An Integrated Risk Reduction Intervention can reduce body mass index in individuals being treated for bipolar I disorder: results from a randomized trial.

OBJECTIVES: We conducted a randomized, controlled trial comparing the efficacy of an Integrated Risk Reduction Intervention (IRRI) to a control condition with the objective of improving mood stability and psychosocial functioning by reducing cardiometabolic risk factors in overweight/obese patients with bipolar I disorder. METHODS: A total of 122 patients were recruited from our outpatient services and randomly allocated to IRRI (n = 61) or psychiatric care with medical monitoring (n = 61). Individuals allocated to IRRI received psychiatric treatment and assessment, medical monitoring by a nurse, and a healthy lifestyle program from a lifestyle coach. Those allocated to the control condition received psychiatric treatment and assessment and referral, if indicated, for medical problems. A mixed-effects model was used to examine the impact of the interventions on body mass index (BMI). Exploratory moderator analyses were used to characterize those individuals likely to benefit from each treatment approach. RESULTS: Analyses were conducted on data for the IRRI (n = 58) and control (n = 56) participants with ≥ 1 study visit. IRRI was associated with a significantly greater rate of decrease in BMI (d = -0.51, 95% confidence interval: -0.91 to -0.14). Three variables (C-reactive protein, total cholesterol, and instability of total sleep time) contributed to a combined moderator of faster decrease in BMI with IRRI treatment. CONCLUSIONS: Overweight/obese patients with bipolar disorder can make modest improvements in BMI, even when taking medications with known potential for weight gain. Our finding that a combination of three baseline variables provides a profile of patients likely to benefit from IRRI will need to be tested further to evaluate its utility in clinical practice.

Screening for obstructive sleep apnea in patients with bipolar I disorder: comparison between subjective and objective measures.

OBJECTIVES: Many of the first-line screening tools for obstructive sleep apnea (OSA) may not be accurate in patients with bipolar disorder due to confounding factors, such as chronic depressive symptoms, weight gain, and sedation due to medications. In the present study, we assessed the feasibility of in-home screening for sleep apnea in patients with bipolar disorder and assessed the validity of a screening questionnaire versus an objective measure of apnea-hypopnea index (AHI). METHODS: A total of 28 subjects with bipolar I disorder (19 females,and nine males; mean age 41.7 ± 9.8 years) completed the Berlin Questionnaire for sleep apnea screening and their AHI was objectively measured with a portable in-home device. RESULTS: Eleven subjects (39%) had an AHI ≥ 5. The Berlin Questionnaire showed a poor positive and negative predictive value for identifying sleep apnea in patients with bipolar disorder. CONCLUSIONS: While OSA may be relatively prevalent among patients with bipolar disorder, self-report screening tools used in clinical practice may be highly inaccurate for this population. In-home screening with a patient-operated monitoring device may be a valid and feasible alternative for patients with bipolar disorder.

Adherence to escitalopram treatment in depression: a study of electronically compiled dosing histories in the 'Depression: the search for phenotypes' study.

Poor adherence to depression treatment is common. Understanding determinants of poor adherence to therapy is crucial to ensure optimal clinical outcomes. The aim of this study was to describe characteristics of dosing history in participants with depression receiving once daily escitalopram. Participants were randomly assigned to interpersonal psychotherapy (IPT) or pharmacotherapy. Participants assigned to IPT who did not evidence a response or remission had escitalopram added to their treatment. Adherence to pharmacotherapy was assessed using an electronically monitored pill cap (MEMS). Fifty-four participants on escitalopram alone and 32 on escitalopram+IPT were monitored. After 200 days, 71.7% of the participants in the escitalopram group and 54.8% of those in the escitalopram+IPT group were still engaged with the dosing regimen. Of those engaged in the dosing regimen, 17.9% (average over 210 days) of the participants did not take their medication (nonexecution). In 69% of the days participants took the correct dosage required. On average, participants had three drug holidays and the mean length of a holiday was 7 days per patient. No difference in adherence patterns was observed between patients receiving escitalopram alone vs. IPT+escitalopram. Early discontinuation of treatment and suboptimal daily execution of the prescribed regimen are the most common facets of poor adherence in this study population.

Addressing the challenges of a cross-national investigation: lessons from the Pittsburgh-Pisa study of treatment-relevant phenotypes of unipolar depression.

BACKGROUND: To date, no cross-national RCT has addressed the mechanisms underlying the relative success of pharmacological and psychotherapeutic interventions for depression. A multi-site clinical trial that includes psychotherapy as one of the treatments presents numerous challenges related to cross-site consistency and communication. PURPOSE: This report describes how those challenges were met in the study "Depression: The Search for Treatment Relevant Phenotypes'', being carried out at the University of Pittsburgh and the University of Pisa, Italy. METHODS: Implementing the study required the investigators to address methodological and practical challenges related to the different requirements of the two Institutional Review Boards (IRBs), psychotherapy training, independent evaluator training, patient recruitment, development of common tools for data entry, quality control and generation of weekly reports of patient progress as well as establishing a similar clinical and research framework in two countries with substantially different health care systems. RESULTS: By having bilingual investigators and staff members who spent time at one another's sites, making use of frequent conference-call staff meetings and being flexible within the bounds of the sometimes contradictory requirements of the IRBs, the investigators were able to meet the human subjects protection requirements of both institutions, surmount language barriers to consistent therapist and evaluator training and develop common tools for study management. As a result, recruitment goals were met at both sites and retention rates were high. One instance of inconsistent implementation of the protocol was corrected within the first year. LIMITATIONS: This study was conducted in two Western cultures by researchers with long-standing collaboration. Our findings may not be generalizable to other countries or research settings. CONCLUSIONS: The implementation of a cross-national protocol and the adoption and maintenance of common procedures is possible when investigators are aware of the challenges this may present and are proactive in trying to address them.

Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms.

OBJECTIVES: Attenuation of protein kinase C (PKC) is a mechanism common to both established (lithium, valproate) and some novel (tamoxifen) antimanic agents. Verapamil, although primarily known as a calcium channel blocker, also has PKC inhibitory activity. Verapamil has shown antimanic activity in some but not all studies. Therefore, we investigated verapamil, used alone or as an adjunctive treatment, in manic patients who did not respond to an initial adequate trial of lithium. METHODS: Each study phase lasted three weeks. Subjects were treated openly with lithium in Phase 1 (n = 45). Those who failed to respond were randomly assigned to double-blind treatment in Phase 2 with either verapamil (n = 10) or continued-lithium (n = 8). Phase 2 nonresponders (n = 10) were assigned to combined verapamil/lithium in Phase 3. RESULTS: Response in Phase 2 did not differ significantly between verapamil and continued-lithium. During Phase 3, response to combined treatment was significantly better than overall response to monotherapy in Phase 2 (Fisher's Exact test, p = 0.043). Mania ratings improved during combined treatment in Phase 3 by 88.2% (linear mixed model analysis, F = 4.34, p = 0.013), compared with 10.5% improvement during Phase 2. CONCLUSIONS: In this preliminary investigation, verapamil monotherapy did not demonstrate antimanic efficacy. By contrast, the combination of verapamil plus lithium was highly efficacious. Our findings thus suggest that verapamil may have potential utility as an adjunct to lithium. This effect may be mediated by additive actions on PKC inhibition, which may be an important mechanism for antimanic agents in general.

A placebo-controlled, random-assignment, parallel-group pilot study of adjunctive topiramate for patients with schizoaffective disorder, bipolar type.

OBJECTIVES: This pilot study evaluated the efficacy and safety of adjunctive topiramate compared with placebo in the treatment of patients with a diagnosis of schizoaffective disorder, bipolar type (SAD-BT). METHODS: A sample of 48 adult patients with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnosis of SAD-BT (supported by the Structured Clinical Interview for DSM-IV Axis I Disorder, Patient Edition) were randomly assigned in a 2:1 ratio (favoring topiramate) to 8 weeks of double-blind treatment with topiramate (100-400 mg/day) or placebo. Patients who had achieved a > or =20% decrease from baseline in their Positive and Negative Syndrome Scale (PANSS) total scores were given the opportunity to continue for an additional 8 weeks of double-blind treatment. The dosage of the study medicine was continued unchanged from the earlier 8-week study period. At the end of the study period, the study medicine was tapered and discontinued over a 2-week period. Primary efficacy was assessed at 8 weeks using the mean change between treatment groups of the PANSS total scores in the intent-to-treat population of randomized patients. Several secondary measures were also assessed. Safety analyses included monitoring of adverse events, vital signs, electrocardiogram (ECG) and laboratory values. RESULTS: Even though both treatments reduced scores on various psychopathology rating scales, adjunctive topiramate treatment (nearly 275 mg/day) did not show increased efficacy relative to placebo on the primary outcome measure (PANSS scale) or any of the secondary outcome measures. Topiramate-treated patients lost significantly more body weight than placebo-treated patients, which led to a significant reduction in body mass index (BMI). Relative to adjunctive placebo, topiramate-treated patients experienced higher rates of paresthesia, sedation, word-finding difficulty, sleepiness, and forgetfulness, but these differences were not statistically significant. There were no clinically significant abnormalities in either the ECG or laboratory results. There were no serious adverse events in the study. Further, there was no worsening of the PANSS total scores (to > or =10% from baseline), and no significant differences between the treatments on worsening of total Montgomery-Asberg Depression Rating Scale (MADRS) scores [1/13 (7.7%) for placebo; 1/25 (4.0%) for topiramate]. CONCLUSIONS: This pilot study did not support clinical efficacy for adjunctive topiramate treatment in patients with SAD-BT. There were no major safety or tolerability issues in this study. Confirming the results of other studies, topiramate-treated patients did experience greater body weight loss and reduction in BMI.