A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis.

BACKGROUND: Clozapine is uniquely effective in treatment-resistant psychosis but remains underutilised, partly owing to psychotic symptoms leading to non-adherence to oral medication. An intramuscular formulation is available in the UK but outcomes remain unexplored. AIMS: This was a retrospective clinical effectiveness study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis over a 3-year period. METHOD: Successful initiation of oral clozapine after intramuscular prescription was the primary outcome. Secondary outcomes included all-cause clozapine discontinuation 2 years following initiation, and 1 year after discharge. Discontinuation rates were compared with a cohort prescribed only oral clozapine. Propensity scores were used to address confounding by indication. RESULTS: Among 39 patients prescribed intramuscular clozapine, 19 received at least one injection, whereas 20 accepted oral clozapine when given an enforced choice between the two. Thirty-six (92%) patients successfully initiated oral clozapine after intramuscular prescription; three never transitioned to oral. Eight discontinued oral clozapine during the 2-year follow-up, compared with 83 out of 162 in the comparator group (discontinuation rates of 24% and 50%, respectively). Discontinuation rates at 1-year post-discharge were 21%, compared with 44% in the comparison group. Intramuscular clozapine prescription was associated with a non-significantly lower hazard of discontinuation 2 years after initiation (hazard ratio 0.39, 95% CI 0.14-1.06) and 1 year after discharge (hazard ratio 0.37, 95% CI 0.11-1.24). The only reported adverse event specific to the intramuscular formulation was injection site pain and swelling. CONCLUSIONS: Intramuscular clozapine prescription allowed transition to oral maintenance in an initially non-adherent cohort. Discontinuation rates were similar to patients only prescribed oral clozapine and comparable to existing literature.

Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged 65 years and over: data from a therapeutic drug monitoring service, 1996-2010.

OBJECTIVE: To investigate the effect of dose and other factors on plasma clozapine concentrations in patients aged 65 years and over. METHOD: Audit of clozapine therapeutic drug monitoring data, 1996-2010. RESULTS: There were 1930 samples [778 patients, 363 men aged (median, range) 67 (65-100) years and 415 women aged 68 (65-90) years]. There was no significant difference in the mean plasma clozapine concentration between men (0.56 mg/l) and women (0.58 mg/l), although the mean dose was higher in men (323 mg/d) than women (264 mg/d). The higher proportion of men (46%) compared with women (37%) smokers could explain this finding. Overall, 32% of samples had plasma clozapine below, and 37% above, a target range of 0.35-0.60 mg/l. Overall, the median dose decreased from 300 (65-70 years) to 200 mg/d (age 85 years and over). However, prescription of >350 mg/d was associated with a 50% likelihood that the plasma clozapine would exceed 0.60 mg/l. For a subgroup of 196 patients (114 men, 82 women), mean plasma clozapine was significantly higher after age 65 despite significantly lower dosage. CONCLUSION: Clozapine dosage in elderly patients should be reviewed regularly to minimise the risk of adverse effects.

There Is Life After the UK Clozapine Central Non-Rechallenge Database.

BACKGROUND AND AIMS: In the United Kingdom, patients on clozapine whose hematological parameters fall below certain thresholds are placed on the Central Non-Rechallenge Database (CNRD), meaning that they cannot be prescribed clozapine again except under exceptional circumstances. This practice was discontinued in the United States in 2015 by expanding the hematological monitoring guidelines, allowing more patients to receive clozapine. Our objective was to investigate the implications this policy change would have on clozapine utilization in the United Kingdom. METHODS: This was an observational, retrospective analysis of patients registered on the CNRD in a large mental health trust. The first objective was to compare the number of patients placed on the CNRD under the United Kingdom and the US Food and Drug Administration (FDA) criteria. The second objective was to explore the hematological and clinical outcomes of CNRD patients. The third objective was to investigate the hematological outcomes of patients rechallenged on clozapine after nonrechallengeable status. RESULTS: One hundred and fifteen patients were placed on CNRD from 2002 to 2019, of whom 7 (6%) met the equivalent criteria for clozapine discontinuation under the FDA guidelines. Clinical outcomes, as measured by the Clinical Global Impression-Severity scale, were worse 3 months after clozapine cessation than on clozapine (t = -7.4862; P < .001). Sixty-two (54%) patients placed on CNRD were rechallenged. Fifty-nine of those (95%) were successfully rechallenged; 3 patients were placed back on CNRD, only one of which would have had to stop clozapine again under FDA criteria. CONCLUSION: Implementation of the updated FDA's monitoring criteria in the United Kingdom would significantly reduce clozapine discontinuation due to hematological reasons. The evidence suggests an urgent need for revising the UK clozapine monitoring guidelines to improve outcomes in treatment-resistant schizophrenia.

Real-world effectiveness of admissions to a tertiary treatment-resistant psychosis service: 2-year mirror-image study.

BACKGROUND: Treatment-resistant schizophrenia is a major disabling illness which often proves challenging to manage in a secondary care setting. The National Psychosis Unit (NPU) is a specialised tertiary in-patient facility that provides evidence-based, personalised, multidisciplinary interventions for complex treatment-resistant psychosis, in order to reduce the risk of readmission and long-term care costs. AIMS: This study aimed to assess the long-term effectiveness of treatment at the NPU by considering naturalistic outcome measures. METHOD: Using a mirror image design, we compared the numbers of psychiatric and general hospital admissions, in-patient days, acuity of placement, number of psychotropic medications and dose of antipsychotic medication prescribed before and following NPU admission. Data were obtained from the Clinical Records Interactive Search system, an anonymised database sourced from the South London and Maudsley NHS Trust electronic records, and by means of anonymous linkage to the Hospital Episode Statistics system. RESULTS: Compared with the 2 years before NPU admission, patients had fewer mental health admissions (1.65 ± 1.44 v. 0.87 ± 0.99, z = 5.594, P < 0.0001) and less mental health bed usage (335.31 ± 272.67 v. 199.42 ± 261.96, z = 5.195 P < 0.0001) after NPU admission. Total in-patient days in physical health hospitals and total number of in-patient days were also significantly reduced (16.51 ± 85.77 v. 2.83 ± 17.38, z = 2.046, P = 0.0408; 351.82 ± 269.09 v. 202.25 ± 261.05, z = 5.621, P < 0.0001). The reduction in level of support required after treatment at the NPU was statistically significant (z = -8.099, P < 0.0001). CONCLUSIONS: This study demonstrates the long-term effectiveness of a tertiary service specialising in treatment-resistant psychosis.