Pharmacopsychiatry 2002; 35(5): 165-174
DOI: 10.1055/s-2002-34119
Original Paper

© Georg Thieme Verlag Stuttgart · New York

Trimipramine in Primary Insomnia: Results of a Polysomnographic Double-Blind Controlled Study

D. Riemann1 , U. Voderholzer1 , S. Cohrs2 , A. Rodenbeck2 , G. Hajak2 , E. Rüther2 , M. H. Wiegand3 , G. Laakmann4 , T. Baghai4 , W. Fischer5 , M. Hoffmann6 , F. Hohagen7 , G. Mayer8 , M. Berger1
  • 1Department of Psychiatry and Psychotherapy, University of Freiburg, Germany
  • 2Department of Psychiatry and Psychotherapy, University of Göttingen, Germany
  • 3Department of Psychiatry and Psychotherapy, Technical University of Munich, Germany
  • 4Department of Psychiatry, University of Munich, Germany
  • 5Aventis Pharma GmbH, Bad Soden, Germany
  • 6Department of Psychiatry, University of Erlangen-Nuremberg, Germany
  • 7Department of Psychiatry and Psychotherapy, University of Lübeck, Germany
  • 8Neurological Hospital Hephata, Schwalmstadt-Treysa, Germany
The study was supported and sponsored by Aventis Pharma GmbH, Bad Soden, Germany (formerly Rhône Poulenc Rorer GmbH, Cologne, Germany)
Further Information

Publication History

Received: 20. 8. 2001 Revised: 8. 3. 2002

Accepted: 8. 3. 2002

Publication Date:
18 September 2002 (online)

In recent years, sedating antidepressants have been increasingly used to treat primary insomnia. Up to now, only one open pilot study with trimipramine and one double-blind placebo-controlled study with doxepin have leant scientific support for this approach in treating primary insomnia.

In order to test the hypothesis that sedating antidepressants are useful in the treatment of primary insomnia, the effect of trimipramine on objectively and subjectively measured parameters of sleep was investigated in a double-blind placebo- and lormetazepam-controlled study in a sample of 55 patients with primary insomnia attending outpatient sleep-disorder clinics.

Trimipramine was selected since it has shown positive effects on sleep continuity with a lack of REM sleep suppression in studies on depressed patients and in one pilot study on patients with primary insomnia.

Trimipramine at an average dose of 100 mg over a period of 4 weeks significantly enhanced sleep efficiency, but not total sleep time (which had been the primary target variable) compared to placebo as measured by polysomnography. Changes in objective sleep parameters were paralleled by changes in subjective sleep parameters. Trimipramine did not suppress REM sleep. Lormetazepam decreased wake time and sleep stage 3 and increased REM sleep compared to placebo.

After switching trimipramine to placebo, sleep parameters returned to baseline. There was no evidence of any rebound effect from trimipramine. Side effects from trimipramine were only marginal.

This first double-blind placebo-controlled study with trimipramine suggests its efficacy in the treatment of primary insomnia. However, due to the large intra- and interindividual variance in the parameters of interest before and during treatment a larger sample size would have been necessary to strengthen the validity of our findings.

References

  • 1 American Psychiatric Association ( APA). Diagnostic and Statistical Manual of Mental Disorders, third edition revised (DSM-III-R). Washington; 1987 Deutsche Bearbeitung: Wittchen, HU, Zaudig, M, Koehler, K, Saß H. Weinheim Beltz; 1989
  • 2 American Psychiatric Association ( APA). Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Washington; APA 1994 Deutsche Bearbeitung: Wittchen, HU, Zaudig, M, Koehler, K, Saß H. Weinheim; Beltz 1994
  • 3 Armitage R, Rush J, Trivedi M, Cain J, Roffwarg H P. The effects of nefazodone on sleep architecture in depression.  Neuropsychopharmacology. 1994;  10 123-127
  • 4 Armitage R, Yonkers K, Cole D, Rush J. A multicenter, double-blind comparison of the effects of nefazodone and fluoxetine on sleep architecture and quality of sleep in depressed outpatients.  J Clin Psychopharmacol. 1997;  17 161-168
  • 5 Backhaus J, Hohagen F, Voderholzer U, Riemann D. Long-term effectiveness of a short-term cognitive-behavioral group treatment for primary insomnia.  Eur Arch Psychiatry Clin Neurosci. 2001;  251 35-41
  • 6 Berger M, Riemann D. REM sleep in depression - an overview.  J Sleep Res. 1993;  2 211-223
  • 7 Berger M, Gastpar M. Trimipramine: a challenge to current concepts on antidepressives.  Eur Arch Psychiatry Clin Neurosci. 1996;  246 235-239
  • 8 Borbély A A, Loepfe M, Mattmann P, Tober I. Midazolam and triazolam: hypnotic action and residual effects after a single bedtime dose.  Arzneimittelforschung. 1983;  33 1500-1502
  • 9 Borbély A A, Mattmann P, Loepfe M, Strauch I, Lehmann D. Effect of benzodiazepine hypnotics on all-night sleep EEG spectra.  Hum Neurobiol. 1985;  4 189-194
  • 10 Buysse D, Reynolds C F, Monk T H, Berman S R, Kupfer D J. The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research.  Psychiatry Res. 1989;  28 193-213
  • 11 Feige B, Voderholzer U, Riemann D, Hohagen F, Berger M. Independent sleep EEG slow wave and spindle band dynamics associated with 4 weeks of continuous application of short-half-life hypnotics in healthy subjects.  Clin Neurophysiology. 1999;  110 1965-1974
  • 12 Ford D E, Kamerow D B. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention.  J Am Med Assoc. 1989;  262 1479-1484
  • 13 Gillin J C, Rapaport M, Erman M K, Winokur A, Albala B J. A comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: A double-blind, 8-week clinical trial.  J Clin Psychiatry. 1997;  58 185-192
  • 14 Görtelmeyer R. Schlaffragebogen SF-A and SF-B. In Collegium Internationale Psychiatriae Scolarum (CIPS). Herausgeber. Internationale Skalen für Psychiatrie Weinheim; Beltz 1981
  • 15 Hajak G, Rüther E. Insomnie. Berlin; Springer 1995
  • 16 Hajak G, Rodenbeck A, Voderholzer U, Riemann D, Cohrs S, Hohagen F, Berger M, Rüther E. Doxepin in the treatment of primary insomnia - a placebo-controlled, double-blind, polysomnographic study.  J Clin Psychiatry. 2001;  62 453-463
  • 17 Hohagen F, Rink K, Käppler C, Schramm E, Riemann D, Weyerer S, Berger M. Prevalence and treatment of insomnia in general practice.  Eur Arch Psychiatry Clin Neurosci. 1993;  242 329-336
  • 18 Hohagen F, Fritsch Montero R, Weiss E, Lis S, Schönbrunn E, Dressing H, Riemann D, Berger M. Treatment of primary insomnia with trimipramine: an alternative to benzodiazepine hypnotics?.  Eur Arch Psychiatry Clin Neurosci. 1994;  244 65-72
  • 19 Hohagen F, Käppler C, Schramm E, Rink K, Weyerer S, Riemann D, Berger M. Prevalence of insomnia in elderly general practice attenders and the current treatment modalities.  Acta Psychiat Scand. 1994;  90 102-108
  • 20 Holbrook A M, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia.  CMAJ. 2000;  162 p 225-233
  • 21 Kales A, Bixler E O, Soldatos C R, Mitsky D J, Kales J D. Dose-response studies of lormetazepam: Efficacy, side effects, and rebound insomnia.  J Clin Pharmacol. 1982;  22 520-530
  • 22 Kripke D F. Chronic hypnotic use: deadly risks, doubtful benefit.  Sleep Med Rev. 2000;  4 5-20
  • 23 Mashiko H, Niwa S -I, Kumashiro H, Kaneko Y, Suzuki S, Numata Y, Horikoshi R, Watanabe Y. Effect of trazodone in a single dose before bedtime for sleep disorders accompanied by a depressive state: Dose-finding study with no concomitant use of hypnotic agent.  Psychiat Clin Neurosci. 1999;  53 193-194
  • 24 Merz W, Ballmer U. Symptoms of the barbiturate/benzodiazepine withdrawal syndrome in healthy volunteers: Standardized assessment by a newly developed self-rating scale.  J Psychoactive Drugs. 1983;  15 71-84
  • 25 Montgomery S A, Asberg M. Montgomery-Asberg Depression Rating Scale. In Collegium Internationale, European Edition (CIPS), editors Rating Scales for Psychiatry. Weinheim; Beltz Test GmbH 1986
  • 26 Morin C M. Insomnia - Psychological assessment and management. New York; The Guilford Press 1993
  • 27 Morin C M, Culbert J P, Schwartz S M. Nonpharmacological interventions for insomnia: A meta-analysis of treatment efficacy.  Am J Psychiatry. 1994;  151 1172-1180
  • 28 Murtagh D R, Greenwood K M. Identifying effective psychological treatments for insomnia: A meta-analysis.  J Consult Clin Psychology. 1995;  63 79-89
  • 29 Nair N P, Amin M, Schwartz G, Dastoor D, Thavundayil J X, Mirmiran J, MacDonald C, Phillips R. A comparison of the cardiac safety and therapeutic efficacy of trimi-pramine versus doxepin in geriatric depressed patients.  J Am Geriatr Soc. 1993;  41 863-867
  • 30 Nowell P D, Mazumdar S, Buysse D J, Dew M A, Reynolds C F, Kupfer D. Benzodiazepines and zolpidem for chronic insomnia.  JAMA. 1997;  278 p 2170-2177
  • 31 Nowell P D, Reynolds C F, Buysse D J, Dew M A, Kupfer D J. Paroxetine in the treatment of primary insomnia: Preliminary clinical and electroencephalogram sleep data.  J Clin Psychiatry. 1999;  60 89-95
  • 32 Perlis M L, Giles D E, Mendelson W B, Bootzin R R, Wyatt J K. Psychophysiological insomnia: The behavioural model and a neurocognitive perspective.  J Sleep Res. 1997;  6 179-188
  • 33 Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington, DC; US Government Printing Office, Public Health Service 1968
  • 34 Riemann D, Löw H, Schredl M, Wiegand M, Dippel B, Berger M. Investigations of morning and laboratory dream recall and content in depressive patients during baseline condition and under antidepressive treatment with trimipramine.  Psychiat J Univ Ottawa. 1990;  15 93-99
  • 35 Riemann D, Backhaus J. Behandlung von Schlafstörungen - Ein psychologisches Gruppenprogramm. Weinheim; Beltz 1996
  • 36 Riemann D, Berger M. Sleep disorders and mental disorders.  Curr Opin Psychiat. 1998;  11 327-331
  • 37 Riemann D, Berger M, Voderholzer U. Sleep and depression - results from psychobiological studies: an overview.  Biol Psychology. 2001;  57 67-103
  • 38 Sandor P, Shapiro C M. Sleep patterns in depression and anxiety: Theory and pharmacological effects.  J Psychosom Res. 1994;  38 125-139
  • 39 Schramm E, Hohagen F, Grasshoff U, Riemann D, Hajak G, Weeß H -G, Berger M. Test-retest reliability and validity of the Structured Interview for Sleep Disorders according to DSM-III-R.  Am J Psychiatry. 1993;  150 867-872
  • 40 Schramm E, Hohagen F, Käppler C, Grasshoff U, Berger M. Psychiatric comorbidity of insomnia in general practice attenders using DSM-III-R.  Acta Psychiat Scand. 1995;  91 16-17
  • 41 Schwabe U, Paffrath D. Arzneiverordnungs-Report 1999 - Aktuelle Daten, Kosten, Trends und Kommentare. Berlin, Heidelberg, New York; Springer 2000
  • 42 Simen S, Hajak G, Schlaf G, Westenhöfer J, Rodenbeck A, Band B, Pudel V, Rüther E. Chronifizierung von Schlafbeschwerden.  Nervenarzt. 1995;  66 686-695
  • 43 Smith M T, Perlis M L, Park A, Smith M S, Pennington J, Giles D E, Buysse D J. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia.  Am J Psychiatry. 2002;  159 5-11
  • 44 Sonntag A, Rothe B, Guldner J, Yassouridis A, Holsboer F, Steiger A. Trimipra-mine and imipramine exert different effects on the sleep EEG and on nocturnal hor- mone secretion during treatment of major depression.  Depression. 1996;  4 1-13
  • 45 Vogel G W. Sleep laboratory study of lormetazepam in older insomniacs. In Hindmarch, I, Ott H, Roth T, editors Sleep laboratory study of lormetazepam in older insomniacs. Berlin-Heidelberg; Springer-Verlag 1984: pp. 69-78
  • 46 Walsh J K, Schweitzer P K. Ten-year trends in the pharmacological treatment of insomnia.  Sleep. 1999;  22 371-375
  • 47 Ware J C, Brown F W, Moorad P J, Pittard J T, Cobert B. Effects on sleep: A double-blind study comparing trimipramine to imipramine in depressed insomniac patients.  Sleep. 1989;  12 537-549
  • 48 Ware J C, Pittard J T. Increased deep sleep after trazodone use: A double-blind placebo-controlled study in healthy young adults.  J Clin Psychiatry. 1990;  51 18-22
  • 49 Weyerer S, Dilling H. Prevalence and treatment of insomnia in the community: Results from the upper bavarian field study.  Sleep. 1991;  14 392-398
  • 50 Wiegand M, Berger M, Zulley J, von Zerssen D. The effect of trimipramine on sleep in patients with major depressive disorder.  Pharmacopsychiatry. 1986;  19 198-199
  • 51 Wiegand M, Berger M. Action of trimipramine on sleep and pituitary hormone secretion.  Drugs. 1989;  38 35-42
  • 52 Wittchen H U, Krause P, Höfler M, Pittrow D, Winter S, Spiegel B, Hajak G, Riemann D, Steiger A, Pfister H. NISAS-2000 - Die ‘Nationwide Insomnia Screening and Awareness Study’ - Prävalenz und Verschreibungsverhalten in der allgemeinärztlichen Versorgung.  Fortschr Med. 2001;  1 1-11
  • 53 Wittchen H U, Krause P, Höfler M, Winter S, Spiegel B, Hajak G, Riemann D, Pittrow D, Steiger A, Pfister H. NISAS-2000 - Die ‘Nationwide Insomnia Screening and Awareness Study’ - Insomnien und Schlafstörungen in der allgemeinärztlichen Versorgung.  Nervenheilkunde. 2001;  20 4-16
  • 54 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 1-6

Prof. Dr. Dieter Riemann

Department of Psychiatry and Psychotherapy

University of Freiburg


Hauptstrasse 5

79104 Freiburg

Phone: +49 (761) 270-6919

Fax: +49 (761) 270-6667

Email: dieter_riemann@psyallg.ukl.uni-freiburg.de

    >