Global Impressions-Severity Of Illness Score Research Articles

Effects of Long-acting Injectable 3-Monthly Paliperidone Palmitate on the Clinical and Social Performance of Patients with Schizophrenia

To investigate the effects of long-acting injectable 3-monthly paliperidone palmitate on the clinical and social functioning of patients with schizophrenia. This study enrolled patients with schizophrenia receiving long-acting injectable 1-monthly paliperidone palmitate for at least 4 months and who subsequently received 3-monthly paliperidone palmitate. Accordingly, 418 patients were followed up for 24 weeks. Their clinical symptoms and social functioning were measured using the Clinical Global Impression-Severity of Illness and Personal and Social Performance scales. The Personal and Social Performance total score was significantly higher after 3-monthly paliperidone palmitate treatment than at baseline (baseline vs. week 24: 54.3 ± 18.0 vs. 61.0 ± 14.5 [mean ± standard deviation]; p < 0.001; Wilcoxon signed-rank test); the proportion of patients in the mildly ill group (scores 71-100) also increased significantly (baseline vs. week 24: 16.5% vs. 20.6%; p < 0.001; McNemar-Bowker test). The mean Clinical Global Impression-Severity of Illness score decreased significantly (baseline vs. week 24: 3.7 ± 1.0 vs. 3.4 ± 0.9; p < 0.001; Wilcoxon signed-rank test), as did the proportion of patients in the severely ill group (baseline vs. week 24: 4.1% vs. 2.1%; p < 0.001; McNemar-Bowker test). Continuous 3-monthly paliperidone palmitate treatment significantly enhances the personal and social performance of patients with schizophrenia and reduces the proportion of those with severe illness. These findings suggest that long-acting injectable antipsychotic administration at intervals longer than 1 month might improve the social functioning of and promote return to activities of daily living in patients with schizophrenia.

Comparison of pramipexole versus ropinirole in the treatment of Parkinson's disease.

Parkinson's disease is a progressive neurodegenerative disease characterized by motor and non-motor symptoms. Levodopa is the most effective drug in the symptomatic treatment of the disease. Dopamine receptor agonists provide sustained dopamin-ergic stimulation and have been found to delay the initiation of levodopa treatment and reduce the frequency of various motor complications due to the long-term use of levodopa. The primary aim of this study was to compare the efficacy of potent nonergoline dopamine agonists pramipexole and ropinirole in both "dopamine agonist monotherapy group" and "levodopa add-on therapy group" in Parkinson's disease. The secondary aims were to evaluate the effects of these agents on depression and the safety of pramipexole and ropinirole. A total of 44 patients aged between 36 and 80 years who were presented to the neurology clinic at Ministry of Health Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey and were diagnosed with idiopathic Parkinson's disease, were included into this randomized parallel-group clinical study. Dopamine agonist monotherapy and levodopa add-on therapy patients were randomized into two groups to receive either pramipexole or ropinirole. The maximum daily dosages of pramipexole and ropinirole were 4.5 mg and 24 mg respectively. Patients were followed for 6 months and changes on Unified Parkinson's Disease Rating Scale, Clinical Global Impression-severity of illness, Clinical Global Impression-improvement, Beck Depression Inven-tory scores, and additionally in advanced stages, changes in levodopa dosages were evaluated. Drug associated side effects were noted and compared. In dopamine agonist monotherapy group all of the subsections and total scores of Unified Parkinson's Disease Rating Scale and Clinical Global Impression-severity of illness of the pramipexole subgroup showed significant improvement particularly at the end of the sixth month. In the pramipexole subgroup of levodopa add-on therapy group, there were significant improvements on Clinical Global Impression-severity of illness and Beck Depression Inventory scores, but we found significant improvement on Clinical Global Impression-severity of illness score at the end of the sixth month in ropinirole subgroup too. The efficacy of pramipexole and ropinirole as antiparkinsonian drugs for monotherapy and levodopa add-on therapy in Parkinson's disease and their effects on motor complications when used with levodopa treatment for add-on therapy have been demonstrated in several previous studies. This study supports the effectiveness and safety of pramipexole and ropinirole in the monotherapy and levodopa add-on therapy in the treatment of Parkinson's disease.

Vilazodone May Be Safer Option to Treat Adult MDD

Back to table of contents Previous article Next article PsychopharmacologyFull AccessVilazodone May Be Safer Option to Treat Adult MDDJoAnn BlakeJoAnn BlakeSearch for more papers by this authorPublished Online:26 Dec 2017https://doi.org/10.1176/appi.pn.2018.pp11b2AbstractThe FDA requires clinical trials of new psychotropic drugs include a prospective assessment of suicidal ideation and behavior.Vilazodone appears to pose little or no risk of treatment-emergent suicidal ideation or behavior in adults with major depressive disorder (MDD) or generalized anxiety disorder (GAD), according to a study in the journal International Clinical Psychopharmacology.Treatment-emergent suicidal ideation and behavior remain ongoing concerns with antidepressants, says Michael Thase, M.D.Data pooled from four double-blind, placebo-controlled vilazodone trials for MDD (including 2,233 patients) and three for GAD (including 1,475 patients) revealed that suicide-related adverse events occurred in less than 1 percent of patients treated with vilazodone and placebo. Vilazodone, which is approved for the treatment of MDD in adults, has also been evaluated as a possible treatment for adults with GAD. “We found this result reassuring, and it might steer us to picking this drug more often,” said lead author Michael Thase, M.D., a professor of psychiatry at Perelman School of Medicine at the University of Pennsylvania. For other types of antidepressants, the risk of suicide ideation may be as high as 4 percent compared with 2 percent for placebo, he said. The Food and Drug Administration (FDA) requires clinical trials of new psychotropic drugs to include a prospective assessment of suicidal ideation and behavior. “The FDA’s duty is to warn when there is evidence of some risk of initiating treatment,” Thase said. “In the previous decade, comprehensive reviews suggested a small, but real increase—not due to chance—in suicidal thoughts compared with placebo.” For the vilazodone meta-analysis, Thase and colleagues evaluated treatment-emergent suicidal ideation using adverse event reporting and Columbia Suicide Severity Rating Scale (C-SSRS) monitoring. They analyzed treatment-emergent suicide by C-SSRS category shift from no suicidal ideation (C-SSRS=0) at baseline to suicidal ideation (C-SSRS=1-5). Studies in the meta-analysis included MDD patients with 17-item Hamilton Depression Rating Scale (HAMD17) total score ≥22 and item 1 (depressed mood) score ≥2 or HAMD17 total score ≥18; and Montgomery-Åsberg Depression Rating Scale total score ≥26. Key eligibility criteria for GAD studies included patients with Hamilton Anxiety Rating Scale total score ≥20, item 1 (anxious mood) score ≥2, and item 2 (tension) score ≥2; Clinical Global Impressions-Severity of Illness score ≥4; and HAMD17 total score ≤17.Incidences of suicidal ideation/behavior were as follows: MDD (vilazodone=19.9 percent, placebo=24.7 percent); GAD (vilazodone=7.7 percent, placebo=9.4 percent). Shifts from no suicidal ideation/behavior at baseline to suicidal ideation during treatment are as follows: MDD (vilazodone=9.4 percent, placebo=10.3 percent); GAD (vilazodone=4.4 percent, placebo=6.1 percent). The difference between any suicidal ideation during vilazodone treatment and any suicidal ideation during placebo treatment is statistically significant, Thase said. Among patients who entered these studies with no recent suicidal ideation or behavior at baseline, more than 85 percent continued to have no suicidality during treatment. “I think the Thase data showing a favorable profile with respect to treatment-emergent suicidal features in the manufacturer’s pooled trials are compelling, credible, and useful,” said Joseph Goldberg, M.D., a clinical professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York. Goldberg said he has prescribed the medication extensively with success for patients with major depression and depression with prominent anxiety. Vilazodone, a serotonin partial agonist-reuptake inhibitor (SPARI), was introduced in the United States in 2011. SPARI medications have the potential for faster onset of action, greater efficacy, and better tolerability, according to a 2014 study.This medication also could have benefits for subgroups of people with depression, including those with anxiety disorders, and might have fewer sexual side effects than selective serotonin reuptake inhibitors (SSRIs), according to a 2015 study on vilazodone.Thase told Psychiatric News that treatment-emergent suicidal ideation and behavior remain ongoing concerns with antidepressants. He cautioned that all patients be monitored for suicidal thoughts and behaviors during antidepressant treatment. The study was funded by Forest Research Institute Inc., an Allergan affiliate, makers of vilazodone (Viibryd). Thase reported a potential conflict of interest in his role as an advisor or consultant for Allergan and Forest Laboratories. The other authors on the study acknowledged a potential conflict of interest as full-time employees of Allergan or Forest Research Institute at time of study. ■Back to Psychopharmacology Newsletter Table of Contents ISSUES NewArchived

Repetitive Transcranial Magnetic Stimulation Over Presupplementary Motor Area May Not Be Helpful in Treatment-Refractory Obsessive-Compulsive Disorder: A Case Series.

A significant proportion of patients with obsessive-compulsive disorder (OCD) fail to improve with standard medication and cognitive behavior therapy. Repetitive transcranial magnetic stimulation (rTMS) has been investigated for its role in treating OCD. Low-frequency rTMS over the presupplementary motor area (pre-SMA) has shown mixed results. Moreover, it has not been studied in highly treatment refractory OCD. We analyzed the outcome of low-frequency rTMS over pre-SMA in OCD patients refractory to multiple serotonin reuptake inhibitors (SRIs), augmenting agents, and cognitive behavior therapy. Low-frequency (1-Hz stimulus at 100% motor threshold) rTMS was delivered over the pre-SMA using a previously described protocol. At least 25% reduction Yale-Brown Obsessive Compulsive Scale scores and 2-point reduction in Clinical Global Impression-Severity of Illness scores were used to assess treatment response. Seventeen patients were initiated on rTMS. Three of them dropped out within 9 sittings. Only 1 patient met the criteria for response after 1 month of treatment initiation. No major adverse effects were observed in any of them. The study is a retrospective analysis of outcomes when rTMS was administered as part of routine clinical care. Assessments of the patients were done by trained but different raters, and interrater reliability was not measured. Low-frequency rTMS over the pre-SMA may not be effective in treatment refractory OCD. Further studies, taking note of the possible reasons for ineffectiveness discussed in the study, may help elucidate the role of rTMS in OCD.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Aripiprazole in Children and Adolescents With Tourette’s Disorder

To examine the short-term efficacy and tolerability of aripiprazole for children and adolescents with Tourette's disorder. This 10-week multicenter, double-blind, randomized, placebo-controlled trial was conducted from August 2008 to April 2010. Children and adolescents (aged 6-18 years) with a DSM-IV diagnosis of Tourette's disorder and a Yale Global Tic Severity Scale total tic score of 22 or more were randomly assigned (1:1 ratio) to placebo or aripiprazole. The primary outcome measure was mean change from baseline in the total tic score on the Yale Global Tic Severity Scale (last observation carried forward). Assessments of safety and tolerability included spontaneously reported adverse events, extrapyramidal symptoms, serum prolactin level, metabolic variables, and other laboratory evaluations. Of 61 subjects, 89% completed the study. Patients who received aripiprazole demonstrated a significant reduction from baseline to end of study on the mean (SD) total tic score of the Yale Global Tic Severity Scale compared to those who received placebo (-15.0 [8.4] and -9.6 [8.8], respectively, P=.0196). Response rate on the Tourette's Syndrome Clinical Global Impression-Improvement was 66% and 45% in the aripiprazole and placebo groups, respectively. Mean decrease in the Tourette's Syndrome Clinical Global Impression-Severity of Illness score was significantly different between the groups (P=.0321). In general, aripiprazole was well tolerated and there were no early discontinuations due to adverse events. The incidence of treatment-emergent adverse events between the groups was not significantly different (P=.7550). While aripiprazole decreased serum prolactin concentration (P<.0001), it increased mean body weight, body mass index, and waist circumference significantly (P=.0055, P=.0142, and P=.0270, respectively). In comparison with placebo, aripiprazole was efficacious, generally tolerated and safe in the short-term treatment of children and adolescents with Tourette's disorder. ClinicalTrials.gov identifier:NCT00706589.

Prevention of Relapse With Maintenance Electroconvulsive Therapy in Elderly Patients With Major Depressive Episode

To evaluate the effectiveness and safety of maintenance electroconvulsive therapy (mECT) in elderly patients with treatment-resistant Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition major depressive episode. Seven elderly patients with treatment-resistant major depressive episode were treated with a complete ECT cycle. Thereafter, they received one monthly ECT session as maintenance for 1 year. Response to treatment was defined as at least a 50% drop from baseline on the Hamilton Depression Rating Scale (HamD) and remission as not meeting criteria for major depression, a HamD score of 7 or less, and Clinical Global Impressions-Severity of Illness score of 1. We compared their response with the response of 7 elderly patients with treatment-resistant major depression who were treated with a full cycle of ECT but did not receive mECT (non-mECT). We compared the 2 groups for the number of relapses or recurrences of major depressive episodes after remission was achieved; a relapse or a recurrence occurred when HamD scores were 14 or higher, or when Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision major depressive episode criteria were met, or when Clinical Global Impressions-Severity of Illness score was 3 or higher and increased by at least 2 points from response/remission. The mECT group (4 women and 3 men; mean age, 73 years) had significantly less mean relapses/recurrences (0 vs 1.57) and hospitalizations (0 vs 1) and received less drug treatment than the nonMECT group (similar for age and sex composition) during the 12-month follow-up period. All patients with mECT improved during treatment and did not relapse. Maintenance ECT protected elderly patients from recurrent depressive episodes from relapsing/recurring more than standard ECT.

The Vasopressin V1bReceptor Antagonist SSR149415 in the Treatment of Major Depressive and Generalized Anxiety Disorders

These studies were designed to evaluate the efficacy and tolerability of the first nonpeptide vasopressin V(1b) receptor antagonist, SSR149415, in the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Studies were randomized 8-week, double-blind, placebo-controlled trials evaluating 100- and 250-mg twice daily doses of SSR149415, placebo, and escitalopram 10 mg/day or paroxetine 20 mg/day, conducted from August 2006 through February 2008. Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for MDD or GAD. Baseline Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) total scores were ≥ 24 and 18, respectively, and in the GAD trial baseline Hamilton Anxiety Rating Scale (HARS) score was ≥ 22. Primary efficacy variables included changes from baseline in total score on HDRS or HARS and MADRS, and the secondary variable included changes in the Clinical Global Impressions-Severity of Illness score (CGI-S). A 4-week, double-blind, placebo-controlled study evaluating the effect of 100- and 250-mg twice daily doses of SSR149415 on the hypothalamic-pituitary-adrenal (HPA) axis in MDD patients was also conducted. In the GAD trial, SSR149415 did not separate from placebo on the primary (HARS-100 mg: P = .29; 250 mg: P = .21) and secondary (CGI-S-100 mg: P = .18; 250 mg: P = .24) outcome measures, while paroxetine demonstrated efficacy (HARS: P = .003; CGI-S: P = .01). In 2 MDD trials, SSR149415-treated patients did not show significant improvement from baseline on any outcome measure compared with placebo-treated patients (HDRS-100 mg: P = .21 and .48, respectively; 250 mg: P = .22 and P = .46, respectively; CGI-S-100 mg: P = .64 and P = .82, respectively; 250 mg: P = .33 and P = .08, respectively). In the third MDD study, SSR149415 250 mg (P = .04), but not escitalopram (P = .15), demonstrated significant improvement compared to placebo on the HDRS total score at week 8. SSR149415 had no deleterious effects on the HPA axis. These studies demonstrate that SSR149415 may not be useful for the treatment of GAD and that its antidepressant potential needs to be further evaluated. ClinicalTrials.gov identifiers: NCT00374166 (Sanofi ID number: DFI5880), NCT00361491 (Sanofi ID number: DFI5879), NCT00358631 (Sanofi ID number: DFI5878), NCT01606384 (Sanofi ID number: PDY5467).

Early Response and Remission as Predictors of a Good Outcome of a Major Depressive Episode at 12-Month Follow-Up

The goal of treating major depressive disorder (MDD) should be not only achieving remission in a particular episode but also avoiding relapses and attaining long-term recovery. The current study was designed to evaluate whether response and remission achieved within the first 6 weeks of antidepressant treatment are associated with a 12-month good outcome (achieving remission by 6 months and remaining in remission until the end of follow-up). This prospective, longitudinal, multicenter study included adult outpatients who had a DSM-IV diagnosis of MDD, baseline scores ≥ 15 on the 17-item Hamilton Depression Rating Scale (HDRS(17)), Clinical Global Impressions-Severity of Illness scores ≥ 4, and a minimum remission period of 12 weeks between the index episode and the immediately prior episode (or who were in their first MDD episode). The primary efficacy measure was early response (a 50% decrease from baseline in HDRS(17) score by week 6). The secondary efficacy measure was early remission (HDRS(17) score ≤ 7 by week 6). Among the total of 930 patients included from December 2006 to June 2007, 38.2% showed early response, and 20.5% showed early remission. Of the early responders, 76.1% had a 12-month good outcome as compared to 81.1% of early remitters. Logistic regression showed that factors associated with a good outcome included early response (odds ratio [OR] = 4.14), being employed, and the absence of physical comorbidities. Early remission was also strongly associated with a good outcome (OR = 4.72). Either response or remission achieved by week 6 is the strongest prognostic factor for the 12-month good outcome of an episode of MDD.

A Randomized, Double-Blind Study of Once-Daily Extended Release Quetiapine Fumarate (Quetiapine XR) Monotherapy in Patients With Generalized Anxiety Disorder

This study evaluated once-daily, extended-release quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder (GAD). This was a 10-week (8-week active treatment/2-week posttreatment drug-discontinuation/tapering phase), double-blind, randomized, placebo-controlled study (D1448C00009). Primary end point was change from randomization at week 8 in Hamilton Anxiety Rating Scale (HAM-A) total score. Overall, 951 patients with GAD were randomized (quetiapine XR: 50 mg/d, n = 234; 150 mg/d, n = 241; 300 mg/d, n = 241; placebo, n = 235). At week 8, HAM-A total scores significantly (P < 0.001) improved versus placebo (-11.10) with quetiapine XR 50 mg/d (-13.31) and 150 mg/d (-13.54), but not 300 mg/d (-11.87; P = 0.240). At week 1, HAM-A total scores significantly improved versus placebo (-5.94) with quetiapine XR 50 mg/d (-7.47; P < 0.01), 150 mg/d (-8.19; P < 0.001), and 300 mg/d (-7.23; P < 0.01). Versus placebo at week 8, quetiapine XR 50 and 150 mg/d significantly improved HAM-A psychic (P < 0.01 and P < 0.001, respectively) and somatic (P < 0.001; P < 0.01, respectively) cluster scores, HAM-A response (≥ 50% total score reduction; P < 0.05), and Clinical Global Impression-Improvement categorical changes (P < 0.05). For quetiapine XR 150 mg/d, significant (P < 0.05) improvements were seen for HAM-A remission (total score, ≤ 7) and Clinical Global Impression-Severity of Illness scores. For quetiapine XR 300 mg/d, improvements in these secondary variables were not significantly different versus placebo. Pittsburgh Sleep Quality Index global scores improved with all 3 doses (quetiapine: XR 50 mg/d, -4.07 [P < 0.05]; 150 mg/d, -4.38 [P < 0.05]; 300 mg/d, -3.97 [P < 0.05], versus -3.31 with placebo). Adverse events (>10% with quetiapine XR) were dry mouth, somnolence, sedation, dizziness, headache, and fatigue. Quetiapine XR (50/150 mg/d) monotherapy was effective at week 8 in patients with GAD; symptom improvement was seen at week 1 for all doses (50/150/300 mg/d). Safety and tolerability were consistent with the known profile of quetiapine.

Efficacy of Bupropion XR in Treatment-Resistant Elderly Patients

Many of the patients with depression fail to achieve an adequate response to a given antidepressant. Depression is often overlooked in elderly persons, which may produce a greater risk of suicide in this age group. The antidepressive characteristic of bupropion has been already validated in several studies. However, to the best of our knowledge, there is no research concerning treatment-resistant depressive elderly patients with bupropion. We present a consecutive series of elderly patients (13 subjects: 6 men and 7 women) with major depression. All patients were older than 60 years, with diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and were treatment resistant. Patients were treated openly for 6 weeks with bupropion XR (300 mg/d). Efficacy was assessed at baseline and every 3 weeks using the Hamilton Depression Rating Scale, the Montgomery-Asberg Depressive Rating Scale, and the Clinical Global Impression--Severity of Illness Scale. The treatment was generally well tolerated without serious events. In all patients, the average Hamilton Depression Rating Scale scores diminished from 41.1 to 17.2 at the sixth week (P < 0.0001), the Montgomery-Asberg Depressive Rating Scale scores diminished from 44.0 to 19.9 (P < 0.0001), and Clinical Global Impression-Severity of Illness scores diminished from 5.7 to 3.2 (P < 0.0001). Of the 13 patients, 9 patients had marked and very marked improvement, and 4 patients did not demonstrate any mental state change. Treatment-resistant depressive elderly patients positively responded to and tolerated bupropion XR well. This case series demonstrates that bupropion could be a promising alternative therapy for elderly patients with treatment-resistant major depressive disorder. Further randomized controlled studies are necessary.

Long-term safety and tolerability of open-label aripiprazole augmentation of antidepressant therapy in major depressive disorder.

Background:Effective management of major depressive disorder often includes the long-term use of multiple medications, and the longer-term utility and safety of adjunctive aripiprazole has not been evaluated in a controlled setting.Patients and methods:Patients (n = 706) completing one of two 14-week double-blind studies of aripiprazole augmentation, as well as de novo patients (n = 296) nonresponsive to current antidepressant therapy, were enrolled in this open-label study. Patients received open-label aripiprazole for up to 52 weeks.Results:Open-label treatment was completed by 323 patients (32.2%). At endpoint (n = 987), the mean dose of aripiprazole was 10.1 mg/day. Common (>15% of patients) spontaneously reported adverse events were akathisia (26.2%), fatigue (18.0%), and weight gain (17.1%). The incidence of serious adverse events was 4.0%. Four spontaneous reports of possible tardive dyskinesia were submitted (0.4%); all resolved within 45 days of drug discontinuation. Mean weight change was 4.4 kg; 36.6% experienced ≥7% increase in weight from baseline (observed case analysis, n = 303). No clinically relevant changes in other metabolic parameters were seen. At the end of open-label treatment, 221 patients (69.7%) had a Clinical Global Impression-Severity of Illness score of 1 (not at all ill) or 2 (borderline ill).Conclusion:Long-term adjunctive aripiprazole therapy was well tolerated with an acceptable long-term safety and tolerability profile in patients with major depressive disorder who had not responded to treatment with one or more antidepressant therapies. Clinically significant weight gain was observed in about one-third of patients. Overall, the adverse event profile was consistent with that reported in the short-term trials and readily managed clinically.

A Double‐Blind, Placebo‐Controlled Study With Quetiapine as Adjunct Therapy With Lithium or Divalproex in Bipolar I Patients With Coexisting Alcohol Dependence

This study evaluated the efficacy of quetiapine versus placebo as an adjunct to lithium or divalproex in reducing alcohol consumption in patients with bipolar I disorder and coexisting alcohol dependence. Male and female outpatients (21 to 60 years) with a history of bipolar I disorder and alcohol dependence were included in this 12-week, placebo-controlled study. Patients treated with lithium or divalproex (ongoing or assigned at screening) were randomized to receive quetiapine (dosed up to 400 mg/d over 7 days, followed by 300 to 800 mg/d flexible dosing until study end) or placebo. The primary outcome measure was the change in the proportion of heavy drinking days from baseline to Week 12 (as derived from the Timeline Followback method). Secondary outcome measures included time to the first consecutive 2 weeks of abstinence, changes from baseline to Week 12 in the proportion of nondrinking days, mean number of standardized drinks per day, and Clinical Global Impressions-Severity of Illness score. Of 362 enrolled patients (mean 38.6 years), 176 were randomized to receive quetiapine and 186 to placebo. The mean proportion of heavy drinking days at baseline was 0.66 in the quetiapine group and 0.67 in the placebo group. At Week 12, the mean change in the proportion of heavy drinking days was -0.36 with quetiapine and -0.36 with placebo (p = 0.93). No statistically significant differences in any of the secondary outcome measures were noted between the quetiapine and placebo groups. The incidence of adverse events was consistent with the previously known tolerability profile of quetiapine. The efficacy of quetiapine in the treatment of bipolar disorder is already well established. In this study, however, quetiapine added to lithium or divalproex did not result in significantly greater improvement compared with placebo in measures of alcohol use and dependence in patients with bipolar I disorder and alcohol dependence.

Relapse Prevention and Residual Symptoms

Analyses of data from 4 relapse-prevention studies with escitalopram were conducted in order to compare patients with and without residual symptoms with regard to relapse rates and global illness during double-blind, 24-week continuation periods. Clinical Global Impressions-Severity of Illness scores and relapse status in 4 studies published from 2005 to 2007, 1 each in major depressive disorder (MDD), generalized anxiety disorder, social anxiety disorder, and obsessive-compulsive disorder (OCD), were analyzed using mixed-effects model repeated measures as a function of Montgomery-Asberg Depression Rating Scale (MADRS) scores on items 1, 3, and 7 at randomization. All studies showed a statistically significant (P < .0001) standardized effect size of about 0.7 for escitalopram versus placebo, with a number needed to treat approximately 4. Patients with residual symptoms (MADRS score > 0) and without residual symptoms (MADRS score = 0) at the start of continuation treatment were defined by how patients scored on 3 core items of the MADRS: depressed mood (observed), inner or psychic tension, and lassitude. At randomization, patients with a residual symptom were globally more ill than patients without such a symptom. Patients who did not continue active treatment worsened, even if they were initially free of a residual symptom. In contrast, patients who continued receiving escitalopram remained stable or further improved, regardless of residual symptoms or diagnosis. No clear picture emerged regarding whether patients with residual symptoms had a higher relapse rate. The presence of residual symptoms is associated with significantly worse overall illness severity in all 4 diagnostic groups and with a higher (although not significantly) risk of relapse for patients with MDD or OCD. The greatest difference in all of the studies was between patients treated with escitalopram (relapse rates ~ 20%) and placebo (relapse rates of about 50%).

Switching to Duloxetine From Selective Serotonin Reuptake Inhibitor Antidepressants

To compare 2 methods of switching selective serotonin reuptake inhibitor (SSRI) non-responders or partial responders to duloxetine. Adult outpatients with DSM-IV major depressive disorder, a Hamilton Rating Scale for Depression (HAM-D(17)) total score of >or= 15, and a Clinical Global Impressions-Severity of Illness score of >or= 3 despite at least 6 weeks of SSRI treatment were randomly assigned to either abrupt discontinuation of SSRI immediately followed by initiation of duloxetine (direct switch [DS]; N = 183) or tapered discontinuation of SSRI over 2 weeks and simultaneous administration of duloxetine (start-taper switch [STS]; N = 185). Efficacy, safety, and tolerability outcomes associated with these 2 switch methods were compared following switch and after 10 weeks of duloxetine treatment. The study was conducted from August 2004 to March 2006. There was a significant improvement in depressive symptom severity in both switch groups as measured by mean change in HAM-D(17) total score (p <or= .001), but no difference between the switch groups (-10.23 DS vs. -10.49 STS). Criteria for noninferiority of the DS group to the STS group, which was the primary objective of the study, were met. Response rates (54.4% DS vs. 59.6% STS), remission rates (35.7% DS vs. 37.2% STS), and other secondary outcome measures were similar for both switch groups. Few patients discontinued the study due to adverse events (6.6% DS vs. 3.8% STS). Headache, dry mouth, and nausea were the most frequently reported adverse events in both switch groups. Switch to duloxetine was associated with significant improvements in both emotional and painful physical symptoms of depression and was well tolerated and safe, regardless of which of the switch methods was used. clinicaltrials.gov Identifier: NCT00191932.

D2 Receptor Occupancy of Olanzapine Pamoate Depot Using Positron Emission Tomography: An Open-label Study in Patients with Schizophrenia

A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D(2) receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months. No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores, although seven patients received oral olanzapine supplementation during the first four injection cycles. To minimize impact on D(2) occupancy, positron emission tomography (PET) scans were not completed during injection cycles that required supplemental oral olanzapine. Two patients reported transient injection site adverse events, which did not result in discontinuation. The most frequently reported treatment-emergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D(2) receptor occupancy, as measured by [(11)C]-raclopride PET, was 69% on oral olanzapine (5-20 mg/day) and 50% (trough) on OP depot at steady state. Following an initial decline, occupancy returned to 84% of baseline oral olanzapine occupancy after six injections. Over the study period, D(2) receptor occupancy and plasma olanzapine concentrations were significantly correlated (r=0.76, P</=0.001). OP depot resulted in mean D(2) receptor occupancy of approximately 60% or higher at the end of the 6-month study period, a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles.

Placebo-controlled trial of agomelatine in the treatment of major depressive disorder

The efficacy and safety of flexible dosing with the antidepressant agomelatine (25–50 mg/day) was evaluated in a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients who met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria for major depressive disorder—current major depressive episode. Patients receiving agomelatine (25 mg and 50 mg/day) had a significantly lower mean Hamilton Rating Scale for Depression (HAM-D) score at endpoint compared with those who received placebo (14.1±7.7 vs. 16.5±7.4, p=0.026). Agomelatine significantly improved the response rate (49.1%; p=0.03), time to first response (p=0.032), and Clinical Global Impression-Severity of Illness score (p=0.017), compared with placebo. These results were confirmed in a subgroup of patients with greater symptom severity. Agomelatine 50 mg also appeared to be effective and well tolerated in patients who failed to show improvement after 2 weeks on a dose of 25 mg/day. These results support the prescription of agomelatine 25 mg as the usual therapeutic dose, and suggest that increasing the dose to 50 mg may be beneficial for some patients without reducing tolerability.