Antecedent life events, social supports and response to antidepressants in depressed patients.

We evaluated 355 subjects who entered one of six double-blind placebo-controlled antidepressant drug trials with respect to the occurrence of antecedent adverse life events and their meaning to the patient. Patients were also assessed with regard to the degree of social support they received for the negative life event. The groups differed as to whether they did or did not meet the criteria for melancholic depression; 43 one-week placebo responders were statistically significantly more likely to believe that adverse life events predisposed them to depressive illness and that such life events precipitated their current depression, compared to 312 one-week placebo non-responders. Of the 312 patients who went on to the double-blind phase in which they were treated with either drug (n = 204) or placebo (n = 108), it was noted that, for both melancholic and non-melancholic patients, responders to drug treatment (but not placebo) had a more favourable ratio of social support received/social support desired than non-responders. Non-melancholic responders to both drug and placebo were statistically significantly more likely to report fewer adverse life events and have a less strong belief that adverse life events predispose one to depressive illness than non-responders. Melancholic patients did not show this trend.

Relationship between hypomania and personality disorders before and after successful treatment.

OBJECTIVE: To examine the effect of hypomanic states on maladaptive personality traits and personality disorders, the authors evaluated personality traits and disorders of patients during an episode of hypomania and after successful somatic treatment. METHOD: The authors used the Structured Interview for DSM-III Personality Disorders to study 66 outpatients who had a lifetime diagnosis of bipolar disorder and who met the minimum Research Diagnostic Criteria for hypomania. All patients had a knowledgeable informant separately undergo the Structured Interview for DSM-III Personality Disorders during the patient's hypomanic state. Outpatients who successfully recovered from the hypomanic episode (N = 47) and their informants were read-ministered the interview 4-8 weeks after the initial assessment. RESULTS: During the hypomanic state, informants generally reported higher levels of maladaptive personality traits among patients than patients themselves. For the patients who recovered successfully from the hypomanic episode, a reduction in all maladaptive personality traits except schizoid and dependent traits was reported by both patients and their informants; however, the decrease reported by patients generally was much greater than that reported by informants. In addition, schizoid traits actually increased after successful treatment according to patient reports but were unchanged according to informant reports. CONCLUSIONS: Hypomania may be associated with an exacerbation of maladaptive personality traits, which may be attenuated after successful treatment. Even with the attainment of euthymic mood, however, about 50% of the cohort had at least one personality disorder, which suggests that a high degree of comorbidity may exist between bipolar disorders and maladaptive personality traits or personality disorders.

Patients' and informants' reports of personality traits during and after major depression.

The influence of major depression on patients' and informants' reports of personality traits was examined using the Structured Interview for DSM-III Personality Disorder, both before and after successful antidepressant or placebo treatment (N = 58). According to patients' reports, Cluster A and C traits decreased significantly from pre- to posttreatment, but Cluster B traits were unchanged, excluding an increase in histrionic traits. According to informants' reports, Cluster A and B traits did not change from pre- to posttreatment, but Cluster C traits decreased significantly after treatment, not including passive-aggressive traits. Moreover, informants generally reported much higher levels of maladaptive personality traits than patients themselves. These results suggest that informants should be used in future research on personality disorders until better assessment techniques are developed.

A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3.

In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p < 0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder.

Personality traits during depression and after clinical recovery.

We investigated whether and how acute depressive symptoms affect the self-report of maladaptive personality traits. Sixty-eight acutely depressed patients underwent the Structured Interview for DSM-III Personality Disorder (SIDP) before and after pharmacological treatment, allowing us to determine whether self-reported maladaptive personality traits are different during depression and after successful clinical recovery. After the initial SIDP administration (during an episode of major depression), patients received desipramine treatment (dose range 150-300 mg/day) over a course of 4-5 weeks before readministration of the SIDP. For those who recovered from their depression (n = 39), cluster III trait scores were significantly lower than those assessed at baseline, and there was a lower frequency of cluster III categorical diagnoses for a personality disorder after treatment than before treatment. Recovered patients also had significantly lower cluster I personality trait scores after treatment as compared with baseline ratings. For those who did not recover from their depression after treatment (n = 29), cluster I trait scores were in fact higher than those measured at baseline, but there were no differences in categorical diagnoses before and after treatment. Cluster II personality traits and categorical diagnoses were not different between those who did and did not recover from their depression. Thus, depression may have a significant effect on the assessment of cluster I and cluster III personality traits. It is possible that cluster I and III 'personality traits' may be interwoven with depressive features and therefore subject to state influences, whereas cluster II personality traits may entail enduring, long-term characteristic modes of thinking, feeling, and behaving.

Lithium prophylaxis of bipolar illness. The value of combination treatment.

Using a longitudinal life-table analysis, we assessed the efficacy of lithium alone, administered within the context of a naturalistic clinical setting, by calculating the probability of patients remaining free of an affective episode (manic or depressive) over a five-year course. In addition, for those who suffered a manic or depressive relapse, we attempted to analyse the subsequent course of patients who suffered a manic/hypomanic or depressive relapse and were then restabilised on lithium plus either a neuroleptic, carbamazepine, or a benzodiazepine, or lithium plus an antidepressant. Lithium alone offered an average 83% probability against an affective relapse after one year, 52% after three years, and 37% after five years. For patients who failed on lithium alone, it appeared that combination treatment offered greater protection against subsequent affective relapse than the initial course on lithium alone.

A study comparing paroxetine placebo and imipramine in depressed patients.

These data provide evidence for the antidepressant efficacy of paroxetine. Paroxetine- and imipramine-treated patients were significantly different from placebo-treated patients, but little different to each other, on all depressive outcome measures. However, paroxetine appeared to have a possibly greater and earlier beneficial effect on anxiety symptoms associated with depression, when compared with imipramine. Both active therapies were effective in treating patients with severe depression. Side effects for paroxetine were typical of other serotonin (5-HT) uptake inhibitors but different from those of imipramine. In particular, anticholinergic and cardiovascular symptoms were reduced, and premature withdrawal less likely.

Melancholic/endogenous depression and response to somatic treatment and placebo.

OBJECTIVE: The authors' goals were to examine the effects of somatic treatment and placebo in patients with and without endogenous/melancholic depression. METHOD: Before entry into one of four trials of antidepressant drugs versus placebo, 231 patients were assessed as to whether they met Research Diagnostic Criteria for definite endogenous depression and/or DSM-III criteria for major depressive episode with melancholia. These patients were prospectively assessed for subsequent response to antidepressant treatment or placebo. Previous studies of the effect of endogenous/melancholic depression on treatment response were also reviewed. RESULTS: Of the 76 patients with DSM-III melancholia given active medication, 41 (54%) had a complete or partial response, but only 10 (23%) of the 44 patients with melancholia given placebo had a complete or partial response. Of the 76 depressed patients without melancholia given active medication, 46 (61%) had a complete or partial response, and 15 (43%) of the 35 depressed patients without melancholia given placebo had a complete or partial response. Moderately depressed patients with DSM-III melancholia had a significantly better response to active medication than did severely depressed patients with melancholia and showed the greatest difference between response to active medication and response to placebo. The results of the review of previous studies of the effect of endogenous/melancholic depression on treatment response were mixed. CONCLUSIONS: Depressed patients with melancholia were not particularly different from depressed patients without melancholia in their responses to antidepressant medication but did differ from patients without melancholia in their responses to active medication versus placebo, particularly if their depression was moderate and not severe. This suggests that patients with DSM-III melancholia may be unresponsive to nonsomatic treatments.

Sociotropy and autonomy: relationship to antidepressant drug treatment response and endogenous-nonendogenous dichotomy.

This study evaluated the relationship of sociotropic and autonomous personality traits with response to pharmacotherapy for 217 depressed outpatients using the Sociotropy-Autonomy Scale. Sociotropy was related to nonendogenous depression, whereas autonomy was related to endogenous depression. Subjects who had high autonomous-low sociotropic traits showed greater response to antidepressants (and greater drug-placebo differences) than those who had high sociotropic-low autonomous traits (who showed no drug-placebo differences). Hierarchical multiple regression analysis showed that the sociotropy-autonomy, but not the endogenous-nonendogenous, distinction was a predictor of drug treatment response. The combination of endogeneity and autonomy predicted response to placebo. If replicated, these findings may enable better matching of patient traits to various treatment modalities for depression.

Personality traits and response to desipramine.

We attempted to prospectively examine the effects of personality traits in 68 acutely depressed patients treated with desipramine over 4-5 weeks to assess whether the presence or absence of these traits played a role in response to antidepressant treatment. Overall the 39 responders had statistically significantly lower cluster III personality trait scores than non-responders, and a trend toward lower cluster I and cluster II scores. We then followed the 39 desipramine responders for up to 6 months on the dose to which they responded in accordance with standard clinical practice. Overall 23 of the 39 sustained their initial improvement, with eight relapsing and eight dropping out between 5 weeks and 6 months. When comparing these three groups with the 29 initial non-responders, those who sustained the 6-month response had statistically significantly lower cluster II, cluster III, and total personality scores than initial responders who relapsed, initial responders who dropped out and did not complete 6 months of treatment, and initial non-responders.

Two combined, multicenter double-blind studies of paroxetine and doxepin in geriatric patients with major depression.

Depressive illness among the elderly is an important public health concern. However, treatment of the elderly may be complicated by age-related changes in physiology, general medical status, and susceptibility to side effects. There is therefore a need for improved treatment modalities for depressed elderly patients. Paroxetine is an antidepressant that acts through selective inhibition of serotonin reuptake. It lacks the anticholinergic and cardiovascular side effects of most first- and second-generation antidepressants. The authors present the combined data from two similarly designed comparisons of paroxetine and doxepin in outpatients over 60 years of age with major depression. The results show that paroxetine was an effective as doxepin in alleviating depression as measured on the Hamilton Rating Scale for Depression (HAM-D) total score, the Montgomery and Asberg Depression Rating Scale (MADRS), and the Hopkins Symptom Checklist (SCL) depression factor score. Paroxetine was significantly superior to doxepin on the Clinical Global Impressions (CGI) scale for severity of illness, the HAM-D retardation factor, and the HAM-D depressed mood item. Doxepin produced significantly more anticholinergic effects, sedation, and confusion. Paroxetine was associated with more reports of nausea and headache. These results suggest that paroxetine may be a valuable tool for the treatment of major depression in the elderly.

Depressive attributional style and the dexamethasone suppression test: relationship to the endogenous/melancholic distinction and to each other.

The dexamethasone suppression test (DST) and the depressive attributional style questionnaire (ASQ) were administered to 105 depressed patients prior to participation in a double-blind outpatient study and to 29 normal controls. The depressed patients were classified into three groups (1) met criteria for both research diagnostic criteria for definite endogenous depression and DSM III melancholia; (2) met criteria for neither, and (3) met criteria for one but not both. The group that met criteria for both RDC endogenous depression and DSM-III melancholia had a statistically greater frequency of abnormal DST versus the group that met neither criteria and the normal controls. With regard to ASQ, patients who met both criteria had statistically higher bad event internality scores but statistically lower bad event stability and globality scores as opposed to the group that met neither criteria. In general, normal controls had significantly lower bad event ASQ scores than the three depressive groups. There was no correlation between ASQ and DST, as both DST suppressors and nonsuppressors had similar ASQ scores and there was no correlation between ASQ bad event attributions and initial severity of depression.

Relationship of dose to antidepressant prophylactic efficacy.

We studied 75 patients on prophylactic antidepressants (imipramine or amitriptyline) to examine the effect of antidepressant dose on long-term prophylaxis of depression and to see whether lowering the dose during the prophylactic period affected subsequent relapse. There was no statistically significant difference in maintenance and prophylactic doses between the group that completed the 2 years free of a depressive episode, the group that had a depressive relapse and the group that dropped out of treatment before the end of the prophylactic period. However, the group that completed the 2 years free of a depressive episode had significantly less of a difference between the maintenance and prophylactic doses than the other 2 groups. Overall, 11/31 who remained on the same dose during the prophylactic period vs the maintenance period relapsed vs 17/25 who had their dose lowered during the prophylactic period vs the maintenance period. The difference was statistically significant.

A comparison of paroxetine, imipramine and placebo in depressed out-patients.

To compare the safety and antidepressant efficacy of paroxetine, imipramine, and placebo, data from six centres using the same protocol were pooled. A double-blind parallel-group design was used, with therapy lasting six weeks. From week 2 onwards, both the 240 paroxetine-treated and the 237 imipramine-treated patients were significantly different from the 240 placebo-treated patients, but no different from each other. Side-effects with paroxetine were less likely to lead to drop-out than with imipramine. Paroxetine had a possible earlier antidepressant effect than imipramine, and a possible earlier beneficial effect on anxiety symptoms associated with depression.

Disappearance of memory deficits in outpatient depressives responding to imipramine.

We evaluated learning and memory in 50 depressed patients prior to and following 4 week treatment with imipramine compared to 21 normal controls tested at corresponding times. At baseline, the depressives did worse than normals on most memory tasks with the difficult memory tasks, regardless of store, modality or type of task best distinguishing between depressive and normal memory. Following imipramine treatment, responders performed better than nonresponders on the difficult memory tasks, and not significantly differently from controls on most tasks. This, as well as the fact that the responders improved to a greater degree than controls on most measures (in a few cases the difference was statistically significant) and the fact that at 4 weeks complete responders to imipramine did significantly better than partial responders to imipramine, indicates that relief from depression is highly related to improved memory functioning. The finding that complete responders to imipramine were not significantly worse than normal controls suggests that imipramine did not have significant adverse effects on memory.

The prophylactic efficacy of tricyclic antidepressants--a five year followup.

1. In order to evaluate the efficacy of antidepressants in the prevention of recurrent depression, a longitudinal life-table analysis was carried out involving 217 unipolar patients whose depressive symptoms had remitted following treatment with one of five standard tricyclics (imipramine, amitriptyline, desipramine, nortriptyline, and doxepin). 2. Following six months continued euthymic mood these patients were maintained on the medication to which they initially responded to in a clinical setting over a 5 year period. These patients were compared against a group of 28 individuals who were treated acutely for their depression and responded to one of the above the 5 standard antidepressants, but following 5-6 months continuation treatment were taken off the antidepressant at their own request. 3. Though there was a lower rate of relapse in patients receiving active medication vs the no treatment group, the frequency of relapse was high for the group on active drug. 4. Using the longitudinal life-table method of Fleiss there was a pessimistic-optimistic average relapse rate of 30%, 50%, and 60%, at 1, 2, and 3 years respectively while on active drug vs a 51%, 74%, and 83% relapse rate on no treatment. Overall 87 of 217 patients on active drug (40.1%) were observed to have suffered a depressive relapse over the 5 year course.

Dysfunctional attitudes in depressed patients before and after clinical treatment and in normal control subjects.

To evaluate the role of maladaptive thinking patterns in depression, the authors administered the Dysfunctional Attitude Scale to 112 depressed patients before and after 3-6 weeks of treatment with antidepressants or placebo. Twenty-two normal subjects were also assessed twice. Depressed patients had a significantly higher initial mean score than control subjects, but during treatment their score significantly decreased, and the posttreatment score of those with complete recoveries was nearly as low as the control subjects' final score. The higher the initial dysfunctional attitude score the poorer the response to treatment. Patients with endogenous depression had significantly lower scores than nonendogenously depressed patients.

The predictive value of the dexamethasone suppression test. A placebo-controlled study.

We evaluated the dexamethasone suppression test (DST) as a predictor of response to drugs and placebo in 105 patients, in a large double-blind placebo-controlled out-patient trial to determine the efficacy of paroxetine HCl, a selective serotonin reuptake inhibitor, compared with that of imipramine HCl and placebo. The presence of a positive or negative DST did not predict response to either paroxetine or imipramine. However, a positive DST predicted a poorer response to placebo: only 3 out of 18 patients who showed DST non-suppression responded to placebo, as opposed to 11 out of 21 who exhibited DST suppression (P less than 0.05). A positive DST was associated with a 61% response to drugs and a 16% response to placebo. This finding suggests that the presence of a positive DST implies the need for active somatic treatment.