Trazodone (Desyrel)

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

History

Trazodone, a phenylpiperazine–triazolopyridine antidepressant, was originally discovered and developed in Italy in the 1960s by Angelini research laboratories. This agent was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that depression is associated with a decreased pain threshold 27. In contrast to other antidepressants available at the time of its development, trazodone demonstrated minimal effects on muscarinic cholinergic receptors.

In Italy, this drug is fully reimbursed by the National Health System and is available in tablets, drops and injectable solution. Trazodone was patented and marketed in many countries all over the world and became the market leader in the United States during the 1980s.

FDA approved indications

• Major Depressive Disorder

Off-label & Investigational uses

• insomnia and sleep problems 2, 3, 9, 12
• panic disorder 4
• generalized anxiety disorder 5
• diabetic neuropathy 6
• migraine 7
• bulimia nervosa 8
• obsessive-compulsive disorder 14, 23
• alcohol withdrawal 17, 19
• schizophrenia 16, 20
• erectile dysfunction 21
• behavioral disorders in dementia 15
• sleep disturbances in patients Alzheimer disease 30

Panic disorder
There was significant improvement on all symptom dimensions, which suggests that trazodone may have specific antipanic and antiphobic actions and underscores the importance of serotonergic mechanisms in these anxiety disorders.

Migraine
A double-blind, placebo-controlled cross-over trial showed that, trazodone is a valid prophylactic agent for juvenile migraine. The study has been shown that trazodone can reduce frequency and the duration of the migraine episodes 7.

Bulimia nervosa
Trazodone appears to be effective in the treatment of bulimia nervosa. It is particularly attractive treatment for bulimia nervosa because of its low anticholinergic side-effects profile.

Chronic schizophrenia and tardive dyskinesia
Results of double-blind, placebo-controlled study 16 indicated that trazodone, when used in conjunction with neuroleptics, is safe and effective for treating negative symptoms in elderly patients with chronic schizophrenia. Results also indicated a possible beneficial effect of trazodone in treating tardive dyskinesia.

Erectile dysfunction
While trazodone is not designed for treatment of erectile dysfunction, its combined central and peripheral activity does improve erectile function in men with mild ED. Trazodone may be especially helpful for problems dealing with male arousal.

Trazodone may be beneficial in the management of SSRI-induced sexual dysfunction11.

The study have been shown that combination of yohimbine and trazodone may be a safe and effective treatment for psychogenic impotence 22.

Alcohol withdrawal
Trazodone is helpful in the treatment of lasting alcohol withdrawal symptoms, such as sleep disturbances and cravings. This agent is also efficient for the treatment of the acute phase of alcohol withdrawal treatment.

Trazodone "pros" and "cons"

Advantages:

• Not addictive or habit forming
• No restrictions on long-term use
• In comparison with tricyclic antidepressants, trazodone is relatively safe in overdose and has fewer cardiovascular and anticholinergic side effects 10
• Effective as amitriptyline, imipramine, and fluoxetine in relieving depressive symptoms 10
• Low incidence of serious adverse effects
• May be helpful in men with erectile dysfunction and psychogenic erectile dysfunction 13
• Beneficial for insomnia combined with depression or anxiety
• Trazodone has an advantage over traditional hypnotics in that it does not depress respiration. This characteristic is important in patients with sleep apnea.
• Can increase libido in women 18
• Trazodone does not affect driving performance or cognitive function under acute or repeated administrations 29
• Useful for anxiety and when antipsychotics aren't tolerated
• Low cost - trazodone is considerably cheaper than Z-drugs

Disadvantages:

• Drowsiness and sedation may limit its use, especially in the elderly patients and those with psychomotor retardation.
• Risk of serious, though uncommon, adverse effects such as orthostatic hypotension and cardiovascular effects 25, 26
• Trazodone-induced priapism 24 (prolonged erection in the absence of sexual stimulation). Priapism occurs very rarely -- in 0.1-0.01% of men who take this medication.
• Frequently causes headache, sometimes quite severe28

Mechanism of action

Trazodone acts as a dual 5-HT agonist and 5-HT reuptake inhibitor. Both trazodone and its metabolite m-chlorophenylpiperazine act on signal-sending neurons and on receptors located on the message-receiving neuron. The action of trazodone on the synapses of the message-sending neuron prevents neurotransmitter re-uptake, especially of serotonin. In this way, it facilitates the delivery of the message to the destination receptor. This partly explains why trazodone is effective in the treatment of depression.

The action on receptors located along the receiving neuron is another of the drug-induced effects, including side effects. In fact, when trazodone binds to special types of such receptors, this agent prevents the neurotransmitter - serotonin - from delivering the message to the receiving neuron. With trazodone, the resulting pharmacological activity is mostly sedative, and this side effect can be a benefit for patients, especially if they also suffer from sleeplessness.

Is trazodone addictive?

Trazodone is non-addictive and not habit forming antidepressant.

Time to clear out of the system

Trazodone has biphasic elimination with a redistribution half-life of about one hour and an elimination half-life of 10-12 hours.

Onset of action

• Antidepressant effect: it takes about 1-3 weeks to notice effects.

Further reading

• Trazodone (Desyrel) vs Mirtazapine (Remeron)
• Trazodone for Insomnia

References

• 1. U.S. FDA Trazodone Prescribing Information. Available in PDF format
• 2. Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-associated insomnia. Am J Psychiatry 1994 Jul;151(7):1069-72.
• 3. Saletu-Zyhlarz GM, Abu-Bakr MH, Anderer P, Gruber G, Mandl M, Strobl R, Gollner D, Prause W, Saletu B. Insomnia in depression: differences in objective and subjective sleep and awakening quality to normal controls and acute effects of trazodone. Prog Neuropsychopharmacol Biol Psychiatry. 2002 Feb;26(2):249-60. PubMed
• 4. Mavissakalian M, Perel J, Bowler K, Dealy R. Trazodone in the treatment of panic disorder and agoraphobia with panic attacks. Am J Psychiatry. 1987 Jun;144(6):785-7.
• 5. Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 1993 Nov;50(11):884-95. PubMed
• 6. Wilson RC. Trazodone in the treatment of painful diabetic neuropathy.J Am Podiatr Med Assoc. 1999 Sep;89(9):468-71.
• 7. Battistella PA, Ruffilli R, Cernetti R, Pettenazzo A, Baldin L, Bertoli S, Zacchello F. A placebo-controlled crossover trial using trazodone in pediatric migraine. Headache. 1993 Jan;33(1):36-9. PubMed
• 8. Pope HG Jr, Keck PE Jr, McElroy SL, Hudson JI. A placebo-controlled study of trazodone in bulimia nervosa. J Clin Psychopharmacol. 1989 Aug;9(4):254-9. PubMed
• 9. Kaynak H, Kaynak D, Gozukirmizi E, Guilleminault C. The effects of trazodone on sleep in patients treated with stimulant antidepressants. Sleep Med. 2004 Jan;5(1):15-20. PubMed
• 10. Haria M, Fitton A, McTavish D. Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging. 1994 Apr;4(4):331-55. PubMed
• 11. Stryjer R, Spivak B, Strous RD, Shiloh R, Harary E, Polak L, Birgen M, Kotler M, Weizman A. Trazodone for the treatment of sexual dysfunction induced by serotonin reuptake inhibitors: a preliminary open-label study. Clin Neuropharmacol. 2009 Mar-Apr;32(2):82-4.
• 12. Doroudgar S, Chou TI, Yu J, Trinh K, Pal J, Perry PJ. Evaluation of trazodone and quetiapine for insomnia: an observational study in psychiatric inpatients. Prim Care Companion CNS Disord. 2013;15(6). PubMed
• 13. Fink HA, MacDonald R, Rutks IR, Wilt TJ. Trazodone for erectile dysfunction: a systematic review and meta-analysis. BJU Int. 2003 Sep;92(4):441-6. PubMed
• 14. Prasad A. Efficacy of trazodone as an anti obsessional agent. Pharmacol Biochem Behav. 1985 Feb;22(2):347-8. PubMed
• 15. Osváth P. Current treatment of depression and agitation in the elderly -- clinical use of trazodone. Neuropsychopharmacol Hung. 2013 Sep;15(3):147-55. PubMed
• 16. Hayashi T, Yokota N, Takahashi T, Tawara Y, Nishikawa T, Yano T, Furutani M, Fujikawa T, Horiguchi J, Yamawaki S. Benefits of trazodone and mianserin for patients with late-life chronic schizophrenia and tardive dyskinesia: an add-on, double-blind, placebo-controlled study. Int Clin Psychopharmacol. 1997 Jul;12(4):199-205. PubMed
• 17. Le Bon O, Murphy JR, Staner L, Hoffmann G, Kormoss N, Kentos M, Dupont P, Lion K, Pelc I, Verbanck P. Double-blind, placebo-controlled study of the efficacy of trazodone in alcohol post-withdrawal syndrome: polysomnographic and clinical evaluations. J Clin Psychopharmacol. 2003 Aug;23(4):377-83. PubMed
• 18. Gartrell N. Increased libido in women receiving trazodone. Am J Psychiatry. 1986 Jun;143(6):781-2.
• 19. Borras L, de Timary P, Constant EL, Huguelet P, Eytan A. Successful treatment of alcohol withdrawal with trazodone. Pharmacopsychiatry. 2006 Nov;39(6):232. PubMed
• 20. Decina P, Mukherjee S, Bocola V, Saraceni F, Hadjichristos C, Scapicchio P. Adjunctive trazodone in the treatment of negative symptoms of schizophrenia. Hosp Community Psychiatry. 1994 Dec;45(12):1220-3
• 21. Stryjer R, Spivak B, Strous RD, Shiloh R, Harary E, Polak L, Birgen M, Kotler M, Weizman A. Trazodone for the treatment of sexual dysfunction induced by serotonin reuptake inhibitors: a preliminary open-label study. Clin Neuropharmacol. 2009 Mar-Apr;32(2):82-4. PubMed
• 22. Montorsi F, Strambi LF, Guazzoni G, Galli L, Barbieri L, Rigatti P, Pizzini G, Miani A. Effect of yohimbine-trazodone on psychogenic impotence: a randomized, double-blind, placebo-controlled study. Urology. 1994 Nov;44(5):732-6.PubMed
• 23. Pigott TA, L'Heureux F, Rubenstein CS, Bernstein SE, Hill JL, Murphy DL. A double-blind, placebo controlled study of trazodone in patients with obsessive-compulsive disorder. J Clin Psychopharmacol. 1992 Jun;12(3):156-62. PubMed
• 24. Carson CC 3rd, Mino RD. Priapism associated with trazodone therapy. J Urol. 1988 Feb;139(2):369-70. PubMed
• 25. van de Merwe TJ, Silverstone T, Ankier SI, Warrington SJ, Turner P. A double-blind non-crossover placebo-controlled study between group comparison of trazodone and amitriptyline on cardiovascular function in major depressive disorder. Psychopathology. 1984;17 Suppl 2:64-76. PubMed
• 26. Krahn LE, Hanson CA, Pileggi TS, Rummans TA. Electroconvulsive therapy and cardiovascular complications in patients taking trazodone for insomnia. J Clin Psychiatry. 2001 Feb;62(2):108-10. PubMed
• 27. Silvestrini B. Trazodone: from the mental pain to the "dys-stress" hypothesis of depression. Clin Neuropharmacol. 1989;12 Suppl 1:S4-10. PubMed
• 28. Chen HC, Tsai SJ. Trazodone-induced severe headache. Psychiatry Clin Neurosci. 2011 Dec;65(7):681-2.
• 29. Sasada K, Iwamoto K, Kawano N, Kohmura K, Yamamoto M, Aleksic B, Ebe K, Noda Y, Ozaki N. Effects of repeated dosing trazodone, or placebo on driving performance and cognitive function in healthy volunteers. Hum Psychopharmacol. 2013 May;28(3):281-6. PubMed
• 30. Camargos EF, Louzada LL, Quintas JL, Naves JO, Louzada FM, Nóbrega OT. Trazodone Improves Sleep Parameters in Alzheimer Disease Patients: A Randomized, Double-Blind, and Placebo-Controlled Study. Am J Geriatr Psychiatry. 2014 Jan 4. PubMed

Published: March 31, 2008
Last updated: March 24, 2019