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

Abstract

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.

Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

“…Exploring our results further via sensitivity analyses, we saw little change in our schizophrenia PRS association by restricting the sample to only individuals of European genetic ancestry (n=2577; β= 11.46, [95% CI: 3.169-19.75], P = 0.007), and established that this result is specific to schizophrenia genetic liability by assessing a wider range of psychiatric, cognitive and personality PRS, none of which were significantly associated with clozapine doses (Supplementary Figure 2). We also confirmed that our main detected effects were still consistent and significant when restricting our dataset to observations at clozapine plasma concentration thresholds investigated in previous research on therapeutic response to the drug (20), either between 350-600 ng/L (n= 1089; β= 14.952, [95% CI: 3.167-26.737], P= 0.0131) or above (n= 1283; β= 17.258, [95% CI: 5.823-28.692], P= 0.0031).…”

“…We hypothesized that, given official prescription guidelines suggesting that once in the therapeutic dose range, doses should only be increased in case of non-response to the treatment, it is reasonable to postulate that higher dosing could be a proxy phenotype for poorer treatment response in the absence of adverse effects. Although this hypothesis cannot be formally tested in our data, previous studies have suggested that individuals requiring higher doses of clozapine could be an indicator of poor treatment response (20). In any case, our results show that individuals with a high schizophrenia PRS are more likely to be prescribed a high clozapine dose.…”

“…Clinical caution to avoid adverse effects, which even in mild instances can be debilitating, might also lead to individuals spending weeks or months on a given dose without apparent benefits before they are escalated to a higher one (19). Additionally, simply increasing clozapine doses does not warrantee better responses to the drug, with meta-analytic evidence pointing to the need of taking drug metabolism into account in clinical practice (20). In this sense, therapeutic drug monitoring (TDM) schemes, when available, can facilitate fine-tuning clozapine metabolite concentrations (or “levels”) for optimal response, but are particularly suited for the identification of extremely poor or rapid metabolizers (21), a subset of the general population that does not fully account for the rate of clozapine non-responders (22).…”

Clozapine blood level assessment using a point-of-care device: feasibility and reliability

“…Serum drug levels are affected by age, medical conditions, genetics, drug-drug interactions, and pharmacokinetic variability; all can differ immensely between patients and during the patient’s life course. 7 Clozapine blood levels are correlated with clinical outcome: response is associated with blood levels above 350 ng/ml, 9 , 10 whereas levels higher than 600 ng/ml might be associated with increased risk to develop side effects. 10 Yet, measuring clozapine levels is complicated and often avoided.…”

“… 7 Clozapine blood levels are correlated with clinical outcome: response is associated with blood levels above 350 ng/ml, 9 , 10 whereas levels higher than 600 ng/ml might be associated with increased risk to develop side effects. 10 Yet, measuring clozapine levels is complicated and often avoided. The current available customary analytic method of liquid chromatography tandem mass spectrometry (LC-MS/MS) requires transportation to a special lab and a multistep analysis process that may take several days.…”