Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: This study was designed to evaluate the efficacy and safety of reduced B vitamins as monotherapy in adults with major depressive disorder (MDD) who were also positive for at least 1 methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with depression and further test the hypothesis that reduced (metabolized) B vitamins will lower homocysteine in a majority of clinically responding patients. METHODS: 330 adult patients with MDD (DSM-5) and positive for either MTHFR C677T or A1298C polymorphism were enrolled in a trial conducted between August 1, 2014, and April 3, 2015. 160 patients received placebo, while 170 received a capsule containing a combination of reduced B vitamins. Plasma homocysteine levels were measured at baseline and week 8. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate efficacy for MDD. RESULTS: 159 of 170 vitamin-treated patients and 123 of 160 placebo-treated patients were completers. Of the active treatment group, 131 (82.4%) showed a reduction in homocysteine (for a mean in this subgroup of 25%, P < .001), while 28 (17.6%) showed no significant change. Placebo patients demonstrated a small elevation in homocysteine. Active-treatment patients demonstrated, on average, a 12-point reduction on the MADRS by week 8, and 42% achieved full remission (P < .001). No side effect was significantly different between groups. No patients experienced mania. CONCLUSIONS: A combination of reduced B vitamins and micronutrients, when used in the treatment of MDD in patients with MTHFR polymorphism, resulted in a separation from placebo by week 2, and 42% of the treatment arm achieved remission by week 8. Further, clinical improvement correlated with a significant reduction in homocysteine levels in a majority of responders. These results support the homocysteine theory of depression and the safety and therapeutic benefit of reduced B vitamins as monotherapy for MDD, particularly in patients with MTHFR polymorphism. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02709668.

High-dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms: the ZEBRAS study.

Uncontrolled studies have suggested that increasing the dose of ziprasidone above the standard maximum daily dose of 160 mg may be more effective for some patients with schizophrenia. To test this hypothesis, we conducted an 8-week, placebo-controlled, fixed-dose escalation trial comparing ziprasidone 160 versus 320 mg/d in individuals with schizophrenia or schizoaffective disorder who remained symptomatic despite treatment with ziprasidone 160 mg/d for at least 3 weeks. Of 75 randomized patients, 42 completed the study. Serum ziprasidone concentrations increased significantly in the high-dose group compared with the standard-dose group at week 4 but did not differ between groups at week 8. Both treatment groups exhibited significant symptomatic improvement. Response did not differ between treatment groups; however, in the high-dose group, higher ziprasidone serum concentrations were associated with better response at a trend level. Higher ziprasidone concentrations were also associated with reductions in diastolic blood pressure and, at a trend level, with more prominent negative symptoms and greater QTc prolongation. In summary, increasing the ziprasidone dose to 320 mg/d did not produce a sustained elevation in serum concentrations or symptomatic improvement compared with a standard ziprasidone dose of 160 mg/d.

Ziprasidone monotherapy in bipolar II depression: an open trial.

BACKGROUND: The use of atypical neuroleptics for bipolar depression is currently being studied extensively. Given ziprasidone's favorable side effect profile as compared to other atypical neuroleptics, and the dearth of studies of this drug in depressed bipolar patients, we initiated an 8 week open monotherapy trial in bipolar II patients suffering major depressive episodes. METHOD: Patients met DSM IV criteria for bipolar II disorder, were in a major depressive episode, and had a 17 item HAM-D score of 18 or greater. Ziprasidone was begun at 20 mg bid and raised step wise to 60 mg bid if needed and tolerated. Change was assessed on the HAM-D (primary outcome measure), HAM-A, MADRS, YMRS, CGI-S, CGI-I, BDI and Q-LES-Q scales. Safety and tolerability were assessed. The study was approved by Asentral IRB and all patients gave written informed consent. RESULTS: Thirty patients (including 6 early terminators) completed the study. Significant improvement was seen at all visits on HAM-D, CGI-S and BDI (beginning week 1), and on MADRS and HAM-A (beginning week 2). Nine patients (30%) were responders and 5 (17%) remitters at week 1; 18 (60%) were responders and 13 (43%) remitters by the end of treatment. There was one serious AE's that was not study drug related, and no patient became manic. Occasional mild hypomania responded to dosage reduction. Mean end of study dose was 58 mg/day. LIMITATIONS: Given the small sample size and lack of placebo control, the results must be considered preliminary. CONCLUSIONS: Ziprasidone at a relatively low dose appears to be a rapid, effective and generally well tolerated treatment for bipolar II patients experiencing major depression. However, larger, placebo-controlled trials are needed to confirm these findings.