Chemistry:Sertindole

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Short description: Antipsychotic medication
Sertindole
Sertindole.svg
Sertindole ball-and-stick model.png
Clinical data
Trade namesSerdolect, Serlect
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: C
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability75%[1]
Protein binding99.5%[1]
MetabolismLiver (mostly via CYP2D6 and CYP3A4)[2][3]
Elimination half-life3 days[2]
ExcretionFaecal (the majority), Kidney (4% metabolites; 1% unchanged)[2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC24H26ClFN4O
Molar mass440.95 g·mol−1
3D model (JSmol)
  (verify)

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.[citation needed]

Medical Uses

Sertindole appears effective as an antipsychotic in schizophrenia.[4] 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.[5]

Adverse effects

Very common (>10% incidence) adverse effects include:[2]

  • Headache
  • Ejaculation failure
  • Insomnia
  • Dizziness

Common (1–10% incidence) adverse effects include:[2]

  • 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)[5][6]
  • Ejaculation disorder
  • Erectile dysfunction
  • Orthostatic hypotension[6]
  • Weight gain (which it seems to possess a similar propensity for causing as quetiapine)[5]

Uncommon (0.1–1% incidence) adverse effects include:[2]

  • 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)[5]
  • Seizures
  • Galactorrhoea


Rare (<0.1% incidence) adverse effects include:[2]

Unknown frequency adverse events include:[2]

  • 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)[5]
  • 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)[5]

Pharmacology

Biologic protein Binding affinity (Ki[nM])[7] Notes
5-HT1A 280
5-HT1B 60
5-HT1D 96
5-HT1E 430
5-HT1F 360
5-HT2C 0.9 Likely responsible for its propensity for causing weight gain.[8]
5-HT6 5.4
5-HT7 28
α1A 1.8 Likely responsible for the orthostatic hypotension seen in patients on sertindole.[8]
α2A 640
α2B 450
α2C 450
β1 5000
β2 5000
M1 >10000 [8]
M3 2692
D2 2.35 Believed to be responsible for the drug's efficacy against positive symptoms.[8]
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.[9]

Safety and status

United States

Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996,[10] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.[11] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.[12] 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.[13] 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.[14] (As of October 2010), the drug has not been approved by the FDA for use in the USA.[15][failed verification]

European Union

In the European Union, sertindole was approved and marketed in 19 countries from 1996,[12] but its marketing authorization was suspended by the European Medicines Agency in 1998[16] and the drug was withdrawn from the market. In 2002, based on new data, the EMA's 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.[17][18] (As of September 2020), sertindole is authorized in several states of the European Union.[19]

References

  1. 1.0 1.1 "Drug safety and efficacy evaluation of sertindole for schizophrenia". Expert Opinion on Drug Safety 11 (6): 1047–62. November 2012. doi:10.1517/14740338.2012.726984. PMID 22992213. 
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 "PRODUCT INFORMATION SERDOLECT TABLETS" (PDF). TGA eBusiness Services. Lundbeck Australia Pty Ltd. 16 January 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-07697-3. 
  3. "Sertindole in the management of schizophrenia". Journal of Central Nervous System Disease 3: 75–85. May 2011. doi:10.4137/JCNSD.S5729. PMID 23861640. 
  4. "Sertindole for schizophrenia". The Cochrane Database of Systematic Reviews 2005 (3): CD001715. July 2005. doi:10.1002/14651858.CD001715.pub2. PMID 16034864. 
  5. 5.0 5.1 5.2 5.3 5.4 5.5 "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–62. September 2013. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
  6. 6.0 6.1 The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. 2012. ISBN 978-0-470-97948-8. 
  7. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. 12 January 2011. http://pdsp.med.unc.edu/pdsp.php. 
  8. 8.0 8.1 8.2 8.3 Cite error: Invalid <ref> tag; no text was provided for refs named GG
  9. "TRC | Details of CAS = 173294-84-3, ChemicalName = Dehydrosertindole, synonym = 1-[2-[4-[5-Chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-Imidazol-2-one; Lu 28-092, MolFormula = C24H24ClFn4O". http://www.trc-canada.com/detail.php?CatNum=D230095&CAS=173294-84-3&Chemical_Name=Dehydrosertindole&Mol_Formula=C24H24ClFN4O&Synonym=1-%5B2-%5B4-%5B5-Chloro-1-(4-fluorophenyl)-1H-indol-3-yl%5D-1-piperidinyl%5Dethyl%5D-1,3-dihydro-2H-Imidazol-2-one;%20Lu%2028-092. 
  10. Zeneca's Seroquel Nears Market Approval - The Pharma Letter, 16 July 1997
  11. Abbott Labs Withdraws Sertindole NDA Sertindole - The Pharma Letter, 12 Jan 1998
  12. 12.0 12.1 "WHO Pharmaceuticals Newsletter 1998, No. 03&04: Regulatory actions: Sertindole - approval application withdrawn". http://apps.who.int/medicinedocs/en/d/Js2256e/1.12.html#Js2256e.1.12. 
  13. FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia - Lundbeck press release, 8 Apr 2009
  14. Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
  15. "Welcome to Lundbeck's global site". http://www.serdolect.com. 
  16. EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) - National electronic Library for Medicines, NHS
  17. COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE - European Medicines Agency, 13 Sep 2002
  18. Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) - MHRA, 2002
  19. Sertindole: List of nationally authorised medicinal products - PSUSA/00002695/202001 (Report). European Medicines Agency (EMA). 3 September 2020. EMA/270645/2015. https://www.ema.europa.eu/documents/psusa/sertindole-list-nationally-authorised-medicinal-products-psusa/00002695/202001_en.pdf. 

External links