The relationship between plasma clozapine concentration and clinical outcome: a cross‐sectional study

Yada, Yuji; Kitagawa, Keisuke; Sakamoto, Shinji; Ozawa, Atsushi; Nakada, Akihiro; Kashiwagi, Hiroko; Okahisa, Yuko; Takao, Soshi; Takaki, Manabu; Kishi, Yoshiki; Yamada, Norihito

doi:10.1111/acps.13264

Cited by 35 publications

(33 citation statements)

References 41 publications

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“…Eight high‐quality studies with 358 participants had data on clozapine dose as well as C/D ratio, with no difference between lower or higher clozapine dose or C/D ratio and response 17,18,20,23,24,26,30,35 . ( and ).…”

Section: Resultsmentioning

confidence: 99%

Clozapine levels as a predictor for therapeutic response: A systematic review and meta‐analysis

Siskind

Sharma

Pawar

et al. 2021

Acta Psychiatr Scand

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Objectives Clozapine levels may be a more useful predictor of therapeutic response than the dose, given the variability in clozapine metabolism between individuals. We therefore systematically reviewed and meta‐analysed the impact of clozapine levels on response and/or relapse to provide guidance on optimal clozapine levels. Methods We systematically searched PubMed, PsycInfo and Embase for studies exploring clozapine levels and response and/or relapse. Our primary meta‐analysis was rates of response above and below clozapine level thresholds of 350 ng/ml and 600 ng/ml. Secondary analyses were undertaken of mean clozapine levels, dose and concentration/dose (C/D) ratio and response and/or relapse. A meta‐regression by study duration was conducted. Results Twenty studies met inclusion criteria. Clozapine levels above 350 ng/ml were associated with statistically significantly higher rates of response (OR 2.27 95% CI 1.40–3.67, p < 0.001), but not above 600 ng/ml (OR 1.40 95% CI 0.85–2.31, p = 0.19). Higher mean clozapine levels were associated with better rates of response (SMD 0.24, 95% CI 0.00–0.49, p = 0.05), and lower rates of relapse (SMD −0.72, 95% CI −1.26 to −0.19, p = 0.008). By contrast, neither clozapine dose nor C/D ratio was associated with differing rates of response. Similarly, study duration did not affect outcome. Conclusions Our findings are in keeping with current guidelines that recommend targeting clozapine levels above 350 ng/ml before augmentation is considered. As some clozapine associated ADRs are dose dependent, levels above 600 ng/ml may have an unfavourable risk‐benefit ratio.

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Section: Resultsmentioning

confidence: 99%

Clozapine levels as a predictor for therapeutic response: A systematic review and meta‐analysis

Siskind

Sharma

Pawar

et al. 2021

Acta Psychiatr Scand

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“…It appears that a proportion of patients require a minimum level around 350 ng/ml, while others would require concentrations of around 650 ng/ml to achieve significant symptom reduction. A similar study 12 found higher clozapine plasma concentrations (above 1000 ng/ml) to be associated with better clinical response, however more adverse effects. The exact pharmacological mechanism by which clozapine exerts its clinical efficacy is still unknown.…”

Section: Discussionmentioning

confidence: 64%

“… 9 Yet substantial conflicting data exist regarding any relationship between clozapine plasma concentrations and therapeutic response. 10 – 12 …”

Section: Introductionmentioning

confidence: 99%

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Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

Krivoy

Whiskey

Webb-Wilson

et al. 2021

Therapeutic Advances in Psychopharmacology

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Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement.

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“…However, the total cumulative dose of clozapine achieved after six months of treatment was significantly describing the exposure to the drug, taking into account both the dose and time. Recently, higher clozapine doses, concentrations, and treatment durations were reported in responders as compared to non-responders [ 32 ]. Furthermore, waiting for a delayed clozapine response for persistent positive symptoms was recommended over plasma level-guided dose escalation in the recent consensus recommendations by the TRRIP working group [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

A Repeated Time-to-Positive Symptoms Improvement among Malaysian Patients with Schizophrenia Spectrum Disorders Treated with Clozapine

et al. 2021

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Clozapine remains the drug of choice for resistant schizophrenia. However, its dose-response relationship is still controversial. The current investigation aimed to develop a repeated time-to-positive symptoms improvement following the onset of clozapine treatment in Malaysian schizophrenia spectrum disorder patients. Data from patients’ medical records in the Psychiatric Clinic, Penang General Hospital, were retrospectively analyzed. Several parametric survival models were evaluated using nonlinear mixed-effect modeling software (NONMEM 7.3.0). Kaplan–Meier-visual predictive check (KM-VPC) and sampling-importance resampling (SIR) methods were used to validate the final model. A total of 116 patients were included in the study, with a mean follow-up of 306 weeks. Weibull hazard function best fitted the data. The hazard of positive symptoms improvement decreased 4% for every one-year increase in age over the median of 41 years (adjusted hazard ratio (aHR), 0.96; 95% confidence intervals (95% CI), (0.93–0.98)). However, patients receiving a second atypical antipsychotic agent had four-folds higher hazard (aHR, 4.01; 95% CI, (1.97–7.17)). The hazard increased 2% (aHR, 1.02; 95% CI, (1.01–1.03)) for every 1 g increase in the clozapine six months cumulative dose over the median of 34 g. The developed model provides essential information on the hazard of positive symptoms improvement after the first clozapine dose administration, including modifiable predictors of high clinical importance.

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The relationship between plasma clozapine concentration and clinical outcome: a cross‐sectional study

Cited by 35 publications

References 41 publications

Clozapine levels as a predictor for therapeutic response: A systematic review and meta‐analysis

Clozapine levels as a predictor for therapeutic response: A systematic review and meta‐analysis

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

A Repeated Time-to-Positive Symptoms Improvement among Malaysian Patients with Schizophrenia Spectrum Disorders Treated with Clozapine

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