Quetiapine adjunct to selective serotonin reuptake inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a randomized, placebo-controlled pilot study

This double-blind, placebo-controlled study examined the efficacy and tolerability of quetiapine in combination with selective serotonin reuptake inhibitors (SSRIs)/venlafaxine in 58 patients with major depressive disorder, comorbid anxiety symptoms (HAM-A-14 score > or =14), and residual depressive symptoms (HAM-D-17 score > or =18, CGI-S score > or =4). Patients had received an SSRI/venlafaxine (at a predefined therapeutic dose) for > or =6 weeks. Overall, 62% (18/29) of quetiapine- and 55% (16/29) of placebo-treated patients completed the study. The mean change in HAM-D and HAM-A total scores from baseline to Week 8 (primary endpoint) was significantly greater with quetiapine (mean dose 182 mg/day) than placebo: -11.2 vs. -5.5 (P=.008) and -12.5 vs. -5.9 (P=.002), respectively. The onset of quetiapine efficacy (HAM-D/HAM-A/CGI-I) was rapid (by Week 1) and continued through to Week 8. Significant differences (P<.05) from baseline to Week 8 were observed between groups in 7/17 HAM-D (including feelings of guilt, suicide) and 6/14 HAM-A items (including tension, cardiovascular symptoms). Response (> or =50% decrease in total score) was higher for quetiapine than placebo: HAM-D, 48% vs. 28% (not significant, NS); HAM-A, 62% vs. 28% (P=.02). Remission (total score < or =7) was higher for quetiapine than placebo: HAM-D, 31% vs. 17% (NS); HAM-A, 41% vs. 17% (NS). CGI-S, CGI-I, and the Global Assessment Scale showed that quetiapine was significantly more effective than placebo. For quetiapine, adverse events (AEs) were similar to those previously observed; sedation/somnolence/lethargy was the most commonly reported. Here quetiapine was shown to be effective as augmentation of SSRI/venlafaxine therapy in patients with major depression, comorbid anxiety, and residual depressive symptoms, with no unexpected tolerability issues. Further studies are warranted.     

Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness.

BACKGROUND: Partial response, no response, or residual symptoms following antidepressant therapy is common in clinical psychiatry. This study evaluated modafinil in patients with major depressive disorder (MDD) who were partial responders to adequate selective serotonin reuptake inhibitor (SSRI) therapy and excessive sleepiness and fatigue. METHODS: This retrospective analysis pooled the data of patients (18-65 yrs) who participated in two randomized, double-blind, placebo-controlled studies of modafinil (6-week, flexible-dose study of 100-400 mg/day or 8-week, fixed-dose study of 200 mg/day) plus SSRI therapy. Patients (n=348) met criteria for several residual symptoms (Epworth Sleepiness Scale [ESS] score>or=10; 17-item Hamilton Depression Scale [HAM-D] score between 4 and 25; and Fatigue Severity Scale [FSS] score>or=4). RESULTS: Compared to placebo, modafinil augmentation rapidly (within 1 week) and significantly improved overall clinical condition (Clinical Global Impression-Improvement), wakefulness (ESS), depressive symptoms (17-item HAM-D), and fatigue (FSS) (p<.01 for all). At final visit, patients receiving modafinil augmentation experienced statistically significant improvements in overall clinical condition, wakefulness, and depressive symptoms. Modafinil was well tolerated in combination with SSRI. CONCLUSIONS: Results of this pooled analysis provide further evidence suggesting that modafinil is an effective and well-tolerated augmentation therapy for partial responders to SSRI therapy, particularly when patients continue to experience fatigue and excessive sleepiness.     

A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness

BACKGROUND: Up to one half of depressed patients have partial or no response to antidepressant monotherapy. This multicenter, placebo-controlled study evaluated the efficacy of modafinil augmentation in major depressive disorder (MDD) patients with fatigue and excessive sleepiness despite selective serotonin reuptake inhibitor (SSRI) monotherapy. METHOD: Patients (18-65 years) with a DSM-IV diagnosis of MDD and partial response to SSRI monotherapy (> or = 8 weeks) at a stable dose for > or = 4 weeks were eligible. Patients had screening/baseline 31-item Hamilton Rating Scale for Depression (HAM-D) scores of 14 to 26, Epworth Sleepiness Scale (ESS) scores > or = 10, and Fatigue Severity Scale (FSS) scores > or = 4. Patients were randomly assigned to augmentation therapy with modafinil 200 mg/day or placebo for 8 weeks. Assessments included the ESS, Clinical Global Impressions-Improvement scale (CGI-I), 31- and 17-item HAM-D, FSS, Brief Fatigue Inventory (BFI), and Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Of 311 enrolled patients who received > or = 1 dose of study drug, 158 were randomly assigned to modafinil (70% women) and 153 to placebo (72% women); 85% of each treatment group completed the study. At final visit, modafinil significantly improved patients' overall clinical condition compared with placebo on the basis of CGI-I scores (p = .02), and there were trends toward greater mean reductions in ESS, 31- and 17-item HAM-D, and MADRS scores versus placebo. Modafinil significantly reduced BFI scores for worst fatigue at final visit (p < .05 vs. placebo). There were no significant differences between modafinil and placebo at final visit in FSS or BFI total scores. Adverse events significantly more common during modafinil compared with placebo treatment were nausea (9% vs. 2%; p = .01) and feeling jittery (4% vs. 1%; p = .03). CONCLUSION: These findings suggest that modafinil is a well-tolerated and potentially effective augmenting agent for SSRI partial responders with fatigue and sleepiness.     

Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or placebo.

BACKGROUND: Most examinations of the clinical efficacy of drugs used to treat depression pool subjects across gender and age groups. This investigation compared these patient subpopulations on the basis of remission and response rates associated with venlafaxine and selective serotonin reuptake inhibitor (SSRI) treatment. METHOD: A meta-analysis of original data from 8 comparable double-blind, active-controlled, randomized clinical trials (4 also placebo-controlled) was conducted. Antidepressant efficacy was assessed for patients (N = 2,045) aged 18 to 83 years (subgroups: < or = 40, 41-54, 55-64, and > or = 65 years) who met DSM-III-R criteria for major depression or DSM-IV criteria for major depressive disorder and were randomly assigned to receive venlafaxine (immediate release, N = 474; extended release, N = 377), one of several SSRIs (N = 748), or placebo (N = 446) for up to 8 weeks. Symptoms of depression were assessed using the Hamilton Rating Scale for Depression (HAM-D). Remission was defined as a HAM-D-17 score < or = 7, response was defined as > or = 50% decrease in HAM-D-21 score, and absence of depressed mood was defined as a HAM-D depressed mood item score of 0. RESULTS: We detected no significant age-by-treatment, gender-by-treatment, or age-by-gender-by-treatment interactions; men and women of different ages within a given antidepressant treatment group exhibited similar rates of remission, response, and absence of depressed mood. Regardless of age or gender, remission rates during venlafaxine therapy were significantly higher than during SSRI therapy (remission rates at week 8: venlafaxine, 40%-55% vs. SSRI, 31%-37%; p < .05). Regardless of patient age or gender, onset of remission was more rapid with venlafaxine than with SSRI treatment. By contrast, rates of absence of depressed mood with venlafaxine (34%-42%) and SSRIs (31%-37%) did not differ significantly and tended to be similar for all patient subgroups. CONCLUSION: These data suggest that men and women have comparable responses to SSRIs and venlafaxine across various age groups. Moreover, patients exhibited a more rapid onset and a greater likelihood of remission with venlafaxine therapy than with SSRI therapy regardless of age or gender.     

Zolpidem for persistent insomnia in SSRI-treated depressed patients.

BACKGROUND: Depressed individuals effectively treated with selective serotonin reuptake inhibitors (SSRIs) often report persistent insomnia and require adjunctive sleep-promoting therapy. METHOD: Men (N = 40) and women (N = 150) with a mean age of 41.6 years who had persistent insomnia in the presence of effective and stable treatment (at least 2 weeks) with fluoxetine (< or =40 mg/day), sertraline (< or =100 mg/day), or paroxetine (< or =40 mg/day) for DSM-IV major depressive disorder, dysthymic disorder, or minor depressive disorder of mild-to-moderate severity (and score of < or =2 on item 3 of the Hamilton Rating Scale for Depression [HAM-D]) participated in this randomized, double-blind, parallel-group study. At study entry, patients were required to score < or =12 on the HAM-D. During a 1-week single-blind placebo period, patients had to report on at least 3 nights a latency of > or =30 minutes or a sleep time of <6.5 hours and clinically significant daytime impairment. Patients received either placebo (N = 96) or zolpidem, 10 mg (N = 94) nightly, for 4 weeks and single-blind placebo for 1 week thereafter. Sleep was measured with daily questionnaires and during weekly physician visits. RESULTS: Compared with placebo, zolpidem was associated with improved sleep: longer sleep times (weeks 1 through 4, p<.05), greater sleep quality (weeks 1 through 4, p<.01), and reduced number of awakenings (weeks 1, 2, and 4; p<.05), together with feeling significantly more refreshed, less sleepy, and more able to concentrate. After placebo substitution, the zolpidem group showed significant worsening relative to pretreatment sleep on the first posttreatment night in total sleep time and sleep quality, reverted to pretreatment insomnia levels on the other hypnotic efficacy measures, or maintained improvement (fewer number of awakenings). There was no evidence of dependence or withdrawal from zolpidem (DSM-IV criteria). Incidence rates of adverse events were similar in both treatment groups (74% and 83% for placebo and zolpidem, respectively), but 7 zolpidem patients discontinued compared with 2 placebo patients. CONCLUSION: In this defined patient population, zolpidem, 10 mg, was effectively and safely co-administered with an SSRI, resulting in improved self-rated sleep, daytime functioning, and well-being.     

Substitution of an SSRI with bupropion sustained release following SSRI-induced sexual dysfunction

BACKGROUND: We examine changes in sexual functioning and depressive symptoms in patients' transition from a selective serotonin reuptake inhibitor (SSRI), which induced both a therapeutic response and sexual dysfunction, to bupropion sustained release (SR) over the course of an 8-week trial. METHOD: The study included 11 adults (8 women and 3 men) who had a DSM-IV diagnosis of major depressive disorder in remission (Hamilton Rating Scale for Depression [HAM-D] score < 11) and were receiving an SSRI. Depression (using the HAM-D) and sexual dysfunction (using the Changes in Sexual Functioning Questionnaire) were assessed at baseline, 2 weeks after bupropion SR was added to the current antidepressant (combined treatment), 2 weeks after taper of the SSRI was initiated and completed, and after 4 weeks of bupropion SR monotherapy. T tests were performed to assess changes in depression and sexual function. RESULTS: Patient participation dropped from the initial group of 11 at week 2 to 9 at week 4 and to 6 by week 8. Sexual functioning improved from week 0 (baseline) to week 2 and from week 2 to week 4. The patients showed no significant change in mean HAM-D scores in weekly comparisons during the study period; 55% of patients completed the substitution without significant adverse events or recurrence of depressive symptoms. CONCLUSION: Bupropion SR as a treatment for depression also alleviates sexual dysfunction due to SSRI treatment. Results show that sexual functioning improves after the addition of bupropion SR to SSRI treatment and continues to improve, after discontinuation of the SSRI, with bupropion SR treatment alone.     

Efficacy of controlled-release paroxetine in the treatment of late-life depression

BACKGROUND: Depression is the second most common neuropsychiatric disorder in older Americans, with significant clinical and public health costs. Despite advances in treatment, late-life depression remains a clinical challenge. Although the selective serotonin reuptake inhibitors (SSRIs) are the most common pharmacologic intervention for late-life depression, few placebo-controlled trials have assessed the efficacy of SSRIs for this condition. METHOD: In this 12-week, multicenter, placebo-controlled, flexible-dose, double-blind, randomized trial, 319 elderly patients (mean age = 70 years) were treated with controlled-release paroxetine (paroxetine CR) up to 50 mg/day (N = 104), immediate-release paroxetine (paroxetine IR) up to 40 mg/day (N = 106), or placebo (N = 109). Patients met DSM-IV criteria for major depressive disorder and had a total score of 18 or more on the 17-item Hamilton Rating Scale for Depression (HAM-D). The primary efficacy measure was change from baseline to endpoint in HAM-D total score. RESULTS: The primary efficacy analysis showed an adjusted difference between change from baseline in HAM-D score for paroxetine CR and placebo of -2.6 (95% confidence interval [CI] = -4.47 to -0.73, p = .007) at the week 12 last-observation-carried-forward (LOCF) endpoint. The adjusted difference between paroxetine IR and placebo was -2.8 (95% CI = -4.65 to -0.99, p = .003) at week 12. Paroxetine CR and IR were more effective than placebo, with mean +/- SD endpoint HAM-D total scores of 10.0 +/- 7.41 and 10.0 +/- 7.10, respectively, for the active treatments compared with 12.6 +/- 7.34 for placebo. Response, defined as a score of 1 or 2 on the Clinical Global Impressions-global improvement scale, was achieved by 72% of paroxetine CR patients (LOCF; p < .002 vs. placebo), 65% of paroxetine IR patients (p = .06 vs. placebo), and 52% of placebo patients. Remission, defined as a HAM-D total score < or = 7, was achieved by 43% of paroxetine CR patients (LOCF; p = .009 vs. placebo), 44% of paroxetine IR patients (p = .01 vs. placebo), and 26% of placebo patients. In a post hoc analysis, mean HAM-D improvement for paroxetine CR and paroxetine IR was greater than for placebo in both chronically depressed patients (duration > 2 years) and those with short-term (< or = 2 years) depression. Dropout rates due to adverse events were 12.5% for paroxetine CR, 16.0% for paroxetine IR, and 8.3% for placebo. CONCLUSION: Paroxetine CR and paroxetine IR are effective and well tolerated treatments for major depressive disorder in elderly patients, including those with chronic depression.     

Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial

BACKGROUND: Studies of pindolol augmentation of antidepressants in major depressive disorder have produced mixed results, and data in treatment-resistant patients are limited. Here, we report on a double-blind, randomized, controlled 6-week study of pindolol augmentation of selective serotonin reuptake inhibitors (SSRIs) in depressed outpatients resistant to SSRI monotherapy. METHOD: Forty-two outpatients with DSM-IV major depressive disorder who had an insufficient response to an adequate trial of an SSRI (fluoxetine, paroxetine, or sertraline) were randomly assigned to pindolol, 2.5 mg t.i.d., or sham augmentation, in addition to continued SSRI administration. For separate analysis, the control group underwent a single-blinded switch to pindolol, 2.5 mg t.i.d., from week 4 through week 6, while the active group was continued on pindolol augmentation (hemi-crossover design). Change in Hamilton Rating Scale for Depression (HAM-D) score from baseline to the end of week 3 was the primary outcome measure. Data were gathered from February 1994 to August 1998. RESULTS: Thirty-eight patients completed at least 1 week on protocol, with 21 and 17 randomly assigned to the pindolol and control groups, respectively. After 3 weeks on protocol, partial response rates (i.e., minimum 50% decrease from baseline in HAM-D score and maximum absolute score of 15) for the pindolol (19% [4/21]) and control (24% [4/17]) groups were comparable. At 3 weeks, the pindolol and control groups demonstrated mean +/- SD decreases in HAM-D scores of 6.5 +/- 9.8 and 9.7 +/- 7.2, respectively. There were no significant differences in antidepressant response or side effects between the 2 groups. CONCLUSION: These results do not support the efficacy of pindolol in augmenting clinical response to SSRIs in treatment-resistant depressed patients.     

Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial

Background

Despite evolution of new antidepressant treatment, clinicians still encounter challenges in the treatment of depressed patients. Looking for new medications that can potentiate the effects of current antidepressants seems to be necessary. Our objective is to survey the efficacy of topiramate augmentation in resistant major depressive disorder (MDD).

Method

This augmentation trial was designed as an 8-week randomized, placebo-controlled, double-blind study. Fifty three patients with DSM-IV diagnosis of MDD who had failed to respond to at least 8 weeks of treatment with an adequate dose of one of the SSRIs (fluoxetine, citalopram or serteraline) were included in the study. Patients were randomized to receive a flexible dose of topiramate (100-200 mg/day) or placebo beside their current antidepressant medication for a period of eight weeks. Outcome measures were Hamilton Depression Scale (HAM-D) and Clinical Global Impression (CGI).

Results

42 patients completed the study and there were 6 and 5 dropouts in topiramate and placebo groups, respectively. The topiramate group demonstrated significant improvement over the study period based on mean HAM-D score at week 8 compared to baseline (P = .000, Z = 3.699). Those receiving topiramate demonstrated to have a mean decrease of 32.0% in HAM-D score, compared to only 5.5% for those receiving placebo. Depressed mood, suicidality, insomnia (early, middle and late), agitation and anxiety symptoms were significantly improved in the topiramate group.

Conclusion

Our double-blind placebo-controlled study demonstrated that topiramate augmentation potentiate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treatment of resistant major depressive disorder. Of note is that our study is preliminary and larger double-blind studies are needed to confirm the results.     

A double-blind,randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes

BACKGROUND: Evidence of the antidepressant efficacy of lamotrigine is increasing, although there are no placebo-controlled trials of lamotrigine augmentation in depression. The aim of this study was to assess if augmentation with lamotrigine was superior to placebo in patients who were receiving fluoxetine for resistant major depressive episodes. METHOD: Twenty-three patients who had experienced at least 1 major depressive episode that was resistant to at least 1 prior trial of antidepressant therapy were selected. These patients were treated with fluoxetine, 20 mg/day, and concomitantly randomly assigned to receive either lamotrigine (N = 13) or placebo (N = 10) for 6 weeks. The dose of lamotrigine was titrated upward from 25 mg/day to 100 mg/day. Patients suffering from bipolar II disorder (N = 8) or from major depressive disorder (N = 15) (DSM-IV criteria) were enrolled, resulting in heterogeneity of the sample. The primary outcome measure was Hamilton Rating Scale for Depression score. Data were collected from 2000-2001. RESULTS: Lamotrigine was statistically superior to placebo on the Clinical Global Impressions scale at endpoint, both in absolute terms (mean +/- SD Clinical Global Impressions-Severity of Illness scores: lamotrigine, 2.15 +/- 1.28; placebo, 3.40 +/- 1.17; p =.0308) and using a responder analysis, with response defined as a Clinical Global Impressions-Improvement score of 2 or less (lamotrigine, 84.62% [N = 11]; placebo, 30.00% [N = 3]; p =.013). The effect of lamotrigine on Clinical Global Impressions scale scores was seen in both major depressive disorder and bipolar II disorder. Lamotrigine, however, failed to separate statistically from placebo on the Hamilton Rating Scale for Depression and Montgomery-Asberg Depression Rating Scale. This failure to differentiate on a primary outcome measure is essentially a negative study result. This result is most likely an artifact of the small sample size used and the resultant limited power of the study. CONCLUSION: The results of this trial add to the literature suggesting potential efficacy of the antidepressant profile of lamotrigine. In addition, this study points to a possible role of lamotrigine as an augmentation agent in depression.     

Reboxetine,the first selective noradrenaline reuptake inhibitor antidepressant: Efficacy and tolerability in 2613 patients

INTRODUCTION: Reboxetine is the first available selective noradrenaline re-uptake inhibitor (selective NRI). This paper gives an overview of its antidepressant efficacy and tolerability in eight randomized double-blind, multicentre clinical trials. The clinical profile of reboxetine is also compared with that of the tricyclic antidepressants (TCAs) desipramine and imipramine and the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. METHODS: Pooled data were analysed from seven short-term (4 &#45 8 weeks) and one long-term (up to 1 year) trials comparing reboxetine with placebo, imipramine, desipramine or fluoxetine. The tolerability of reboxetine was evaluated in 2613 patients with major depression or dysthymia. Data from 1959 patients with major depressive disorder were included to assess drug efficacy. Efficacy was principally assessed using the Hamilton Depression Rating Scale (HAM-D). RESULTS: Reboxetine was more effective than placebo in three of four short-term trials, and it was as effective as fluoxetine, imipramine and desipramine. In long-term treatment, reboxetine was more effective than placebo in preventing relapse ( &#83 50% increase in HAM-D) and recurrence (HAM-D total score &#104 10). In a subset of severely depressed patients, reboxetine was as effective as imipramine and significantly more effective than fluoxetine. Reboxetine was as effective as imipramine in the elderly, but better tolerated. The most common adverse events among the 1503 patients (adults and elderly) who received reboxetine were dry mouth (22%), constipation (15%), sweating (12%) and insomnia (11%). Overall, reboxetine was well tolerated, as well as the SSRI fluoxetine and better than the TCAs imipramine and desipramine. CONCLUSIONS: Reboxetine is effective and well tolerated in the short and long-term treatment of depression. It is as well tolerated as fluoxetine and better than imipramine and desipramine. ( Int J Psych Clin Pract 2000; 4: 201 - 208)     

Efficacy of venlafaxine extended release in patients with major depressive disorder and comorbid generalized anxiety disorder

BACKGROUND: A subset of patients with comorbid major depressive disorder and generalized anxiety disorder (GAD) was examined from a double-blind. placebo-controlled study comparing the efficacy and safety of venlafaxine extended release (XR) and fluoxetine. METHOD: From a total of 368 patients, 92 patients meeting DSM-IV criteria for major depressive disorder who also had comorbid GAD were identified. The comparison group comprised 276 evaluable noncomorbid patients. Patients received venlafaxine XR (75-225 mg/day), fluoxetine (20-60 mg/day), or placebo for 12 weeks. Efficacy evaluations included Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), and Clinical Global Impressions (CGI) scale. RESULTS: By the final assessment at week 12, comorbid patients in the venlafaxine XR group, but not in the fluoxetine group, showed a significantly greater decrease than those in the placebo group in the primary efficacy variables of mean HAM-D and HAM-A total scores (p < .05, pairwise comparison). In comorbid patients, significant pairwise differences were noted between venlafaxine XR and placebo at week 12 for the secondary variables of HAM-D anxiety-somatization and retardation factors, HAM-D depressed mood item. HAM-A psychic anxiety factor, the Hospital Anxiety and Depression scale (HAD) anxiety subscale score, and the Covi Anxiety Scale score. Fluoxetine was significantly different from placebo only on the HAD depression subscale score. Response, defined as > or = 50% decrease in symptoms score, was achieved in 66% and 59% of the comorbid patients for HAM-D and HAM-A, respectively, in the venlafaxine XR group at week 12. This response was higher than that seen with fluoxetine (52% and 45%) or placebo (36% and 24%). Onset of efficacy appeared to be slower in comorbid than in noncomorbid patients. CONCLUSION: This is the first evidence from a controlled study of the effectiveness of pharmacotherapy in patients with comorbid major depressive disorder and GAD. The delayed improvement in comorbid patients compared with noncomorbid patients suggests that a longer treatment period may be necessary in comorbid patients.     

Gepirone extended-release: new evidence for efficacy in the treatment of major depressive disorder

OBJECTIVE: To assess the efficacy and tolerability of the 5-HT(1A) agonist gepirone in extended-release formulation (gepirone-ER) versus placebo in patients with major depressive disorder. METHOD: Patients aged 18 to 70 years were eligible if they satisfied DSM-IV criteria for moderate-to-severe major depressive disorder and had a baseline 17-item Hamilton Rating Scale for Depression (HAM-D-17) score > or = 20. After a 4- to 7-day placebo washout period, patients were randomly assigned to receive either placebo (N = 106) or gepirone-ER (20-80 mg/day) (N = 103) for 56 days. Assessments were done at weeks 1-4, 6, and 8. RESULTS: Mean change from baseline in HAM-D-17 score within the intent-to-treat group (gepirone, N = 101; placebo, N = 103) was significantly greater with gepirone-ER than placebo at weeks 3 (p =.013) and 8 (p =.018). Significantly (p <.05) more patients receiving gepirone-ER than placebo were HAM-D-17 responders at weeks 3 (33.7% vs. 18.8%, respectively) and 4 (38.6% vs. 24.8%, respectively) and HAM-D-17 remitters at weeks 6 (24.8% vs. 13.9%, respectively) and 8 (28.7% vs. 14.9%, respectively). Mean change from baseline for HAM-D-25 total score was significantly (p < pr =.05) greater with gepirone-ER at all assessments except week 6. The proportion of HAM-D-25 responders was significantly greater (p < or =.05) with gepirone-ER at weeks 3 and 8. Gepirone-ER was well tolerated: 9.8% of the gepirone-ER group and 2.8% of the placebo group discontinued due to adverse events. Common adverse events were considered mild and included dizziness, nausea, and insomnia. Gepirone-ER did not differ statistically compared with placebo in weight gain or sedation. Furthermore, preliminary evidence suggested that gepirone-ER may not be associated with sexual dysfunction. No serious adverse events occurred in gepirone-treated patients. CONCLUSION: Gepirone-ER is effective for the short-term treatment of major depressive disorder and is well tolerated.     

Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder

OBJECTIVE: To determine the efficacy and tolerability of aripiprazole, a dopamine D2 and 5-HT1A receptor partial agonist, as augmentation of antidepressant treatment of partially responding and nonresponding patients with major depressive disorder. METHOD: Fifteen patients with major depressive disorder (diagnosed with a site-generated form described in the text) and an incomplete response or no response to > or = 8 weeks of antidepressant (selective serotonin reuptake inhibitor, venlafaxine, or bupropion) monotherapy were treated with aripiprazole augmentation in an 8-week, open-label study. Data were gathered from July 2003 to March 2004. RESULTS: The mean duration of antidepressant monotherapy at baseline was 43.1 weeks. At baseline, mean Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Depression (HAM-D) scores were 4.3 and 18.9, respectively. After initiation of aripiprazole augmentation, 6 of 15 patients achieved remission (HAM-D score < or = 7) at week 1, and 9 of 15 patients remitted by week 2. All 8 completers achieved remission by study endpoint. Akathisia in 2 patients who withdrew prematurely prompted a reduction in the starting dose of aripiprazole from 10 mg/day to 2.5 mg/day, resulting in a 50% reduction in attrition due to akathisia (2/7 withdrew due to akathisia with the 10-mg starting dose, 1/8 withdrew due to akathisia with the 2.5-mg starting dose). Discontinuation rates after 4 weeks of treatment were lower for the 2.5-mg starting dose (1/8 patients) than for the 10-mg starting dose (3/7 patients). Overall discontinuation rates at endpoint were lower for the 2.5-mg dose (3/8 patients) than the 10-mg dose (4/7 patients). Response to aripiprazole augmentation did not appear to be related to the antidepressant used at study initiation. CONCLUSION: Aripiprazole is an effective augmentation strategy for improving therapeutic response in patients with treatment-resistant major depressive disorder when administered in combination with standard antidepressant therapy. Based on this clinical signal, a double-blind, placebo-controlled trial is warranted.     

Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report

OBJECTIVE: About half of outpatients with major depressive disorder also have clinically meaningful levels of anxiety. The authors conducted a secondary data analysis to compare antidepressant treatment outcomes for patients with anxious and nonanxious major depression in Levels 1 and 2 of the STAR*D study. METHOD: A total of 2,876 adult outpatients with major depressive disorder, enrolled from 18 primary and 23 psychiatric care sites, received citalopram in Level 1 of STAR*D. In Level 2, a total of 1,292 patients who did not remit with or tolerate citalopram were randomly assigned either to switch to sustained-release bupropion (N=239), sertraline (N=238), or extended-release venlafaxine (N=250) or to continue taking citalopram and receive augmentation with sustained-release bupropion (N=279) or buspirone (N=286). Treatment could last up to 14 weeks in each level. Patients were designated as having anxious depression if their anxiety/somatization factor score from the 17-item Hamilton Depression Rating Scale (HAM-D) was 7 or higher at baseline. Rates of remission and response as well as times to remission and response were compared between patients with anxious depression and those with nonanxious depression. RESULTS: In Level 1 of STAR*D, 53.2% of patients had anxious depression. Remission was significantly less likely and took longer to occur in these patients than in those with nonanxious depression. Ratings of side effect frequency, intensity, and burden, as well as the number of serious adverse events, were significantly greater in the anxious depression group. Similarly, in Level 2, patients with anxious depression fared significantly worse in both the switching and augmentation options. CONCLUSIONS: Anxious depression is associated with poorer acute outcomes than nonanxious depression following antidepressant treatment.     

Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients

BACKGROUND: Escitalopram is the single isomer responsible for the serotonin reuptake inhibition produced by the racemic antidepressant citalopram. The present randomized, double-blind, placebo-controlled, fixed-dose multicenter trial was designed to evaluate the efficacy and tolerability of escitalopram in the treatment of major depressive disorder. METHOD: Outpatients with an ongoing DSM-IV major depressive episode (N = 491) were randomly assigned to placebo, escitalopram, 10 mg/day, escitalopram, 20 mg/day, or citalopram, 40 mg/day, and entered an 8-week double-blind treatment period following a 1-week single-blind placebo lead-in. Clinical response was evaluated by the Montgomery-Asberg Depression Rating Scale (MADRS), the 24-item Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions (CGI) scales, the Hamilton Rating Scale for Anxiety (HAM-A), and patient-rated quality-of-life scales. RESULTS: Escitalopram, at both doses, produced significant improvement at study endpoint relative to placebo on all measures of depression; significant separation of escitalopram from placebo was observed within I week of double-blind treatment. Citalopram treatment also significantly improved depressive symptomatology compared with placebo; however, escitalopram, 10 mg/day, was at least as effective as citalopram, 40 mg/day, at endpoint. Anxiety symptoms and quality of life were also significantly improved by escitalopram compared with placebo. The incidence of discontinuations due to adverse events for the escitalopram 10 mg/day group was not different from the placebo group (4.2% vs. 2.5%; p = .50), and not different for the escitalopram 20 mg/day group and the citalopram 40 mg/day group (10.4% vs. 8.8%; p = .83). CONCLUSION: Escitalopram, a single isomer SSRI, is well-tolerated and has demonstrated antidepressant efficacy at a dose of 10 mg/day.     

Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine

OBJECTIVE: In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder. METHOD: Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score < or =12 and 21-item Hamilton Depression Rating Scale [HAM-D] score or =15, HAM-D score > or =15, or hospitalization). RESULTS: Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2). CONCLUSIONS: Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode.     

Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study

BACKGROUND: Although case reports and open studies have reported augmentation with buspirone to be beneficial in the treatment of depression refractory to treatment with a selective serotonin reuptake inhibitor (SSRI), a recently published randomized, placebo-controlled, double-blind study failed to show superiority of buspirone over placebo in this respect. METHOD: One hundred two outpatients who fulfilled DSM-IV criteria for a major depressive episode and who had failed to respond to a minimum of 6 weeks of treatment with either fluoxetine or citalopram were included in this double-blind, randomized, placebo-controlled study. After a single-blind placebo wash-in period of 2 weeks while continuing their SSRI, the patients were randomly assigned to adjunctive treatment with either buspirone, 10 to 30 mg b.i.d., or placebo for 6 weeks. Patients were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions scale (CGI), and visual analogue scales. RESULTS: After the first week of double-blind treatment, there was a significantly greater reduction in MADRS score (p = .034) in the buspirone group as compared with placebo. At endpoint, there was no significant difference between treatment groups as a whole, although patients with initially high MADRS scores (> 30) showed a significantly greater reduction in MADRS score (p = .026) in the buspirone group as compared with placebo. CONCLUSION: Patients with severe depressive symptoms may benefit from augmentation with buspirone. It cannot be excluded that augmentation with buspirone may speed up the antidepressive response of patients refractory to treatment with fluoxetine or citalopram.     

Quetiapine in the treatment of anxiety in patients with bipolar I or II depression: a secondary analysis from a randomized, double-blind, placebo-controlled study

OBJECTIVE: Quetiapine monotherapy shows efficacy in bipolar depression. The analyses in this multicenter, double-blind, randomized, fixed-dose, placebo-controlled study evaluated effects of quetiapine monotherapy on anxiety symptoms in bipolar depression. METHOD: Of 542 outpatients randomly assigned to treatment, 539 with bipolar I (N = 358) or bipolar II (N = 181) disorder experiencing a major depressive episode (DSM-IV) received 8 weeks of quetiapine monotherapy (600 or 300 mg/day) or placebo between September 2002 and October 2003. Anxiety assessments included the Hamilton Rating Scale for Anxiety (HAM-A) and relevant items from the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Rating Scale for Depression (HAM-D). Analyses evaluated the pooled dose groups versus placebo. RESULTS: At week 8, quetiapine 600 and 300 mg/day each demonstrated significant improvements in HAM-A total score versus placebo (-10.8 and -9.9 vs. -6.7, p < .001). Quetiapine (pooled doses) significantly improved HAM-A total score from week 1. In bipolar I depression, quetiapine showed significant improvement in HAM-A total score versus placebo (-10.4 vs. -5.1, p < .001). In bipolar I depression, quetiapine also showed significant improvements versus placebo on the HAM-A anxious mood and tension items, HAM-A psychic and somatic subscales, MADRS inner tension item, and HAM-D psychic anxiety item (all p < .001), but not the HAM-D somatic anxiety item. In bipolar II depression, quetiapine reduced the HAM-A total score more than placebo, but the difference was not statistically significant (-9.8 vs. -9.0, p = .473). In bipolar II depression, quetiapine showed significant improvement versus placebo on the HAM-A anxious mood, MADRS inner tension, and HAM-D psychic anxiety items (all p < .01). CONCLUSION: Quetiapine monotherapy shows efficacy in treating anxiety symptoms in bipolar I depression; however, the anxiolytic effects in bipolar II disorder require further investigation.     

Duloxetine efficacy for major depressive disorder in male vs. female patients: data from 7 randomized, double-blind, placebo-controlled trials

OBJECTIVE: A number of studies have suggested potential gender differences in the efficacy of antidepressant medications. Pooled data from double-blind, placebo-controlled studies were utilized to compare the efficacy of duloxetine in the treatment of major depressive disorder (MDD) in male and female patients. METHOD: Efficacy data were pooled from 7 randomized, double-blind, placebo-controlled clinical trials of duloxetine. These studies represent all available data from U.S. acute-phase, placebo-controlled studies of duloxetine for the treatment of MDD. Patients (aged > or = 18 years) meeting DSM-IV criteria for MDD received duloxetine (40-120 mg/day; men, N = 318; women, N = 578) or placebo (men, N = 242; women, N = 484) for up to 9 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score, HAM-D17 subscales (core, Maier, anxiety, retardation, sleep), the Clinical Global Impressions-Severity of Illness scale (CGI-S) and Patient Global Impression of Improvement scale (PGI-I), the Quality of Life in Depression Scale (QLDS), and Visual Analog Scales (VAS) for pain. The first patient visit was February 1, 1999, and the last patient visit was November 27, 2002. RESULTS: In both male and female patients, duloxetine produced significantly greater improvement in HAM-D17, CGI-S, and PGI-I when compared with placebo (p < .05). Treatment-by-gender interactions did not reach statistical significance, indicating that the magnitude of duloxetine's treatment effects did not differ significantly between male and female patients. However, there was a trend for female patients to show a more robust response than male patients to both duloxetine and placebo. On the basis of VAS assessments of pain severity, duloxetine-treated female patients appeared to exhibit greater improvement than male patients, while women receiving placebo had smaller responses than placebo-treated men. Improvements in quality of life were significantly greater for both men (p = .006) and women (p = .001) receiving duloxetine than placebo and showed no significant difference by gender. CONCLUSION: In this analysis of pooled data, the efficacy of duloxetine did not differ significantly in male and female patients.