Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry. 2000; 57:285290.

74. Alexopoulos GS: Role of executive function in late-life depression. J Clin Psychiatry. 2003; 64:1823.

75. Nebes RD, Butters MA, Houck PR, Zmuda MD, Aizenstein H, Pollock BG, Mulsant BH, Reynolds CF: Dual-task performance in depressed geriatric patients. Psychiatry Res. 2001; 102:139151.

76. Tyrer P, Seivewright H, Johnson T. The core elements of neurosis: mixed anxiety-depression (cothymia) and personality disorder. J Personal Disord. 2003,Apr; 17(2):129-38.

77. Chess, S. and Thomas, A. Origins and evolution of behavior disorders: from infancy to early adult life. BrunnerMazel, New York. 1984.

78. Thomas A, Chess S: Temperament and Development. Brunner-Mazel, New York. 1977.

79. Storr C L, Ialongo N S, Anthony J C, and Breslau N. Childhood Antecedents of Exposure to Traumatic Events and Posttraumatic Stress Disorder. Am J Psychiatry. 2007, January 1; 164(1): 119-125.

80. Leichsenring F., Rabung S., Leibing E. The Efficacy of Short-term Psychodynamic Psychotherapy in Specific Psychiatric Disorders. A Meta-analysis Arch Gen Psychiatry. 2004; 61:1208-1216.

81. Barlow, D. H., Chorpita, B. F., & Turovsky, J. Fear, panic, anxiety, and disorders of emotion. In D. A. Hope (Ed.), Perspectives on anxiety, panic, and fear. The 43rd Annual Nebraska Symposium on Motivation, pp. 251-328. Lincoln, NE: Nebraska University Press. 1996.

82. Ingram RE, Miranda J, Segal ZV: Cognitive Vulnerability to Depression. New York, Guilford Press. 1998.

83. Tomarken, A.J., Davidson, R.J., and Henriques, J.B. Resting frontal brain asymmetry predicts affective responses to films. Journal of Personality and Social Psychology. 1990; 59: 791-801.

84. de Jong, P.J., Merckelbach, H., and Arntz, A. Covariation bias in phobic women: the relationship between a priori expectancy, on-line expectancy, autonomic responding, and a posteriori contingency judgement. Journal of Abnormal Psychology. 1995a; 104: 55-62.

85. de Jong, P.J., van den Hout, M.A., and Merckelbach, H. Covariation bias and the return of fear. Behaviour Research and Therapy. 1995b; 33: 211-13.

86. Duberstein P R and Heisel M J. Personality traits and the reporting of affective disorder symptoms in depressed patients. Journal of Affective Disorders. 2007, Nov; 103 (1-3): 165-171.

87. Fog R; Lader M; Montgomery S. 'Citalopram - a well- documented and novel antidepressant' Int Clin Psychopharmacol. International Clinical Psychopharmacology. 1995; 10/SUPPL. 1 (3).

88. Prien, R. F. & Kupfer, D. J. Continuation drug therapy for major depressive episodes: how long should it be maintained? American Journal of Psychiatry. 1986; 143: 18-23.

89. Melfi, C. A., Chawla A. J., Croghan, T. W., et al. The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression. Archives of General Psychiatry. 1998; 55: 1128-1132.

90. Maj, M., Veltro, F., Pirozzi, R., et al. Pattern of recurrence of illness after recovery from an episode of major depression: a prospective study. American Journal of Psychiatry. 1992; 149: 795-800.

91. Claxton A. J. and McKendrick J. Selective serotonin reuptake inhibitor treatment in the UK: risk of relapse or recurrence of depression. The British Journal of Psychiatry. 2000; 177: 163-168.

92. Segal, Z., Pearson, J. & Thase, M. E. Challenges in preventing relapse in major depression. Report of a National Institute of Mental Health Workshop on state of the science of relapse prevention in major depression. Journal of Affective Disorders. 2007; 77: 97-108.

93. Otto MW, Hinton D, Korbly NB, Chea A, Phalnarith B, Gershuny BS, Pollack MH. Treatment of pharmacotherapy-refractory posttraumatic stress disorder among Cambodian refugees: a pilot study of combination treatment with cognitive-behavior therapy vs sertraline alone. Behav Res Ther. 2003; 41: 12711276.

94. Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC, Nemeroff CB, Russell JM, Thase ME, Madhukar H, Trivedi MH, Zajecka J. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000; 342: 14621470.

95. Thase ME, Greenhouse JB, Frank E, Reynolds CF III, Pilkonis PA, Hurley K, Grochocinski V, Kupfer DJ: Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry. 1997; 54: 10091015.

96. Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C: Combined pharmacotherapy and psychological treatment for depression: a systematic review. Arch Gen Psychiatry. 2004; 61: 714719.

The above article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.