Meta-analysis of Total Effect Decomposition in the Presence of Multiple Mediators: The Example of Schizophrenia Treatment.

Background: Causal mediation analysis addresses mechanistic questions by decomposing and quantifying effects operating through different pathways. Because most individual studies are underpowered to detect mediating effects, we outlined a parametric approach to meta-analyzing causal mediation and interaction analyses with multiple mediators, compared it with a bootstrap-based alternative, and discussed its limitations.

Methods: We employed fixed- and random-effects multivariate meta-analyses to integrate evidence on treatment-mediators and mediators-outcome associations across trials.

The role of weight gain in explaining the effects of antipsychotic drugs on positive and negative symptoms: An analysis of the CATIE schizophrenia trial.

Second-generation antipsychotics are associated with moderate benefits in terms of improved schizophrenia symptoms, but also with higher rates of side-effects such as excessive weight gain (WG); a consensus on their efficacy has not been reached. To date, no study has evaluated the interplay of treatments and side-effects in a single framework, which is a critical step to clarify the role of side-effects in explaining the efficacy of these antipsychotics. We used recent methods for mediation and interaction to clarify the role of WG in explaining the effects of second-generation drugs on schizophrenia symptoms.

The role of PANSS symptoms and adverse events in explaining the effects of paliperidone on social functioning: a causal mediation analysis approach.

To date, no study has evaluated the joint role of symptoms and adverse events as mediators of the effect of second-generation antipsychotics on patients' social functioning. We used recently developed methods for mediation analysis with multiple mediators to clarify the interplay of adverse events and symptoms in explaining the effects of paliperidone (R code for implementing the mediation analysis for multiple mediators is provided). We used data from 490 participants in a 6-week randomized dose-response trial that assigned three fixed dosages of ER OROS paliperidone (3, 9, and 15 mg/day).

Factors associated with length of psychiatric hospitalization.

Objective: Criteria for psychiatric hospitalization have undergone marked changes. Efforts to limit length-of-hospitalization risk greater morbidity at discharge and increased needs for appropriate aftercare. Accordingly, we evaluated factors associated with length of psychiatric hospitalization and aftercare-types.

Metabolic syndrome in psychiatrically hospitalized patients treated with antipsychotics and other psychotropics.

Objective: We evaluated prevalence and risk factors for metabolic syndrome in inpatients treated with antipsychotics, with or without other psychotropic drugs. Although the literature on metabolic syndrome in psychiatry has expanded in recent years, we seek to elucidate some of the remaining gaps by examining a severely and chronically ill population heavily treated with pharmacological agents.

Methods: With data from medical records of 589 adults hospitalized at McLean Hospital in 2010 and 2011, we used standard statistical analyses to characterize risks and covariates of metabolic syndrome.

Marijuana impacts mood in bipolar disorder: a pilot study.

Patients with bipolar disorder (BP) often report subjective mood improvements after smoking marijuana (MJ); however, empirical studies supporting this claim have not been conducted. We conducted this study to determine if marijuana has an impact on mood in bipolar patients who smoke marijuana (MJBP), hypothesizing MJBP participants would experience improved mood after smoking MJ. All participants completed electronic mood ratings three times daily and recorded episodes of MJ use using Palm Pilot devices in their own environments in order to examine the impact of MJ use on mood in MJ-smoking bipolar patients ( = 12) and pure MJ smokers (MJ; = 20).

Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment.

The preferential dopamine D(3)-agonist pramipexole (4.25±0.38 mg/day) or placebo were added for up to 12 weeks to ongoing antipsychotic treatment for 24 adult patients with DSM-IV schizophrenia or schizoaffective disorder.

Use of mood stabilizers for hospitalized psychotic and bipolar disorder patients.

Treatments given to patients with primary psychotic disorders include mood stabilizers (MSs) combined with other psychotropics, despite the limited evidence of efficacy, safety, and lack of regulatory approval. We analyzed records of 636 inpatients at the McLean Hospital (2002-2009), who were diagnosed with bipolar disorder (n=318), a schizoaffective disorder (n=210), or schizophrenia (n=108), to evaluate MS-usage, drug-selections, combinations and doses, improvement, adverse-effect risks, associated factors, and secular trends. Between 2002 and 2009, the use of MSs increased from 53 to 94% of patients, MSs per patient increased by 74%, and the total final doses (lithium-equivalents in milligrams/day) increased by 35%.

International consensus study of antipsychotic dosing.

Objective: Potency equivalents for anti-psychotic drugs are required to guide clinical dosing and for designing and interpreting research studies. Available dosing guidelines are limited by the methods and data from which they were generated.

Method: With a two-step Delphi method, the authors surveyed a diverse group of international clinical and research experts, seeking consensus regarding antipsychotic dosing.

Changes in medication practices for hospitalized psychiatric patients: 2009 versus 2004.

Background: We tested the hypothesis that combinations and total daily doses of psychotropics for hospitalized patients diagnosed with major psychiatric disorders are rising.

Methods: We evaluated McLean Hospital records of 481 consecutive inpatients with DSM-IV schizophrenia, schizoaffective, or bipolar disorders in 2004 (n = 278) or 2009 (n = 203) to compare characteristics and treatments.

Results: In 2009, Clinical Global Impression (CGI)-severity scores were 6% lower at intake and improved 1.

Health and economic burden of metabolic comorbidity among individuals with bipolar disorder.

Objectives: To compare the prevalence and health care costs of metabolic conditions in patients with bipolar disorder to age- and sex-matched control patients using a large insurance claims database.

Methods: A retrospective analysis of medical service and prescription claims from the Thomson Reuters (Healthcare) MarketScan Commercial Database (which includes claims information on >12 million employees with employer-based insurance and their dependents in the United States) was conducted. Claims data for 28,531 patients with bipolar disorder were compared for 1 year with data for 85,593 age- and sex-matched control patients with no mental health disorders and no psychotropic medication use.

Comparison of mania patients suitable for treatment trials versus clinical treatment.

It remains uncertain whether bipolar disorder (BPD) patients in randomized-controlled trials (RCTs) are sufficiently representative of clinically encountered patients as to guide clinical-therapeutic practice. We complied inclusion/exclusion criteria by frequency from reports of 21 RCTs for mania, and applied them in a pilot study of patients hospitalized for DSM-IV BPD manic/mixed states to compare characteristics and clinical responses of patients who did versus did not meet exclusion criteria. From 27 initially identified inclusion/exclusion criteria ranked by citation frequency, we derived six inclusion, and 10 non-redundant-exclusion factors.

Hospital use of antipsychotic drugs: polytherapy.

Objective: Growing acceptance of new psychotropic drugs encouraged a survey of current use of antipsychotic drugs alone and in combinations, with comparisons with previous findings.

Method: Records from a random sample of McLean Hospital (Belmont, Mass) inpatients treated with an antipsychotic from March to May 2004 were reviewed for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, discharge diagnosis; all current psychotropic drug treatments; initial, peak, and final chlorpromazine-equivalent milligram-per-day dose of antipsychotics (APD); initial, peak, and final lithium-equivalent dose (milligram per day) of mood stabilizers (MS); weight change; clinical status at admission and discharge; and days of hospitalization.

Results: In the 305 inpatients sampled (n = 184 women, 60.

An observational study of the effectiveness and safety of intramuscular olanzapine in the treatment of acute agitation in patients with bipolar mania or schizophrenia/schizoaffective disorder.

Objective: To determine the effect of intramuscular (IM) olanzapine in severely agitated patients.

Methods: This was an open-label multicenter 1-week observational study of IM olanzapine treatment in severely agitated inpatients and psychiatric emergency services with bipolar mania (n = 22) or schizophrenia (n = 52). Mean change from baseline to 2 h post-first injection (LOCF) in agitation was assessed by PANSS-Excited Component (PANSS-EC) (score range: 5-35 points) mean change from baseline to 15, 30, 45, 60, 90, and 120 min post-first injection, and visit-wise mean changes from mixed-model repeated measures analysis of variance.

Clinical outcome in patients with bipolar I disorder, obsessive compulsive disorder or both.

Background: Bipolar disorder (BPD) is often comorbid with obsessive-compulsive (OCD) and other anxiety disorders, but the impact of such comorbidity on long-term outcome has not been evaluated systematically.

Methods: Extensive follow-up assessments were carried out at 4.3 years after index hospitalizations in a mixed BPD-OCD group (N=20) compared to matched groups with BPD (N=22) or OCD (N=20) alone.

Use of combinations of antipsychotics: McLean Hospital inpatients, 2002.

Background: The empirical use of combinations of antipsychotic agents appears to be increasing with little research support for the relative efficacy, safety or cost-effectiveness of this practice. Such treatment was evaluated in hospitalized psychiatric patients.

Methods: Samples of consecutive inpatients treated with > or = 2 ('polytherapy') vs 1 antipsychotic ('monotherapy') were matched on age, sex, diagnosis and admission clinical ratings, and these groups were compared on total daily chlorpromazine-equivalent doses, days in hospital, and changes in clinical ratings between admission and discharge.

Aripiprazole: initial clinical experience with 142 hospitalized psychiatric patients.

Background: Aripiprazole is the first dopamine D2 receptor partial-agonist approved for treatment of schizophrenia. Its apparently benign adverse-effect profile encourages broader use in other disorders, especially to limit weight gain associated with other antipsychotic or antimanic agents. We considered the first 6 months of experience with aripiprazole in psychiatric inpatients with a range of disorders.

Antipsychotic drug use: McLean Hospital, 2002.

Objective: Major changes in antipsychotic treatment in recent years encouraged a survey of inpatient practice in 2002, compared with earlier samples.

Methods: Based on records of a random sample of McLean Hospital inpatients prescribed antipsychotics in 2002, the study recorded DSM-IV discharge diagnosis, all psychotropic treatments and doses, initial, peak and final doses of all antipsychotics, clinical status at admission and discharge, and adverse effects reported. Results were compared with similar data from our earlier surveys.

Ziprasidone: first year experience in a hospital setting.

Background: The antipsychotic drug ziprasidone, FDA-approved and introduced in the United States in February 2001 for the treatment of schizophrenia, appears to have similar efficacy but better tolerability than older antipsychotics and requires further evaluation under clinical conditions.

Methods: We analyzed medical records of McLean Hospital inpatients treated with ziprasidone between March 2001 and February 2002, gathering data on DSM-IV diagnoses, presenting symptoms, dosing, concomitant psychotropic medications, clinical changes, adverse effects, and electrocardiographic (ECG) findings.

Results: Ziprasidone was given to 151 inpatients (3.

Clinical comparison of extended-release divalproex versus delayed-release divalproex: pooled data analyses from nine trials.

Divalproex sodium is an effective anticonvulsant, antimanic, and migraine prophylaxis agent. Recently, a new extended-release (ER) formulation of divalproex sodium has become available, which allows for once-daily dosing and provides prolonged therapeutic serum levels. Using data pooled from nine open-label trials involving 321 epilepsy and psychiatry patients, we compared the efficacy and tolerability of divalproex ER with preceding treatment with the older delayed-release (DR) formulation, based on patient reports and analysis by McNemar's test for within-subject paired data.

Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits.

Objective: Since use of multiple drugs to treat psychiatric patients is increasing, and research on this practice is rare, the authors carried out a retrospective case-control study of multiple versus single antipsychotic treatment in psychiatric inpatients.

Method: Inpatient treatment groups receiving either antipsychotic monotherapy or polytherapy were matched in terms of age, sex, diagnostic category, and admission clinical ratings (Global Assessment of Functioning [GAF] and Clinical Global Impression [CGI]), which yielded 70 subject pairs. They were compared in terms of total chlorpromazine-equivalent daily dose, changes in total daily dose, length of hospitalization, incidence of adverse effects, and changes in clinical ratings (CGI, GAF, Positive and Negative Syndrome Scale score) between admission and discharge.

Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.

Background: Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression.

Objective: To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.

Design: Double-blind, 8-week, randomized controlled trial.

Oxcarbazepine: clinical experience with hospitalized psychiatric patients.

Background: Oxcarbazepine (10-keto-carbamazepine) appears to be better tolerated and simpler to use than carbamazepine. It has antimanic effects but, as its potential clinical usefulness and tolerability in broad samples of psychiatric patients remain to be tested, we reviewed both the pharmacology of oxcarbazepine and our early experience with this new agent among psychiatric inpatients.

Methods: We reviewed medical records of all inpatients given oxcarbazepine in the first 15 months of its use at McLean Hospital.