Factors affecting interindividual differences in clozapine response: a review and case report

Bersani, Francesco Saverio; Capra, E; Minichino, Amedeo; Pannese, Rossella; Girardi, Nicoletta; Marini, Isabella; Chiaie, Roberto Delle; Biondi, Massimo

doi:10.1002/hup.1191

Cited by 30 publications

(25 citation statements)

References 72 publications

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“…Moreover, clozapine doses exceeding 500–600 mg/day of clozapine could carry an increased risk of seizures 36. Because the smokers who were treated with clozapine were reported to suffer from serious central nervous side effects after smoking cessation,4 13–16 it is necessary to regulate the clozapine dosage carefully when smokers stop smoking or decrease the amount of smoking. Li et al (2012) applied non-linear mixed-effect modelling to characterise the PKs of clozapine in Chinese patients 37.…”

Section: Discussionmentioning

confidence: 99%

“…Clozapine has been widely used following its introduction, because it induces relatively few extrapyramidal effects, and it shows therapeutic benefits for patients who have failed to respond to other agents 3. Clozapine is absorbed rapidly and undergoes extensive hepatic metabolism 4. Various lines of evidence indicate that CYP1A2 and CYP3A4 play a significant role in the N -oxidation and N -demethylation of the compound, whereas CYP2D6 plays a minor role in N -demethylation 1 4…”

Section: Introductionmentioning

confidence: 99%

“…Clozapine is absorbed rapidly and undergoes extensive hepatic metabolism 4. Various lines of evidence indicate that CYP1A2 and CYP3A4 play a significant role in the N -oxidation and N -demethylation of the compound, whereas CYP2D6 plays a minor role in N -demethylation 1 4…”

Section: Introductionmentioning

confidence: 99%

“…Previous clinical studies with small numbers of patients with schizophrenia reported that smokers had an approximately fivefold lower dose-corrected steady-state plasma olanzapine concentration and a lower decrease in the Brief Psychiatric Rating Scale-total score than non-smokers 8 9. Meanwhile, although the relationship between the clozapine concentration and clinical outcome is controversial,10–12 it was also reported that smokers who were treated with clozapine suffered side effects (ie, auditory hallucinations, hallucinations, hypersalivation, drowsiness, clonic seizures, convulsions and unconsciousness) after smoking cessation 4 13–16…”

Section: Introductionmentioning

confidence: 99%

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Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine

2014

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ObjectiveTo clarify the effects of smoking on the disposition of two commonly used antipsychotics, olanzapine and clozapine, and to create standards to adjust the doses of these drugs in clinical practice based on the smoking status.DesignA meta-analysis was conducted by searching MEDLINE, Scopus and the Cochrane Library for relevant prospective and retrospective studies.Included studiesWe included the studies that investigated the effects of smoking on the concentration to dose (C/D) ratio of olanzapine or clozapine.Primary outcome measureThe weighted mean difference was calculated using a DerSimonian-Laird random effects model, along with 95% CI.ResultsSeven association studies, comprising 1094 patients (652 smokers and 442 non-smokers) with schizophrenia or other psychiatric disorders, were included in the meta-analysis of olanzapine. The C/D ratio was significantly lower in smokers than in non-smokers (p<0.00001), and the mean difference was −0.75 (ng/mL)/(mg/day) (95% CI −0.89 to −0.61). Therefore, it was estimated that if 10 and 20 mg/day of olanzapine would be administered to smokers, about 7 and 14 mg/day, respectively, should be administered to non-smokers in order to obtain the equivalent olanzapine concentration. Four association studies of clozapine were included in the meta-analysis of clozapine, comprising 196 patients (120 smokers and 76 non-smokers) with schizophrenia or other psychiatric disorders. The C/D ratio was significantly lower in smokers than in non-smokers (p<0.00001), and the mean difference was −1.11 (ng/mL)/(mg/day) (95% CI −1.53 to −0.70). Therefore, it was estimated that if 200 and 400 mg/day of clozapine would be administered to smokers, about 100 and 200 mg/day, respectively, should be administered to non-smokers.ConclusionsWe suggest that the doses of olanzapine and clozapine should be reduced by 30% and 50%, respectively, in non-smokers compared with smokers in order to obtain an equivalent olanzapine or clozapine concentration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine

2014

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“…A large body of evidence indicates that both patients with SCZ and those with BD present deficits in some constructs of SC, including ToM and emotional processing, and that these deficits may underlie those areas of the disorders that usually persist despite pharmacological treatments, such as low social functioning, affective flattening, disability, and cognitive deficits 1,12–15…”

Section: Introductionmentioning

confidence: 99%

Facial expression in patients with bipolar disorder and schizophrenia in response to emotional stimuli: a partially shared cognitive and social deficit of the two disorders

Bersani¹,

Polli²,

Valeriani³

et al. 2013

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IntroductionIt has recently been highlighted that patients affected by schizophrenia (SCZ) and those affected by bipolar disorder (BD) undergo gradual chronic worsening of cognitive and social functioning. The objective of the current study was to evaluate and compare (using the Facial Action Coding System [FACS]) the way by which patients with the two disorders experience and display emotions in relation to specific emotional stimuli.Materials and methodsForty-five individuals participated in the study: 15 SCZ patients, 15 BD patients, and 15 healthy controls. All participants watched emotion-eliciting video clips while their facial activity was videotaped. The congruent/incongruent feeling of emotions and the facial expression in reaction to emotions were evaluated.ResultsSCZ and BD patients presented similar incongruent emotive feelings and facial expressions (significantly worse than healthy participants); SCZ patients expressed the emotion of disgust significantly less appropriately than BD patients.DiscussionBD and SCZ patients seem to present a similar relevant impairment in both experiencing and displaying emotions; this impairment may be seen as a behavioral indicator of the deficit of social cognition present in both the disorders. As the disgust emotion is mainly elaborated in the insular cortex, the incongruent expression of disgust of SCZ patients can be interpreted as a further evidence of a functional deficit of the insular cortex in this disease. Specific remediation training could be used to improve emotion and social cognition in SCZ and BD patients.

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Alcohol intake potentiates clozapine adverse effects associated to CYP1A21C* in patients with refractory psychosis

Ortega-Vázquez

Mayén-Lobo

Montellano

et al. 2020

Drug Development Research

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Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation‐dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR = 3.55 CI95 = 1.041–12.269, p = .043) and demonstrated that this effect is doubled by concomitant alcohol consumption (OR = 7.9 CI95 = 1.473–42.369, p = .016). Clinicians should be aware of this information before starting CLZ use, when treating patients with refractory psychosis, who are alcohol drinkers and carriers of this genetic variant in order to prevent CLZ‐related adverse reactions. Nevertheless, our findings should be replicated in larger samples.

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Factors affecting interindividual differences in clozapine response: a review and case report

Cited by 30 publications

References 72 publications

Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine

Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine

Facial expression in patients with bipolar disorder and schizophrenia in response to emotional stimuli: a partially shared cognitive and social deficit of the two disorders

Alcohol intake potentiates clozapine adverse effects associated to CYP1A21C* in patients with refractory psychosis

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Factors affecting interindividual differences in clozapine response: a review and case report

Cited by 30 publications

References 72 publications

Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine

Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine

Facial expression in patients with bipolar disorder and schizophrenia in response to emotional stimuli: a partially shared cognitive and social deficit of the two disorders

Alcohol intake potentiates clozapine adverse effects associated to CYP1A2*1C in patients with refractory psychosis

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Alcohol intake potentiates clozapine adverse effects associated to CYP1A21C* in patients with refractory psychosis