Zotepine Explained

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.[1]

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.[2] [3] [4] 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.[5]

Side effects

Common[6]
Unknown frequency
Rare

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.[8] In addition, its active metabolite, norzotepine, serves as a potent norepinephrine reuptake inhibitor.[9]

Macromolecule (Receptor or transporter protein) Ki [nM]
151
530
3621
470.5
59.5
119
700
2.7
2.6
472
29
6
12
7
5
180
5.35
106
18
140
73
77
260
71
25
D2S 5.4
D2L 11
6.4
18
248
3.21
500
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.[10] [11] [12]

Society and culture

Brand names

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

See also

Further reading

Notes and References

  1. Web site: Zotepine. 16 August 2013. 2 November 2013. Royal Pharmaceutical Society of Great Britain. Martindale: The Complete Drug Reference.
  2. Chan HY, Jou SH, Juang YY, Chang CJ, Chen JJ, Chen CH, Chiu NY . A single-blind, comparative study of zotepine versus haloperidol in combination with a mood stabilizer for patients with moderate-to-severe mania . Psychiatry and Clinical Neurosciences . 64 . 2 . 162–9 . April 2010 . 20447012 . 10.1111/j.1440-1819.2010.02066.x . 27657241 . free .
  3. Harada T, Otsuki S . Antimanic effect of zotepine . Clinical Therapeutics . 8 . 4 . 406–14 . 1986 . 3089626 .
  4. Amann B, Sterr A, Mergl R, Dittmann S, Seemüller F, Dobmeier M, Orth M, Schaefer M, Grunze H . Zotepine loading in acute and severely manic patients: a pilot study . Bipolar Disorders . 7 . 5 . 471–6 . October 2005 . 16176441 . 10.1111/j.1399-5618.2005.00241.x .
  5. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM . Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis . Lancet . 382 . 9896 . 951–62 . September 2013 . 23810019 . 10.1016/S0140-6736(13)60733-3 . 32085212 .
  6. British National Formulary 58. British Medical Association and Royal Pharmaceutical Society of Great Britain; 2009.
  7. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM . Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis . Lancet . 382 . 9896 . 951–62 . September 2013 . 23810019 . 10.1016/S0140-6736(13)60733-3 . 32085212 .
  8. Web site: PDSD Ki Database . 12 January 2011 . 2 November 2013 . University of North Carolina . Chapel Hill (NC) . National Institute of Mental Health . dead . https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php . November 8, 2013 .
  9. Shobo M, Kondo Y, Yamada H, Mihara T, Yamamoto N, Katsuoka M, Harada K, Ni K, Matsuoka N . Norzotepine, a major metabolite of zotepine, exerts atypical antipsychotic-like and antidepressant-like actions through its potent inhibition of norepinephrine reuptake . The Journal of Pharmacology and Experimental Therapeutics . 333 . 3 . 772–81 . June 2010 . 20223878 . 10.1124/jpet.110.166264 . 185592 .
  10. Ueda I, Sato Y, Maeno S, Umio S . The synthesis of 10-(4-methylpiperazino)dibenzo (b,f)thiepin and related compounds. Neurotropic and psychotropic agents . Chemical & Pharmaceutical Bulletin . 23 . 10 . 2223–2231 . October 1975 . 1212752 . 10.1248/cpb.23.2223 . free .
  11. Ueda I, Sato Y, Maeno S, Umio S . Synthesis and pharmacological properties of 8-chloro-10-(2-dimethylaminoethoxy)dibenzo[b,f]thiepin and related compounds. Neurotropic and psychotropic agents. III . Chemical & Pharmaceutical Bulletin . 26 . 10 . 3058–3070 . October 1978 . 31984 . 10.1248/cpb.26.3058 . free .
  12. Web site: Zotepine . Pharmaceutical Substances . Thieme . 2024-07-10 .

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