Linkage disequilibrium mapping of the chromosome 6q21-22.31 bipolar I disorder susceptibility locus.

We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.

Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

OBJECTIVE: Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence. METHOD: The authors examined prospective data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression. RESULTS: Of 1,469 participants symptomatic at study entry, 858 (58.4%) subsequently achieved recovery. During up to 2 years of follow-up, 416 (48.5%) of these individuals experienced recurrences, with more than twice as many developing depressive episodes (298, 34.7%) as those who developed manic, hypomanic, or mixed episodes (118, 13.8%). The time until 25% of the individuals experienced a depressive episode was 21.4 weeks and until 25% experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence. CONCLUSIONS: Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence.

Baseline use of concomitant psychotropic medications to treat schizophrenia in the CATIE trial.

OBJECTIVE: This study examined the prevalence and correlates of concomitant psychotropic medications and use of anticholinergic drugs to treat schizophrenia. METHODS: Concomitant medication use was studied at baseline for participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. RESULTS: Of the 1,380 patients with baseline medication data, 82 percent were taking psychotropic medications. Of this group, 6 percent were taking two antipsychotics (one first generation and one second generation); 38 percent, antidepressants; 22 percent, anxiolytics; 4 percent, lithium, and 15 percent, other mood stabilizers. The strongest predictors of taking several medications were having anxiety or depression, being female, and taking second-generation antipsychotics. Conversely, African Americans and those with better neurocognitive functioning were less likely to be taking several concomitant psychotropic medications. In some cases symptoms that were likely targets of polypharmacy, such as depression, remained prominent, suggesting only partial response. CONCLUSIONS: Concomitant use of psychotropic medications to treat people with schizophrenia is common. Empirical data demonstrating the effectiveness of many of these agents for this population are lacking.

Quality of life during treatment with haloperidol or olanzapine in the year following a first psychotic episode.

OBJECTIVES: Schizophrenia causes significant impairments of quality of life. As treatment approaches have advanced, more attention has been given to re-integrating patients into their psychosocial environments, rather than simply monitoring psychotic symptoms. The development of the second-generation antipsychotics raised hope that these medications would provide better quality of life improvement than conventional antipsychotics. This improvement is particularly relevant early in the course of schizophrenia. METHODS: To address these considerations, improvements in measures of general health and social function (determined using the SF-36) were assessed in 195 patients with first-episode schizophrenia for up to one year following randomization to either olanzapine or haloperidol in a double blind clinical trial. We hypothesized that olanzapine would demonstrate better improvement on these measures than haloperidol. In order to test this hypothesis, we used a repeated measure model with SF-36 scores as the outcome, and treatment group, time, time2, time-by-treatment group interaction, and time2-by-treatment group interaction as fixed effects. RESULTS: Both treatments demonstrated similar changes on the SF-36. Independent of treatment, patients demonstrated significant improvements in most of the SF-36 subscales, which approached normative scores by the end of one year of treatment. Forty-six of 100 olanzapine-treated patients and 37 of 95 haloperidol-treated patients completed the one year of this study (p<.4). CONCLUSIONS: These results suggest an important initial treatment goal for patients with new onset schizophrenic disorders, namely that they can expect to recover significant quality of life and social function at least initially in treatment.

The Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical comparison of subgroups with and without the metabolic syndrome.

UNLABELLED: The metabolic syndrome (MS) is highly prevalent among patients with schizophrenia (current estimates 35-40%), yet no data exist on the correlation of this diagnosis with illness severity, neurocognitive or quality of life measures in this population. METHODS: Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assignment of MS status was performed using an updated definition derived from the National Cholesterol Education Program (NCEP) criteria. Those with and without MS were compared on the basis of primary and secondary variables of interest from baseline data encompassing psychiatric, neurocognitive and quality of life measures. RESULTS: Of 1460 subjects enrolled at baseline, MS status could be reliably assigned for 1231 subjects, with a prevalence of 35.8% using the NCEP derived criteria. After adjustment for age, gender, race, ethnicity and site variance, those with MS rated themselves significantly lower on physical health by SF-12 (p < .001), and scored higher on somatic preoccupation (PANSS item G1) (p = .03). There were no significant differences between the two cohorts on measures of symptom severity, depression, quality of life, neurocognition, or self-rated mental health. Neither years of antipsychotic exposure nor alcohol usage were significant predictors of MS status when adjusted for age, gender, race, and ethnicity. CONCLUSIONS: The metabolic syndrome is highly prevalent in this large cohort of schizophrenia patients and is strongly associated with a poor self-rating of physical health and increased somatic preoccupation. These results underscore the need for mental health practitioners to take an active role in the health monitoring of patients with schizophrenia to minimize the impact of medical comorbidity on long-term mortality and on daily functioning. Outcomes data from CATIE will provide important information on the metabolic and clinical impact of antipsychotic treatment for those subjects with MS and other medical comorbidities.

Antidepressant augmentation using the N-methyl-D-aspartate antagonist memantine: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Intravenous N-methyl-d-aspartate (NMDA) antagonists have shown promising results in rapidly ameliorating depression symptoms, but placebo-controlled trials of oral NMDA antagonists as monotherapy have not observed efficacy. We conducted a randomized, double-blind, placebo-controlled trial of the NMDA antagonist memantine as an augmentation treatment for patients with DSM-IV major depressive disorder. METHOD: Adult outpatients with major depressive disorder and partial response or nonresponse to their current antidepressant (as indicated by a 17-item Hamilton Depression Rating Scale score of ≥ 16 at baseline) were randomized (from July 2006-December 2011) to add memantine (flexible dose 5-20 mg/d, with all memantine group participants reaching the dose of 20 mg/d) (n = 15) or placebo (n = 16) to their existing treatment for 8 weeks. The primary outcome, change in Montgomery-Asberg Depression Rating Score (MADRS), was evaluated with repeated-measures mixed effects models using last-observation-carried-forward methods. Secondary outcomes included other depression and anxiety rating scales, suicidal and delusional ideation, and other adverse effects. RESULTS: 84% of participants completed the trial, including 93% of participants receiving memantine. Participants receiving memantine did not show a statistically or clinically significant change in MADRS scores compared to placebo, either over the entire study (ß = 0.133, favoring placebo, P = .74) or at study completion (week 8 mean [SD] MADRS score change = -7.13 [6.61] [memantine]; -7.25 [11.14] [placebo]; P = .97). A minimal to small effect size (comparing change to baseline variability) favoring placebo was observed (Cohen d = 0.19). Similarly, no substantial effect sizes favoring memantine nor statistically significant between-group differences were observed on secondary efficacy outcomes. CONCLUSIONS: This trial did not detect significant statistical or effect size differences between memantine and placebo augmentation among nonresponders or poor responders to conventional antidepressants. While the small number of participants is a limitation, this study suggests memantine lacks substantial efficacy as an augmentation treatment for major depressive disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00344682.

Feasibility and pilot efficacy results from the multisite Cognitive Remediation in the Schizophrenia Trials Network (CRSTN) randomized controlled trial.

BACKGROUND: The true benefit of pharmacologic intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multisite studies using cognitive remediation at clinical trials sites has not been established. METHOD: 53 adult patients with DSM-IV schizophrenia from 9 university-affiliated sites were randomized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly Neuropsychological and Educational Approach to Remediation (NEAR) "bridging groups" or a control condition of computer games and weekly healthy lifestyles groups. Patients were expected to complete 3 to 5 one-hour sessions weekly for 40 sessions or 12 weeks, whichever came first. The primary outcomes were feasibility results as measured by rate of enrollment, retention, and completion rate of primary outcome measures. The study was conducted from July 2009 through January 2010. RESULTS: During a 3-month enrollment period, 53 (of a projected 54) patients were enrolled, and 41 (77%) met criteria for study completion. Thirty-one patients completed all 40 sessions, and all patients completed all primary outcome measures. Preliminary efficacy results indicated that, after 20 sessions, patients in the cognitive remediation condition demonstrated mean MATRICS Consensus Cognitive Battery composite score improvements that were 3.7 (95% CI, 0.05-7.34) T-score points greater than in patients in the computer-games control group (F(1,46) = 4.16, P = .047). At the end of treatment, a trend favoring cognitive remediation was not statistically significant (F(1,47) = 2.26, P = .14). CONCLUSION: Multisite clinical trials of cognitive remediation using the Posit Science Brain Fitness auditory training program with the NEAR method of weekly bridging groups at traditional clinical sites appear to be feasible. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00930150.

Metabolic profiles of second-generation antipsychotics in early psychosis: findings from the CAFE study.

OBJECTIVE: To further define the metabolic profiles of second-generation antipsychotics during the treatment of young patients with early psychosis, with a view to better inform prescribing clinicians. METHOD: Weight, body mass index (BMI), glucose, and serum lipids were measured in the 52-week Comparison of Atypicals for First Episode (CAFE) study, in which olanzapine, quetiapine, and risperidone were evaluated, and whose primary outcomes have been reported elsewhere. These metabolic data were analyzed using a mixed random coefficients model for continuous longitudinal measures and a logistic regression model for categorical responses. RESULTS: Of the 400 patients recruited, 31% were overweight and 18% were obese at baseline, and 17 (4.3%) patients met criteria for metabolic syndrome. After 12 and 52 weeks of treatment, weight gain >or=7% from baseline was reported in 29.2% and 50.0% of quetiapine-treated patients, 59.8% and 80.0% of olanzapine-treated patients, and 32.5% and 57.6% of risperidone-treated patients, respectively. Weight gain after 12 and 52 weeks of treatment was estimated as [Least Squares Mean (SE)] 15.6 (+/-1.1) and 24.2 (+/-1.9) lb for olanzapine, 8.6 (+/-1.1) and 14.0 (+/-1.9) lb with risperidone and 7.9 (+/-1.1) and 12.1 (+/-1.8) lb for quetiapine respectively. In women, greater weight gain occurred during risperidone treatment compared with quetiapine treatment. By week 52, increases in BMI >or=1 unit occurred with significantly higher frequency in olanzapine-treated patients compared with quetiapine- or risperidone-treated patients. By 52 weeks, treatment-emergent metabolic syndrome was reported in 51 individuals (13.4% of the total population), of whom 22 were receiving olanzapine, 18 quetiapine, and 11 risperidone. Risperidone was associated with the smallest elevations in triglyceride and total cholesterol levels. CONCLUSION: Weight gain and metabolic syndrome occur commonly even in young patients receiving antipsychotic treatment for early psychosis. Targeted interventions are therefore warranted from the onset of antipsychotic therapy.