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CNS Drugs

, Volume 9, Issue 2, pp 153–175 | Cite as

Zotepine

A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy in the Management of Schizophrenia
  • Amitabh PrakashEmail author
  • Harriet M. Lamb
Adis Drug Evaluation

Summary

Synopsis

Zotepine is an atypical antipsychotic with high affinity for serotonin 5- HT2A and 5- HT2C and dopamine D2, D3, D1 and D4.2 receptors and is a potent inhibitor of reuptake of nor adrenaline (norepinephrine). The major metabolite of zotepine, norzotepine is pharmacologically active and possesses affinity for dopaminergic receptors similar to the parent compound. Pharmacodynamic data suggest that at low doses the drug increases dopaminergic neurotransmission, while at higher doses it acts as a dopaminergic receptor antagonist.

In double- blind trials zotepine 150 to 300 mg/day was as effective as typical antipsychotics such as haloperidol, chlorpromazine, perazine and thiothixene in controlling symptoms of schizophrenia. Although improvement occurred with both zotepine and haloperidol in patients with predominantly negative schizophrenic symptoms, only zotepine achieved significant reductions in most individual negative symptom scores versus baseline. Results from 1 study suggest that maintenance therapy with zotepine for up to 1 year was effective in preventing relapse in schizophrenic patients. In 2 trials in patients with treatment- resistant schizophrenia, some improvement occurred in most patients after the initiation of zotepine either in place of previous drugs or as add- on therapy.

Zotepine is generally well tolerated; constipation, dry mouth, insomnia, sleepiness, asthenia and bodyweight gain are the commonly encountered adverse effects. The incidence of extrapyramidal symptoms with zotepine is low (8 to 29%) and significantly less than that seen with haloperidol and chlorpromazine; however, there were no differences between zotepine and some other typical antipsychotics in this respect. Dosages ≥ 300 mg/day are associated with an increased risk of generalised convulsions.

Thus, zotepine is as effective as typical antipsychotic agents in the management of acute exacerbations of schizophrenia and may be useful for the prevention of relapse. Initial trials have found the drug to be effective in the management of patients with negative schizophrenic symptoms and those with treatment- resistant schizophrenia.

Pharmacodynamic Properties

Zotepine is a dibenzothiepine tricyclic antipsychotic agent which has high affinity for serotonin 5-HT2A and 5-HT2C receptors and dopamine D2, D3, D1 and D4.2 receptors. Norzotepine, the major metabolite of zotepine in humans and animals, is pharmacologically active and shows affinity for dopaminergic receptors which is similar to that of zotepine. In rats and mice, zotepine potently inhibited noradrenaline (norepinephrine) reuptake. In addition to showing central antidopaminergic and antiserotonergic activities in animal models, zotepine was as effective as haloperidol and more effective than clozapine in inhibiting N-methyl D-aspartate glutamate receptor antagonist—induced animal behaviours.

Administration of zotepine in animals revealed a dichotomic effect on dopaminergic receptors; at low doses zotepine increases dopaminergic activity, while at higher doses it has an inhibitory effect on dopaminergic neurotransmission. There was improvement in cognitive dysfunction in 13 patients treated with zotepine (150 to 450 mg/day) over 6 weeks. Administration of zotepine 150 to 250 mg/day for 4 weeks did not significantly affect thyroid function tests, although blood thyroxine levels tended to decrease from pretreatment values.

Pharmacokinetic Properties

Data on the pharmacokinetics of zotepine in humans are limited consequently animal data have been included where necessary for completeness. There is almost complete absorption of zotepine after oral administration in animals. Plasma concentrations of zotepine peaked at approximately 13 to 31 μg/L about 3 hours after a single oral dose of zotepine 50mg in healthy volunteers. Most of the drug is metabolised by the liver and only 0.03 to 0.07% of the drug is excreted unchanged in urine. There appears to be some degree of enterohepatic circulation. The elimination half-life of zotepine ranges from about 15 to 24 hours. Zotepine plasma concentrations are elevated in the elderly and in patients receiving concomitant benzodiazepines but not anticholinergic drugs.

Therapeutic Efficacy

In double-blind comparative trials, zotepine was as effective as typical antipsychotic agents in the management of patients with positive and negative schizophrenic symptoms. There are no trials comparing the efficacy and tolerability of zotepine with those of other atypical antipsychotics such as risperidone, quetiapine or amisulpiride in patients with schizophrenia.

Administered in a double-blind fashion, zotepine (150 to 300 mg/day) was as effective as haloperidol (6 to 20 mg/day) in improving schizophrenic symptoms. In other double-blind trials the efficacy of zotepine was similar to that of chlorpromazine, perazine and thiothixene.

Zotepine was also effective in treating patients with predominantly negative schizophrenic symptoms in noncomparative and comparative studies. One 7-week, double-blind, randomised trial reported significant improvements over baseline in 4 of 5 negative schizophrenic symptoms with zotepine (50 to 150 mg/day) but not with haloperidol (2 to 6 mg/day). Zotepine (106 to 396 mg/day) was as effective as perazine (214 to 575 mg/day) in treating patients with negative schizophrenic symptoms.

In a multicentre trial, administration of zotepine (up to ≈300 mg/day), alone or in combination with other drugs, was associated with significant improvement in 29 of 35 patients with treatment-resistant schizophrenia. The administration of zotepine 50 to 500 mg/day for 1 to 36 months (mean 12 months) lead to a moderate to marked improvement in the overall severity of disease in 17 of 22 patients with treatment resistant schizophrenia.

A placebo-controlled, double-blind study in 121 patients with schizophrenia with a recent history of relapse found zotepine (150 to 300 mg/day) to be significantly better than placebo in preventing relapse over 26 weeks.

Tolerability

Randomised, double-blind comparative studies have reported a significantly lower incidence of extrapyramidal symptoms (EPS) with zotepine (8 to 29%) than with haloperidol and chlorpromazine. However, the incidence of EPS with zotepine was similar to that seen with perazine and thiothixene.

At the dosage used to manage schizophrenic patients zotepine was generally well tolerated. Adverse events seen in zotepine recipients include insomnia, reduced salivation, sleepiness, constipation, asthenia and bodyweight gain (individual incidence 10 to 39%). Aretrospective review of 110 schizophrenic patients found significantly greater bodyweight gain in patients treated with zotepine than in those treated with typical antipsychotics for ≥2 weeks (3.6 vs 1.3kg). An increase in the risk of generalised convulsions has been observed with zotepine at dosages >300 mg/day (above the maximum recommended dosage for nonsevere disease), especially if being administered in combination with other antipsychotic agents. Monitoring of tolerability of zotepine is recommended in the elderly. No clinically relevant haematological abnormalities have been reported to date.

Dosage and Administration

Zotepine should be initiated at total daily doses of 75 to 150mg in 3 divided doses. Based on the clinical response the daily dose may be gradually increased up to 300mg. In severely ill, hospitalised patients 450 mg/day may be used. Monitoring of EEG is recommended in patients receiving zotepine >300 mg/day concurrently with other antipsychotic agents.

Keywords

Schizophrenia Adis International Limited Haloperidol Clozapine Negative Symptom 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Harada T, Otsuki S. Antimanic effect of zotepine. Clin Ther 1986; 8: 406–14PubMedGoogle Scholar
  2. 2.
    Fujiwara Y, Harada T, Otsuki S. Double-blind comparative study of zotepine and lithium carbonate on mania [abstract]. Neuropsychopharmacology 1994 May; 10 Suppl. (Pt 2): 40Google Scholar
  3. 3.
    Wolfersdorf M, König F, Straub R. Pharmacotherapy of delusional depression: experience with combinations of anti-depressants with the neuroleptics zotepine and haloperidol. Neuropsychobiology 1994; 29(4): 189–93PubMedGoogle Scholar
  4. 4.
    Wolfersdorf M, Barg T, König F. et al. Paroxetine as antidepressant in combined antidepressant-neuroleptic therapy in delusional depression: observation of clinical use. Pharmacopsychiatry 1995 Mar; 28: 56–60PubMedGoogle Scholar
  5. 5.
    Peacock L, Lubin H, Gerlach J. The effects of dopamine D1 and D2 receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptic treatment. Eur J Pharmacol 1990; 186: 49–59PubMedGoogle Scholar
  6. 6.
    Schotte A, Janssen PF, Gommeren W, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 1996 Mar; 124: 57–73Google Scholar
  7. 7.
    Needham PL, Atkinson J, Skill MJ, et al. Zotepine: preclinical tests predict antipsychotic efficacy and an atypical profile. Psychopharmacol Bull 1996; 32(1): 123–8PubMedGoogle Scholar
  8. 8.
    Heal DJ, Needham PL. Comparison of the pharmacological profiles of zotepine and norzotepine [abstract]. Eur Neuropsychopharmacol 1996 Jun; 6Suppl. 3: 105Google Scholar
  9. 9.
    Bersani G, Grispini A, Marini S, et al. 5-HT2 antagonist ritanserin in neuroleptic-induced parkinsonism: a double-blind with orphenadrine and placebo. Clin Neuropharmacol 1990; 13: 500–6PubMedGoogle Scholar
  10. 10.
    Leysen JE, Schotte A, Janssen PFM, et al. Interaction of new antipsychotics with neurotransmitter receptors in vitro and in vivo: pharmacological to therapeutic evidence. In: Fog R, Gerlach J, Hemmingsen R, editors. Schizophrenia, an integrated view. Munksgaard, Copenhagen: Alfred Benson Symposium, 1995: 344–60Google Scholar
  11. 11.
    Shimomura K, Satoh H, Hirai O, et al. The central anti-serotonin activity of zotepine, a new neuroleptic, in rats. Jpn J Pharmacol 1982 Jun; 32: 405–12PubMedGoogle Scholar
  12. 12.
    Needham PL, Atkinson J, Cheetham SC, et al.Binding of zotepine, clozapine and haloperidol to 5-HT receptor subtypes [abstract]. Br J Pharmacol 1996 Apr; 117 Proc. Suppl.: 140PGoogle Scholar
  13. 13.
    Leysen JE, Janssen PMF, Schotte A, et al. Interaction of anti-psychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology 1993; 112 Suppl.: S40–54PubMedGoogle Scholar
  14. 14.
    Needham PL, Skill MJ, Cheetham SC, et al. Zotepine: preclinical support for antidepressant activity. Nottingham: Knoll Pharmaceuticals Research and Development. (Data on file)Google Scholar
  15. 15.
    Kanba S, Yagi G, Oguchi E, et al. Neuropharmacology of zotepine, an antimanic drug: a potent blocker of D2 and 5-HT2 receptors of human brain. Jpn J Psychiatry Neurol 1991 Mar; 45: 133–4PubMedGoogle Scholar
  16. 16.
    Uchida S, Honda F, Otsuka M, et al. Pharmacological study of [2-chloro-11-(2-dimethylaminoethoxy) dibenzo[b,f]thiepine] (zotepine), a new neuroleptic drug. Arzneimittelforschung 1979; 29: 1588–94PubMedGoogle Scholar
  17. 17.
    Lai H, Carino MA, Sperry R, et al. Effects of microinjection of 2-chloro-11 (2-dimethylaminoethoxy)-dibenzo[b,f]-thiepine (zotepine), thioridazine and haloperidol into the striatum and nucleus accumbens on Stereotypic behaviour and motor activity. J Pharm Pharmacol 1981 Apr; 33: 252–4PubMedGoogle Scholar
  18. 18.
    Satoh H, Satoh Y, Mori J. Effect of zotepine and various drugs on apomorphine- and methamphetamine-induced rotational behaviour in rats with unilateral lesions of the substantia nigra. Jpn J Pharmacol 1983 Apr; 33: 363–72PubMedGoogle Scholar
  19. 19.
    Satoh H, Fujiwara T, Mori J, et al. Effect of zotepine on fenfluramine-induced hyperthermia in rats. Jpn J Pharmacol 1984 Feb; 34: 261–3PubMedGoogle Scholar
  20. 20.
    Yamamoto T, Tazoe N, Ueki S, et al. Effect of zotepine on head-twitch induced by L-5-hydroxytryptophan, mescaline and 2,5-dimethoxy-4-methylamphetamine in mice and rats. Jpn J Pharmacol 1983 Apr; 33: 319–25PubMedGoogle Scholar
  21. 21.
    Kakigi T, Maeda K, Kaneda H, et al. Repeated administration of antidepressant drugs reduces regional somatostatin concentrations in rat brain. J Affect Disord 1992 Aug; 25: 215–20PubMedGoogle Scholar
  22. 22.
    Czyrak A, Skuza G, Rogoz Z, et al. Pharmacological action of zotepine and other antipsychotics on central 5-hydroxytryptamine receptor subtypes. Arzneimittelforschung 1994 Feb; 44: 113–8PubMedGoogle Scholar
  23. 23.
    Gattaz WF, Schummer B, Behrens S. Effects of zotepine, haloperidol and clozapine on MK-801-induced stereotypy and locomotion in rats. J Neural Transm Gen Sect 1994; 96(3): 227–32PubMedGoogle Scholar
  24. 24.
    Rowley HL, Kilpatrick IC, Needham PL, et al. The atypical antipsychotic, zotepine, elevates extracellular noradrenaline in the frontal cortex of freely-moving rats. Nottingham: Knoll Pharmaceuticals Research and Development. (Data on file)Google Scholar
  25. 25.
    Minabe Y, Tanii Y, Tsunoda M, et al. Acute effect of TRH, flunarizine, lithium and zotepine on amygdaloid kindled seizures induced with low-frequency stimulation. Jpn J Psychiatry Neurol 1987 Dec; 41: 685–91PubMedGoogle Scholar
  26. 26.
    Minabe Y, Tanii Y, Kurachi M. Acute effects of some psychotropic drugs on low frequency amygdaloid kindling seizures. Biol Psychiatry 1987 Dec; 22(12): 1444–50PubMedGoogle Scholar
  27. 27.
    Martin JB, Reichlin S. Regulation of prolactin secretion and its disorders. In: Martin JB, Reichlin S, editors. Clinical neuroendocrinology. 2nd ed. Philadelphia: F.A. Davis Company, 1987: 201–31Google Scholar
  28. 28.
    Otani K, Kondo T, Ishida M, et al. Prolactin response to zotepine in schizophrenic patients. Hum Psychopharmacology 1993 Jan–Feb; 8: 35–9Google Scholar
  29. 29.
    Otani K, Kondo T, Kaneko S, et al. Correlation between prolactin response and therapeutic effects of zotepine in schizophrenic patients. Int Clin Psychopharmacol 1994; 9(4): 287–9PubMedGoogle Scholar
  30. 30.
    König F, Wolfersdorf M, Kaschka WP. Changes of thyroid parameters during therapy with zotepine — preliminary results [abstract no. 65–105]. Biol Psychiatry 1997; 42 Suppl.: 182SGoogle Scholar
  31. 31.
    Meyer-Lindenberg A, Grappe H, Bauer U, et al. Improvement of cognitive function in schizophrenic patients receiving clozapine or zotepine: results from a double-blind study. Pharmacopsychiatry 1997 Mar; 30: 35–42PubMedGoogle Scholar
  32. 32.
    Noda K, Suzuki A, Okui M, et al. Pharmacokinetics and metabolism of 2-chloro-11-(2-dimethylaminoethoxy)-dibenzo[b,f]-thiepine (zotepine) in rat, mouse, dog and man. Arzneimittelforschung 1979; 29: 1595–600PubMedGoogle Scholar
  33. 33.
    Kondo T, Tanaka O, Otani K, et al. Possible inhibitory effect of diazepam on the metabolism of zotepine, an antipsychotic drug. Psychopharmacology 1996 Oct; 127: 311–4PubMedGoogle Scholar
  34. 34.
    Velagapudi R, Faulkner R, Hinson JL, et al. The effect of age on the pharmacokinetics of zotepine and its metabolite norzotepine in healthy volunteers. Biol Psychiatry 1997; 42 Suppl.: 46SGoogle Scholar
  35. 35.
    Tanaka O, Kondo T, Kaneko S, et al. A method for rapid determination of zotepine by gas chromatography-mass spectrometry. Ther Drug Monit 1996 Jun; 16: 294–6Google Scholar
  36. 36.
    Otani K, Kondo T, Kaneko S, et al. Steady-state serum kinetics of zotepine. Hum Psychopharmacology 1992 Sep–Oct; 7: 331–6Google Scholar
  37. 37.
    Kondo T, Otani K, Ishida M, et al. A study of the therapeutic spectrum of a fixed-dose of zotepine and its relationship with serum concentrations of the drug. Hum Psychopharmacology 1993 Mar–Apr; 8: 133–9Google Scholar
  38. 38.
    Turton RW, McCormick DJ, Hopper JB, et al. Metabolism of zotepine by man and animals [abstract]. Eur Neuropsychopharmacol 1997; 7Suppl. 2: S221Google Scholar
  39. 39.
    Turton RW, McCormick DJ, Hopper JB, et al. Metabolism of zotepine by animals and man. Nottingham: Knoll Pharmaceuticals, Pennyfoot Street Campus. (Data on file)Google Scholar
  40. 40.
    McCormick DJ, Stewart T, Vowles DT. In vitro investigations of drug-drug interactions with zotepine at CYP450 [abstract no. 65-57]. Biol Psychiatry 1997; 42 Suppl.: 174SGoogle Scholar
  41. 41.
    Otani K, Hirano T, Kondo T, et al. Biperiden and piroheptine do not affect the serum level of zotepine, a new antipsychotic drug. Br J Psychiatry 1990 Jul; 157: 128–30PubMedGoogle Scholar
  42. 42.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington DC: The American Psychiatric Association, 1980Google Scholar
  43. 43.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd rev. ed. Washington DC: The American Psychiatric Association, 1987Google Scholar
  44. 44.
    Degwitz R, Helmchen H, Kokott G, et al. Diagnosen-schlussel und Glossar psychiatrischer Krankheiten. 9. Rev.,5. Aufl. ed. Barlin: Springer Verlag, 1980Google Scholar
  45. 45.
    Klieser E, Lehmann E, Lemmer W, et al. Experimental comparison of the efficacy and tolerance of zotepine and haloperidol in acute schizophrenia [abstract]. Pharmacopsychiatry 1992 Mar; 25: 107Google Scholar
  46. 46.
    Nishizono M. A comparative trial of zotepine, chlorpromazine and haloperidol in schizophrenic patients [abstract]. Neuropsychopharmacology 1994 May; 10 Suppl. (Pt 2): 30Google Scholar
  47. 47.
    Cooper SJ, Raniwalla J, Welch C. Zotepine in acute exacerbation of schizophrenia: a comparison versus chlorpromazine and placebo [abstract]. Eur Neuropsychopharmacol 1996 Jun; 6Suppl. 3: 148Google Scholar
  48. 48.
    Kilpatrick AT, Welch CP, Butler A, et al. The efficacy of zotepine in reducing BPRS total score [abstract]. Eur Neuropsychopharmacol 1997; 7Suppl. 2: S205Google Scholar
  49. 49.
    Higashi Y, Momotani Y, Suzuki E, et al. Clinical and EEG studies of zotepine, a thiepine neuroleptic, on schizophrenic patients. Pharmacopsychiatry 1987; 20(1 Spec. No.): 8–11PubMedGoogle Scholar
  50. 50.
    Dieterle DM, Ackenheil M, Müller-Spahn F, et al. Zotepine, a neuroleptic drug with a bipolar therapeutic profile. Pharmacopsychiatry 1987 Feb; 20(1 Spec. No.): 52–7PubMedGoogle Scholar
  51. 51.
    Fleischhacker WW, Unterweger B, Barnas C, et al. Results of an open phase II study with zotepine — a new neuroleptic compound. Pharmacopsychiatry 1987; 20(1 Spec.No.): 64–6PubMedGoogle Scholar
  52. 52.
    von-Bardeleben U, Benkert O, Holsboer F. Clinical and neuroendocrine effects of zotepine — a new neuroleptic drug. Pharmacopsychiatry 1987 Feb; 20(1 Spec. No.): 28–34PubMedGoogle Scholar
  53. 53.
    Petit M, Raniwalla J, Tweed J, et al. Acomparison of an atypical and typical antipsychotic, zotepine versus haloperidol in patients with acute exacerbation of schizophrenia: a parallel-group double-blind trial. Psychopharmacol Bull 1996; 32(1): 81–7PubMedGoogle Scholar
  54. 54.
    Fleischhacker WW, Barnas C, Stuppäck CH, et al. Zotepine vs haloperidol in paranoid schizophrenia: a double-blind trial. Psychopharmacol Bull 1989 Jan; 25: 97–100PubMedGoogle Scholar
  55. 55.
    Dieterle DM, Müller-Spahn F, Ackenheil M. Efficacy and tolerance of zotepine in a double-blind comparison with perazine in schizophrenics [in German]. Fortschr Neural Psychiatr 1991 Sep; 59Suppl. 1: 18–22Google Scholar
  56. 56.
    Wetzel H, von Bardeleben U, Holsboer F, et al. Zotepine versus perazine in paranoid schizophrenia: a double-blind controlled trial of its antipsychotic efficacy [in German]. Fortschr Neurol Psychiatr 1991 Sep; 59Suppl. 1: 23–9PubMedGoogle Scholar
  57. 57.
    Sarai K, Okada M. Comparison of efficacy of zotepine and thiothixene in schizophrenia in a double-blind study. Pharmacopsychiatry 1987 Feb; 20(1 Spec. No.): 38–46PubMedGoogle Scholar
  58. 58.
    Angrist B, Rotrosen J, Gershon S. Differential effects of amphetamine and neuroleptics on negative versus positive symptoms in schizophrenia. Psychopharmacology 1980; 72: 17–9PubMedGoogle Scholar
  59. 59.
    Lewine RRJ. A discriminant validity study of negative symptoms with a special focus on depression and antipsychotic medication. Am J Psychiatry 1990; 147: 1463–6PubMedGoogle Scholar
  60. 60.
    Barnas C, Stuppäck CH, Miller C. Zotepine in the treatment of schizophrenic patients with prevailingly negative symptoms: a double-blind trial vs haloperidol. Int Clin Psychopharmacol 1992; 7(1): 23–7PubMedGoogle Scholar
  61. 61.
    Müller-Spahn F, Dieterle D, Ackenheil M. Clinical efficacy of zotepine in the treatment of schizophrenic negative symptoms: results of an open and a double-blind controlled trial [in German]. Fortschr Neurol Psychiatr 1991 Sep; 59Suppl. 1: 30–5PubMedGoogle Scholar
  62. 62.
    Fleischhacker WW, Barnas C, Stuppäck C, et al. Zotepine in the treatment of negative symptoms in chronic schizophrenia. Pharmacopsychiatry 1987; 20(1 Spec. No.): 58–60PubMedGoogle Scholar
  63. 63.
    Barnas C, Stuppaeck C, Unterweger B, et al. Treatment of negative symptoms in schizophrenia with zotepine [letter]. J Clin Psychopharmacol 1987 Oct; 7: 370–1PubMedGoogle Scholar
  64. 64.
    Dieterle DM, Ackenheil M, Kapfhammer HP, et al. The effect of zotepine on productive and negative symptoms in schizophrenic patients. Psychiatr Psychobiol 1988; 3(2): 125–30Google Scholar
  65. 65.
    Welch CP, Kilpatrick AT, Butler A, et al. The efficacy of zotepine in reducing negative symptoms [abstract]. Eur Neuropsychopharmacology 1997; 7 Suppl. 2: S213Google Scholar
  66. 66.
    Davies JM, Schaffer CB, Killman GA, et al. Important issues in the treatment of schizophrenia. Schizophr Bull 1980; 6: 70–87Google Scholar
  67. 67.
    Harada T, Otsuki S, Sato M, et al. Effectivity of zotepine in refractory psychoses: possible relationship between zotepine and non-dopamine psychosis. Pharmacopsychiatry 1987; 20(1 Spec. No.): 47–51PubMedGoogle Scholar
  68. 68.
    Harada T, Otsuki S, Fujiwara Y. Efficacy of zotepine in therapy-resistant psychoses: an open, multicenter study in 8 psychiatric hospitals [in German]. Fortschr Neurol Psychiatr 1991 Sep; 59Suppl. 1:41–4PubMedGoogle Scholar
  69. 69.
    Fleischhacker WW, Stuppäck C, Barnas C, et al. Low-dose zotepine in the maintenance treatment of schizophrenia. Pharmacopsychiatry 1987; 20(1 Spec. No.): 61–3PubMedGoogle Scholar
  70. 70.
    Cooper SJ, Butler A, Tweed J, et al. Zotepine in prevention of relapse [abstract no. 14–110]. Biol Psychiatry 1997 July; 42 Suppl.: 41SGoogle Scholar
  71. 71.
    Palmgren K, Tweed JA, Welch CP, et al. A multicentre naturalistic long term study of zotepine. European Congress of the World Psychiatric Association (WPAEC); Geneva, 1997 Apr 23–26Google Scholar
  72. 72.
    Casey DE, Keepers GA. Neuroleptic side effects: acute extra-pyramidal syndromes and tardive dyskinesia. In: Casey DE, Christensen AV, editors. Psychopharmacology: current trends. Berlin: Springer, 1988: 74–93Google Scholar
  73. 73.
    Keepers GA, Clappison VJ, Casey DE. initial anticholinergic prophylaxis for neuroleptic-induced extrapyramidal syndromes. Arch Gen Psychiatry 1983; 40: 1113–7PubMedGoogle Scholar
  74. 74.
    Adler LA, Angrist B, Reiter S, et al. Neuroleptic-induced akathisia: a review. Psychopharmacology 1989; 97: 1–11PubMedGoogle Scholar
  75. 75.
    Hummer M, Fleischhacker WW. Compliance and outcome in patients treated with antipsychotics: the impact of extra-pyramidal syndromes. CNS Drugs 1996; 5Suppl. 1: 13–20Google Scholar
  76. 76.
    Farde L, Nordstrom AL, Weisel FA, et al. Positron emission tomography analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine-relation to extrapyramidal side effects. Arch Gen Psychiatry 1992; 49: 538–44PubMedGoogle Scholar
  77. 77.
    Meltzer HY, Matsubara S, Lee J-C. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin-2 pK(i) values. J Pharmacol Exp Ther 1989; 251(1): 238–46PubMedGoogle Scholar
  78. 78.
    Snyder S, Greenberg D, Yamamura H. Antischizophrenic drugs and brain cholinergic receptors. Arch Gen Psychiatry 1974; 31: 58–61PubMedGoogle Scholar
  79. 79.
    Cooper SJ, Welch CP. A comparison of zotepine and chlorpromazine on BPRS subscores [abstract]. Eur Neuropsychopharmacol 1997; 7Suppl. 2: S225–6Google Scholar
  80. 80.
    Lingjærde O, Ahlfors UG, Bech P, et al. The UKU side effect rating scale: a new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand 1987; 76Suppl. 334: 1–100Google Scholar
  81. 81.
    Kondo T, Otani K, Ishida M, et al. Adverse effects of zotepine and their relationship to serum concentrations of the drug and prolactin. Ther Drug Monit 1994 Apr; 16: 120–4PubMedGoogle Scholar
  82. 82.
    Otani K, Kaneko S, Fukushima Y, et al. NMS and genetic drug oxidation. Br J Psychiatry 1991 Oct; 159: 595–6PubMedGoogle Scholar
  83. 83.
    Yamawaki S, Yano E, Uchitomi Y. Analysis of 497 cases of neuroleptic malignant syndrome in Japan. Hiroshima J Anesth 1990; 26(1): 35–44Google Scholar
  84. 84.
    Tanaka O, Otani K, Kondo T, et al. Paralytic ileus as a prodromal symptom of the neuroleptic malignant syndrome. Hum Psychopharmacology 1993; 8(5): 367–9Google Scholar
  85. 85.
    Lomas J, Boardman RH, Markowe M. Complications of chlorpromazine therapy in 800 mental-hospital patients. Lancet 1955; I: 1144–7Google Scholar
  86. 86.
    Cares RW, Asrican E, Fenichel M, et al. Therapeutic and toxic effects of chlorpromazine among 3,014 hospitalised cases. Am J Psychiatry 1957; 114: 318–27PubMedGoogle Scholar
  87. 87.
    Denber HC, Bird EG. Chlorpromazine in the treatment of mental illness. IV. Final results with analysis of data on 1,523 patients. Am J Psychiatry 1957; 113: 972–8PubMedGoogle Scholar
  88. 88.
    Logothetis J. Spontaneous epileptic seizures and electroencephalographic changes in the course of phenothiazine therapy. Neurology 1967; 17: 869–77PubMedGoogle Scholar
  89. 89.
    Davies RK, Neil JF, Himmelhoch JM. Cerebral dysrhythmias in schizophrenics receiving phenothiazines: clinical correlates. Clin Electroencephalogr 1975; 6: 103–25Google Scholar
  90. 90.
    Kugler J, Lorenzi E, Spatz R, et al. Drug-induced paroxysmal EEG activities. Pharmacopsychiatr Neuropsychopharmakol 1979; 12: 165–72Google Scholar
  91. 91.
    Schlichter W, Bristow ME, Schultz S, et al. Seizures occurring during intensive chlorpromazine therapy. Can Med Assoc J 1956; 74: 364–6Google Scholar
  92. 92.
    Tsuchiya H, Kawahara R, Tanaka Y, et al. Generalized seizure during treatment of schizophrenia with zotepine. Yonago Acta Med 1986; 29(2): 103–11Google Scholar
  93. 93.
    Hori M, Suzuki T, Sasaki M. Convulsive seizures in schizophrenic patients induced by zotepine administration. Jpn J Psychiatry Neurol 1992 Mar; 46: 161–7PubMedGoogle Scholar
  94. 94.
    Manmaru S. Five cases of schizophrenia with convulsive seizures during zotepine administration [in Japanese]. Seishin Igaku 1985; 27: 59–70Google Scholar
  95. 95.
    Reynolds C, Kilpatrick AT, Bratty R. Zotepine, a broad spectrum antipsychotic with low extrapyramidal side effects [abstract]. Eur Neuropsychopharmacol 1997; 7Suppl. 2: S225Google Scholar
  96. 96.
    Wetterling T, Mussigbrodt H. Weight gain: a side effect of zotepine (Nipolept®)? [in German]. Nervenarzt 1996 Mar; 67: 256–61PubMedGoogle Scholar
  97. 97.
    Edwards IR. Pharmacological basis of adverse drug reactions. In: Speight TM, Holford NHG, editors. Avery’s drug treatment. 4th ed. Auckland: Adis International Ltd, 1997: 261–99Google Scholar
  98. 98.
    Anderman B, Griffith RW. Clozapine-induced agranulocytosis: a situation reported up to August 1976. Eur J Clin Pharmacol 1977; 11: 199PubMedGoogle Scholar
  99. 99.
    Pantel J, Schröder J, Eysenbach K, et al. Two cases of deep vein thrombosis associated with a combined paroxetine and zotepine therapy. Pharmacopsychiatry 1997 May; 30: 109–11PubMedGoogle Scholar
  100. 100.
    Kubota T, Ishikura T, Jibiki I. Three cases of alopecia areata induced by zotepine. Acta Neurol Napoli 1993 Jun; 15: 200–3PubMedGoogle Scholar
  101. 101.
    Reynolds JEF, editor. Martindale: the extra pharmacopoeia. 31st ed. London: Royal Pharmaceutical Society of Great Britain: The Pharmaceutical Press, 1996Google Scholar
  102. 102.
    Kammer-Reusch M, editor. Gelbe Liste Pharmindex. 2 Quartal ed. Neu Isenburg, GmbH: MediMedia. Medizinische Medien Informations, 1997Google Scholar
  103. 103.
    Davies LM, Drummond MF. The economic burden of schizophrenia. Psychiatry Bull 1990; 14: 522–5Google Scholar
  104. 104.
    Seeman P. Brain dopamine receptors. Pharmacol Rev 1980; 32: 197–202Google Scholar
  105. 105.
    Seiden L, Sabol K. Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 1993; 32: 639–77Google Scholar
  106. 106.
    Csernansky JG, Brown K, Hollister LE. Is there drug treatment for negative schizophrenic symptoms? Hosp Formul 1986; 21: 790–2Google Scholar
  107. 107.
    Puech AJ, Simon P, Doissier IR. Benzamides and classical neuroleptics: comparison of their actions using apomorphine induced effects. Eur J Pharmacol 1978; 50: 291–300PubMedGoogle Scholar
  108. 108.
    Erard R, Luisada P, Peele R. The PCP psychosis: prolonged intoxication or drug-precipitated functional illness? J Psychedelic Drugs 1980; 12: 235–51PubMedGoogle Scholar
  109. 109.
    Javitt D. Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia. Hillside J Clin Psychiatry 1987; 9: 12–35PubMedGoogle Scholar
  110. 110.
    Duinkerke SJ, Botter PA, Jansen AAI, et al. Ritanserin, a selective 5HT2/1C antagonist, and negative symptoms in schizophrenia: a placebo-controlled double-blind trial. Br J Psychiatry 1993; 163: 451–5PubMedGoogle Scholar
  111. 111.
    King DJ. The effect of neuroleptics on cognitive and psychomotor function. Br J Psychiatry 1990 Dec; 157: 799–811PubMedGoogle Scholar
  112. 112.
    Green JF, King DJ. Cognitive functioning in schizophrenia: effects of drug treatments. CNS Drugs 1996 Nov; 6: 382–98Google Scholar
  113. 113.
    Gallhofer B, Bauer U, Lis S, et al. Cognitive dysfunction in schizophrenia: comparison of treatment with atypical anti-psychotic agents and conventional neuroleptic drugs. Eur Neuropsychopharmacol 1996; 6Suppl. 2: S2–13–S2–20Google Scholar
  114. 114.
    Gallhofer B, Bauer U, Gruppe H, et al. First episode schizophrenia: the importance of compliance and preserving cognitive function. J Pract Psychiatry Behav Health 1996; 2: 16–24Google Scholar
  115. 115.
    Buchanan RW, Holstein C, Breier A. The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance. Biol Psychiatry 1994; 36: 717–25PubMedGoogle Scholar

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© Adis International Limited 1998

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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