Clinical indicators for the use of antidepressants in the treatment of bipolar I depression.

OBJECTIVES: Current guidelines provide little practical information on the clinical characteristics of bipolar I patients who are likely to benefit from the combination of a mood stabilizer and an antidepressant. Rather, guidelines simply state that an adjunctive antidepressant is recommended in cases of 'severe' depression. Our objective was to evaluate the clinical and demographic differences between patients who remitted on a mood stabilizer alone and patients who subsequently required an adjunctive antidepressant to achieve stabilization. METHODS: We retrospectively compared the pharmacological treatment strategies of 39 patients with bipolar I disorder who were in a current depressive episode. Patients who did not respond to mood stabilizer monotherapy were prescribed an adjunctive antidepressant. We evaluated the clinical differences at baseline and week 1, 2 and 3 of treatment between patients stabilizing on a mood stabilizer alone and patients that did not remit until they subsequently received an adjunctive antidepressant. RESULTS: Patients who required an adjunctive antidepressant had significantly higher total Hamilton Depression Rating (HRS-D) scores at week 1, 2 and 3 of treatment, but not at baseline. Patients who remitted on mood stabilizer monotherapy were more likely to be married, achieved stabilization in less time, presented with higher Young Mania Rating Scale (YMRS) scores, and experienced the previous episode of depression more recently than patients who required an antidepressant. CONCLUSIONS: Our findings suggest that rapid improvement after achieving a therapeutic dose of a mood stabilizer is clinically significant and represents a surrogate endpoint in the treatment of bipolar I depression. Larger, prospective, and controlled studies are needed to verify our results and to identify additional indicators for a mood stabilizer and antidepressant combination treatment strategy.

Sleep and treatment response in depression: new findings using power spectral analysis.

This study examined quantitative measures of sleep electroencephalogram (EEG) and phasic rapid eye movements (REM) as correlates of remission and recovery in depressed patients. To address correlates of remission, pre-treatment EEG sleep studies were examined in 130 women outpatients with major depressive disorder treated with interpersonal psychotherapy (IPT). To address correlates of recovery, baseline and post-treatment EEG sleep studies were examined in 23 women who recovered with IPT alone and 23 women who recovered with IPT+fluoxetine. Outcomes included EEG power spectra during non-rapid eye movement (NREM) sleep and REM sleep and quantitative REMs. IPT non-remitters had increased phasic REM compared with remitters, but no significant differences in EEG power spectra. IPT+fluoxetine recoverers, but not IPT recoverers, showed increases in phasic REM and REM percentage from baseline to recovery. In NREM sleep, the IPT+fluoxetine group showed a decrease in alpha power from baseline to recovery, while the IPT group showed a slight increase. The number of REMs was a more robust correlate of remission and recovery than modeled quantitative EEG spectra during NREM or REM sleep. Quantitative REMs may provide a more direct measure of brainstem function and dysfunction during REM sleep than quantitative sleep EEG measures.

Interpersonal psychotherapy and antidepressant medication: evaluation of a sequential treatment strategy in women with recurrent major depression.

BACKGROUND: Few data are available to guide treatment selection in major depression. With increasing pressure to maximize the efficiency and minimize the costs of treatment, it is important to have information that could guide treatment selection or point to treatment strategies that have a high probability of success. METHOD: We used a successive cohort approach to compare 2 highly similar groups of women with recurrent unipolar disorder (DSM-III-R or DSM-IV): one in which the combination of interpersonal psychotherapy (IPT) and pharmacotherapy was initiated at the outset of treatment and a second in which IPT alone was provided first and only those who did not remit with IPT alone were offered the combination treatment. RESULTS: In the group in which the combination was initiated at the outset of treatment (N = 180), the remission rate was 66%, comparable to the remission rate observed in most outpatient treatment studies of major depression. In contrast, among the women in the second cohort who were first treated with IPT alone and only those who did not remit were given combination therapy (N = 159), the remission rate was 79%, significantly greater than that observed in the group that received combination treatment from the outset (chi2 = 6.55, p = .02). CONCLUSION: These results suggest that the strategy of offering IPT to women with recurrent unipolar disorder and, in the absence of remission, adding antidepressant pharmacotherapy can be a highly effective treatment, one that may be particularly attractive to women in the childbearing years. Although slower in its onset of action, this sequential strategy is likely to enable the clear majority of such women to achieve a full remission of depressive symptoms.

Insulin-like growth factor 1 and growth hormone binding protein in depression: a preliminary communication.

This study was undertaken in order to advance our understanding of the distal growth hormone axis in depression. Insulin-like growth factor 1 (IGF-1) and growth hormone binding protein (GHBP) were measured in a group of 19 depressed women and a group of 16 healthy women. Using a generalized linear model, IGF-1 levels were negatively correlated with age (p = 0.0001), influenced by menstrual phase (p = 0.016), and significantly increased in the depressed group (p = 0.02). Using the same type of analysis, GHBP was significantly related to menstrual phase (p = 0.0001) and body mass index (p = 0.0001), but was not significantly different in patients and controls. IGF-1 and GHBP were positively correlated among healthy subjects (r = 0.46, p = 0.08), but not among depressed patients (r = -0.16, p = 0.51), although these correlation coefficients were not statistically significantly different from each other. These findings confirm the importance of several physiological factors in the regulation of IGF-1 and GHBP, and suggest that depression further influences this regulation.

Pretreatment REM sleep and subjective sleep quality distinguish depressed psychotherapy remitters and nonremitters.

BACKGROUND: We compared pretreatment subjective and electroencephalographic sleep measures among depressed patients who remitted with psychotherapy alone and those who did not remit. METHODS: Patients were 111 midlife women with recurrent major depressive disorder. Baseline psychiatric ratings and sleep studies were conducted prior to treatment with weekly interpersonal psychotherapy. Remission was defined as a score of < or = 7 for 3 consecutive weeks on the Hamilton Depression Rating Scale. Clinical and sleep measures were compared between remitters (n = 62) and nonremitters (n = 49) using t tests and random regression. Linear discriminant function analyses were used to categorize remitters and nonremitters on the basis of sleep measures. RESULTS: Treatment nonremitters had significantly worse subjective sleep quality and significantly elevated phasic REM sleep as measured by multivariate and univariate analyses. The linear accumulation of REM activity during sleep occurred at a significantly higher rate in nonremitters than in remitters. Linear discriminant function analyses based on subjective sleep quality and REM activity correctly identified 68.3% of nonremitters and 68.5% of remitters. CONCLUSIONS: These findings highlight the role of subjective and REM sleep measures as correlates of short-term psychotherapy treatment response in major depressive disorder. Disturbed sleep may be a physiological indicator of increased limbic and brain stem arousal.

Latent structure of EEG sleep variables in depressed and control subjects: descriptions and clinical correlates.

In this study, we aimed to determine the latent structure of multiple EEG sleep variables in patients with major depressive disorder (MDD) and in healthy control subjects and to examine associations between sleep factors and clinical variables. Subjects included 109 women with MDD and 54 healthy control women. EEG sleep data were collected prior to any treatment. Principal components analysis (PCA) was conducted on a set of 24 sleep variables. Separate PCAs were run for patients with MDD, control subjects, and a matched group of patients and controls. Other analyses included correlations, t-tests and MANOVA. Each PCA identified four sleep factors that explained 70% of the total variance in individual sleep variables: slow wave sleep, REM sleep, sleep continuity and REM latency/delta sleep ratio (RL/DSR). Patients with MDD and healthy controls differed on the mean value of the sleep continuity factor, and a multivariate analysis of variance based on the PCA identified MDD-control differences in REM sleep and sleep continuity. In the MDD group, slow wave sleep correlated inversely with age and personality disorder symptoms; sleep continuity correlated with subjective sleep quality and anxiety; and RL/DSR correlated inversely with age. The mean value of the REM factor was higher among treatment non-responders than responders. EEG sleep variables have a similar latent structure in women with MDD and in healthy controls. These sleep factors are supported conceptually and empirically, and correlate with clinical measures in women with MDD. Multivariate statistical techniques decrease the risk of Type I and Type II errors when using a large number of collinear sleep measures, and can clarify conceptual issues related to sleep and depression.

Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal EEG sleep profiles.

OBJECTIVE: The authors tested the hypothesis that patients whose episodes of major depression evidenced more neurobiological disturbance would be less responsive to psychotherapy. METHOD: The study subjects were outpatients who were given a diagnosis of recurrent major depressive disorder (unipolar or bipolar II), according to the Research Diagnostic Criteria, following an interview with the Schedule for Affective Disorders and Schizophrenia. They were classified into a group with normal sleep profiles (N = 50) and a group with abnormal sleep profiles (N = 41) on the basis of a validated index score derived from three EEG sleep variables monitored for 2 nights: sleep efficiency, REM latency, and REM density. The groups' responses to short-term interpersonal psychotherapy were compared by means of chi-square tests and life table and random effects model analyses. Responses to the addition of pharmacotherapy for subjects who did not respond to interpersonal psychotherapy were also compared. RESULTS: The patients with abnormal sleep profiles had significantly poorer clinical outcomes with respect to symptom ratings, attrition rates, and remission rates than the patients with more normal sleep profiles. Seventy-five percent of the patients who did not respond to interpersonal psychotherapy had remissions during subsequent pharmacotherapy. CONCLUSIONS: These findings help to define further a neurobiological "boundary" that may limit response to psychotherapy in depression. An abnormal sleep profile may reflect a more marked disturbance of CNS arousal that warrants pharmacotherapy.

Electroencephalographic sleep correlates of episode and vulnerability to recurrence in depression.

The study of electroencephalogram (EEG) sleep in depressed patients before and after treatment with psychotherapy can distinguish episode-related and persistent biological features. With longitudinal follow-up, we can also assess whether EEG sleep measures are associated with recurrence of depression. In the current study, we examined EEG sleep during the depressed state and during symptomatic remission after treatment with interpersonal psychotherapy in 42 outpatients with major depression. Analyses included both visually-scored and computer-analyzed measures. Patients showed significant increases in sleep latency (p = .01) and rapid eye movement (REM) latency (p = .04) from baseline to remission, as well as a decrease in REM sleep percent (p = .03). Total delta EEG counts decreased from baseline to remission (p = .03), specifically in the second nonrapid eye movement (NREM) period (p = .03); as a result, the relative distribution of delta activity shifted toward sleep onset (i.e., increased delta sleep ratio; p = .03). Automated REM counts also decreased from depression to remission (p = .006). Compared to patients who remained well through one year of follow-up, those who suffered a recurrence of depression had less delta EEG activity at baseline and remission (p = .01), particularly in the lowest delta frequency band of 0.5-1.0 Hz. Specific components of sleep (total delta activity, delta ratio, REM activity) constitute episode-related biological features. Other components (slowest delta activity) may represent vulnerability factors for recurrence.