Placebo-controlled adjunctive trial of pramipexole in patients with bipolar disorder: targeting cognitive dysfunction.

OBJECTIVE: Patients with bipolar disorder suffer from significant cognitive impairment that contributes directly to functional disability, yet few studies have targeted these symptoms for treatment, and the optimal study design remains unclear. We evaluated the effects of the dopamine D2/D3 receptor agonist pramipexole on cognition in bipolar disorder. METHOD: Fifty stable outpatients with DSM-IV-diagnosed bipolar I or bipolar II disorder enrolled in an 8-week, double-blind, randomized, placebo-controlled cognitive enhancement trial between July 2006 and April 2010. Patients completed neurocognitive testing at baseline and at week 8, and the primary outcome measures were change scores calculated for each of the 11 tasks. Symptoms and side effects were monitored weekly. RESULTS: Forty-five patients completed the study (placebo, n = 24; pramipexole, n = 21), and groups were well matched on demographic and clinical features. Primary cognitive analyses indicated no compelling cognitive benefit of pramipexole versus placebo; however, secondary analyses highlight several important methodological issues for future trials and identify a subgroup of patients who might benefit more readily from cognitive enhancement strategies. This outcome suggests that the study design played a very important role in the results-implying a failed rather than altogether negative trial. Specifically, we found that even very subtle, subsyndromal mood symptoms at baseline had a significant influence on the degree of improvement due to active drug, with strictly euthymic patients faring best (multivariate analysis of variance, P = .03 in euthymic subgroup). In addition, the extent of baseline cognitive impairment also contributed to the likelihood of treatment response. Finally, concomitant medications may weaken, or in some cases enhance, response to cognitive treatment and should be accounted for in study design. CONCLUSIONS: Although our results point toward a lack of clear effect of pramipexole on cognition in bipolar patients, our data revealed a potentially beneficial effect of pramipexole in a subgroup, providing some enthusiasm for pursuing this line of research in the future. Moreover, this study emphasizes the importance of rigorous subject selection for cognitive trials in bipolar illness. Future studies will be necessary to determine the possible clinical and functional implications of these results. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00597896.

Clinical and pharmacogenetic studies of iloperidone.

Antipsychotic drugs have become the mainstay treatment of schizophrenia. However, patients who receive antipsychotic treatment differ with respect to treatment response and adverse events. The problem of antipsychotic response variability has stimulated further search for agents with improved effectiveness and tolerability. Equally intense is the search for novel ways of using DNA information to personalize treatment with antipsychotic drugs. Iloperidone is an investigational, atypical antipsychotic drug of the serotonin/dopamine type. The US FDA is currently reviewing the new drug application for an oral formulation of iloperidone for the treatment of schizophrenia. Data from 35 clinical trials and approximately 3000 patients treated with iloperidone were included in the new drug application submission, as well as data from pharmacogenetic studies of iloperidone. Given the emerging role of pharmacogenetics, knowledge of genetic biomarkers of iloperidone response could lead to personalized medicine.

Individualizing antipsychotic drug therapy in schizophrenia: the promise of pharmacogenetics.

The first- and second-generation antipsychotic drugs have become mainstay drug treatment for schizophrenia. However, patients who receive antipsychotic drugs differ with respect to treatment response and drug-induced adverse events. The biological predictors of treatment response are being researched worldwide, with emphasis on molecular genetic predictors of treatment response. Because of the rapid and exciting developments in the field, we reviewed the recent studies of the molecular genetic basis of treatment response in schizophrenia. The accumulating data suggest that DNA information in the pathways for drug metabolism and drug target sites may be an important predictor of treatment response in schizophrenia. The data suggest that clinicians may soon be using a patient's genotype to decide initial choice of antipsychotic drug treatment in schizophrenia. The pharmacogenetics of schizophrenia can improve the prospects of individualized treatment and drug discovery. Pharmacogenetic investigations of schizophrenia susceptibility loci, and genes controlling drug target site receptors, drug-metabolizing enzymes, the blood-brain barrier systems, and epigenetic mechanisms could lead to a molecular classification of treatment response and adverse events of psychotropic drugs.

Neuropsychiatric effects of cocaine use disorders.

Individuals who use cocaine report a variety of neuropsychiatric symptoms that are yet to be adequately targeted with treatment modalities. To address this problem requires an understanding of these symptoms and their neurobiological origins. Our paper reviewed the existing data on the neuropsychiatic implications of cocaine. We conducted a Medline search from 1984-2004 using terms, such as "cocaine", "cocaine addiction", "cocaine abuse", "cocaine neuropsychiatry" and "dual diagnosis". The search produced additional reference materials that were used in this review, although we focused on data that have likely clinical implications. The literature evidence suggested that, whereas acute cocaine overdose is potentially fatal, the ingestion of mild-to-moderate doses could result in fatal or nonfatal neuropsychiatric events. Also, chronic cocaine use may be associated with deficits in neurocognition, brain perfusion and brain activation patterns. Some of these deficits were unresolved with periods of abstinence ranging from 3-200 days. Taken together, these studies suggest the need for further investigations to fully characterize the neurobiological substrates of cocaine use disorders (CUDs) with the future possibility of more efficient treatment modalities.

Genetics and psychopharmacology: prospects for individualized treatment.

This article provides a clear and succinct description of the components of inheritance, such as trait transmission, genetic variability, and gene interaction. Genetic sequences constitute the prime focus of pharmacogenetic studies. Variations in drug-metabolizing enzyme systems tend to be monogenic, whereas the pharmacologic effects of medications appear to be polygenic, i.e., complex phenotypes shaped by the interaction of genes and environment. Translated into clinical terms, a history of a good response to a drug in a close relative of a patient is presumed to predict a good response to the same medication by the patient. This seems to hold for antidepressants, antipsychotics, and lithium, but the evidential studies generally have meaningful limitations. Bit by bit, information about the relationship between particular genetic formations and the effectiveness of these medications as well as their side effects, is appearing. The authors cite a number of examples, one such being an association between impaired antidepressant activity and the short allele of SLC6A4. This research promises to strengthen the accuracy, effectiveness, safety, and cost of our psychopharmacological practices.

Pharmacogenetics in mood disorder.

PURPOSE OF REVIEW: Not all patients with mood disorder respond well to drug treatment. Emerging data suggest that genetic mechanisms could be involved. We searched the literature database and highlighted recent molecular genetic studies pertaining to drug response in mood disorders. RECENT FINDINGS: Recent pharmacogenetic studies in mood disorders have reported generally positive findings supporting the view that genotyping may improve the confidence of prospectively identifying treatment response and adverse outcomes. SUMMARY: The evidence documenting genotype-based response to drug treatment is rapidly expanding. Genes encoding target receptors and signal transduction systems may predict the efficacy of drug therapy in mood disorders. Additional predictors of treatment response in bipolar disorder may include the immediate early genes, mitochondrial genes and epigenetic mechanisms, although some of these studies are still preliminary.