Sertindole

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Sertindole, sold under the brand name Serdolect among others, is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.

Sertindole is not approved for use in the United States and was discontinued in Australia in January 2014.Template:Citation needed

Medical Uses

Sertindole appears effective as an antipsychotic in schizophrenia.<ref>Template:Cite journal</ref> In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, sertindole was found to be slightly less effective than haloperidol, quetiapine, and aripiprazole, as effective as ziprasidone, approximately as effective as chlorpromazine and asenapine, and slightly more effective than lurasidone and iloperidone.<ref name=Lancet>Template:Cite journal</ref>

Adverse effects

Very common (>10% incidence) adverse effects include:<ref name = "TGA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• Headache
• Ejaculation failure
• Insomnia
• Dizziness

Common (1–10% incidence) adverse effects include:<ref name = "TGA" />

• Urine that tests positive for red and/or white blood cells
• Sedation (causes less sedation than most antipsychotic drugs according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs. Causes only slightly [and non-significantly] more sedation than amisulpride and paliperidone)<ref name=Lancet/><ref name="Maudsley">Template:Cite book</ref>
• Ejaculation disorder
• Erectile dysfunction
• Orthostatic hypotension<ref name = "Maudsley" />
• Weight gain (which it seems to possess a similar propensity for causing as quetiapine)<ref name=Lancet/>

Uncommon (0.1–1% incidence) adverse effects include:<ref name = "TGA" /> Template:Div col

• Substernal chest pain
• Face oedema
• Influenza-like illness
• Neck rigidity
• Pallor
• Peripheral vascular disorder
• syncope
• Torsades de pointes
• Vasodilation
• Suicide attempt
• Amnesia
• Anxiety
• Ataxia
• Confusion
• Incoordination
• Libido decreased
• Libido increased
• Miosis
• Nystagmus
• Personality disorder
• Psychosis
• Reflexes decreased
• Reflexes increased
• Stupor
• Suicidal tendency
• Urinary retention
• Vertigo
• Diabetes mellitus
• Abnormal stools
• Gastritis
• Gingivitis
• Glossitis
• Increased appetite
• Mouth ulceration
• Rectal disorder
• Rectal haemorrhage
• Stomatitis
• Tongue disorder
• Ulcerative stomatitis
• Anaemia
• Ecchymosis
• Hypochromic anaemia
• Leukopenia
• Hyperglycaemia
• Hyperlipemia
• Oedema
• Bone pain
• Myasthenia
• Twitching
• Bronchitis
• Hyperventilation
• Pneumonia
• Sinusitis
• Furunculosis
• Herpes simplex
• Nail disorder
• Psoriasis
• Pustular Rash
• Skin discolouration
• Skin hypertrophy
• Skin ulcer
• Abnormal vision
• Keratoconjunctivitis
• Lacrimation disorder
• Otitis externa
• Pupillary disorder
• Taste perversion
• Anorgasmia
• Penis disorder (gs)
• Urinary urgency
• Hyperprolactinaemia (which it seems to cause with a higher propensity than most other atypical antipsychotics do)<ref name=Lancet/>
• Seizures
• Galactorrhoea

Rare (<0.1% incidence) adverse effects include:<ref name = "TGA" />

• Neuroleptic malignant syndrome
• Tardive dyskinesia

Unknown frequency adverse events include:<ref name = "TGA" />

• Extrapyramidal side effects (EPSE; e.g. dystonia, akathisia, muscle rigidity, parkinsonism, etc. These adverse effects are probably uncommon/rare according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs which found it had the 2nd lowest effect size for causing EPSE)<ref name=Lancet/>
• Venous thromboembolism
• QT interval prolongation (probably common; in a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to be the most prone to causing QT interval prolongation)<ref name=Lancet/>

Pharmacology

Biologic protein	citation	CitationClass=web }}</ref> !! Notes
5-HT1A	280
5-HT1B	60
5-HT1D	96
5-HT1E	430
5-HT1F	360
5-HT2A	0.39	The receptor believed to mediate the atypicality of atypical antipsychotics.<ref name="GG">Template:Cite book</ref>
5-HT2C	0.9	Likely responsible for its propensity for causing weight gain.<ref name = GG/>
5-HT6	5.4
5-HT7	28
α1A	1.8	Likely responsible for the orthostatic hypotension seen in patients on sertindole.<ref name = GG/>
α2A	640
α2B	450
α2C	450
β1	5000
β2	5000
M1	>10000	<ref name = GG/>
M3	2692
D2	2.35	Believed to be responsible for the drug's efficacy against positive symptoms.<ref name = GG/>
D3	2.30
D4	4.92
hERG	3	Responsible for the QT interval prolongation and torsade de pointes
H1	130
NK1	1000

Sertindole is metabolized in the body to dehydrosertindole.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Safety and status

United States

Abbott Labs first applied for US Food and Drug Administration (FDA) approval for sertindole in 1996,<ref>Zeneca's Seroquel Nears Market Approval - The Pharma Letter, 16 July 1997</ref> but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.<ref name="pharma1">Abbott Labs Withdraws Sertindole NDA Sertindole - The Pharma Letter, 12 January 1998</ref> In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.<ref name="who1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone.<ref>FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia Template:Webarchive - Lundbeck press release, 8 April 2009</ref> Nevertheless, in April 2009, an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe.<ref>Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009</ref> Template:As of, the drug has not been approved by the FDA.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Failed verification

European Union

In the European Union, sertindole was approved and marketed in 19 member states from 1996,<ref name="who1"/> but its marketing authorization was suspended by the European Medicines Agency (EMA) in 1998<ref>EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) Template:Webarchive - National electronic Library for Medicines, NHS</ref> and the drug was withdrawn from the market. In 2002, based on new data, the EMA's Committee for Medicinal Products for Human Use (CHMP) suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment.<ref>COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE Template:Webarchive - European Medicines Agency, 13 September 2002</ref><ref>Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) Template:Webarchive - MHRA, 2002</ref> Template:As of, sertindole is authorized in several member states of the European Union.<ref>Template:Cite report</ref>