Do Indian patients with schizophrenia need half the recommended clozapine dose to achieve therapeutic serum level? An exploratory study

Suhas, Satish; Kumar, Vijay; Dinakaran, Damodharan; Sharma, Priyamvada; Rao, Naren P.; Varambally, Shivarama; Venkatasubramanian, Ganesan; Murthy, Pratima; Gangadhar, Bangalore N.

doi:10.1016/j.schres.2020.05.057

Cited by 33 publications

(18 citation statements)

References 21 publications

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“…On the other hand, there are ethnic differences in pharmacokinetic profiles of clozapine[ 122 ]. More specifically, several studies among Asian patients have consistently indicated that they require about half the standard dose of clozapine due to their lowered clozapine metabolism[ 131 - 135 ]. The dose of clozapine required for adequate response among Asians varies from 150mg/d among women to 300 mg/d for men who smoke.…”

Section: Preventing Resistance To Clozapine Treatmentmentioning

confidence: 99%

Clozapine resistant schizophrenia: Newer avenues of management

Chakrabarti¹

2021

WJP

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About 40%-70% of the patients with treatment-resistant schizophrenia have a poor response to adequate treatment with clozapine. The impact of clozapine-resistant schizophrenia (CRS) is even greater than that of treatment resistance in terms of severe and persistent symptoms, relapses and hospitalizations, poorer quality of life, and healthcare costs. Such serious consequences often compel clinicians to try different augmentation strategies to enhance the inadequate clozapine response in CRS. Unfortunately, a large body of evidence has shown that antipsychotics, antidepressants, mood stabilizers, electroconvulsive therapy, and cognitive-behavioural therapy are mostly ineffective in augmenting clozapine response. When beneficial effects of augmentation have been found, they are usually small and of doubtful clinical significance or based on low-quality evidence. Therefore, newer treatment approaches that go beyond the evidence are needed. The options proposed include developing a clinical consensus about the augmentation strategies that are most likely to be effective and using them sequentially in patients with CRS. Secondly, newer approaches such as augmentation with long-acting antipsychotic injections or multi-component psychosocial interventions could be considered. Lastly, perhaps the most effective way to deal with CRS would be to optimize clozapine treatment, which might prevent clozapine resistance from developing. Personalized dosing, adequate treatment durations, management of side effects and non-adherence, collaboration with patients and caregivers, and addressing clinician barriers to clozapine use are the principal ways of ensuring optimal clozapine treatment. At present, these three options could the best way to manage CRS until research provides more firm directions about the effective options for augmenting clozapine response.

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Section: Preventing Resistance To Clozapine Treatmentmentioning

confidence: 99%

Clozapine resistant schizophrenia: Newer avenues of management

Chakrabarti¹

2021

WJP

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“…Beginning smoking is therefore a clinically relevant risk for relapse and inadequate response to clozapine treatment (9) and smoking cessation among clozapine users can induce severe clozapine intoxication (10). Ethnicity (Asian heritage) (11,12), gender (13), age (13)(14)(15), CYP-polymorphisms (16), caffeine (17), and comedication with clinically relevant CYP1A2-interaction (9) can also influence clozapine blood levels through the CYP-450 system. In this context, for example, people of Asian heritage are presumed to need a lesser clozapine dose compared with Caucasian or American populations (12,18) which might be due to a relatively reduced CYP1A2 activity (11).…”

Section: Introductionmentioning

confidence: 99%

“…Ethnicity (Asian heritage) (11,12), gender (13), age (13)(14)(15), CYP-polymorphisms (16), caffeine (17), and comedication with clinically relevant CYP1A2-interaction (9) can also influence clozapine blood levels through the CYP-450 system. In this context, for example, people of Asian heritage are presumed to need a lesser clozapine dose compared with Caucasian or American populations (12,18) which might be due to a relatively reduced CYP1A2 activity (11). On a similar note, the clinical relevance of CYP1A2 can be observed in smoking patients after transition to electronic cigarettes, where the termination of CYP1A2 induction also induces a clinically relevant increase in clozapine blood levels (19).…”

Section: Introductionmentioning

confidence: 99%

Impact of smoking behavior on clozapine blood levels – a systematic review and meta‐analysis

Wagner

McMahon

Falkai

et al. 2020

Acta Psychiatr Scand

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Objective Tobacco smoking significantly impacts clozapine blood levels and has substantial implications on individual efficacy and safety outcomes. By investigating differences in clozapine blood levels in smoking and non‐smoking patients on clozapine, we aim to provide guidance for clinicians how to adjust clozapine levels for patients on clozapine who change their smoking habits. Methods We conducted a meta‐analysis on clozapine blood levels, norclozapine levels, norclozapine/clozapine ratios, and concentration to dose (C/D) ratios in smokers and non‐smokers on clozapine. Data were meta‐analyzed using a random‐effects model with sensitivity analyses on dose, ethnic origin, and study quality. Results Data from 23 studies were included in this meta‐analysis with 21 investigating differences between clozapine blood levels of smokers and non‐smokers. In total, data from 7125 samples were included for the primary outcome (clozapine blood levels in ng/ml) in this meta‐analysis. A meta‐analysis of all between‐subject studies (N = 16) found that clozapine blood levels were significantly lower in smokers compared with non‐smokers (Standard Mean Difference (SMD) −0.39, 95% confidence interval (CI) −0.55 to −0.22, P < 0.001, I2 = 80%). With regard to the secondary outcome, C/D ratios (N = 16 studies) were significantly lower in the smoker group (n = 645) compared with the non‐smoker group (n = 813; SMD −0.70, 95%CI −0.84 to −0.56, P < 0.00001, I2 = 17%). Conclusion Smoking behavior and any change in smoking behavior is associated with a substantial effect on clozapine blood levels. Reductions of clozapine dose of 30% are recommended when a patient on clozapine stops smoking. Reductions should be informed by clozapine steady‐state trough levels and a close clinical risk‐benefit evaluation.

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“… 33 In a report by Suhas and colleagues on serum trough clozapine concentrations among 142 patients in India, the concentrations were within, below, and above the recommended range among 30.3%, 20.4%, and 49.3% of them. 34 Thus, approximately 20–30% of the samples have been reported to be within the recommended range regardless of geographical region, although samples were taken more than once in some patients in the former two studies. 12 , 33 On the other hand, the proportion of patients presenting with higher concentrations seems greater among Asian patients, as shown in our study and in Indian patients.…”

Section: Discussionmentioning

confidence: 99%

“… 12 , 33 On the other hand, the proportion of patients presenting with higher concentrations seems greater among Asian patients, as shown in our study and in Indian patients. 34 This may indicate that they require a higher concentration for successful treatment, or that they are excessively dosed in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive assessment of exposure to clozapine in association with side effects among patients with treatment-resistant schizophrenia: a population pharmacokinetic study

Nomura¹,

Kitagawa

et al. 2021

Therapeutic Advances in Psychopharmacology

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Background: There have been scarce data on the distribution of clozapine concentrations in comparison with the recommended range (350–600 ng/ml) or their relationship with side effects among patients with treatment-resistant schizophrenia. Furthermore, no studies have assessed the association between side effects and overall exposure to the drug by calculating the 24-h area-under-curve (AUC). Methods: In- and outpatients with schizophrenia or schizoaffective disorder (ICD-10) who were receiving a stable dose of clozapine for ⩾2 weeks were included. Side effects were assessed using the Glasgow antipsychotic side-effects scale for clozapine (GASS-C). Using two collected plasma samples, plasma clozapine and norclozapine concentrations at peak and trough and their 24-h AUC were estimated using population pharmacokinetic models. Results: A total of 108 patients completed the study (mean ± SD age, 43.0 ± 10.1 years; clozapine dose, 357.5 ± 136.9 mg/day); 33 patients (30.6%) showed estimated trough concentrations of clozapine within the recommended range (350–600 ng/ml) whereas the concentrations were higher and lower than this range among 37 (43.5%) and 28 (25.9%) patients (%), respectively. There were no significant correlations between estimated peak or trough concentrations or 24-h AUC of both clozapine or norclozapine, and GASS-C total or individual scores. No significant differences were found between GASS-C total or individual item scores between the patients with estimated trough concentrations of clozapine of >600 ng/ml and the other subjects. Conclusion: The results suggest that clozapine or norclozapine concentrations are not linked directly to the extent of side effects experienced in clozapine-treated patients with treatment-resistant schizophrenia while the cross-sectional study design limits the interpretation of any causal relationships. These findings indicate that side effects associated with clozapine may occur at any dose or concentration.

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Do Indian patients with schizophrenia need half the recommended clozapine dose to achieve therapeutic serum level? An exploratory study

Cited by 33 publications

References 21 publications

Clozapine resistant schizophrenia: Newer avenues of management

Clozapine resistant schizophrenia: Newer avenues of management

Impact of smoking behavior on clozapine blood levels – a systematic review and meta‐analysis

Comprehensive assessment of exposure to clozapine in association with side effects among patients with treatment-resistant schizophrenia: a population pharmacokinetic study

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