Richard H. Weisler

Efficacy of Quetiapine Monotherapy in Bipolar I and Ii Depression: A Double-blind, Placebo-controlled Study (the Bolder Ii Study)

This study evaluated the efficacy and tolerability of quetiapine monotherapy for depressive episodes in patients with bipolar I or II disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) who were randomized to 8 weeks of double-blind treatment with quetiapine (300 or 600 mg/d; once daily, evening dosing) or placebo. Patients were assessed weekly using the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D). The primary end point was change in MADRS total score from baseline to Week 8 (analysis of covariance/last-observation-carried-forward analysis). Of 509 patients randomized, 59% completed the study. Improvements from baseline in mean MADRS total scores were significantly greater with quetiapine 300 and 600 mg/d than with placebo from first evaluation (Week 1) through Week 8 (both P ≤ 0.001 vs. placebo). Therapeutic effect sizes at Week 8 were 0.61 and 0.54 for quetiapine 300 and 600 mg/d, respectively. Improvements in mean HAM-D scores were also significantly greater with both quetiapine doses than with placebo (P < 0.001) as early as Week 1 and throughout the study. The MADRS response and remission rates were also significantly greater in both quetiapine dose groups compared with placebo. Improvements in primary and secondary outcomes were observed with both 300 and 600 mg/d quetiapine without major differences between the doses. Common adverse events included dry mouth, sedation, somnolence, dizziness, and constipation. The incidence of treatment-emergent mania or hypomania was lower with quetiapine treatment than placebo. This study demonstrates that quetiapine monotherapy is an effective and well-tolerated treatment for depressive episodes in bipolar disorder, confirming the results observed from a previous study (BipOLar DEpRession [BOLDER] I).

Treatment of social phobia with gabapentin: A placebo-controlled study

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of social phobia. Sixty-nine patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 900 and 3,600 mg daily in three divided doses) or placebo for 14 weeks. A significant reduction (p < 0.05) in the symptoms of social phobia was observed among patients on gabapentin compared with those on placebo as evaluated by clinician- and patient-rated scales. Results were similar for the intent-to-treat and week-2 completer populations. Adverse events were consistent with the known side effect profile of gabapentin. Dizziness (p = 0.05), dry mouth (p = 0.05), somnolence, nausea, flatulence, and decreased libido occurred at a higher frequency among patients receiving gabapentin than among those receiving placebo. No serious adverse events or deaths were reported. On the basis of these limited data, it seems that gabapentin offers a favorable risk-benefit ratio for the treatment of patients with social phobia. Further studies are required to confirm this effect and to determine whether a dose-response relationship exists.

A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II).

OBJECTIVE The aim of this study was to evaluate the efficacy and tolerability of quetiapine and paroxetine monotherapy for major depression in bipolar disorder. METHOD 740 patients (478 bipolar I, 262 bipolar II) with major depressive episodes (DSM-IV) were randomly assigned to quetiapine 300 mg/d (n = 245), quetiapine 600 mg/d (n = 247), paroxetine 20 mg/d (n = 122), or placebo (n = 126) for 8 weeks. The primary end point was the change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from May 2005 to May 2007. RESULTS Mean MADRS score change from baseline at 8 weeks was -16.19 for quetiapine 300 mg, -16.31 for quetiapine 600 mg, -13.76 for paroxetine, and -12.60 for placebo (P < .001 for both quetiapine doses, P = .313 for paroxetine, vs placebo). Quetiapine-treated (both doses), but not paroxetine-treated, patients showed significantly greater improvements (P < or = .05) in most secondary outcomes measures at week 8 versus the placebo group. Paroxetine significantly improved Hamilton Anxiety Rating Scale scores versus placebo (P < .05) but not MADRS or Hamilton Depression Rating Scale (HDRS) scores. Both quetiapine doses were associated with greater improvements than paroxetine for MADRS and HDRS scores. The most common adverse events were dry mouth, somnolence, sedation, and dizziness with quetiapine (both doses) and dry mouth, sedation, headache, insomnia, and nausea with paroxetine. The incidence of treatment-emergent mania/hypomania was lower with quetiapine compared with paroxetine and placebo. CONCLUSIONS Quetiapine (300 or 600 mg/d), but not paroxetine, was more effective than placebo for treating acute depressive episodes in bipolar I and II disorder. Quetiapine treatment was generally well tolerated. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00119652.

Trauma, resilience and saliostasis: effects of treatment in post-traumatic stress disorder.

There has been growing interest in the concept of resilience and the question as to whether psychotropic medications or psychosocial treatments might have resilience-enhancing effects. This pilot study investigates resilience in a sample of patients with post-traumatic stress disorder (PTSD) before and after treatment. Effects of treatment with tiagabine, fluoxetine, sertraline alone, and sertraline with cognitive behavioural therapy on resilience were assessed using the Connor-Davidson Resilience Scale (CD-RISC). Changes in resilience after treatment were measured and response to treatment was predicted from demographic, resilience and baseline disability measures. Changes in resilience following treatment were statistically significant. Items that showed the greatest change related to confidence, control, coping, knowing where to turn for help and adaptability. Items showing the least change related to religious and existential aspects of resiliency, effort, acting on a hunch, decision-making and goals. In linear and logistic regression models, gender, baseline CD-RISC score, baseline Sheehan Disability Scale score and an individual item from the CD-RISC scale, ‘Sense of Humor’, were significant predictors of response to treatment. Treatment of PTSD significantly improved resilience and reduced symptoms in this sample. Further controlled studies are indicated.

Mirtazapine vs. placebo in posttraumatic stress disorder: a pilot trial

BACKGROUND Based on an earlier pilot study, as well as a theoretical consideration of its mechanism of action, we undertook a placebo-controlled, double-blind trial of mirtazapine in posttraumatic stress disorder. METHODS Twenty-nine patients were randomized to receive drug up to 45 mg/day or placebo double-blind on a 2:1 ratio for 8 weeks, with data being available for analysis in 26. Primary outcome measures comprised the Short Posttraumatic Stress Disorder Rating Interview (SPRINT) Global Improvement item and total score. Secondary measures comprised the Davidson Trauma Scale, Structured Interview for Posttraumatic Stress Disorder and Hospital Anxiety Depression Scale. Adverse events were also measured. RESULTS On the Short Posttraumatic Stress Disorder Rating Interview Global Improvement measure, rates of response were 64.7% and 20.0% for mirtazapine and placebo. Treatment effects in favor of mirtazapine were noted on the Short Posttraumatic Stress Disorder Rating Interview global, Structured Interview for Posttraumatic Stress Disorder, and Hospital Anxiety Depression Scale anxiety subscale scores. The drug was well tolerated. CONCLUSIONS Mirtazapine was more effective than placebo on some measures in posttraumatic stress disorder and general anxiety symptoms.

A National Epidemic of Unintentional Prescription Opioid Overdose Deaths: How Physicians Can Help Control It

Both the usage of prescription drugs such as opioid analgesics and benzodiazepines and overdoses involving them have increased dramatically in the United States since the 1990s. Patients using these drugs often have a combination of painful conditions, substance abuse, and other forms of mental illness. Psychiatrists and many primary care physicians might not be familiar with existing evidence-based guidelines for opioid prescribing or with programs designed to reduce the abuse of prescription drugs such as state prescription drug monitoring programs. Psychiatrists need to be informed regarding this problem to partner effectively with both pain specialists and primary care providers in their community.

Continuation of Quetiapine Versus Switching to Placebo or Lithium for Maintenance Treatment of Bipolar I Disorder (Trial 144: A Randomized Controlled Study)

OBJECTIVE Quetiapine, combined with lithium or divalproex, demonstrates efficacy in the maintenance treatment of bipolar I disorder. This study investigated the efficacy and safety of quetiapine monotherapy as maintenance treatment in bipolar I disorder compared with switching to placebo or lithium. METHOD Patients aged ≥ 18 years with DSM-IV-diagnosed bipolar I disorder and a current or recent manic, depressive, or mixed episode received open-label quetiapine (300-800 mg/d) for 4-24 weeks. Patients achieving stabilization were randomized to continue quetiapine or to switch to placebo or lithium (0.6-1.2 mEq/L) for up to 104 weeks in a double-blind trial. Outcome measures included times to recurrence of any mood event (primary outcome measure), manic event, or depressive event. Safety assessments included adverse events and laboratory values. The study was terminated early after planned interim analysis provided positive results. The study was conducted between March 2005 and July 2007. RESULTS Of 2,438 patients starting open-label quetiapine, 1,226 (50.3%) were randomized to double-blind treatment, including 1,172 (95.6%) in the intent-to-treat population. Time to recurrence of any mood event was significantly longer for quetiapine versus placebo (hazard ratio [HR] = 0.29; 95% CI, 0.23-0.38; P < .0001) and for lithium versus placebo (HR = 0.46; 95% CI, 0.36-0.59; P < .0001). Quetiapine and lithium significantly increased time to recurrence of both manic events (quetiapine: HR = 0.29; 95% CI, 0.21-0.40; P < .0001; lithium: HR = 0.37; 95% CI, 0.27-0.53; P < .0001) and depressive events (quetiapine: HR = 0.30; 95% CI, 0.20-0.44; P < .0001; lithium: HR = 0.59; 95% CI, 0.42-0.84; P < .004) compared with placebo. Overall rates of adverse events were generally similar between treatment groups, and safety findings for quetiapine were consistent with its known profile. CONCLUSIONS In patients stabilized during acute quetiapine treatment, continuation of quetiapine significantly increased time to recurrence of any mood, manic, or depressive event compared with switching to placebo. Switching to lithium was also more effective than placebo for the prevention of manic and depressive events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00314184.

Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study.

INTRODUCTION Once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy was evaluated in major depressive disorder (MDD). METHOD This was an 8-week (6-week randomized-phase; 2-week drug-discontinuation/tapering phase), double-blind, parallel-group, placebo-controlled study. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) total score randomization-to-Week 6 change. Other assessments included the Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety, and adverse events (AEs). RESULTS 723 patients were randomized: 182, 178, 179, and 184 to quetiapine XR 50, 150, 300 mg/day, and placebo, respectively. At Week 6, significant reductions occurred in MADRS score with quetiapine XR 50 mg/day (-13.56; P<.05), 150 mg/day (-14.50; P<.01) and 300 mg/day (-14.18; P<.01) versus placebo (-11.07); at Day 4, reductions for quetiapine XR (titrated to 50 or 150 mg/day according to dose group) versus placebo (-2.9) were: -4.7 (P<.01), -5.2 (P<.001), and -5.1 (P<.001), respectively. At endpoint, MADRS response (>or=50% reduction in score) was 42.7% (P<.01), 51.2% (P<.001), and 44.9% (P<or= .001) for quetiapine XR 50, 150, and 300 mg/day, respectively; 30.3% for placebo. Overall, quetiapine XR 150 mg/day provided consistently more positive secondary efficacy results than 50 mg/day and 300 mg/day versus placebo. The most common AEs in quetiapine XR-treated patients were dry mouth, sedation, somnolence, headache, and dizziness. CONCLUSION In patients with MDD, quetiapine XR monotherapy (50/150/300 mg/day) is effective in reducing depressive symptoms, with improvement from Day 4 onwards. Safety and tolerability were consistent with the known profile of quetiapine.

MRI correlates of Suicide attempt history in unipolar depression

BACKGROUND Suicide represents a major health problem in the United States, and prediction of suicide attempts is difficult. No structural neuroimaging studies have been done to specifically examine findings in patients who have attempted suicide. The objective of this study was to compare MRI findings in unipolar patients with and without a history of a suicide attempt. METHODS In this post hoc analysis, 20 unipolar subjects with a history of a suicide attempt were matched by age and gender to unipolar subjects without a history of an attempt. Subjects were also matched on parameters such as cardiovascular history, electroconvulsive treatment history, and history of psychosis. Subjects with a history of any neurologic condition were excluded. There were no significant differences in age of onset of depression, number of episodes of depression, and Hamilton Depression scores between the two groups. T2-weighted magnetic resonance imaging (MRI) scans were rated using the Coffey and Boyko rating scales. RESULTS Unipolar patients with a history of a suicide attempt demonstrated significantly more subcortical gray matter hyperintensities compared with patients without such a history. CONCLUSIONS Patients with abnormal MRI findings may be at higher risk for mood disorders and suicide attempts because of disruption of critical neuroanatomic pathways. Gray matter hyperintensities in the basal ganglia may be especially associated with risk for suicide attempts.

Comparison of Bupropion and Trazodone for the Treatment of Major Depression

Bupropion and trazodone were compared in a two-center, double-blind clinical trial of outpatients with moderate to severe major depression. After a 1-week placebo lead-in, 124 patients were randomly assigned to receive either bupropion (N = 63) or trazodone (N = 61) for 6 weeks; data from 111 patients were used in the efficacy analysis. Dosing ranged from 225 to 450 mg/day for bupropion and 150 to 400 mg/day for trazodone. The overall efficacy for each of the two drugs was similar; although improvement in the trazodone treatment group was significantly greater on day 7 because of the effects on sleep. At the end of treatment, 58% of the bupropion-treated patients and 46% of the trazodone-treated patients were considered much or very much improved. Weight measurements at the time of discontinuation indicated a 2.5-lb mean weight loss for the bupropion treatment group and a 1.2-lb mean weight gain for the trazodone treatment group. The adverse experience profiles for bupropion and trazodone were consistent with their known pharmacologic profiles (i.e., activating versus sedating). Anorexia and anxiety were reported significantly more often for the bupropion treatment group, whereas somnolence, appetite increase, and edema were reported significantly more often for the trazodone treatment group.