Antipsychotic Efficacy of the Antidepressant Trimipramine: A Randomized, Double-blind Comparison with the Phenothiazine Perazine

Background: The tricyclic antidepressant trimipramine exhibits several features (e. g., dopaminergic effect, molecular structure similar to a neuroleptic, receptor-binding profile similar to clozapine) that suggest its potential as an antipsychotic medication. The aim of the study was to investigate the antipsychotic potential of trimipramine in a controlled clinical trial comparing its antipsychotic efficacy with that of a neuroleptic. Method: In a German multi-center, randomized, double-blind trial, the antipsychotic efficacy of trimipramine was compared with that of the phenothiazine neuroleptic perazine, using the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impressions (CGI). Antidepressant efficacy of both agents was measured by use of the Bech-Rafaelsen Melancholia Scale (BRMES). Ninety-five patients with acute schizophrenia (DSM-III-R) and a BPRS total score > 40 at baseline were treated with either 300-400 mg trimipramine or 450-600 mg perazine for 5 weeks. Results: Therapeutic equivalence of both treatments (in the dosages used) could not be demonstrated (change in BPRS total score, per-protocol [PP] analysis, one-sided equivalence testing). However, intention-to-treat (ITT) as well as PP analysis showed a statistically significant decrease in the BPRS total scores in both treatment groups (PP: trimipramine, 56.5 ± 9.8 to 44.1 ± 17.9; perazine, 56.4 ± 10.8 to 37.9 ± 12.9). Significant decreases in all BPRS and PANSS subscores as well as CGI results and response rate support the antipsychotic efficacy of trimipramine. The BRMES total scores significantly decreased in both treatment groups without showing a significant difference between the two agents. Trimipramine was better tolerated than perazine and did not elicit extrapyramidal symptoms. Conclusion: Trimipramine failed to exhibit therapeutic equivalence to perazine in the dosages used. However, there was evidence of a substantial antipsychotic effect of trimipramine. It may be a useful medication if depressive symptoms in psychotic patients require antidepressant treatment or if other antipsychotics cannot be administered.

References

• 1 Akiskal H S, Arana G W, Baldessarini R J, Barreira P J. A clinical report of thymoleptic-responsive atypical paranoid psychoses.  Am J Psychiatry. 1983;  140 1187-1190
• 2 Bech P, Rafaelsen O J. The use of rating scales exemplified by a comparison of the Hamilton and the Bech-Rafaelsen Melancholia Scale.  Acta Psychiatr Scand. 1980;  62[suppl 285] 128-131
• 3 Benkert O, Müller-Siecheneder F, Wetzel H. Negative and depressive symptoms in acute schizophrenic episodes - do they improve under neuroleptic treatment?.  Eur Psychiatry. 1996;  11[suppl 4] 158s-159s
• 4 Berger M, Gastpar M. Trimipramine: a challenge to current concepts on antidepressives.  Eur Arch Psychiatry Clin Neurosci. 1996;  246 235-239
• 5 Declaration of Helsinki, revised version. Hong Kong: The World Medical Association, Inc. 41st Assembly. 
• 6 Eap C B, Bender S, Fischer W, Powell K, Jonzier-Perey M, Cochard N, Berger M, Gastpar M, Baumann P. Steady-state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients.  Ther Drug Monit. 2000;  22 209-214
• 7 Eikmeier G, Berger M, Lodemann E, Muszynski K, Kaumeier S, Gastpar M. Trimipramine - an atypical neuroleptic?.  Int Clin Psychopharmacol. 1991;  6 147-153
• 8 Eikmeier G, Muszynski K, Berger M, Gastpar M. High-dose trimipramine in acute schizophrenia: preliminary results of an open trial.  Pharmacopsychiatry. 1990;  23 212-214
• 9 Gaebel W. Perazin - ein klassisches Neuroleptikum aus der Gruppe der piperazinsubstituierten Phenothiazine.  Fundamenta Psychiatrica. 1993;  7 48-57
• 10 Gastpar M. Clinical originality and new biology of trimipramine.  Drugs. 1989;  38 [suppl 1] 43-48
• 11 Gross G, Xin X, Gastpar M. Trimipramine: pharmacological reevaluation and comparison with clozapine.  Neuropharmacology. 1991;  30 1159-1166
• 12 Guy W. ECDEU assessment manual for psychopharmacology. Rev ed. Betehsda, MD US Department of Health, Education and Welfare 1976: 217-222
• 13 Hausmann A, Fleischhacker W W. Depression in patients with schizophrenia: prevalence, and diagnostic and treatment considerations.  CNS Drugs. 2000;  14 289-299
• 14 Heinrich K. Die gezielte Symptomprovokation mit monoaminooxydasehemmenden Substanzen in Diagnostik und Therapie schizophrener Psychosen.  Nervenarzt. 1960;  31 507-512
• 15 Hemmeter U, Annen B, Bischof R, Bruderlin U, Hatzinger M, Rose U, Holsboer-Trachsler E. Polysomnographic effects of adjuvant ginkgo biloba therapy in patients with major depression medicated with trimipramine.  Pharmacopsychiatry. 2001;  34 50-59
• 16 Kay S R, Opler L A, Fiszbein A. Positive and Negative Syndrome Scale (PANSS) Manual. Toronto; Multi-Health Systems 1992
• 17 Klein D F, Fink M. Psychiatric reaction pattern to imipramine.  Am J Psychiatry. 1962;  119 432-438
• 18 Klieser E. Psychopharmakologische Differentialtherapie endogener Psychosen. Stuttgart, New York; Thieme 1990
• 19 Lapierre Y D. A review of trimipramine: 30 years of clinical use.  Drugs. 1989;  38 [suppl 1] 17-24
• 20 Levinson D F, Umapathy C, Musthaq M. Treatment of schizoaffective disorder and schizophrenia with mood symptoms.  Am J Psychiatry. 1999;  156 1138-1148
• 21 Maj J, Rogoz Z, Skuza G, Margas W. Repeated trimipramine induces dopamine D₂/D₃ and α₁-adrenergic up-regulation.  J Neur Transm Gen Sect. 1998;  105 329-342
• 22 Meltzer H Y. Treatment-resistant schizophrenia - the role of clozapine.  Curr Med Res Opin. 1997;  14 1-20
• 23 Naber D, Krausz M, Lambert M, Bender S. Refractory schizophrenia. In Lader M, Naber D, editors Difficult clinical problems in psychiatry. London; Martin Dunitz 1999: p. 3-22
• 24 Notification of Principles for the Proper Conduct of Clinical Trials (GCP). Drugs made in Germany 1989 32: 21-23
• 25 Overall J E, Gorham D R. The Brief Psychiatric Rating Scale.  Psychol Rep. 1962;  10 799-812
• 26 Plasky P. Antidepressant usage in schizophrenia.  Schizophr Bull. 1991;  17 649-657
• 27 Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro.  J Pharmacol Exp Ther. 1984;  230 94-102
• 28 Riemann D, Vorderholzer U, Cohrs S, Rodenbeck A, Hajak G, Rüther E, Wiegand M H, Laakmann G, Baghai T, Fischer W, Hoffmann M, Hohagen F, Mayer G, Berger M. Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study.  Pharmacopsychiatry. 2002;  35 165-174
• 29 Seeman P. Dopamine receptor sequences: therapeutic levels of neuroleptics occupy D₂ receptors, clozapine occupies D₄ .  Neuropsychopharmacology. 1992;  7 261-284
• 30 Settle E C, Ayd F J. Trimipramine: twenty years’ worldwide clinical experience.  J Clin Psychiatry. 1980;  41 266-274
• 31 Sokoloff P. Research report on trimipramine. Paris: Unité de neurobiologie et pharmacologie. Centre Paul Broca de l’inserm 1996
• 32 Sonntag A, Frieboes R, Zobel A, Steiger A. Trimipramine in the treatment of psychotic depression.  Pharmacopsychiatry. 1997;  30 215
• 33 Vliegen J. Die Einheitspsychose: Geschichte und Problem. Stuttgart; Enke 1980
• 34 Waldmeier P C. Effects of antidepressant drugs on dopamine uptake and metabolism.  J Pharm Pharmacol. 1982;  34 391-394
• 35 Wetzel H, von Bardeleben U, Holsboer F, Benkert O. Zotepine versus perazine in patients with paranoid schizophrenia: a double-blind controlled trial of its effectiveness.  Fortschr Neurol Psychiatr. 1991;  59 [suppl 1] 23-29
• 36 Wolf R, Dykierek P, Gattaz W F, Maras A, Kohnen R, Dittmann R W, Geuppert M, Riemann D, Berger M. Differential effects of trimipramine and fluoxetine on sleep in geriatric depression.  Pharmacopsychiatry. 2001;  34 60-65