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

Abstract

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.

Treatment resistance in psychiatry: state of the art and new directions

“…Co-prescription of psychiatric medications that act as CYP450 inducers (e.g., lamotrigine and carbamazepine) can reduce plasma levels of some antipsychotics [124] Co-prescription of psychiatric medications that act as CYP450 inducers (e.g., lamotrigine, carbamazepine) can reduce plasma levels of some antidepressants, including TCAs, SSRIs and bupropion [125] Liver drug metabolism: influence of co-prescribed physical health medication Co-prescription of medications that act as CYP450 inducers (e.g., omeprazole, phenytoin, St John's wort, rifampicin) can reduce plasma levels of some antipsychotics [122] Co-prescription of medications that act as CYP450 inducers (e.g., St John's wort, phenytoin) may reduce plasma levels of some antidepressants [126] Tobacco smoking Smoking reduces plasma levels of those antipsychotics metabolised via CYP1A2 (e.g., olanzapine, clozapine) [127] Smoking reduces plasma concentrations of various antidepressants [128] Sex Male gender predicts lower plasma levels of some antipsychotics [129] Male gender predicts lower plasma levels of some antidepressants [130] Alternative Diagnosis Symptoms of other disorders, such as bipolar affective disorder, obsessive compulsive disorder or autism spectrum disorder, may be mistaken for schizophrenia [31,32] A minority of apparently resistant unipolar depression may in fact be depression associated with bipolar disorder [33,34] Further evidence is provided in eTable 1.…”

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

“…Since the polycyclic aromatic hydrocarbons in tobacco smoke mainly affect CYP1A2, most data on smoking behavior and changes in plasma concentration pertain to SGAs such as clozapine and olanzapine, which are CYP1A2 substrates. In general, smokers have lower serum levels of clozapine and olanzapine than non-smokers when treated with the same oral dose [33,67,[213][214][215][216][217][218][219]. Published reports document 20-40% lower mean serum clozapine concentrations in smokers (up to 14 cigarettes per day) compared with nonsmokers due to enzyme induction [67].…”

“…Published reports document 20-40% lower mean serum clozapine concentrations in smokers (up to 14 cigarettes per day) compared with nonsmokers due to enzyme induction [67]. When a patient stops smoking, dose reduction of clozapine of 30-50% is recommended [213,215]. In a Chinese study of 354 adult psychiatric patients, olanzapine elimination was increased 1.23-fold by smoking [214]; therefore, Tsuda et al suggest that the dose of olanzapine should be reduced by 30% in non-smokers compared with smokers to obtain an equivalent olanzapine concentration [213].…”

“…Overall, blood levels are highly variable. In addition to smoking behavior and interindividual differences (e.g., genetic variations like a novel variant in the nuclear factor 1 B-type gene associated with reduced clozapine levels [220]) drug concentrations are also influenced by other factors such as age, gender, origin, and co-medication [214,215,[217][218][219]. However, previous research has demonstrated that, after clozapine dosage itself, smoking is the factor that most affects clozapine plasma concentration [67].…”

Addressing physical health in mental illness: the urgent need to translate evidence-based interventions into routine clinical practice

“…It is likely that lifestyle interventions alone would not be sufficient to counteract these adverse effects, and therefore, early use of interventions such as metformin are indicated (Siskind et al 2016). Targeting these lifestyle factors in those who are prescribed clozapine could derive multiple benefits, for example, employing strategies to reduce the prevalence of smoking (Siskind et al 2020), could result in achieving a therapeutic response with lower doses (Wagner et al 2020), which in turn could lead to less metabolic side effects. Additionally, addressing obstructive sleep apnea, which is highly prevalent in this population, as demonstrated in this issue (Myles et al 2020), could potentially lead to better mental health and physical outcomes.…”