The metabolism of many neuroleptics cosegregates catalyzed by the polymorphic cytochrome P450 CYP2D6. The population can be phenotyped into extensive metabolizers (EM) and poor metabolizers (PM) with respect to this enzyme's activity. PM are likely to achieve higher than average concentrations of neuroleptic drugs in plasma, with an increased risk of extrapyramidal side effects, possibly including tardive dyskinesia. Sixteen white schizophrenic patients who had developed tardive dyskinesia during long-term neuroleptic treatment were phenotyped with debrisoquine and genotyped by CYP2D6-specific DNA amplification and EcoRI restriction fragment length polymorphism analysis. Only 1 (6%) of the 16 patients had a PM genotype, 8 (50%) were homozygous, and 7 (44%) were heterozygous EM. None had a CYP2D6 genotype indicative of ultrarapid debrisoquine hydroxylation capacity. The patients were also phenotyped with mephenytoin, a probe drug for another polymorphic cytochrome P450, CYP2C19. One patient was a PM of S-mephenytoin, which corresponds to the frequency found in healthy white volunteers. In conclusion, there was no overrepresentation of PM of debrisoquine or of S-mephenytoin among the 16 patients with neuroleptic-induced tardive dyskinesia. However, the PM of debrisoquine had the highest score on the Simpson-Angus Rating Scale and the second highest on the Abnormal Involuntary Movement Scale, despite a very low neuroleptic dose. Also, the debrisoquine MR correlated significantly with the SARS score (rs = 0.685, p < 0.05, N = 10), indicating a relationship between the degree of impaired CYP2D5 activity and the severity of extrapyramidal side effects during neuroleptic treatment.

Haloperidol and several other antipsychotic drugs are at least partially metabolized by the polymorphic cytochrome P450 2D6 (CYP2D6). The interindividual variation in metabolic capacity of CYP2D6 might be of importance when dosing. In this study, 26 outpatients with schizophrenia and depot haloperidol as monotherapy were genotyped. The authors found 1 patient with no functional alleles, 8 with one functional allele, 16 with two functional alleles, and 1 with three functional alleles. The daily dose of haloperidol ranged from 0.45 to 14.29 mg. Steady state plasma concentrations were measured at peak (range, 1.6-67 nmol/L) and at trough (range, 1.0-49 nmol/L). The Positive and Negative Syndrome scale for Schizophrenia and the Extrapyramidal Symptom Rating Scale were used to evaluate the clinical effect. The authors found a clear correlation between haloperidol plasma concentration and number of active CYP2D6 alleles. No correlation was found between plasma concentration of haloperidol or number of CYP2D6 alleles and treatment outcome or side effects. A model to predict plasma concentration from dose and number of active CYP2D6 alleles was formed from the obtained data by means of multiple linear regression.

IntroductionLurasidone is an atypical antipsychotic that was approved in Europe in 2014 for the treatment of schizophrenia in adults aged ≥ 18 years. Clinical experience with lurasidone in Europe is currently limited, and there is therefore a need to provide practical guidance on using lurasidone for the treatment of adults with schizophrenia.MethodsA panel of European psychiatrists with extensive experience of prescribing lurasidone was convened to provide recommendations on using lurasidone to treat adults with schizophrenia.ResultsExtensive evidence from clinical trials and the panel’s clinical experience suggest that lurasidone is as effective as other atypical agents, with the possible exception of clozapine. Lurasidone is associated with a lower propensity for metabolic side effects (in particular, weight gain) and hyperprolactinaemia than most other atypical antipsychotics and has a relatively benign neurocognitive side effect profile. Patients switching to lurasidone from another antipsychotic may experience weight reduction and/or improvements in the ability to focus/concentrate. Most side effects with lurasidone (such as somnolence) are transitory, easily managed and/or ameliorated by dose adjustment. Akathisia and extrapyramidal symptoms may occur in a minority of patients, but these can be managed effectively with dose adjustment, adjunctive therapy and/or psychosocial intervention.ConclusionsGiven the crucial importance of addressing the physical as well as mental healthcare needs of patients, lurasidone is a rational therapeutic choice for adults with schizophrenia, both in the acute setting and over the long term.FundingSunovion Pharmaceuticals Europe Ltd.Electronic supplementary materialThe online version of this article (10.1007/s40120-019-0138-z) contains supplementary material, which is available to authorized users.

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