Chronic depression: medication (nefazodone) or psychotherapy (CBASP) is effective when the other is not.

CONTEXT: Although various strategies are available to manage nonresponders to an initial treatment for depression, no controlled trials address the utility of switching from an antidepressant medication to psychotherapy or vice versa. OBJECTIVE: To compare the responses of chronically depressed nonresponders to 12 weeks of treatment with either nefazodone or cognitive behavioral analysis system of psychotherapy (CBASP) who were crossed over to the alternate treatment (nefazodone, n = 79; CBASP, n = 61). DESIGN: Crossover trial. SETTING: Twelve academic outpatient psychiatric centers. PATIENTS: There were 140 outpatients with chronic major depressive disorder; 92 (65.7%) were female, 126 (90.0%) were white, and the mean age was 43.1 years. Thirty participants dropped out of the study prematurely, 22 in the nefazodone group and 8 in the CBASP group. INTERVENTIONS: Treatment lasted 12 weeks. The dosage of nefazodone was 100 to 600 mg/d; CBASP was provided twice weekly during weeks 1 through 4 and weekly thereafter. MAIN OUTCOME MEASURES: The 24-item Hamilton Rating Scale for Depression, administered by raters blinded to treatment, the Clinician Global Impressions-Severity scale, and the 30-item Inventory for Depressive Symptomatology-Self-Report. RESULTS: Analysis of the intent-to-treat sample revealed that both the switch from nefazodone to CBASP and the switch from from CBASP to nefazodone resulted in clinically and statistically significant improvements in symptoms. Neither the rates of response nor the rates of remission were significantly different when the groups of completers were compared. However, the switch to CBASP following nefazodone therapy was associated with significantly less attrition due to adverse events, which may explain the higher intent-to-treat response rate among those crossed over to CBASP (57% vs 42%). CONCLUSIONS: Among chronically depressed individuals, CBASP appears to be efficacious for nonresponders to nefazodone, and nefazodone appears to be effective for CBASP nonresponders. A switch from an antidepressant medication to psychotherapy or vice versa appears to be useful for nonresponders to the initial treatment.

Self-reported depressive symptom measures: sensitivity to detecting change in a randomized, controlled trial of chronically depressed, nonpsychotic outpatients.

This study evaluated and compared the performance of three self-report measures: (1) 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR30); (2) 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16); and (3) Patient Global Impression-Improvement (PGI-I) in assessing clinical outcomes in depressed patients during a 12-week, acute phase, randomized, controlled trial comparing nefazodone, cognitive-behavioral analysis system of psychotherapy (CBASP), and the combination in the treatment of chronic depression. The IDS-SR30, QIDS-SR16, PGI-I, and the 24-item Hamilton Depression Rating Scale (HDRS24) ratings were collected at baseline and at weeks 1-4, 6, 8, 10, and 12. Response was defined a priori as a > or =50% reduction in baseline total score for the IDS-SR30 or for the QIDS-SR16 or as a PGI-I score of 1 or 2 at exit. Overall response rates (LOCF) to nefazodone were 41% (IDS-SR30), 45% (QIDS-SR16), 53% (PCI-I), and 47% (HDRS17). For CBASP, response rates were 41% (IDS-SR30), 45% (QIDS-SR16), 48% (PGI-I), and 46% (HDRS17). For the combination, response rates were 68% (IDS-SR30 and QIDS-SR16), 73% (PGI-I), and 76% (HDRS17). Similarly, remission rates were comparable for nefazodone (IDS-SR30=32%, QIDS-SR16=28%, PGI-I=22%, HDRS17=30%), for CBASP (IDS-SR30=32%, QIDS-SR16=30%, PGI-I=21%, HDRS17=32%), and for the combination (IDS-SR30=52%, QIDS-SR16=50%, PGI-I=25%, HDRS17=49%). Both the IDS-SR30 and QIDS-SR16 closely mirrored and confirmed findings based on the HDRS24. These findings raise the possibility that these two self-reports could provide cost- and time-efficient substitutes for clinician ratings in treatment trials of outpatients with nonpsychotic MDD without cognitive impairment. Global patient ratings such as the PGI-I, as opposed to specific item-based ratings, provide less valid findings.

Randomized, placebo-controlled trial of nefazodone maintenance treatment in preventing recurrence in chronic depression.

BACKGROUND: Maintenance treatment to prevent recurrences is recommended for chronic forms of major depressive disorder (MDD), but few studies have examined maintenance efficacy of antidepressants with chronic MDD. This randomized, placebo-controlled study of the efficacy and safety of nefazodone in preventing recurrence was conducted for patients with chronic MDD. METHODS: A total of 165 outpatients with chronic, nonpsychotic MDD, MDD plus dysthymic disorder ("double-depression"), or recurrent MDD with incomplete inter-episode recovery, who achieved and maintained a clinical response during acute and continuation treatment with either nefazodone alone or nefazodone combined with psychotherapy, were randomized to 52 weeks of double-blind nefazodone (maximum dose 600 mg/day) or placebo. The occurrence of major depressive episodes during maintenance treatment was assessed with the 24-item Hamilton Rating Scale for Depression, a DSM-IV MDD checklist, and a blinded review of symptom exacerbations by a consensus committee of research clinicians. RESULTS: Application of a competing-risk model that estimated the conditional probability of recurrence among those patients remaining on active therapy revealed a significant (p =.043) difference between nefazodone (n = 76) and placebo (n = 74) when the latter part of the 1-year maintenance period was emphasized. At the end of 1 year, the conditional probability of recurrence was 30.3% for nefazodone-treated patients, compared with 47.5% for placebo-treated patients. Prior concomitant psychotherapy during acute/continuation treatment, although enhancing the initial response, was not associated with lower recurrence rates. Discontinuations due to adverse events were relatively low for both nefazodone (5.3%) and placebo (4.8%). Somnolence was significantly greater among the patients taking active medication (15.4%), compared with placebo (4.6%). CONCLUSIONS: Nefazodone is well-tolerated and is an effective maintenance therapy for chronic forms of MDD.

Does psychosocial functioning improve independent of depressive symptoms? A comparison of nefazodone, psychotherapy, and their combination.

BACKGROUND: Although it is known that antidepressant treatment improves psychosocial functioning, whether such changes occur independent of depressive symptoms is not known. This study compared efficacy of nefazodone, psychotherapy, and their combination in improving psychosocial functioning in chronically depressed outpatients. METHODS: Patients with chronic forms of major depressive disorder were randomized to 12 weeks of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or combined nefazodone/CBASP. Psychosocial assessments measured overall psychosocial functioning, work functioning, interpersonal functioning, and general health. RESULTS: Relative to community norms, patients with chronic major depression evidenced substantially impaired psychosocial functioning at baseline. Combined treatment produced significantly greater psychosocial improvement than either CBASP alone or nefazodone alone on all primary measures. Combined treatment remained superior to nefazodone on primary measures of work, social, and overall functioning, and superior to CBASP on social functioning when depressive symptoms were controlled. Unlike the two groups receiving nefazodone, CBASP alone's effect on psychosocial function was relatively independent of symptom change. Psychosocial functioning improved more slowly than depressive symptoms, and moderate psychosocial impairments remained at end point. CONCLUSIONS: Combined treatment had greater effect than either monotherapy. Change in depressive symptoms did not fully explain psychosocial improvement. Moderate residual psychosocial impairment remained, suggesting the need for continuation/maintenance treatment.

Symptomatic and syndromal anxiety in chronic forms of major depression: effect of nefazodone, cognitive behavioral analysis system of psychotherapy, and their combination.

BACKGROUND: Limited information is available on treatment response of anxiety symptoms in chronic forms of major depression. Concurrent anxiety disorders are prevalent in chronic depression, but the responsiveness of patients with such comorbidity to different treatments is largely unknown. This study investigated the comparative efficacy of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), and their combination in improving anxiety symptoms in patients with chronic forms of major depression, including those with a concurrent anxiety disorder. METHOD: 681 patients with chronic major depressive disorder (DSM-IV criteria) participated in a multicenter study of 12 weeks of acute treatment with nefazodone (N = 226), CBASP (N = 228), or the combination (N = 227). The Hamilton Rating Scale for Anxiety (HAM-A), the HAM-A psychic anxiety factor, and the anxiety/arousal subscale of the 30-item Inventory for Depressive Symptomatology-Self Report (IDS-SR-30) were used to assess anxiety symptoms. RESULTS: In the full sample. without controlling for change in depressive symptoms, combination therapy was superior to both monotherapies on all 3 anxiety measures both in the rate of change and at endpoint. When change in depressive symptoms was controlled for, there were no treatment differences in rate of change from baseline to week 12 on any of the 3 anxiety measures. In those patients with a concurrent anxiety disorder, however, the combination was superior to CBASP on the HAM-A and the IDS-SR-30. Nefazodone alone and combination therapy were both superior to CBASP on the HAM-A psychic anxiety factor. CONCLUSION: For patients with chronic depression, combination therapy is superior to CBASP or nefazodone alone. Among patients with a concurrent anxiety disorder, nefazodone. either alone or in combination with CBASP, improves anxiety symptoms faster than CBASP alone, independent of depressive symptom reduction.

Differential effects of nefazodone and cognitive behavioral analysis system of psychotherapy on insomnia associated with chronic forms of major depression.

BACKGROUND: The antidepressant nefazodone and the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) were recently found to have significant, additive effects in a large multicenter study of chronic forms of major depression. As nefazodone-mediated blockade of serotonin-2 receptors may directly relieve insomnia associated with depression, we examined the more specific effects of CBASP and nefazodone, singly and in combination, on sleep disturbances. METHOD: A total of 597 chronically depressed outpatients (DSM-III-R criteria) with at least 1 insomnia symptom were randomly assigned to 12 weeks of treatment with nefazodone (mean final dose = 466 mg/day), CBASP (mean = 16.0 sessions), or the combination (mean dose = 460 mg/day plus a mean of 16.2 CBASP sessions). Continuous and categorical insomnia outcomes, derived from standard clinician- and self-rated assessments, were compared. RESULTS: Patients receiving nefazodone (either alone or in combination with CBASP) obtained significantly more rapid and greater ultimate improvement in insomnia ratings when compared with those treated with CBASP alone. This difference was maximal by the fourth week of therapy and sustained thereafter. Combined treatment did not result in markedly better insomnia scores than treatment with nefazodone alone on most measures, although patients receiving both CBASP and nefazodone were significantly more likely (p < .001) to achieve > or = 50% decrease in insomnia severity. CONCLUSION: Despite comparable antidepressant efficacy, monotherapy with nefazodone or CBASP resulted in markedly different effects on the magnitude and temporal course of insomnia symptoms associated with chronic forms of major depression. Patients receiving the combination of psychotherapy and pharmacotherapy benefited from both the larger and more rapid improvements in insomnia associated with nefazodone therapy and the later-emerging effects of CBASP on the overall depressive syndrome.

Sexual function and satisfaction in the treatment of chronic major depression with nefazodone, psychotherapy, and their combination.

BACKGROUND: Changes in sexual interest/satisfaction and function are frequently associated with major depression and the use of some antidepressant treatments. This study compares the effects of antidepressant medication, psychotherapy, and combined treatment on sexual interest/satisfaction and function in patients with chronic major depression. METHOD: Outpatients with chronic forms of DSM-IV major depressive disorder (N = 681) were randomly assigned to 12 weeks of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or combined nefazodone/CBASP. The Modified Rush Sexual Inventory was used to assess sexual functioning, and the 24-item Hamilton Rating Scale for Depression was used to assess depressive symptoms. RESULTS: At baseline, 65% of men and 48% of women reported some sexual dysfunction. Statistically significant linear improvement in sexual interest/satisfaction was noted across all 3 treatment groups (p < .001). Additionally, significant improvement in sexual function was observed across all 3 treatment groups on a composite measure of female sexual function (p < .001). Controlling for depressive symptoms and gender, combined treatment produced greater improvement in total sexual interest/satisfaction than CBASP alone (p = .007), but was not significantly different from nefazodone alone. Improvement in depressive symptoms was associated with improved sexual interest/satisfaction for men and women and, for men, improved sexual functioning. CONCLUSION: Chronic depression is associated with high rates of sexual dysfunction. Treatment with nefazodone, CBASP, and combined treatment improved sexual interest/satisfaction, with greatest improvement observed with combined treatment.

Therapeutic alliance in depression treatment: controlling for prior change and patient characteristics.

Although many studies report that the therapeutic alliance predicts psychotherapy outcome, few exclude the possibility that this association is accounted for by 3rd variables, such as prior improvement and prognostically relevant patient characteristics. The authors treated 367 chronically depressed patients with the cognitive-behavioral analysis system of psychotherapy (CBASP), alone or with medication. Using mixed effects growth-curve analyses, they found the early alliance significantly predicted subsequent improvement in depressive symptoms after controlling for prior improvement and 8 prognostically relevant patient characteristics. In contrast, neither early level nor change in symptoms predicted the subsequent level or course of the alliance. Patients receiving combination treatment reported stronger alliances with their psychotherapists than patients receiving CBASP alone. However, the impact of the alliance on outcome was similar for both treatment conditions.

Group comparisons of DSM-IV subtypes of chronic depression: validity of the distinctions, part 2.

The nosology of chronic depression in Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV, American Psychiatric Association, 1994) is highly complex and requires clinicians to differentiate among several chronic course subtypes. This study replicates an earlier investigation (J. McCullough et al., 2000; see record 2000-05424-007) that found few differences among Diagnostic and Statistical Manual of Mental Disorders (3rd ed. rev.; DSM-III-R; American Psychiatric Association, 1987) categories of chronic depression. In the present study, 681 outpatients with chronic major depression, double depression, recurrent major depression without full interepisode recovery, and chronic major depression superimposed on antecedent dysthymia were compared. Few differences were observed on a broad range of demographic, clinical, psychosocial, family history, and treatment response variables. The authors suggest that chronic depression should be viewed as a single, broad condition that can assume a variety of clinical course configurations.

Continuation treatment of chronic depression: a comparison of nefazodone, cognitive behavioral analysis system of psychotherapy, and their combination.

Little is known about the relative benefits of psychotherapy, medication, and combined treatment as continuation therapies for chronic forms of major depressive disorder (MDD) after a positive response to acute treatment. We hypothesize that combined treatment would demonstrate superior continuation phase outcomes compared to either monotherapy, as evidenced by lower relapse rates and greater rates of improvement from partial to full remission. We report 16-week continuation phase outcomes for 324 patients who had participated in either the acute phase of a randomized multicenter trial of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or combination therapy (COMB) for chronic forms of MDD. Patients entering the continuation phase had either fully or partially remitted after 12 weeks of acute phase treatment. The primary efficacy measure was the 24-item Hamilton Rating Scale for Depression. For patients in remission at acute phase exit, 73.3% (107/146) maintained their remitted status at endpoint of the continuation phase. Of those having a partial remission at acute phase exit, 52.9% (92/174) achieved full remission by end of continuation. A greater proportion of patients maintained a partial or full remission status on COMB (90%) compared to nefazodone (80%, p=0.011) or to CBASP (82%, p=0.042). These differences reflected greater symptom re-emergence in the partial remission groups on CBASP and nefazodone monotherapy compared to COMB. Continuation treatment assignment was not randomized or blinded. There was no placebo group. Most patients with chronic forms of MDD sustained their acute phase response and more than 50% of partial remitters achieved full remission while continuing treatment with nefazodone, CBASP, or COMB. COMB was associated with less symptom re-emergence during the continuation phase than either monotherapy, particularly for partial remitters.