Focus on Sertindole Ben Green , MB, ChB, MRCPsych

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Sertindole (Serdolect®, Serlect®, Esertia®) was a novel antipsychotic agent introduced in 1996 by Lundbeck.

Indications

Indications included paranoid, simple, hebephrenic and residual schizophrenia.

Studies have shown a significant improvement in comparison with placebos with respect to positive and negative symptoms.

Sertindole at doses of 20-24 mg/day also appears to be more effective at treating negative symptoms than haloperidol at low doses.

Pharmacology

Conventional antipsychotics eg chlorpromazine and haloperidol probably work as a consequence of their blockade of D₂ receptors within the Central Nervous System. Additional actions at other receptors account for many of the side effects traditionally associated with antipsychotics eg drowsiness, dry mouth, postural hypotension and blurred vision. Not only do these conventional antipsychotics act at a range of receptors, but their actions are not confined to any one portion of the CNS or indeed the body.

The ideal antipsychotic would therefore have a limited effect in terms of receptor and brain site activity and yet retain the same or superior antipsychotic ability.

Sertindole promises a restricted receptor and brain site activity. Its activity appears to be specific to D₂, 5-HT₂ and alpha-1 adrenergic receptors and largely confined to the limbic dopamine system of the brain (without inhibiting activity in the nigrostriatal dopamine system), at least in animal in vivo and in vitro studies.

Sertindole is reported to have an anxiolytic property, to be not sedating and not to impair cognitive functions.

Studies

In phase II/III studies sertindole was evaluated in 1446 patients and was demonstrated to have a generally good tolerability.

Structure

Sertindole is a phenylindole derivative. Its chemical name is:
1-[2-4-[5-chloro-1-(4-flluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl-2-imidazolidinone

Pharmacodynamics and kinetics

Sertindole is well-absorbed when administered orally with good penetration of the blood-brain barrier. It is 99.5% plasma protein bound.

Its elimination half-life is three days. Sertindole is metabolised in the liver mediated by cytochromes p450 2D6 and P450 3A.

Some individuals withe reduced P450 2D6 metabolism have a 33-50% reduced clearance of sertindole. Co-administration of fluoxetine or paroxetine may increase sertindole plasma levels. Co-administration of carbamazepine or phenytoin my decrease serum levels.

Metabolites of sertindole do not appear to have any therapeutic effect.

Pharmacokinetics do not appear to be significantly affected by age, sex, race or renal impairment. Hepatic impairment implies that care is needed in calculating effective dosages.

Side Effects

The most common adverse effects in phase II/III studies were nasal congestion, decreased ejaculatory volume, dizziness and dry mouth. These adverse events did not appear to be dose-dependent.

Adrenergic side effects such as postural hypotension and sinus tachycardia tend to diminish with continued dosing.

Extrapyramidal symptoms do not exceed those of placebo.

There appears to be no tendency to increase or initiate tardive dyskinesia or akathisia.

There is some evidence to suggest short-term prolactin increases in some, patients. These are not generally clinically significant. Some patients show a rise in SGPT/ALT levels.

Weight changes are of major concern to many patients taking antipsychotics. In long-term studies sertindole increases body mass by about 5%.

The QT interval on ECG may be prolonged. European restrictions include ECG monitoring before and during sertindole therapy i.e. at 1-2 weeks, after 4-6 weeks, after 6 months and yearly thereafter.

Cautions

Sertindole is contraindicated with drugs known to prolong the QT interval like terfenadine, astemizole, thioridazine, quinidine, procainamide, betrylium, sotalol, tricyclic and teteracyclic antidepressants.

It is also containdicated in patients who have 'significant' cardiac disease, uncorrected hypokalaemia, hepatic impairment, pregnancy and lactation

Dose range

The clinically effective dose range is 12-20mg/day, however some patients may require up to 24 mg/day. Administration is once daily.

The initial dose should be at 4mg/day, increasing by 4mg steps every 4-5 days to 12-20mg depending upon clinical response. slower dose titration may be required in the elderly, because of postural hypotension.

Update

Presentations on Sertindole from the Lundbeck Schizophrenia Congress, Vittel, France, September 24th-26th 1996.

Daniel Casey, Department of Veteran Affairs, USA Older antipsychotics had a narrow therapeutic/toxic index. The novel antipsychotics had therefore a goal of a separation between the dose-response curve for antipsychotic and EPS inducing curves.

The pathophysiology of EPS include Ach, 5-HT, and D2 receptors. When 80% of D2 receptors are blocked EPS start to appear. Strategic to develop new antipsychotics and reducing EPS would therefore look at altering dopamine blockade and use of partial receptors agonists, and neuroanatomic selective blockade (reducing striatal blockade).

Sertindole spares these striatal dopamine receptors, has a reduced tendency to induce catalepsy in rodents and EPS in primates.

However, the separation between antipsychotic and EPS dose response curves is still not as great as that of clozapine, which does not produce EPS at even grossly elevated doses. Sertindole presents an advance towards this ideal.

Professor T Hale (Sheffield, UK)

5 pivotal double blind studies comparing sertindole with placebo and haloperidol. DSM diagnoses of inpatients. M93-113 Landmark study with dose ranges of sertindole and dose ranges of haloperidol (unusually) which also showed an effective minimum dose for haloperidol of 3-7.5mg daily for producing legitimate antipsychotic effects. That is to say that doses of haloperidol need to be much lower generally. Unfortunately EPS start coming in at doses of haloperidol a low as 4mg daily.

PANSS negative subscale reductions found at 20 mg sertindole.

Second pivotal US study (M93-098) found significant reduction in negative symptoms on PANSS at 24mg a day.

93302 Europe study (n=617) found that negative symptoms dropped with 16-24 mg of sertindole.

Onset of action for negative symptoms is later than for positive symptoms - about 6 weeks

Long-term CGI improvements appear and continue over the first 6 months with sertindole.

As might be expected clinicians use anti-EPS medication with sertindole no more than with placebo.

Dr C Muldoon (Medical Director, Lundbeck, UK)

Sertindole discovered by Lundbeck 1985. Clinical trials in Europe, US, Canada and Japan. Licence application within 6 years - considerably faster than many drugs.

2194 studied patients on company database. Up to 2 years of treatment in some cases. 74% were male.

Alpha effects lead to nasal congestion (27%) and decreased ejaculatory volume in 13%, dizziness in 12%.. Prolongation of QT interval in about 2%

Reduced akathisia and other EPS than haloperidol and similar to placebo.

Mortality rate not higher than would be expected in a similar population. Appears to be relatively safe in overdose on its own.

No evidence of ventricular arrhythmia noted. Weight increase of 5% noted

Drug clearance reduced by 50% in hepatic impairment.

Professor J M Kane (Hillside Hospital, New York, US)

About 68% of patient treated with conventional antipsychotics are poor or partial responders at 4 weeks.

Waiting to see response on further treatment with the same drug or switching to another conventional drug did not work so well. Switching to an atypical or newer antipsychotic may be more appropriate than waiting or switching to another conventional antipsychotic.

There is a real need for studies that compare novel antipsychotics against each other as opposed to using older drugs in trials.

Novel antipsychotics in recent times (risperidone, quetiapine, olanzapine, clozapine, sertindole) suggest reduced EPS and improvements in negative symptoms.

The clinical role for sertindole
Dr Tonmoy Sharma
Institute of Psychiatry, London, UK


"Sertindole is licensed for the treatment of acute and chronic schizophrenia
and schizoaffective psychoses including positive and negative symptoms. The
advantages of sertindole over current classical antipsychotics include lack
of sedation, no significant effects on serum prolactin levels and,
especially, efficacy against negative as well as positive symptoms together
with an extraphyamidal symptom (EPS) profile indistinguishable from placebo.

Sertindole therefore has an ideal profile for patients maintained
inadequately on their existing therapy, either due to lack of efficacy or
intolerable side-effects. However, these benefits are not confined to
existing patients. New patients should also benefit from more effective and
better tolerated drugs. Improvements in symptoms together with only mild
and well tolerated side-effects, especially placebo-level EPS, should give
the patient confidence in the need for continuing treatment, and may improve
compliance in the long-term. This may, in turn, result in economic
advantages. Indeed, a US study revealed a significant reduction in the
number of days spent in hospital by patients receiving sertindole compared
with patients receiving 'usual care' including available antipsychotics.
This reduction was not reflected by an increased use of outpatient
resources. Mild prolongation of the QT interval is seen in a very small
number of patients. Any risks which may be associated with this phenomenon
can be controlled effectively by performing a pre-treatment ECG to exclude
patients whose QT interval is already prolonged, and by avoiding
co-administration of drugs also known to have this effect.

Postural hypotension can occur if treatment is initiated too quickly. Tolerance to
this effect develops rapidly and can be avoided by following the initial
dose titration schedule while checking blood pressure during this titration
phase and during early follow-up on maintenance doses. This can be
accomplished with the patient in hospital or in the community."

Percentage Preference in Psychiatry On-Line Prescribers' Antipsychotic Survey c. 1997.

Comment: Sertindole's post-launch ECG strictures have adversely affected its place in people's preference. Initially sertindole was picking up well, but this accelerating trend was halted by concern expressed about its effects on ECG findings. The product appears not to have recovered, although a long-term growth in popularity may gradually occur.

Conclusion

Sertindole, introduced in 1996, is an antipsychotic drug given orally in doses of 12-20 mg once a day. It has a reduced side effect profile compared to standard antipsychotics and has effect against positive and negative effects of schizophrenia. It has been shown to reduce usage of inpatient services without a corresponding increase in out patient service usage.

In its early days of marketing life it is too early yet to judge its likely impact in the field or to be certain that there are not hitherto unknown adverse problems. The likelihood is that this drug represents a minor, but significant advance in the management of schizophrenia.

There is a real need for studies that compare novel antipsychotics against each other as opposed to using older drugs in trials.

References

Casey D E (1996) Behavioral effects of sertindole, risperidone, clozapine and haloperidol in Cebus monkeys. Psychopharmacology,124,134-140.

Coenen AML, Ates N, Skarsfeldt T, van Luitejelaar ELJM. (1995) Effects of sertindole on sleep-wake states, electroencephalogram, behavioural patterns and epileptic activity of rats. Pharmaco. Biochem. Rev, 51, 353-357.

Domeny AM, Arnt J, Costall B, Naylor RJ, Sánchez C, Smith Ag. (1994) Effect of sertindole on raised mesolimbic dopaminergic activity in the rat. Drug.Dev.Res., 31, 175-185.

Larsen F et al (1996) Pharmacokinetics of sertindole in relationship to CY2D6 and CYP2C19 polymorphism and CYP3A4 activity in healthy volunteers. 3rd Jerusalem Conference on Pharmaceutical Sciences and Clinical Pharmacology, Jerusalem 1996.

Nabulsi AA et al. (1996) Reduction of hospital days in sertindole treated patients - one year findings. Presented as a poster at 149th annual meeting of the American Psychiatric Association, New York, 4-9 May 1996.

Sánchez C et al. (1991) Neurochemical and in vivo pharmacological profile of sertindole, a limbic-selective neuroleptic compound. Drug Dev Res, 22(3), 2329-250.

Sánchez C et al. (1995) Sertindole: a limbic selective neuroleptic with potent anxiolytic effects. Drug Dev Res, 34, 19-29

Van Kammen DP et al. (1996) A randomised, controlled, dose-ranging trial of sertindole in patients with schizophrenia. Psychopharmacology, 124, 168-175.