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.
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References
Harada T, Otsuki S. Antimanic effect of zotepine. Clin Ther 1986; 8: 406–14
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): 40
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): 189–93
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: 56–60
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: 49–59
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: 57–73
Needham PL, Atkinson J, Skill MJ, et al. Zotepine: preclinical tests predict antipsychotic efficacy and an atypical profile. Psychopharmacol Bull 1996; 32(1): 123–8
Heal DJ, Needham PL. Comparison of the pharmacological profiles of zotepine and norzotepine [abstract]. Eur Neuropsychopharmacol 1996 Jun; 6Suppl. 3: 105
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: 500–6
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: 344–60
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: 405–12
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.: 140P
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.: S40–54
Needham PL, Skill MJ, Cheetham SC, et al. Zotepine: preclinical support for antidepressant activity. Nottingham: Knoll Pharmaceuticals Research and Development. (Data on file)
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: 133–4
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: 1588–94
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: 252–4
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: 363–72
Satoh H, Fujiwara T, Mori J, et al. Effect of zotepine on fenfluramine-induced hyperthermia in rats. Jpn J Pharmacol 1984 Feb; 34: 261–3
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: 319–25
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: 215–20
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: 113–8
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): 227–32
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)
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: 685–91
Minabe Y, Tanii Y, Kurachi M. Acute effects of some psychotropic drugs on low frequency amygdaloid kindling seizures. Biol Psychiatry 1987 Dec; 22(12): 1444–50
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: 201–31
Otani K, Kondo T, Ishida M, et al. Prolactin response to zotepine in schizophrenic patients. Hum Psychopharmacology 1993 Jan–Feb; 8: 35–9
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): 287–9
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.: 182S
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: 35–42
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: 1595–600
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: 311–4
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.: 46S
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: 294–6
Otani K, Kondo T, Kaneko S, et al. Steady-state serum kinetics of zotepine. Hum Psychopharmacology 1992 Sep–Oct; 7: 331–6
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: 133–9
Turton RW, McCormick DJ, Hopper JB, et al. Metabolism of zotepine by man and animals [abstract]. Eur Neuropsychopharmacol 1997; 7Suppl. 2: S221
Turton RW, McCormick DJ, Hopper JB, et al. Metabolism of zotepine by animals and man. Nottingham: Knoll Pharmaceuticals, Pennyfoot Street Campus. (Data on file)
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.: 174S
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: 128–30
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington DC: The American Psychiatric Association, 1980
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd rev. ed. Washington DC: The American Psychiatric Association, 1987
Degwitz R, Helmchen H, Kokott G, et al. Diagnosen-schlussel und Glossar psychiatrischer Krankheiten. 9. Rev.,5. Aufl. ed. Barlin: Springer Verlag, 1980
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: 107
Nishizono M. A comparative trial of zotepine, chlorpromazine and haloperidol in schizophrenic patients [abstract]. Neuropsychopharmacology 1994 May; 10 Suppl. (Pt 2): 30
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: 148
Kilpatrick AT, Welch CP, Butler A, et al. The efficacy of zotepine in reducing BPRS total score [abstract]. Eur Neuropsychopharmacol 1997; 7Suppl. 2: S205
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.): 8–11
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.): 52–7
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.): 64–6
von-Bardeleben U, Benkert O, Holsboer F. Clinical and neuroendocrine effects of zotepine — a new neuroleptic drug. Pharmacopsychiatry 1987 Feb; 20(1 Spec. No.): 28–34
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): 81–7
Fleischhacker WW, Barnas C, Stuppäck CH, et al. Zotepine vs haloperidol in paranoid schizophrenia: a double-blind trial. Psychopharmacol Bull 1989 Jan; 25: 97–100
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: 18–22
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: 23–9
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.): 38–46
Angrist B, Rotrosen J, Gershon S. Differential effects of amphetamine and neuroleptics on negative versus positive symptoms in schizophrenia. Psychopharmacology 1980; 72: 17–9
Lewine RRJ. A discriminant validity study of negative symptoms with a special focus on depression and antipsychotic medication. Am J Psychiatry 1990; 147: 1463–6
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): 23–7
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: 30–5
Fleischhacker WW, Barnas C, Stuppäck C, et al. Zotepine in the treatment of negative symptoms in chronic schizophrenia. Pharmacopsychiatry 1987; 20(1 Spec. No.): 58–60
Barnas C, Stuppaeck C, Unterweger B, et al. Treatment of negative symptoms in schizophrenia with zotepine [letter]. J Clin Psychopharmacol 1987 Oct; 7: 370–1
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): 125–30
Welch CP, Kilpatrick AT, Butler A, et al. The efficacy of zotepine in reducing negative symptoms [abstract]. Eur Neuropsychopharmacology 1997; 7 Suppl. 2: S213
Davies JM, Schaffer CB, Killman GA, et al. Important issues in the treatment of schizophrenia. Schizophr Bull 1980; 6: 70–87
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.): 47–51
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. 1:41–4
Fleischhacker WW, Stuppäck C, Barnas C, et al. Low-dose zotepine in the maintenance treatment of schizophrenia. Pharmacopsychiatry 1987; 20(1 Spec. No.): 61–3
Cooper SJ, Butler A, Tweed J, et al. Zotepine in prevention of relapse [abstract no. 14–110]. Biol Psychiatry 1997 July; 42 Suppl.: 41S
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 23–26
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: 74–93
Keepers GA, Clappison VJ, Casey DE. initial anticholinergic prophylaxis for neuroleptic-induced extrapyramidal syndromes. Arch Gen Psychiatry 1983; 40: 1113–7
Adler LA, Angrist B, Reiter S, et al. Neuroleptic-induced akathisia: a review. Psychopharmacology 1989; 97: 1–11
Hummer M, Fleischhacker WW. Compliance and outcome in patients treated with antipsychotics: the impact of extra-pyramidal syndromes. CNS Drugs 1996; 5Suppl. 1: 13–20
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: 538–44
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): 238–46
Snyder S, Greenberg D, Yamamura H. Antischizophrenic drugs and brain cholinergic receptors. Arch Gen Psychiatry 1974; 31: 58–61
Cooper SJ, Welch CP. A comparison of zotepine and chlorpromazine on BPRS subscores [abstract]. Eur Neuropsychopharmacol 1997; 7Suppl. 2: S225–6
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: 1–100
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: 120–4
Otani K, Kaneko S, Fukushima Y, et al. NMS and genetic drug oxidation. Br J Psychiatry 1991 Oct; 159: 595–6
Yamawaki S, Yano E, Uchitomi Y. Analysis of 497 cases of neuroleptic malignant syndrome in Japan. Hiroshima J Anesth 1990; 26(1): 35–44
Tanaka O, Otani K, Kondo T, et al. Paralytic ileus as a prodromal symptom of the neuroleptic malignant syndrome. Hum Psychopharmacology 1993; 8(5): 367–9
Lomas J, Boardman RH, Markowe M. Complications of chlorpromazine therapy in 800 mental-hospital patients. Lancet 1955; I: 1144–7
Cares RW, Asrican E, Fenichel M, et al. Therapeutic and toxic effects of chlorpromazine among 3,014 hospitalised cases. Am J Psychiatry 1957; 114: 318–27
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: 972–8
Logothetis J. Spontaneous epileptic seizures and electroencephalographic changes in the course of phenothiazine therapy. Neurology 1967; 17: 869–77
Davies RK, Neil JF, Himmelhoch JM. Cerebral dysrhythmias in schizophrenics receiving phenothiazines: clinical correlates. Clin Electroencephalogr 1975; 6: 103–25
Kugler J, Lorenzi E, Spatz R, et al. Drug-induced paroxysmal EEG activities. Pharmacopsychiatr Neuropsychopharmakol 1979; 12: 165–72
Schlichter W, Bristow ME, Schultz S, et al. Seizures occurring during intensive chlorpromazine therapy. Can Med Assoc J 1956; 74: 364–6
Tsuchiya H, Kawahara R, Tanaka Y, et al. Generalized seizure during treatment of schizophrenia with zotepine. Yonago Acta Med 1986; 29(2): 103–11
Hori M, Suzuki T, Sasaki M. Convulsive seizures in schizophrenic patients induced by zotepine administration. Jpn J Psychiatry Neurol 1992 Mar; 46: 161–7
Manmaru S. Five cases of schizophrenia with convulsive seizures during zotepine administration [in Japanese]. Seishin Igaku 1985; 27: 59–70
Reynolds C, Kilpatrick AT, Bratty R. Zotepine, a broad spectrum antipsychotic with low extrapyramidal side effects [abstract]. Eur Neuropsychopharmacol 1997; 7Suppl. 2: S225
Wetterling T, Mussigbrodt H. Weight gain: a side effect of zotepine (Nipolept®)? [in German]. Nervenarzt 1996 Mar; 67: 256–61
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: 261–99
Anderman B, Griffith RW. Clozapine-induced agranulocytosis: a situation reported up to August 1976. Eur J Clin Pharmacol 1977; 11: 199
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: 109–11
Kubota T, Ishikura T, Jibiki I. Three cases of alopecia areata induced by zotepine. Acta Neurol Napoli 1993 Jun; 15: 200–3
Reynolds JEF, editor. Martindale: the extra pharmacopoeia. 31st ed. London: Royal Pharmaceutical Society of Great Britain: The Pharmaceutical Press, 1996
Kammer-Reusch M, editor. Gelbe Liste Pharmindex. 2 Quartal ed. Neu Isenburg, GmbH: MediMedia. Medizinische Medien Informations, 1997
Davies LM, Drummond MF. The economic burden of schizophrenia. Psychiatry Bull 1990; 14: 522–5
Seeman P. Brain dopamine receptors. Pharmacol Rev 1980; 32: 197–202
Seiden L, Sabol K. Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 1993; 32: 639–77
Csernansky JG, Brown K, Hollister LE. Is there drug treatment for negative schizophrenic symptoms? Hosp Formul 1986; 21: 790–2
Puech AJ, Simon P, Doissier IR. Benzamides and classical neuroleptics: comparison of their actions using apomorphine induced effects. Eur J Pharmacol 1978; 50: 291–300
Erard R, Luisada P, Peele R. The PCP psychosis: prolonged intoxication or drug-precipitated functional illness? J Psychedelic Drugs 1980; 12: 235–51
Javitt D. Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia. Hillside J Clin Psychiatry 1987; 9: 12–35
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: 451–5
King DJ. The effect of neuroleptics on cognitive and psychomotor function. Br J Psychiatry 1990 Dec; 157: 799–811
Green JF, King DJ. Cognitive functioning in schizophrenia: effects of drug treatments. CNS Drugs 1996 Nov; 6: 382–98
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–S2–20
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: 16–24
Buchanan RW, Holstein C, Breier A. The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance. Biol Psychiatry 1994; 36: 717–25
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An erratum to this article is available at http://dx.doi.org/10.1007/BF03257358.
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Prakash, A., Lamb, H.M. Zotepine. Mol Diag Ther 9, 153–175 (1998). https://doi.org/10.2165/00023210-199809020-00006
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DOI: https://doi.org/10.2165/00023210-199809020-00006