It appears that the current safety-related threshold is not supported by evidence. There may be an upper threshold for clinical response, beyond which chance of response falls off, although further studies are warranted.

Atypical antipsychotics may "directly" influence glucose homeostasis, increasing risk of type 2 diabetes independently of changes in adiposity. Animal models suggest direct effects after even a single dose of certain atypical antipsychotics on glucose dysregulation. Here, we investigated effects of a single-dose olanzapine (OLA) on glucose metabolism in healthy volunteers, thereby minimizing confounding effects of the illness of schizophrenia and adiposity. In a randomized double-blind crossover design, 15 subjects were administered 10 mg of OLA or placebo at 7:00 A.M. on separate study dates. A frequently sampled intravenous glucose tolerance test was initiated 4.25 hours later to assess changes in glucose homeostasis, including an index of insulin sensitivity, disposition index, glucose effectiveness, and acute insulin response to glucose. We also examined effects on cortisol, prolactin, fasting free fatty acids (FFAs), insulin-mediated suppression of FFAs, and adipocytokines (leptin, adiponectin, C-reactive protein, interleukin 6, and tumor necrosis factor α). Complete data for both visits were analyzed for 12 subjects. Olanzapine treatment significantly decreased glucose effectiveness (P = 0.041) and raised fasting glucose over 4.25 hours (P = 0.03) as compared to placebo. Olanzapine was associated with lower serum cortisol (P = 0.003), lower fasting FFA (P = 0.042), and increased prolactin levels (P < 0.0001). We therefore suggest that a single dose of OLA may invoke early changes in some parameters of glucose and lipid metabolism, as well as endocrine indices.

Clozapine remains the only treatment indicated in TRS, but it is dramatically underutilized. Clearly there are serious side effects associated with its use, and while the focus has historically been on hematologic concerns, we highlight other side effects that also demand systematic monitoring. Because it is the only effective treatment option we have for TRS, though, efforts must be implemented that ensure its use in this population while maximizing safety.

Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and is linked to a need for mandatory hematological monitoring. Besides agranulocytosis, other hematological aberrations have resulted in premature termination in some cases. Considering clozapine's role in immunomodulation, we proceeded to investigate the impact of clozapine on the following 3 main hematological cell lines: red blood cells, platelets, white blood cells (WBCs), and its differential counts. Data were extracted from patients initiated on clozapine between January 2009 and December 2010 at a single hospital. Patients with a preclozapine complete blood count, who were receiving clozapine during the 1-year follow-up period, were included in the present investigation. Counts of red blood cells, platelets, WBC, and its differential including neutrophils, lymphocytes, monocytes, eosinophils, and basophils were extracted and trajectories plotted. One hundred one patients were included in this study and 66 remained on clozapine at the end of 1 year. There was a synchronized but transient increase in WBC, neutrophils, monocytes, eosinophils, basophils, and platelets beginning as early as the first week of clozapine treatment. There were no cases of agranulocytosis reported in this sample, and five developed neutropenia. A spike in neutrophils immediately preceded the onset of neutropenia in three of the five. The cumulative incidence rates were 48.9% for neutrophilia, 5.9% for eosinophilia, and 3% each for thrombocytosis and thrombocytopenia. Early hematological aberrations are visible across a range of cell lines, primarily of the myeloid lineage. These disturbances are transient and are probably related to clozapine's immunomodulatory properties. We do not suggest discontinuing clozapine as a consequence of the observed aberrations.

Despite the product monograph recommendation, clozapine is frequently prescribed once daily in North America. Further studies are needed to compare clinical outcomes between once-daily vs. divided clozapine dosing.