Journal of Affecme Elsevier


19 (1990) 149-152


JAD 00706

Short Communication

Prodromal symptoms in primary major depressive disorder Giovanni A. Fava, Silvana Grandi, Renzo Canestrari and George Molnar Affective Disorders Program, Department of Psychology, University of Bologna, Bologna, Italy, and Department State University of New York at Buffalo, Buffalo, U.S.A.

of Psychiatry

(Received 5 September 1989) (Revision received 3 November 1989) (Accepted 13 November 1989)

Summary Prodromal symptomatology was investigated, by means of a modified version or Paykel’s Clinical Interview for Depression, in 15 outpatients at their first episode of primary major depressive disorder. Compared to normals, generalized anxiety and irritability were significantly more frequent. Impaired work and interests, fatigue, initial and delayed insomnia were also reported. Four patients who relapsed upon discontinuation of antidepressant treatment displayed the same prodromal symptomatology as in the initial episode.

Key words: Anxiety;




Introduction Little is known about prodromal symptoms of unipolar major depressive disorders. Hays (1964) examined prodromal symptoms in 81 ‘endogenously’ depressed patients. By visual inspection of the data, four symptom patterns emerged: (a) sudden-onset depressions (associated with melancholic features and bipolar disorder); (b) gradualonset depressions, where mood disorder takes months to develop and is related to common stressful life events; (c) neurotic-onset depressions, commonly preceded by anxiety disorders; (d)

Address for correspondence: Dr. G.A. Fava, Dipartimento di Psicologia, Universitk degli Studi di Bologna, Viale Berti Pichat 5, I-40127 Bologna, Italy. 0165-0327/90/$03.50

0 1990 Elsevier Science Publishers



‘fluctuating-onset’ depressions, where symptoms display considerable fluctuations before reaching full force. Hopkinson (1965) interviewed 43 inpatients suffering from ‘depressive psychosis’. About 30% showed a prodromal phase characterized by ‘tension and vague feelings of anxiety’, and more rarely symptoms such as indecision and impaired concentration. Other studies dealt with the rapidity of onset of depressive symptoms. Winokur (1976) found, in a sample of 216 patients, that depression spectrum disease patients, i.e., patients who had alcoholism in first-degree relatives, were much less likely to have an acute or abrupt onset than other depressive patients. Young and Grabler (1985) reported that, in 11 depressed patients, a rapid onset of symptoms was associated with the endogenous subtype, the absence of past or current non-affective disorders, older age and fewer stressful life events.

B.V. (Biomedical



The aim of this preliminary investigation was to explore prodromal symptomatology in unipolar depression by means of standardized methods that had been used in panic disorder with agoraphobia (Fava et al., 1988). The occurrence of depressed mood was regarded as the onset of illness, and the prodromal symptomatology in the 6 months preceding it was investigated. Method The subjects were 15 consecutive depressed outpatients satisfying the criteria described below and a control group of 15 relatives of university employees matched for age (in decades), sex, marital status, and educational level. The patients’ diagnoses were established by the consensus of a psychiatrist and a psychologist independently using the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer, 1978). Patients had to meet the following criteria: (a) current diagnosis of primary major depressive disorder according to Research Diagnostic Criteria (Spitzer et al., 1985); (b) they had to be in their first episode of depressive illness; (c) no history of manic, hypomanic, or cyclothymic features. All patients had been referred to the Psychological Medicine Service of the University of Bologna School of Medicine, Bologna, Italy. All patients gave informed consent after the procedures were explained to them. There were nine men and six women. The mean + SD age was 45.0 (k 11.7) years. Eleven patients were married, and four were single. After initial diagnostic evaluations, all patients were treated with antidepressant medication only (in seven cases amitriptyline, in five desipramine, in two imipramine, and in one mianserin), according to a standardized protocol (Paykel, 1979) by the same psychiatrist. Antidepressants, after patients showed response, were continued for 6 months, with doses of at least 100 mg amitriptyline or its equivalent per day. Drugs were then withdrawn in three steps (Paykel, 1979). A 6-month drug-free follow-up was carried out. A semi-structured interview for eliciting prodromal symptoms, based on Paykel’s Clinical Interview for Depression (Paykel, 1985), was performed 2-3 months after the initial evaluations, when the patients’

symptoms had improved. The interview has been described in detail elsewhere (Fava et al., 1988). It was performed by a clinical psychologist independently of treatment. The same psychologist interviewed the 15 control subjects, after obtaining informed consent, using the same instrument. The time period for which prodromal symptoms were recorded was the 6 months immediately before the onset of depressed mood in the patients or the 6 months preceding the interview in the control subjects. Also because of the recent history of depressive illness (no longer than 1 year), all patients were able to identify the time span when depressed mood ensued. Significant family members, when available, were asked to provide additional information about prodromal symptoms. Nine family members were interviewed. In seven cases, the relatives were able to confirm the patients’ accounts. In two instances there were discrepancies between the family members’ and patients’ reports; these were enquired about until satisfactory agreement was reached. No relatives of the control subjects were interviewed. To compare the occurrence of prodromal symptoms in patients and control subjects, the chisquare test (with Yate’s correction) was used when appropriate. To adjust for multiple testing, only results with P < 0.01were regarded as significant, instead of those below the conventional 5% level of probability. Results Each of the 15 patients reported having had at least one prodromal symptom before the onset of depressed mood. Generalized anxiety was present in 13 cases and irritability in nine (see Table 1). Impaired work performance and loss of interests were reported by eight patients; other symptoms involved fatigue, initial, and delayed insomnia (five cases each). As in the previous investigation concerned with panic disorder (Fava et al., 1988) a symptom was scored as positive only when a rating of at least 4 (moderate intensity) in the Clinical Interview for Depression was assigned. The same cut-off on the assessment items that was used with the patients was also used with the control subjects. According to that criterion, symptoms were reported by only a few of the




Patients (n =15)

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Work and interests Suicidal tendencies Depersonalization Obsessional symptoms Energy and fatigue Generalized anxiety * Phobic anxiety Phobic avoidance Somatic anxiety Anorexia Increased appetite Irritability ** Initial insomnia Middle insomnia Delayed insomnia Increased sleep Hysterical symptoms Hypochondriasis Guilt and lowered self-esteem

Controls (n =15) 2 0 0 0

13 0 0 3 0 9



0 0 0 0

Comparisons of groups were made by means of &i-square analysis with Yate’s correction (df =l). *x2 =16,21, P -C 0.001; **x2 = 7.35, P < 0.01.

control subjects (Table l), and there were significant differences between the patients and the control subjects in generalized anxiety and irritability. During the 6-month follow-up, while off medication, four patients relapsed and required further antidepressant drug treatment. In all cases prodromal symptoms of relapse mirrored those of the first episode. Discussion

In a previous investigation on bipolar disorder (Molnar et al., 1988), we found that manic and depressive prodromes showed much interindividual variation. However, within individuals, the duration and symptoms of successive prodromes of the same polarity were strikingly consistent. The results of this study on unipolar depression lend support to this notion. Paykel et al. (1976) also found some consistency in symptom patterns of 33 depressives between initial ratings at the

height of a depressive illness and subsequent relapse several months later, after intervening recovery. In all 15 patients there was at least one psychiatric symptom prior to the onset of depressed mood, unlike in previous investigations (Hays, 1964; Hopkinson, 1965). The methods, however, were different. Exclusion of patients suffering from bipolar disorder or secondary depression, careful dating of the onset of symptoms in patients in their first episode of illness (therefore eliminating the spurious consequences of chronic or residual depressions), rigorous symptom definition (in terms of both frequency and intensity) by a reliable and validated probe, cross-checking with relatives’ accounts, and delay of the interview until the acute disturbance has passed, characterized this investigation. Generalized anxiety was the most common prodrome (86.7% of patients), as reported also by Hopkinson (1965). Often, sadness supervened upon a setting of irritable mood and/or impaired work and initiative. Symptoms, however, seemed to be vague and non-specific, unlike in panic disorder with agoraphobia where a specific cluster (phobic avoidance, generalized anxiety and hypochondriasis) could be ascertained. Only three of the 15 patients met Research Diagnostic Criteria for the endogenous subtype of depression (Spitzer et al., 1985). Within-group comparisons were thus not possible as to rapidity of symptom onset. These data confirm classical phenomenological descriptions such as the one contained in the Mayer-Gross-Slater-Roth (1969) handbook: ‘The history of change in the patient’s behaviour is characteristic and important; he retires from usual social activities, avoids his friends in the street, and, if forced into company, seems bored and inattentive and takes little interest in topics that usually elicit an active response (. . . . . . ). An initial mood of indifference in depressive states may last for a considerable time, but sooner or later is replaced by the one of sadness, . . . . . .’ (pp. 207208). Hamilton (1989) emphasized the high frequency of the symptoms of anxiety, both psychic and somatic, in depressed patients. Also patients with primary major depression were found to report more symptoms of anxiety, as well as


global neuroticism, somatization and hostility, than normal controls (Fava, 1982). Since these symptoms often remit upon antidepressant treatment (Fava et al., 1986a,b), they are generally conceptualized as being secondary to depressed mood. Our findings, however, indicate that anxiety and irritable mood may frequently precede the onset of depressed mood. The issue of relapse of depressed patients after effective continuation therapy is attracting increasing attention (Frank et al., 1989; Georgotas and McCue, 1989). In our study, four of the 15 patients relapsed after antidepressant discontinuation. They displayed the same prodromes as in their first episodes. Since the appearance of prodromal symptoms generally precedes the full syndrome by weeks or months, the findings in unipolar depression, as well as in bipolar disorder (Molnar et al., 1988) and schizophrenia (Herz, 1986) suggest the clinical utility of such enquiry. If patients and their family members are educated to recognize the patient’s characteristic prodromal symptoms, recurrences of affective disorder could be treated earlier and perhaps more effectively. Kupfer et al. (1989) outlined the advantages of early treatment intervention in recurrent depression. It is conceivable, even though it is yet to be tested, that treatment of prodromal symptoms of unipolar depression may result in lower dosage requirements of antidepressants and in a shorter time of their administration compared to the fullblown episode. The findings in this study should be viewed as preliminary. Their tentative nature is suggested by a number of issues. First, this investigation involved a small number of depressed patients with specific characteristics. Further, lack of information on prodromal symptoms of a number of psychiatric illnesses such as generalized anxiety disorder precluded conclusions about the specificity of the symptom cluster. Finally, the research methods for exploring subclinical and prodromal symptomatology are still at an initial phase of development. Acknowledgements

The Affective Disorders Program is supported in part by a grant from the Minister0 della Pub-

blica Istruzione, Rome, Italy. MS Luisella Pezzoli provided secretarial assistance. References Endicott, J. and Spitzer, R.L. (1978) A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch. Gen. Psychiatry 35, 837-844. Fava, G.A. (1982) Neurotic symptoms and major depressive illness. Psych&r. Clin. 15, 231-238. Fava, G.A., Kellner, R., Lisansky, J., Park, S.. Perini, G.I. and Zielezny, M. (1986a) Rating depression in normals and depressives. J. Affect. Disord. 11, 29-33. Fava, G.A., Kellner, R., Lisansky, J., Park, S., Perini, G.I. and Zielezny, M. (1986b) Hostility and recovery from melancholia. J. Nerv. Ment. Dis. 174, 414-417. Fava, G.A., Grandi, S. and Canestrari, R. (1988) Prodromal symptoms in panic disorder with agoraphobia. Am. J. Psychiatry 145. 1564-1567. Frank, E., Kupfer, D.J. and Perel, J.M. (1989) Early recurrence in unipolar depression. Arch. Gen. Psychiatry 46, 397-400. Georgotas, A. and McCue. R.E. (1989) Relapse of depressed patients after effective continuation therapy. J. Affect. Disord. 17, 159-164. Hamilton, M. (1989) Frequency of symptoms in melancholia (depressive illness). Br. J. Psychiatry 154, 201-206. Hays, P. (1964) Modes of onset of psychotic depression. Br. Med. J. ii, 779-784. Herz, M.I. (1986) Toward an integrated approach to the treatment of schizophrenia. Psychother. Psychosom. 46, 45-57. Hopkinson, G. (1965) The prodromal phase of the depressive psychosis. Psychiatr. Neurol. 149, l-6. Kupfer, D.J., Frank, E. and Perel, J.M. (1989) The advantage of early treatment intervention in recurrent depression. Arch. Gen. Psychiatry 46, 771-775. Mayer-Gross, W., Slater, E. and Roth, M. (1969) Clinical Psychiatry, 3rd edn., revised. Bailliere and Tindall, London. Molnar, G., Feeney, M.G. and Fava, G.A. (1988) Duration and symptoms of bipolar prodromes. Am. J. Psychiatry 145, 1576-1578. Paykel, E.S. (1979) Management of acute depression. In ES Paykel and A. Coppen (Eds.), Psychopharmacology of Affective Disorders. Oxford University Press, Oxford. pp. 235-247. Paykel, ES. (1985) The Clinical Interview for Depression. J. Affect. Disord. 9, 85-96. Paykel, ES., Prusoff, B.A. and Tanner, J. (1976) Temporal stability of symptom patterns in depression. Br. J. Psychiatry 128, 369-374. Spitzer, R.L., Endicott, J. and Robins, E. (1985) Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disturbances, 3rd edn., updated. New York State Psychiatric Institute, New York, NY. Winokur, G. (1976) Duration of illness prior to hospitalization (onset) in the affective disorders. Neuropsychobiology 2, 87-93. Young, M.A. and Grabler, P. (1985) Rapidity of symptom onset in depression. Psychiatr. Res. 16, 309-315.

Prodromal symptoms in primary major depressive disorder.

Prodromal symptomatology was investigated, by means of a modified version of Paykel's Clinical Interview for Depression, in 15 outpatients at their fi...
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