Placebo-controlled Relapse Prevention Studies Research Articles

Relationship between the timing of relapse and plasma drug levels following discontinuation of cariprazine treatment in patients with schizophrenia: indirect comparison with other second-generation antipsychotics after treatment discontinuation.

ObjectiveTo explore the timing of relapse following drug discontinuation and its relationship to estimated plasma levels and elimination half-life by comparing data from a randomized, placebo-controlled discontinuation study of cariprazine with those from similarly designed and conducted randomized control trials of other oral atypical antipsychotics (AAPs).MethodsData from a long-term, randomized, double-blind, placebo-controlled relapse prevention study in participants with schizophrenia (NCT01412060) were analyzed. Similarly designed, published studies of other AAPs were used for comparison. Time to drug-placebo relapse separation and relapse rates were estimated from Kaplan–Meier curves and evaluated descriptively. Separation was defined as a sustained difference of ≥5% incidence of relapse between the AAP and placebo curves.ResultsThe Kaplan–Meier curve for cariprazine showed a time to drug-placebo relapse separation at 6–7 weeks after randomization, compared to the Kaplan–Meier curves for the other AAPs, which showed earlier separation at 1–4 weeks. The placebo relapse rates at 4 weeks after randomization were 5% for cariprazine and 8–34% for other AAPs. Geometric mean values of model-predicted plasma concentrations for total active cariprazine moieties (sum of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine) were 20.0 and 6.1 nM at 2 and 4 weeks after discontinuation, respectively. Elimination half-lives of other AAPs and their active metabolites (<4 days) suggest that plasma concentrations would be low or negligible at 2–4 weeks after last dose.ConclusionDiscontinuation of cariprazine treatment appeared to be associated with a delayed incidence of relapse compared with other AAPs, which may be due to the longer half-life of cariprazine and its active metabolites.

Agomelatine for depression: expanding the horizons?

ABSTRACTIntroduction: Agomelatine is an antidepressant with unique pharmacological actions; it is both a melatonin agonist and selective serotonin antagonist. Both actions combined are necessary for antidepressant efficacy. Effects on melatonin receptors enable resynchronisation of disrupted circadian rhythms with beneficial effects on sleep patterns.Areas covered: The issue of use of an antidepressant for depression co-morbid with somatic disorders is covered by the authors. A review of the literature from 2000 to August 2018 was undertaken using Scopus and Web of Science with the key words: agomelatine, depression, medical illness. Depression in Parkinson’s disease, cardiovascular illness and type II diabetes is reviewed with evidence of efficacy. Bipolar depression and seasonal affective disorder may also react favourably. Agomelatine may have specific efficacy on symptoms of anhedonia.Expert opinion: Despite approval in some major jurisdictions, the drug has failed to gain registration in the United States. A defining issue may be questions about longer term efficacy: unequivocal effectiveness in placebo-controlled relapse prevention studies has not always been demonstrated. Continuation studies suggest maintenance of clinical responsiveness. A major disadvantage of the drug is its’ potential hepatotoxicity and the need for repeated clinical laboratory tests.

T45. A COMPARISON OF SCHIZOPHRENIA RELAPSE RATES OF 3 PALIPERIDONE FORMULATIONS, ONCE-DAILY, ONCE-MONTHLY AND ONCE EVERY-3-MONTH: POST-HOC ANALYSIS FROM 3 RANDOMIZED CONTROLLED TRIALS

BackgroundPoor adherence to antipsychotic treatment in patients with schizophrenia can result in recurrent relapses, worsening disease, functional impairment and reduction in treatment responsiveness. Long-acting antipsychotic formulations can maintain therapeutic plasma levels for longer durations, reducing dosing frequency and delaying time to relapse compared to oral formulations. Consequently, relatively lower rates of relapse can be expected in patients on long-acting injectables (LAIs) who have discontinued treatment versus those discontinuing oral medications of the same antipsychotic. However, there is no available evidence to support this association. In this post hoc analysis, the percentage of patients who relapsed and the time to relapse for three different formulations of the same molecule (oral paliperidone extended release [ER]; paliperidone palmitate once monthly [PP1M] LAI, and paliperidone palmitate three monthly [PP3M] LAI) were evaluated in adults with schizophrenia, comparing the active and placebo arms.MethodsData from three similarly designed, randomized, double-blind, placebo-controlled relapse prevention studies in adult patients with schizophrenia (DSM-IV-TR criteria) with similar inclusion/exclusion and relapse criteria were analyzed. Patients stabilized during an open-label stabilization phase with either paliperidone ER, PP1M or PP3M were then randomized to receive either placebo (analogous to non-adherent patients in the real-world) or the same active treatment used during stabilization phase (analogous to adherent patients). The primary outcome in each study was the time to relapse after entering the randomization phase, estimated using Kaplan-Meier method. In this report, the percentage of patients who relapsed as well as time to relapse in the three studies were indirectly compared.ResultsIn total 922 patients were included in this analysis, 473 continued to receive the same active treatment and 449 patients were randomized to receive placebo. The percentage of patients who relapsed was lowest with PP3M as compared with PP1M and paliperidone ER in both the active treatment group (PP3M, 9% < PP1M, 18% < paliperidone ER, 22%) and placebo group (PP3M, 29% < PP1M, 48% < paliperidone ER, 52%) patients. The post discontinuation median time to relapse (95% confidence interval) in placebo group was highest with PP3M, 395 days (274 days to not reached) > PP1M, 172 days (134 to 222 days) > paliperidone ER, 58 days (42 to 114 days) but was not estimable in the paliperidone group.DiscussionTreatment with longer acting formulations of paliperidone are associated with lower percentage of relapse and longer time to relapse in patients with schizophrenia. Lower percentage of patients with relapse observed with LAI therapy (PP1M and PP3M) could presumably be due to ensured therapeutic plasma levels. The lower percentage of relapse observed with PP3M treatment as compared with PP1M and oral paliperidone ER treatment in the placebo group could be advantageous to non-adherent patients, as this mimics the real-world scenario where patients discontinue their antipsychotics suddenly. These findings are of relevance in schizophrenia patients as fewer and delayed relapses over the course of a lifetime of schizophrenia may provide higher protection against grey matter damage and help preserve functioning.

Recent guidelines for evidence-based pharmacological treatment of social anxiety disorder

Pharmacological and psychological treatmentsThe findings of meta-analyses and randomized placebo-controlled treatment studies indicate that a range of approaches are efficacious in acute treatment. Pharmacological and psychological treatments, when delivered singly, have broadly similar efficacy in acute treatment. However, acute treatment with cognitive therapy (group or individual) may be associated with a reduced risk of symptomatic relapse at follow-up. Cognitive behaviour therapy is efficacious in adults and children: cognitive therapy appears superior to exposure therapy, but the evidence for the efficacy of social skills training is less strong. It is unlikely that the combination of pharmacological with psychological treatments is associated with greater overall efficacy than with either treatment, when given alone, as only 1 of 4 studies of the relative efficacy of combination treatment found evidence for superior efficacy.Efficacy and length of acute pharmacological treatmentAntidepressant drugs with proven efficacy include most SSRIs, the SNRI venlafaxine, the MAOI phenelzine and the RIMA moclobemide: the potential efficacy of tricyclic antidepressants is unknown. Some benzodiazepines and anticonvulsants and the antipsychotic olanzapine also appear efficacious in acute treatment. A number of small single-dose placebo-controlled crossover studies together suggest that beta-blockers can be beneficial in reducing anxiety symptoms in individuals with ‘performance anxiety’ (for example, when speaking in public), which overlaps with mild non-generalized social anxiety disorder. Acute treatment studies indicate that the proportion of responding patients increases steadily over time. A post-hoc analysis of the clinical trial database with paroxetine indicates that many non-responders to treatment at 8 weeks become responders with a further 4 weeks of double-blind treatment: however a post-hoc analysis of the clinical trial database for escitalopram indicates that response is unlikely if there is no onset of clinical effect within the first 4 weeks of treatment.Longer-term treatment and further treatment after non-responseThe findings of randomized placebo-controlled relapse prevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (clonazepam, escitalopram, paroxetine, pregabalin, sertraline) for up to six months. Fixed-dose randomized controlled trials do not provide consistent evidence of a dose-response relationship with antidepressant drugs: but a fixed-dose study of pregabalin found that only the higher daily dosage was efficacious. A double-blind randomized controlled dosage escalation trial found no advantage for increasing to a higher daily dosage (of duloxetine), when compared to continuing treatment with a lower dosage. Switching between treatments with proven efficacy may be helpful. An uncontrolled study of augmentation of SSRI treatment with buspirone found some evidence of beneficial effects; but a placebo-controlled crossover-study of the augmentation of paroxetine with pindolol found no evidence of efficacy. A small placebo-controlled study of the augmentation of paroxetine with clonazepam found the combination was marginally short of superiority, when compared to paroxetine alone.Disclosure of interestThe author has not supplied his declaration of competing interest.

Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies

BackgroundIncreasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available.MethodsThis post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fisher's exact tests. No adjustment was made for multiplicity.ResultsApproximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46–4.35; p < 0.001]. Similarly, risk of relapse after withdrawal of paliperidone ER treatment (placebo group of the paliperidone ER study) was higher than after withdrawal of PP (paliperidone ER placebo/PP placebo HR, 2.25; 95% CI, 1.59–3.18; p < 0.001). Stabilised schizophrenic subjects treated with PP maintained functioning demonstrated by the same proportions of subjects with mild to no difficulties in functioning at DB baseline and end point [Personal and Social Performance (PSP) scale total score >70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar.ConclusionsThis analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings.

Publication Bias and Outcome Reporting Bias: Agomelatine as a Case Example

Publication bias and outcome reporting bias contribute to distorted perceptions of drug efficacy and the underreporting of adverse events. To demonstrate these biases, this article describes how the clinical profile of the antidepressant agent agomelatine (Valdoxan(®)) has been presented in the literature. Agomelatine has been systematically assessed in 10 short-term placebo-controlled studies and three long-term placebo-controlled relapse prevention studies. Five published trials demonstrated clinically modest but statistically significant benefits over placebo. Five unpublished trials did not find agomelatine more effective than placebo, but in two of these studies the active comparison drug (fluoxetine [Prozac(®)] or paroxetine [Paxil(®)]) was more effective than placebo. Agomelatine was more effective than placebo in one of three relapse prevention studies, but only the positive study was published. Based on what is evident in the entire published and unpublished dataset, agomelatine does not have a tremendously superior sleep and sexual effects profile. The risk of liver toxicity is also not prominently highlighted in the published literature.

Meta-Analysis of Relapse Prevention Antidepressant Trials in Depressive Disorders

Continuation therapy with antidepressants is recommended for depressed patients who have responded to initial treatment. We quantified its efficacy in preventing relapse of depression in a meta-analysis of 54 double-blind placebo-controlled relapse prevention studies (patient n = 9268). Relapse prevention studies in primary depression and depression subtypes were identified in a systematic literature search. The primary efficacy comparison was relapse rates between active and placebo arms calculated as odds ratios (ORs) using Review Manager version 5.0. Effects of patient age, drug class, diagnostic system and duration of therapy on ORs was examined, along with ORs calculated using different statistical methods. Continuation antidepressants produced robust reduction in relapse (OR = 0.35; 95%CI 0.32-0.39). Pooled ORs were not affected by patient age, drug class, depression subtype or treatment duration, and were similar when calculated by different statistical methods. Patients with primary depression diagnosed by earlier diagnostic systems had slightly lower ORs than those diagnosed using DSM criteria. This meta-analysis emphasizes the importance of continuation treatment following acute response in depressive disorders. The robust findings of relapse prevention designs contrast with acute antidepressant efficacy studies, and may be due to enrichment of the patient population.

Long-term symptomatic remission of schizophrenia with once-daily extended release quetiapine fumarate: post-hoc analysis of data from a randomized withdrawal, placebo-controlled study

Despite available effective medications, many patients with schizophrenia do not become completely symptom free. We report analyses of data from a randomized, double-blind, placebo-controlled relapse prevention study of extended release quetiapine fumarate (quetiapine XR) using Remission in Schizophrenia Working Group criteria for symptomatic remission. During 16-week open-label stabilization, patients with stable schizophrenia were switched from their current antipsychotic to quetiapine XR (400, 600 or 800 mg/day flexibly dosed). One hundred and ninety-seven patients were randomized to either quetiapine XR or placebo (planned for 1 year or until relapse). The study was terminated early because the planned interim analysis showed quetiapine XR to be statistically superior to placebo in the primary outcome variable (time to schizophrenia relapse). One hundred and eighty of 195 (92.3%) patients with an available Positive and Negative Syndrome Scale assessment met symptomatic remission criteria at randomization (following 16 weeks' quetiapine XR). The risk of losing symptomatic remission was statistically significantly higher with placebo versus quetiapine XR: hazard ratio 0.39 (95% confidence interval: 0.19-0.81, P=0.009), that is, 61% risk reduction for quetiapine XR-treated versus placebo-treated patients. At 6 months postrandomization, the probability that patients would be in remission was 76% for quetiapine XR and 52% for placebo. Once-daily quetiapine XR was effective in preserving symptomatic remission in the longer-term treatment of patients with schizophrenia.

The Pharmacologic Treatment of Patients With Generalized Anxiety Disorder: Where Are We Now and Where Are We Going?

Evidence-based guidelines for the pharmacologic management of patients with generalized anxiety disorder (GAD) recommend initial treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). However, response rates to initial treatment with an SSRI or SNRI can be disappointing, and it remains impossible to predict reliably which patients will respond positively or negatively to treatment. Due to the dearth of longitudinal studies of outcome in GAD and the relatively small number of placebo-controlled relapse prevention studies, the optimal duration of treatment after a satisfactory response to acute treatment is still uncertain. Furthermore, there have been few studies on the management of patients who do not respond to initial treatment. Also, there is a clear need for further randomized controlled trials of augmentation treatment in patients who do not respond to SSRI, SNRI, or other initial pharmacologic approaches. Future guidelines will be influenced by emerging data with both established and novel drug treatments, and through better identification of patient groups that are likely to respond preferentially to particular interventions.

Room for Improvement in the Pharmacological Treatment of Anxiety Disorders

Anxiety disorders are common in community settings and in primary and secondary medical care. The associated societal burden is considerable, but many of those who might benefit from pharmacological or psychological treatment are not recognised or treated. By contrast, some patients receive unnecessary or inappropriate interventions. Recent evidence-based guidelines for pharmacological management of patients with anxiety disorders recommend initial treatment with either a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor. However, there is considerable room for improvement in both the efficacy and tolerability of pharmacological treatment. For example, response rates to initial treatment can be disappointing and it is still not possible to predict reliably which patients will respond well and which will show only a limited response to treatment. Furthermore, many patients fear or experience unwanted and distressing adverse effects and this limits the effectiveness of pharmacological treatments in clinical practice. Because of the relative lack of longitudinal studies of clinical outcomes in anxiety disorders and the small number of placebo-controlled relapse prevention studies, the optimal duration of treatment after a satisfactory response to acute treatment is still uncertain. There have been comparatively few studies of the further management of patients who do not respond to initial treatment and there is a clear need for further randomised controlled trials of augmentation treatment, in patients who do not respond to a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor or other initial pharmacological approaches. Future treatment guidelines will be influenced by emerging data with both established and novel pharmacological interventions and through better identification of patient sub-groups that are likely to respond preferentially to particular interventions.

Efficacité et tolérance de l’escitalopram dans les troubles anxieux : revue de la littérature

Anxiety disorders are highly prevalent and disabling disorders, for which selective serotonin reuptake inhibitor (SSRI) antidepressants are an effective treatment. Escitalopram is the most selective SSRI available. Beyond its well-established efficacy in depression with or without anxiety, preclinical studies have demonstrated that escitalopram has a broad spectrum of anxiolytic activity. This review focuses on the therapeutic use and the tolerability issues of escitalopram in the treatment of adult patients with panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, and obsessive-compulsive disorder (OCD), on the basis of numerous recent short-term and long-term controlled studies in these disorders. In a 10-week randomised, double-blind trial in patients with panic disorder, escitalopram (flexible doses 5-10 mg/d) was significantly more effective than placebo in reducing the panic attack frequency, with a faster onset of action than citalopram. Fifty percent of escitalopram recipients and 38% of placebo recipients experienced no panic attacks, with a similar incidence of the most common adverse events for both groups. LITERATURE FINDINGS IN PD: In an open-label study in elderly (>65 years) patients with panic disorder, improvement in panic attack frequency and secondary efficacy variables occurred more rapidly in escitalopram than citalopram recipients. LITERATURE FINDINGS IN GAD: In four double-blind, comparative, eight- to 12-week studies in patients with GAD, escitalopram was more effective than placebo and at least as effective as paroxetine in reducing the mean Hamilton Rating Scale for Anxiety total score. Escitalopram 10-20 mg/d demonstrated continued efficacy in a 24-week extension study of short double-blind trials and in a placebo-controlled, double-blind, 24/76-week relapse-prevention study. In this trial, escitalopram recipients showed a significantly longer time to relapse and reduced risk of relapse than placebo recipients, and the risk of relapse was 4.04 times higher in the placebo group than in the escitalopram group. Escitalopram was well tolerated and only 7% patients withdrew, due to adverse events in the escitalopram group, versus 8% in the placebo group. LITERATURE FINDINGS IN SOCIAL PHOBIA: In two randomised, double-blind, 12- and 24-week studies in patients with social anxiety disorder (social phobia), escitalopram 10-20 mg/d was generally more effective than placebo and at least as effective as paroxetine in reducing the mean Liebowitz Social Anxiety Scale total scores. In a 24-week double-blind, placebo-controlled relapse-prevention study, escitalopram recipients had a longer time to relapse and reduced risk of relapse compared with placebo recipients, and significantly fewer escitalopram than placebo recipients relapsed (22% versus 50%). In these studies, the treatment effects of escitalopram were independent of gender, symptom severity and chronicity, and comorbid depressive symptoms, and the drug was tolerated well. LITERATURE FINDINGS IN OCD: Finally, in patients with OCD, escitalopram 20mg/d for 12 weeks was more effective than placebo, and at least as effective as paroxetine 40 mg/day, with respect to a mean reduction from baseline in the Yale-Brown Obsessive Scale total score. In a 24-week, randomised, placebo-controlled relapse-prevention study, the proportion of patients who relapsed in the escitalopram group (23%) was 2.74 times lower than in the placebo group (52%). In both groups, the majority of adverse events reported were mild to moderate. On the whole, numerous clinical data indicate that escitalopram, 10-20 mg/d, is an effective and well-tolerated first-line treatment option for the management of panic disorder, GAD, social anxiety and OCD. Beyond short-term demonstrations of efficacy in these disorders, several controlled relapse-prevention studies showed the necessity and utility of maintaining the treatment six months or more after the remission has been obtained.

A double-blind randomized placebo-controlled relapse prevention study in remitted first-episode psychosis patients following one year of maintanence therapy

A double-blind randomized placebo-controlled relapse prevention study in remitted first-episode psychosis patients following one year of maintanence therapy

Aripiprazole Monotherapy for Maintenance Therapy in Bipolar I Disorder

A 26-week, double-blind, placebo-controlled relapse prevention study of aripiprazole was designed a priori with a prospective, 74-week, double-blind, placebo-controlled extension phase. Efficacy and tolerability of aripiprazole for relapse prevention in bipolar I disorder was, therefore, evaluated for 100 weeks. Patients with DSM-IV bipolar I disorder, recent manic or mixed episode, received open-label aripiprazole 15 or 30 mg/day (started at 30 mg/day) for 6 to 18 weeks. Patients achieving stabilization (Young Mania Rating Scale score <or= 10 and Montgomery-Asberg Depression Rating Scale score <or= 13 for 6 consecutive weeks) entered the double-blind phase, at which point they were randomly assigned to double-blind treatment with aripiprazole or placebo for 26 weeks. The primary endpoint was time to relapse for any mood episode. Patients who completed the 26-week stabilization continued in a double-blind fashion with aripipra-zole or placebo for an additional 74 weeks and were monitored for relapse, efficacy, and tolerability. The study was conducted from March 2000 to June 2003. In total, 161 patients met the stabilization criteria and were randomly assigned to aripiprazole (N = 78) or placebo (N = 83). At 100 weeks, time to relapse was significantly longer with aripiprazole (N = 7) than placebo (N = 5; hazard ratio = 0.53 [p = .011; 95% CI = 0.32 to 0.87]); however, a further 24 patients had discontinued due to study closure. Aripiprazole was superior to placebo in delaying time to manic relapse (p = .005; hazard ratio = 0.35 [95% CI = 0.16 to 0.75]); however, no significant differences were observed in time to depressive relapse (p = .602; hazard ratio = 0.81 [95% CI = 0.36 to 1.81]). The adverse events reported during 100 weeks of treatment with aripiprazole versus placebo (>or= 5% incidence and twice placebo rate) were tremor, akathisia, dry mouth, hypertension, weight gain, vaginitis, abnormal thinking, pharyngitis, and flu syndrome. Mean weight change from baseline to 100 weeks (last observation carried forward) was +0.4 +/- 0.8 kg with aripiprazole and -1.9 +/- 0.8 kg with placebo. Over a 100-week treatment period, aripiprazole monotherapy was effective for relapse prevention in patients who were initially stabilized on aripiprazole for 6 consecutive weeks, and it maintained a good safety and tolerability profile. ClinicalTrials.gov identifier NCT00036348.

Relapse Prevention With Gepirone ER in Outpatients With Major Depression

To evaluate long-term efficacy and tolerability of the serotonin 5-HT1A receptor agonist, gepirone extended release (ER), a multicenter, randomized, placebo-controlled relapse prevention study was performed in patients with recurrent major depression (DSM-IV criteria). Patients 18 to 70 years, with a primary diagnosis of recurrent major depression (DSM-IV; 296.3) and a screening and baseline HAMD-17 total score >/=20 were eligible. After a 3- to 14-day (dependent on pretrial medication) single-blind placebo washout period, eligible patients entered an 8- or 12-week (depending on time to remission) open-label gepirone ER treatment period. They initially received a dose of 20 mg/d gepirone ER and were titrated to a dose of 40 to 80 mg/d. Patients who achieved remission (HAMD-17 total score </=8) were randomized to double-blind continuation of their gepirone ER treatment or placebo for 40 to 44 weeks. The primary end point was a comparison of the relapse rates between gepirone ER and placebo. Relapse was defined as a HAMD-17 total score >/=16 or discontinuation for lack of efficacy. A total of 420 patients were treated in the open-label phase. Of these, 303 (72.1%) completed the open-label phase and 250 (59.5%) fulfilled the criteria for remission and were randomized into the double-blind continuation phase (gepirone ER: n = 126; placebo: n = 124). The mean (+/-SD) final titrated dose of gepirone ER was 61.9 (+/-17.0) mg/d in the double-blind continuation phase. The relapse rate in the gepirone ER group was statistically significantly lower than that in the placebo group, 23.0% versus 34.7%, respectively (P = 0.024). During the open-label phase, adverse events that occurred in more than 5% of patients were nausea (15.7%), dizziness (13.1%), headache (12.9%), insomnia (6.2%), and vertigo (6.0%). During the continuation phase, the incidence of newly or re-emerging adverse events was similar with gepirone ER (43.7%) and placebo (42.7%). Adverse events different from those occurring during the open-label phase were not apparent. All adverse events occurred in less than 5% of patients with the exception of flu syndrome and headache. In conclusion, gepirone ER at a dose range of 40 to 80 mg/d is effective for relapse prevention in patients with recurrent major depression. It is well tolerated during long-term treatment for up to approximately one year.

Placebo response in schizophrenia

SummaryA review of the literature on placebo-controlled studies in schizophrenia reveals, that the percentage of placebo responders in short-term trials amounts to 0–40%; on active treatment the response rate is 40–60%. In relapse prevention studies 18–100% of patients on placebo relapsed as compared to 0–40% on active treatment. Factors of importance for the variability between studies are discussed. Desirable designs of explanatory and pivotal studies, the importance of placebo controlled relapse prevention studies, and more rigorous assessment methods,egvideo-taped and structured interviews for diagnostic and symptom rating purposes, are proposed as a means to improve the quality of the clinical documentation of new drugs.