Multisite international collaborative clinical trials in mania.

Multi-regional collaborative clinical trials include those conducted across heterogeneous areas of the world under common protocols. Such trials appear to be driven primarily to provide data required for regulatory approval or licensing of new drug products in a relatively rapid and presumably efficient and cost-effective manner. Commonly, they include underserved populations and areas where costs of trials are lower than in most developed countries. In addition, such studies can potentially make innovative treatments widely and rapidly available in vast, international markets. Other potential benefits to collaborating sites may include diffusion of knowledge and improvement of research skills, as well as improvement of treatment and a broader salutary impact on health services and perhaps on employment opportunities and economic growth (Demol +6; Weihrauch, 1997; Glickman et al. 2009; Gopal et al. 2005; Greco +6; Diniz, 2008; ICH Guideline, 2002; Smulevich et al. 2005; U.S. FDA, 1998). Successful conduct of international trials requires compliance with varying local and international laws, regulations and ethical requirements, and confronting a range of systems of review of ethical aspects of subject recruitment, compensation, consenting procedures, research protocols, and provision of aftercare – all which can add complexity. In addition, there is variance among regions, countries and cultures in levels of education, and in the nature of information, financial inducements, clinical care and aftercare provided to research subjects. Complexities arise also from culture-dependent conceptualizations of mental disorders, criteria for diagnosis, and efforts at validating, interpreting and scoring of symptom ratings designed to characterize changes during treatment, and methods for detecting adverse events. In the continuing quest to define core or universal features of psychiatric disorders, it is crucial to consider the anthropological and cultural context in which they develop and are modified (Karno +6; Jenkins, 1993; Lopez-Ibor, 2003;

Factors modifying drug and placebo responses in randomized trials for bipolar mania

Factors modifying drug and placebo responses in randomized trials for bipolar mania. Yildiz A, Vieta E, Tohen M, Baldessarini RJ. Source Department of Psychiatry, Dokuz Eylül University, Izmir, Turkey. [email protected] Abstract Randomized placebo-controlled trials (RCTs) are standard for assessing efficacy and safety of treatments. We pursued preliminary indications that some factors are associated differentially with responses to placebo or drugs in RCTs for bipolar mania. We meta-analysed data from RCTs to assess influences of study-site count, subjects' age, sex distribution, diagnostic subgroups, clinical features, trial-completion rates, and publication year on mean difference (MD) in mania ratings between intake and final assessments. In 38 RCTs involving 3812 placebo-treated and 6988 drug-treated patients, symptomatic improvement was similar in placebo arms of trials of effective (6.77, 95% CI 5.77-7.76) and ineffective (7.61, 95% CI 5.47-8.75) drugs. Lesser placebo responses (MD) and greater drug-placebo differences (Hedges' g) were associated with fewer study sites, younger patients' age, and male sex. More patients with initial psychotic features and more trial completion in drug arms were associated with greater drug-associated improvement (MD) and drug-placebo contrast (Hedges' g), whereas more mixed-state diagnoses decreased both measures. Identifying modifying factors can support more efficient and cost-effective designs of therapeutic trials. In trials for mania, fewer sites may limit placebo response and enhance drug-placebo contrasts

Metabolic Syndrome in Psychotic Disorder Patients Treated With Oral and Long-Acting Injected Antipsychotics

Background: Severe mental illnesses are associated with increased risks for metabolic syndrome (MetS) and other medical disorders, often with unfavorable outcomes. MetS may be more likely with schizoaffective disorder (SzAff) than schizophrenia (Sz). MetS is associated with long-term antipsychotic drug treatment, but relative risk with orally administered vs. long-acting injected (LAI) antipsychotics is uncertain.Methods: Subjects (n = 151 with a DSM-IV-TR chronic psychotic disorder: 89 Sz, 62 SzAff), treated with oral or LAI antipsychotics were compared for risk of MetS, initially with bivariate comparisons and then by multivariate regression modeling.Results: Aside from measures on which diagnosis of MetS is based, factors preliminarily associated with MetS included antipsychotic drug dose, “high-risk” antipsychotics associated with weight-gain, older age and female sex. Defining factors associated with diagnosis of MetS ranked in multivariate regression as: higher fasting glucose, lower LDL cholesterol, higher diastolic blood pressure, and higher BMI. Risk of MetS with antipsychotics ranked: quetiapine ≥ clozapine ≥ paliperidone ≥ olanzapine ≥ risperidone ≥ haloperidol ≥ aripiprazole. Other associated risk factors in multivariate modeling ranked: higher antipsychotic dose, older age, and SzAff diagnosis, but not oral vs. LAI antipsychoticsConclusions: SzAff diagnosis and higher antipsychotic doses were associated with MetS, whereas orally vs. injected antipsychotics did not differ in risk of MetS

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. RESULTS: Initial doses were closely similar at admission for both treatment groups, but the median total final antipsychotic dose was 78% higher for those receiving antipsychotic polytherapy versus monotherapy. Also, median length of stay in the hospital was 55% (8.5 days) longer, and risk of adverse effects was 56% higher with polytherapy, whereas clinical improvement scores were similar (within 11%) for both treatments. CONCLUSIONS: Short-term treatment with multiple antipsychotics was associated with major increases in drug exposure, adverse events, and time in the hospital but with no apparent gain in clinical benefit. These findings require further testing in controlled prospective studies

Comparison of solid-phase radioimmunoassay and competitive protein binding method for post-dexamethasone cortisol levels in psychiatric patients

Results obtained by competitive protein binding assay (PBA) and a solid-phase radioimmunoassay (RIA) for cortisol were compared in 157 samples from 100 psychiatric patients given a dexamethasone suppression test (DST). Cortisol levels in plasma samples obtained at 8:00 a.m. or 4:00 p.m. the day following 1.0 mg dexamethasone orally at bedtime ranged from 0 to 30 [mu]g/dl and correlated closely (r = 0.96). However, RIA gave values that were consistently and significantly lower (average = 8.9%) than those obtained by PBA. When samples were further assayed by a specific RIA for corticosterone, there was a strong correlation between cortisol and corticosterone RIA values (r = 0.79), and corticosterone (7.8% of cortisol levels) accounted for most of the difference between PBA and RIA for cortisol. The relationship between results of the two cortisol assay methods can be expressed (in [mu]g/dl) by the equation: RIA = 0.92(PBA) - 0.10, based on findings obtained in a separate analysis of 127 samples with cortisol values in the 0-10 [mu]g/dl range, critical to the valid interpretation of the DST in melancholia. A reported criterion of a "positive" DST in psychiatry, of plasma cortisol of [ges] 5.0 [mu]g/dl has been suggested by use of a PBA. Use of the present RIA required that this value be adjusted downward, at least to 4.5 [mu]g/dl; application of this criterion increased the clinical sensitivity of the DST by 10%. We urge local, independent verification of criteria to define the DST as "positive" in each laboratory and with each method of assay.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25277/1/0000720.pd

Clinical use of lithium salts: guide for users and prescribers

Lithium has been used clinically for 70 years, mainly to treat bipolar disorder. Competing treatments and exaggerated impressions about complexity and risks of lithium treatment have led to its declining use in some countries, encouraging this update about its safe clinical use. We conducted a nonsystematic review of recent research reports and developed consensus among international experts on the use of lithium to treat major mood disorders, aiming for a simple but authoritative guide for patients and prescribers