James H. Kocsis

Prediction of response of chronic depression to imipramine

Abstract We had previously reported that imipramine was superior to placebo for the treatment of chronic depression. As a part of that study, we subsequently investigated clinical and demographic variables which might be associated with favorable or poor outcome for treatment with imipramine or placebo. Results are reported herein. Eighty-six patients were entered and 53 completed an 8-week protocol. Outcome was assessed based on a 6-week, double-blind treatment phase, which followed a 2-week, single-blind placebo phase. Outcome was not found to significantly relate to demographic variables, severity or course of depression, diagnostic subtype, symptom profile, or DST results. Some modest associations were found between ‘neurotic’ personality traits and poor outcome. Results are discussed and compared with prior studies of prediction of tricyclic antidepressant response in both acute and chronic depressions.

Acute response of social functioning in dysthymic patients with desipramine.

Despite some evidence that short-term antidepressant treatment improves social dysfunction in depressed patients, little is known about the response of specific social impairments in dysthymic patients to antidepressant medication. We examined the effect of acute (10 weeks), open-label desipramine (DMI) treatment on social functioning in subjects with DSM-III-R dysthymia. Social functioning was assessed with the social adjustment scale self-report (SAS-SR) at baseline and at week 10. Compared with DMI nonresponders DMI responders showed significantly greater improvement in overall social functioning (F2,45 = 5.46, P < 0.0001) and in enjoyment of leisure time (F2,45 = 14.38, P < 0.0001) on the SAS-SR. Dysthymic patients who respond to DMI improve significantly in social functioning. Diminished capacity to enjoy leisure time may be a state marker of depression in some chronically depressed patients.

The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression

OBJECTIVE To evaluate the efficacy of rEEG(®)-guided pharmacotherapy for the treatment of depression in those circumstances where rEEG and STAR*D provided different recommendations. MATERIALS AND METHODS This was a randomized, single-blind, parallel group, 12 center, US study of rEEG-guided pharmacotherapy vs. the most effective treatment regimens reported in the NIH sponsored STAR*D study. Relatively treatment-resistant subjects ≥18 years who failed one or more antidepressants were required to have a QIDS-16-SR score ≥13 and a MADRS score ≥26 at baseline. All subjects underwent a washout of all current medications (with some protocol-specified exceptions) for at least five half-lives before receiving a QEEG and rEEG report. Subjects randomized to rEEG were assigned a regimen based on the rEEG report. Control subjects who had failed only SSRIs in their current episode were randomized to receive venlafaxine XR. Control subjects who had failed antidepressants from ≥2 classes of antidepressants were randomized to receive a regimen from Steps 2-4 of the STAR*D study. Treatment lasted 12 weeks. The primary outcome measures were change from baseline for self-rated QIDS-SR16 and Q-LES-Q-SF. RESULTS A total of 114 subjects were randomized and 89 subjects were evaluable. rEEG-guided pharmacotherapy exhibited significantly greater improvement for both primary endpoints, QIDS-SR16 (-6.8 vs. -4.5, p<0.0002) and Q-LES-Q-SF (18.0 vs. 8.9, p<0.0002) compared to control, respectively, as well as statistical superiority in 9 out of 12 secondary endpoints. CONCLUSIONS These results warrant additional studies to determine the role of rEEG-guided psychopharmacology in the treatment of depression. If these results were confirmed, rEEG-guided pharmacotherapy would represent an easy, relatively inexpensive, predictive, objective office procedure that builds upon clinical judgment to guide antidepressant medication choice.

Six months of desipramine for dysthymia: can dysthymic patients achieve normal social functioning?

BACKGROUND There is evidence that antidepressant medication improves social dysfunction during acute treatment in dysthymic patients but it is unknown if the gain in social functioning persists or progresses with longer-term antidepressant treatment. We examine the effect of 6 months of desipramine treatment on social functioning in dysthymic patients. METHODS Forty-six subjects with DSM-III-R dysthymia (70% with superimposed major depression) who had responded to 10 weeks of open-label desipramine (DMI) treatment received 16 additional weeks of continuation DMI. Social functioning was measured at weeks 0, 10 and 26 with the Social Adjustment Scale-Self Report. RESULTS Euthymia was maintained and a marginally significant trend for further improvement in overall social functioning appeared during continuation treatment. Only 24% of subjects achieved normative level of social adjustment after 6 months of DMI treatment. LIMITATIONS The main limitation was the lack of a placebo control group. CONCLUSION Acute improvement in social functioning persists during continuation treatment. However, most dysthymic patients did not achieve a community level of social adjustment. Significant social dysfunction persists in dysthymic patients with low levels of depressive symptomatology after 6 months of intense DMI treatment.

PHARMACOTHERAPY FOR CHRONIC DEPRESSION

There is now strong evidence from controlled studies that antidepressant medication, including SSRIs, tricyclic antidepressants, and MAOIs, is effective in treating both the depressive symptomatology and social dysfunction of many patients with chronic depression. Encouraging data from a controlled long-term trial in progress indicate that desipramine is effective in sustaining recovery during maintenance treatment. Future studies are needed to better understand the optimal duration of treatment, the efficacy of augmentation strategies, and the efficacy of combined treatment with psychotherapy and pharmacotherapy in chronic depression.

Failure to segregate emotional processing from cognitive and sensorimotor processing in major depression.

Most functional neuroimaging studies of major depressive disorder (MDD) employ univariate methods of statistical analysis to localize abnormalities of neural activity. Less has been done to investigate functional relations between these regions, or with regions not usually implicated in depression. Examination of intraneuronal and interneural network relations is important for the advancement of emerging network models for MDD. Principal component analysis (PCA), a multivariate statistical method, was used to examine differences in functional connectivity between 10 unmedicated patients with MDD and 12 healthy subjects engaged in a positive word viewing task. In healthy subjects, principal component (PC) 1 (33% variance) revealed functional connectivity of task-specific sensory, linguistic, and motor regions, along with functional anticorrelations in the default mode network; PC2 (10% variance) displayed functional connectivity of areas involved in emotional processing. This segregation of functions did not occur in the depressed group, where regions involved in emotional functions appeared in PC1 (34% variance) co-varying with those involved in linguistic, motor, and default mode network processing. The lack of segregation of emotional processing from cognitive and sensorimotor functions may represent a systems level neural substrate for a core phenomenon of depression: the interconnection of affective disturbance with experience, cognition, and behavior.