Gopal Vyas

Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms.

Objective Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes. Methods Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23). Results Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo. Conclusions Minocyclines effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

Current status of clozapine in the United States

Clozapine is the only antipsychotic in the United States that has been approved by the Food and Drug Administration (FDA) for treatment-resistant schizophrenia. It provides effective treatment even when patients do not respond to other secondgeneration antipsychotics. [1] It also remains the most effective antipsychotic available. No existing first or second-generation antipsychotic has been consistently found to be as effective as clozapine monotherapy in treatment-resistant patients. [2-6] Among patients who entered Phase 2 of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) because of lack of efficacy in Phase 1 of the study, those treated with clozapine (open label) averaged significantly greater time to treatment discontinuation (10.5 months) compared to patients treated with other antipsychotic medications (2.7-3.3 months). At three months, total symptom scores also improved to a significantly greater degree in the clozapine group compared to those treated with risperidone or quetiapine. [7] Similarly, in the open-label, randomized CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) trial, clozapine treatment was associated with significantly greater improvement in total scores of the Positive and Negative Symptom Scale (PANSS) and better patient subjective ratings compared to risperidone, olanzapine, quetiapine, and amisulpiride. [8] Another large, nonrandomized effectiveness study, the Schizophrenia Outpatient Health Outcomes (SOHO) study, also found clozapine to be superior on clinician and patient ratings at six months compared to other antipsychotics. [9] Based on clinical trials, meta-analyses, and large naturalistic studies clozapine is recommended as the most effective agent in schizophrenia, but the recommendations indicate that it should only be used when other agents fail. [5]

Clozapine in Reducing Aggression and Violence in Forensic Populations

Popular media often portray people with a mental illness as being aggressive, violent, and incarcerated as a result of their behavior. Despite exaggeration in the media, risks for some aggressive behaviors are in fact higher in individuals with schizophrenia. This is often the case with influence of comorbid substance use disorders. It is essential that mental health professionals are aware of treatments that may help with attenuating and treating behaviors that contribute to violence, aggression and incarceration. This paper reviews violence and incarceration in individuals with schizophrenia as well as recommendations, guidelines and benefits for the use of clozapine in this population. Clozapine remains one of the most underutilized evidence-based medications available in the psychiatric arena in the United States. It is a viable and recommended option in the forensic population and it may be helpful on the path to recovery as well as bring substantial savings to the criminal justice system.

Adjunct Aripiprazole Reduces Prolactin and Prolactin-Related Adverse Effects in Premenopausal Women With Psychosis: Results From the DAAMSEL Clinical Trial.

Purpose/Background Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes. Methods/Procedures Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5–15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored. Findings/Results Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain. Implications/Conclusions Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.

Evaluation of the Safety of Clozapine Use in Patients With Benign Neutropenia.

OBJECTIVE To determine if clozapine can be safely utilized in psychiatric patients with benign neutropenia. METHODS A single-center, retrospective chart review study of records from 2001 to 2014 was conducted in an inpatient psychiatric hospital. Patients included had benign neutropenia prior to receiving clozapine and received clozapine using modified monitoring guidelines. All available laboratory values for absolute neutrophil count (ANC) before initiation and during treatment were evaluated. The primary endpoint was difference in ANC after initiation of clozapine from before clozapine. RESULTS A total of 26 patients were reviewed. The mean age at clozapine initiation was 34 years. The majority were African-American (73% [n = 19]), with more men than women (73% [n = 19] vs 27% [n = 7]). The mean lowest ANC value was not significantly different after clozapine initiation compared to before (1.5× 10³ cells/mm³ and 1.4 × 10³ cells/mm³, respectively; P = .22). The overall mean ANC was significantly higher after initiation than before (2.63 × 10³ cells/mm³ and 2.13 × 10³ cells/mm³, respectively; P < .001). There were no cases of severe neutropenia (ANC < 0.5 × 10³ cells/mm³), and no patient was discontinued for falling below modified guideline limits. There were fewer occurrences of mild neutropenia (ANC < 2.0 × 10³ cells/mm³) after clozapine initiation than before (16.0% and 31.4%, respectively; P < .001). There were also fewer occurrences of moderate neutropenia (ANC < 1.5 × 10³ cells/mm³), with 2.1% after clozapine and 13.3% before (P < .001). CONCLUSIONS Twenty-six patients with benign neutropenia were safely treated with clozapine. Pre-clozapine neutropenia did not predict increased risk for severe neutropenia with clozapine. Patients had significantly fewer episodes of mild and moderate neutropenia after receiving clozapine compared to before.