Sertindole

Oral sertindole (Serdolect®) is an atypical antipsychotic approved in the EU for once-daily use in patients with schizophrenia who are intolerant to at least one other antipsychotic agent.

Extensive data from post-marketing studies do not indicate an excess of overall mortality with sertindole. Sertindole is at least as effective as haloperidol and risperidone in the treatment of neuroleptic-responsive schizophrenia. Sertindole improves negative symptoms, and is also effective for the treatment of neuroleptic-resistant schizophrenia. Sertindole is generally well tolerated and is associated with a low rate of extrapyramidal symptoms (EPS). Thus, sertindole is a useful option in the treatment of patients with schizophrenia.

The fundamental mechanism of sertindole action is considered to be selective inhibition of dopamine D₂ receptors in the mesolimbic system (ventral tegmental area) versus the nigrostriatum, together with inhibition of CNS serotonin 5-HT₂ receptors and α₁-adrenoceptors. Although sertindole is associated with QT interval prolongation, it appears that the drug has counter-regulatory properties that protect against ventricular arrhythmias. Sertindole had beneficial effects on cognitive functioning in animal models.

Sertindole is slowly absorbed after oral administration with a time to the maximum plasma concentration of ≈10 hours. The oral bioavailability of sertindole is ≈75%. Sertindole undergoes extensive hepatic metabolism by cytochrome P450 (CYP) 2D6 and CYP3A4 to two principal metabolites, dehydrosertindole and norsertindole. CYP2D6 poor metabolisers may have sertindole clearance reduced by ≈50–67%. Sertindole is almost completely eliminated in the faeces, with a mean terminal elimination half-life of 53–102 hours. Concomitant administration of sertindole and drugs that induce CYP isozymes may result in reduced plasma sertindole concentrations. The concomitant administration of sertindole and potent CYP3A inhibitors is contraindicated and sertindole should be used in combination with CYP2D6 inhibitors with extreme caution.

The efficacy of oral sertindole administered once daily to patients with schizophrenia has been examined in several randomised, double-blind trials.

Sertindole was effective in the treatment of neuroleptic-responsive schizophrenia, according to the results of a placebo-controlled dose-ranging study. Significantly greater improvements from baseline in Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) total scores were seen in recipients of sertindole 20 mg/day compared with placebo. In addition, the Clinical Global Impression-Improvement (CGI-I) score was significantly lower with sertindole 20 mg/day than with placebo.

Sertindole was at least as effective as haloperidol in the treatment of neuroleptic-responsive schizophrenia, according to the results of four trials. Significant improvements from baseline in PANSS and BPRS total scores were seen with both sertindole 12–24 mg/day (i.e. therapeutic dosages) and haloperidol 4–16 mg/day compared with placebo after 8 weeks’ treatment. No significant differences were seen between sertindole (at therapeutic dosages) and haloperidol in terms of improvements from baseline in PANSS or BPRS total scores after 8 or 52 weeks’ treatment. Compared with placebo, CGI-I scores at study end were significantly better with sertindole 12–24 mg/day and haloperidol 8 and 16 mg/day, with no significant difference between the active treatment groups. Significant improvements from baseline in the PANSS positive symptom subscale score occurred with sertindole 20 and 24 mg/day and haloperidol 4–16 mg/day compared with placebo, with no significant differences between sertindole (at therapeutic dosages) and haloperidol. Only sertindole 20 mg/day demonstrated a significantly greater improvement in both PANSS negative symptom subscale and Scale for the Assessment of Negative Symptoms (SANS) total scores, compared with placebo. There were generally no significant differences between active treatment groups in PANSS negative symptom subscale or SANS total scores after 8 weeks’ treatment, although the change from baseline in the PANSS negative component subscale score significantly favoured recipients of sertindole 16 mg/day versus haloperidol in one trial. In the longer-term trial, sertindole reduced the SANS total score from baseline significantly more than haloperidol after 2 months’ treatment, although there was no significant between-group difference after 12 months. In this trial, time to treatment failure was not significantly different between sertindole and haloperidol recipients. However, over 1 year, the times to psychotic decompensation with associated hospitalisation and to premature treatment discontinuation because of patient nonadherence were significantly longer in the sertindole than in the haloperidol group. Sertindole also improved aspects of cognitive functioning in patients with schizophrenia.

Sertindole was at least as effective as risperidone in patients with schizophrenia, according to the results of two trials. There was no significant difference between sertindole and risperidone recipients in the improvement from baseline in the PANSS total score in either patients with treatment-responsive or -refractory schizophrenia after 12 weeks’ treatment, according to the intent-to-treat last-observation-carried-forward analysis. However, in one of these trials, the observed cases analysis revealed a significantly greater decrease in PANSS total score in sertindole than risperidone recipients, as did a repeated-measurement analysis. Sertindole had similar efficacy to risperidone in terms of improvements from baseline in PANSS positive symptom subscale and CGI-Severity scores. In terms of PANSS negative symptom subscale scores, no significant difference between sertindole and risperidone recipients was seen in one study, although a significant difference favouring sertindole recipients was seen in the other trial.

From a tolerability database of approximately 2500 sertindole-treated patients, approximately 90% of patients experienced at least one treatment-emergent adverse event, yet the overall rate of treatment withdrawal because of such events was low. The most commonly occurring adverse events in sertindole recipients included headache, insomnia, rhinitis and abnormal ejaculation (i.e. decreased ejaculatory volume) in men.

Sertindole is associated with moderate weight gain (≈3kg) but is not associated with sedation or anticholinergic-mediated cognitive impairment, and did not increase plasma prolactin levels above the normal reference range. Only 4% of patients had clinically significant increases in serum glucose levels.

Both clinical trial data and epidemiological data revealed sertindole recipients to have all-cause mortality rates that were low (1.52 [95% CI 0.96, 2.13] per 100 patient-years of exposure [PYE] in clinical trials and 0.48 [95% CI 0.21, 0.94] to 2.34 [95% CI 0.94, 4.83] per 100 PYE in epidemiological studies) and generally similar to those in patients receiving other antipsychotics. Suicide rates among sertindole recipients were 0.37 (95% CI 0.15, 0.75) per 100 PYE in clinical trials and 0.12 to 0.73 (95% CI 0.15, 2.12) per 100 PYE in epidemiological studies. Cardiac mortality rates in sertindole recipients were also low (0.31 [95% CI 0.11, 0.68] per 100 PYE in clinical trials and 0.0–0.37 per 100 PYE in epidemiological studies) and similar to those seen in patients receiving other antipsychotics. There were no cases of ventricular arrhythmias or torsade de pointes reported in clinical trials or in epidemiological studies.

Sertindole was associated with a low rate of EPS-related adverse events, with no significant difference between sertindole and placebo recipients, according to the results of clinical trials. By contrast, haloperidol was generally associated with a significantly higher incidence of EPS-related adverse events than sertindole. Rates of medication use to control EPS were similar with sertindole and placebo and significantly lower with sertindole than with haloperidol. Changes from baselines in movement rating scale scores were generally similar in sertindole and placebo or risperidone recipients, although significantly greater improvements from baseline in Abnormal Involuntary Movement Scale, Barnes Akathisia Scale and Simpson-Angus Scale scores were seen with sertindole than with haloperidol.

Sertindole dominated both haloperidol and olanzapine over a 10-year period, according to the results of a Markov modelling study. In addition, prospective collection of resource utilisation data during a 1-year study revealed cost savings with sertindole compared with haloperidol in outpatients with schizophrenia. Sertindole also appeared to be associated with reductions in healthcare resource use in a nonblind, partly retrospective study.