Dale Warfel

Long-term outcome of patients who receive ketamine during research

BACKGROUND To comprehend the pathophysiology of schizophrenia and to facilitate drug discovery, animal and human models of schizophrenia are necessary. Ketamine, a noncompetitive N-methyl-D-aspartate antagonist, has been used to probe glutamatergic function in normal and schizophrenic volunteers. These studies and others have provided data consistent with a putative involvement of a glutamatergic dysfunction in the pathophysiology of schizophrenia; however, these studies have also raised concerns about the distress inflicted on patients, the potential for adverse events, and the serious long-term effects that could possibly be induced by symptom-simulating action. METHODS For all patient volunteers (n = 30) who participated in these studies, we reviewed the acute safety during and in the immediate postketamine administration. Patients available for long-term follow-up (n = 25) were matched to a group of patients (n = 25) who participated in research but did not receive ketamine. We compared their long-term outcome in terms of psychopathology, the need for psychiatric care, and the amount of antipsychotic medication required for optimal therapeutic response. RESULTS There were no serious adverse events in more than 90 ketamine interviews. Distress to patients was minimal, which is shown by the lack of anxiety ratings. Over a mean follow-up period of 8 months, we found no differences between patients who did and did not receive ketamine on any measures of psychopathology, psychiatric care, or the amount of antipsychotic medication. CONCLUSIONS In a controlled environment and paying close attention to subject safety features, administering subanesthetic doses of ketamine causes no adverse events and little distress to schizophrenic volunteers. This study strongly indicates that administering ketamine does not change any aspect of the course of schizophrenic illness.

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.

Treating symptomatic hyperprolactinemia in women with schizophrenia: presentation of the ongoing DAAMSEL clinical trial (Dopamine partial Agonist, Aripiprazole, for the Management of Symptomatic ELevated prolactin).

Prolactin elevations occur in people treated with antipsychotic medications and are often much higher in women than in men. Hyperprolactinemia is known to cause amenorrhea, oligomenorrhea, galactorrhea and gynecomastia in females and is also associated with sexual dysfunction and bone loss. These side effects increase risk of antipsychotic nonadherence and suicide and pose significant problems in the long term management of women with schizophrenia. In this manuscript, we review the literature on prolactin; its physiology, plasma levels, side effects and strategies for treatment. We also present the rationale and protocol for an ongoing clinical trial to treat symptomatic hyperprolactinemia in premenopausal women with schizophrenia. More attention and focus are needed to address these significant side effects and help the field better personalize the treatment of women with schizophrenia.