Atypical Antipsychotics: A Practical Review

Donna A. Wirshing, MD, William C. Wirshing, MD, Stephen R. Marder, MD, C. Scott Saunders, MD, Elizabeth H. Rossotto, PhD, Stephen M. Erhart, MD

Disclosures

Medscape Psychiatry & Mental Health eJournal. 1997;2(5) 

In This Article

Sertindole

Sertindole is an arylpiperidylindole antipsychotic with affinity for 5-HT2c, 5-HT2a, D2, alpha1, and alpha2 receptors (Table I). It will probably be introduced in the US in late 1997. Sertindole is metabolized by CYP2D6 and CYP3A3/4, which indicates that it may have possible pharmacokinetic interactions with a number of drugs, including SSRIs and antidepressants.

A number of double-blind studies (728 patients combined) using both fixed and flexible doses of sertindole have been conducted.73-75 In a study in which dose was determined by the clinician,[73] sertindole was compared with placebo in 38 patients. Patients who received sertindole demonstrated significantly greater improvement when compared with placebo. van Kammen and colleagues[74] compared 3 fixed doses of sertindole (8, 12, or 20mg/day) with placebo in 205 acutely ill patients with schizophrenia. The patients who received 20mg/day of sertindole had significantly more improvement than those assigned to placebo. Although the lower doses of sertindole were not significantly better than placebo, there is a suggestion of a dose-response relationship between 8 and 20mg.

The most important study of sertindole compared 3 fixed doses of sertindole (12, 20, and 24mg/day), 3 doses of haloperidol (4, 8, and 16mg/day), and placebo in 497 patients.[75] This was an 8-week trial carried out in the US and Canada. This 7-armed trial permitted dose-response evaluation of both haloperidol and sertindole within the same study population. Although costly, this design is the most thorough and fair comparison of 2 drug treatments. Using the total PANSS score to measure outcome, all of the active drug groups (including the 12-mg sertindole group) were superior to placebo. On PANSS positive symptoms, 20 and 24mg of sertindole and 8 and 16mg of haloperidol were superior to placebo. Only the group receiving 20-mg sertindole demonstrated significant improvement in negative symptoms.

Sertindole is being used in other psychotic illnesses. It is effective, according to 1 open-label study, in demented elderly patients[76] (Table II). Studies should be under way in the near future in first-break and treatment-refractory patients as well as in patients with affective disorders and other psychotic illnesses.

In clinical trials, the EPS profile of sertindole is very favorable (Table III). EPS was basically no greater for all doses of sertindole than it was for placebo.[77] In the study by Daniel and coworkers,[75] sertindole was actually associated with less EPS on most measures. These findings indicate that EPS will not be a noticeable side effect for patients treated with sertindole. Moreover, sertindole causes only mild increases in serum prolactin, with most treated patients not exceeding levels in the normal range.

Controversy now exists over the issue of cardiac-conduction abnormalities that were seen in patients treated with sertindole. In 1 report, 607 patients treated with sertindole experienced a mean 4% prolongation of the QT interval from baseline, with less than 1% of patients showing an interval >=500msec.[78] This effect has led to a concern that patients receiving sertindole may be vulnerable to developing a potentially fatal ventricular arrhythmia known as torsades des pointes. Thus far, there is a single case of this arrhythmia in a subject who overdosed on 720mg of sertindole. Of note, other antipsychotics can cause QT prolongation--in particular, thioridazine and risperidone. Even the high-potency compound haloperidol has been seen to cause torsades des pointes.

In the UK, where sertindole has been marketed since October 1996, electrocardiograms (ECGs) are recommended during the initiation of treatment and every 6 weeks thereafter. ECG monitoring is not mandatory, however. The FDA and Abbott Laboratories have not come to an agreement about the labeling of the medication and whether the cardiac conduction delay (QT-interval prolongation) will necessitate special warnings and/or recommendations.

Other common side effects of sertindole in the clinical trials were rhinitis and ejaculatory failure in men. van Kammen and associates[74] reported that 17% of men who received 20mg of sertindole daily reported a decrease in ejaculatory volume. This side effect is usually not associated with erectile disturbances or decreases in libido. Nevertheless, this is likely to be a serious concern of young men with schizophrenia who may view the drug as decreasing their sexual potency. Sertindole is also associated with orthostatic hypotension, particularly during the initial titration period.

In summary, sertindole is an effective antipsychotic that has minimal to no EPS when prescribed in doses up to 24mg. Most patients will probably require more than 12mg daily for an optimal response. Because of its tendency to cause orthostatic hypotension, sertindole should be started at 4mg/day and increased by 4mg every 2 to 3 days. Since it has a relatively long elimination half-life (1 to 4 days), once-daily dosing should be adequate. The most serious concern for clinicians is its tendency to prolong QT on ECG. At this early stage, it is unclear if this is a serious problem with the drug. Prior to starting this drug, men should be told about sertindole's tendency to decrease ejaculatory volume and reassured that this is a manageable side effect.

Sertindole has not yet been approved by the FDA. However, it has been well tested in hundreds of patients and is approved in the UK and several other European countries. Like risperidone, it has a narrow therapeutic range. According to most of the clinical trials data, the greatest improvement in positive and negative symptoms occurred at the higher doses, 20 and 24mg. Sertindole does not appear to have linear pharmacokinetics, so an increase of 4mg results in a substantially higher plasma level. As mentioned above, sertindole dosing should begin at 4mg and be increased by 4-mg doses every 2 to 3 days until 20mg is achieved. The only available data on demented patients suggest that 4mg is an effective dose.

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