Parkinson's through a cultural lens: Diversity in disease expression and care.

Clozapine (CLO) is an atypical antipsychotic drug with proven efficacy in the treatment of treatment-resistant schizophrenia (TRS) and schizoaffective disorder [, ]. CLO is commonly used for maintenance treatment to prevent relapse of schizophrenia. Relapse prevention in chronically ill patients with schizophrenia is crucial, as their social functioning can deteriorate with repeated psychotic episodes [, ]. Most studies to date have shown that the use of CLO reduces rehospitalization and treatment discontinuation rates in severely ill patients with schizophrenia [, –]. However, not all available studies provide consistent results []. Some data suggest that the therapeutic response to CLO is dose-dependent at doses up to 600 mg/day and is related to blood drug levels, with higher efficacy observed at levels above 350 ng/ml [, ]. It should be noted that inter-individual rates of CLO metabolism can vary 45-fold. In addition, blood CLO levels may be affected by such factors as smoking, age, sex, concomitant use of certain drugs, ethnicity, and inflammation [–]. Therefore, therapeutic drug monitoring (TDM) is the recommended method for personalized CLO dose titration []. TDM involves measuring blood levels of CLO and norclozapine (N-desmethylclozapine, NCLO), which is the main metabolite of the drug [, , ]. Although plasma NCLO levels have not been shown to be independently associated with clinical response [], the clozapine-to-norclozapine ratio (CNR) represents an important complementary parameter in TDM interpretation of CLO levels, as it may reflect CLO metabolism, treatment adherence, and potential drug–drug interactions [–]. Moreover, NCLO blood levels have been associated with adverse effects linked to impaired functioning, which may be related to reduced treatment adherence []. Unfortunately, there are currently no widely accepted international guidelines recommending routine TDM during long-term outpatient CLO treatment. A recent paper providing pragmatic guidelines for CLO titration identified long-term TDM during the maintenance phase as an area requiring future guidance []. A handful of studies using TDM in CLO maintenance therapy focused on assessing the CLO and NCLO blood levels at which remission was observed during follow-up [–]. In most of those studies, relatively small groups of patients underwent long-term TDM in order to detect a CLO (or NCLO) concentration associated with an elevated risk of relapse. However, rigorous prospective TDM protocols involving monthly blood sampling for 1–2 years [, ] can only be used in stabilized patients who are willing to participate in long-term studies or are treated at specialized tertiary-care centers []. Prospective TDM protocols can easily produce unreliable data in case of numerous withdrawals or missed blood-sampling visits. Moreover, in many clinical situations, TDM is temporarily used in inpatient settings during periods of CLO dose titration and is rarely extended into outpatient care []. Finally, in many countries, clinicians have no ready access to TDM even during CLO dose titration []. Therefore, in the present study, we investigated whether baseline serum CLO and NCLO levels measured only during hospitalization could predict the occurrence of psychiatric readmission. Determining the rate of rehospitalization has been one of the most commonly and systematically used methods for measuring relapse in schizophrenia, particularly in retrospective studies based on registry data [, –].