Clozapine administration in clinical practice: once-daily versus divided dosing.

OBJECTIVE: While it is recommended that clozapine be administered in a divided dosing regimen, it is unclear whether this recommendation is followed in real-world clinical practice. In two large datasets, we examined clozapine dosing frequency and patient characteristics across different dosing regimens. METHOD: We conducted a cross-sectional survey, collecting data on patients receiving clozapine in August/September 2015 from the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada, and The Zucker Hillside Hospital (ZHH) in New York, United States. RESULTS: Of 676 and 308 patients included in CAMH and ZHH datasets, clozapine was prescribed once daily in 75.1% and 74.4%, even though doses exceeding 200 mg/day were administered in 88.6% and 84.4% of the respective samples. No significant difference was found in the rates of positive symptom remission between once-daily vs. divided dosing (79.7% vs. 80.5%, P = 1.00). Higher clozapine dose and use of anticholinergic medications were significantly associated with divided dosing in both datasets. Older age or male gender was related to divided dosing in CAMH or ZHH dataset respectively. CONCLUSION: 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.

Clozapine's critical role in treatment resistant schizophrenia: ensuring both safety and use.

INTRODUCTION: Clozapine was first introduced as an antipsychotic in the 1970's but a cluster of deaths, later linked to the drug's risk of agranulocytosis, led to its withdrawal in most countries. However, work in the 1980's established its unique efficacy in treatment resistant schizophrenia (TRS), which constitutes as many as 30% of those with the illness. Clozapine was reintroduced with this indication shortly thereafter, but because of this risk its use requires routine hematologic monitoring. AREAS COVERED: An update is provided regarding clozapine's risk of neutropenia, agranulocytosis, and associated mortality. In addition, updates are provided on other side effects, specifically myocarditis and bowel obstruction, as evidence suggests these are more common than agranulocytosis and associated with higher mortality rates. EXPERT OPINION: 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.

Motivated to do well: an examination of the relationships between motivation, effort, and cognitive performance in schizophrenia.

The uncertain relationship between negative symptoms, and specifically motivational deficits, with cognitive dysfunction in schizophrenia is in need of further elucidation as it pertains to the interpretation of cognitive test results. Findings to date have suggested a possible mediating role of motivational deficits on cognitive test measures, although findings from formal examinations of effort using performance validity measures have been inconsistent. The aim of this study was to examine the relationships between motivation, effort exerted during cognitive testing, and cognitive performance in schizophrenia. Sixty-nine outpatients with schizophrenia or schizoaffective disorder were evaluated for psychopathology, severity of motivational deficits, effort exerted during cognitive testing, and cognitive performance. Motivation and degree of effort exerted during cognitive testing were significantly related to cognitive performance, specifically verbal fluency, verbal and working memory, attention and processing speed, and reasoning and problem solving. Further, effort accounted for 15% of the variance in cognitive performance, and partially mediated the relationship between motivation and cognitive performance. Examining cognitive performance profiles for individuals exerting normal or reduced effort revealed significant differences in global cognition, as well as attention/processing speed and reasoning and problem solving. These findings suggest that cognitive domains may be differentially affected by impairments in motivation and effort, and highlight the importance of understanding the interplay between motivation and cognitive performance deficits, which may guide the appropriate selection of symptom targets for promoting recovery in patients.

Motivational and neurocognitive deficits are central to the prediction of longitudinal functional outcome in schizophrenia.

OBJECTIVE: Functional impairment is characteristic of most individuals with schizophrenia; however, the key variables that undermine community functioning are not well understood. This study evaluated the association between selected clinical variables and one-year longitudinal functional outcomes in patients with schizophrenia. METHOD: The sample included 754 patients with schizophrenia who completed both baseline and one-year follow-up visits in the CATIE study. Patients were evaluated with a comprehensive battery of assessments capturing symptom severity and cognitive performance among other variables. The primary outcome variable was functional status one-year postbaseline measured using the Heinrichs-Carpenter Quality of Life Scale. RESULTS: Factor analysis of negative symptom items revealed two factors reflecting diminished expression and amotivation. Multivariate regression modeling revealed several significant independent predictors of longitudinal functioning scores. The strongest predictors were baseline amotivation and neurocognition. Both amotivation and neurocognition also had independent predictive value for each of the domains of functioning assessed (e.g., vocational). CONCLUSION: Both motivational and neurocognitive deficits independently contribute to longitudinal functional outcomes assessed 1 year later among patients with schizophrenia. Both of these domains of psychopathology impede functional recovery; hence, it follows that treatments ameliorating each of these symptoms should promote community functioning among individuals with schizophrenia.

Impact of primary negative symptoms on functional outcomes in schizophrenia.

OBJECTIVE: Negative symptoms are known to undermine functional outcomes in people with schizophrenia; however, most studies have not accounted for whether these symptoms were primary or secondary to other psychopathological factors. The present study examined the impact of primary negative symptoms on functional outcomes in patients with schizophrenia. METHOD: The sample included 1427 patients with schizophrenia who completed the baseline visit in the CATIE study. Symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary Depression Scale, extrapyramidal side effects with the Simpson-Angus scale, and functional status with the Heinrichs-Carpenter Quality of Life Scale. RESULTS: Negative symptoms were significantly and inversely related to each domain of functioning examined. These relationships remained after statistically controlling for the influence of potential sources of secondary negative symptoms. In addition, the relationships between negative symptoms and specific domains of functioning remained in patients who had mild/absent positive, depressive, anxiety and extrapyramidal symptoms. Negative symptoms were associated with functional outcomes even in antipsychotic-free patients. CONCLUSIONS: Primary negative symptoms significantly contribute to the functional impairment seen in people with schizophrenia. A better understanding of the etiology and pathobiology of these symptoms is required to guide the search for effective therapeutics that promote functional recovery.