Zotepine is an atypical antipsychotic drug indicated for acute and chronic schizophrenia. It has been used in Germany since 1990 (although it has been discontinued in Germany) and Japan since 1982.

Zotepine is not approved for use in the United States, United Kingdom, Australia, Canada or New Zealand.

Medical uses Zotepine's primary use is as a treatment for schizophrenia although clinical trials have been conducted (with positive results) into its efficacy as an antimanic agent in patients with acute bipolar mania. In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, zotepine demonstrated medium-strong effectivity. Less effective than clozapine, slightly less effective than olanzapine and risperidone, approximately as effective as paliperidone, and slightly more effective than haloperidol, quetiapine, and aripiprazole.

Side effects CommonBritish National Formulary 58. British Medical Association and Royal Pharmaceutical Society of Great Britain; 2009.

Tachycardia Hypotension Orthostatic hypotension Palpitations Hyperprolactinaemia Weight gain (produces a similar degree of weight gain to that seen with clozapine and olanzapine treatment) Somnolence (2nd highest effect size for causing sedation out of fifteen antipsychotics compared in a recent meta-analysis) Extrapyramidal side effects [EPSE] (2nd largest odds ratio for causing EPSE out of fifteen antipsychotics compared in a recent meta-analysis, second only to haloperidol) Constipation Xerostomia (dry mouth) Blurred vision Hypersalivation (drooling) Mydriasis Anxiety Agitation Rhinitis Sexual dysfunction Dyspnoea Diarrhoea Influenza-like symptoms Cough Vertigo Confusion Dyspepsia Flushing dry skin Arthralgia Myalgia Acne Conjunctivitis Thrombocythaemia

Unknown frequency

QT interval prolongation Hyperthermia Hypothermia Increased serum creatinine Hyperglycaemia Hypoglycaemia Hyperlipidaemia Thirst Urinary incontinence

Rare

Angle-closure glaucoma Agranulocytosis Neutropaenia Eosinophilia Leukocytopenia Hypoesthesia Anaemia Myoclonus Myasthenia Alopecia Thrombocytopaenia Bradycardia Epistaxis Abdominal enlargement Deep vein thrombosis Paralytic ileus Leukopenia Tardive dyskinesia Neuroleptic malignant syndrome Laryngeal edema Urinary retention Depression Ataxia Amnesia Seizure (dose-dependent risk) Metabolic syndrome Diabetes mellitus type II Cholestasis Increased liver enzymes Photosensitivity Exanthema Pruritus Hypouricemia Oedema

Pharmacology

Pharmacodynamics The antipsychotic effect of zotepine is thought to be mediated through antagonist activity at dopamine and serotonin receptors. Zotepine has a high affinity for the D1 and D2 receptors. It also affects the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors. In addition, its active metabolite, norzotepine, serves as a potent norepinephrine reuptake inhibitor.

Macromolecule (Receptor or transporter protein) Ki [nM] SERT 151 NET 530 DAT 3621 5-HT1A 470.5 5-HT1B 59.5 5-HT1D 119 5-HT1E 700 5-HT2A 2.7 5-HT2C 2.6 5-HT3 472 5-HT5A 29 5-HT6 6 5-HT7 12 α1A 7 α1B 5 α2A 180 α2B 5.35 α2C 106 M1 18 M2 140 M3 73 M4 77 M5 260 D1 71 D2 25 D2S 5.4 D2L 11 D3 6.4 D4 18 D5 248 H1 3.21 H2 500 H4 1977

Synthesis

The reaction of 2-chloroacetophenone with 4-chlorothiophenol gives a thioether. This is treated with morpholine and sulfur in a Willgerodt–Kindler reaction to give a phenylacetic acid derivative after acid hydrolysis of the amide intermediate. Cyclization of this compound in the presence of polyphosphoric acid forms the dibenzothiepin ring system of the drug. The enol ether, zotepine, is produced when this is treated with the chloroethyl amine and potassium carbonate in methyl isobutyl ketone as solvent. Under these conditions, the undesired product of C-alkylation is minimised.

Society and culture

Brand names Brand names include Losizopilon (JP), Lodopin (ID, JP), Nipolept (DE†), Setous (JP), Zoleptil (CZ, PT, TR, UK†), Zotewin (IN); where † indicates a formulation that has been discontinued.

See also Carbinoxamine, diphenhydramine, doxylamine, orphenadrine — the termination chain is the same Clotiapine - the base is similar Noxiptyline - the termination chain is similar Toll-like receptor 4 — investigating probable antagonistic (antiinflammatory) property of several TCA-based molecules

References

Further reading