Search tips
Search criteria 


Logo of jpnSubmit a ManuscriptEmail AlertsAbout JPNJournal of Psychiatry and Neuroscience
J Psychiatry Neurosci. 2000 September; 25(4): 337–346.
PMCID: PMC1407729

Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects.


OBJECTIVE: Because the initial phase of treatment of depression with a selective serotonin reuptake inhibitor is often complicated by a delayed onset of action of the antidepressant or severe insomnia or both, we investigated whether tryptophan, an amino acid with both antidepressant-augmenting and hypnotic effects, would benefit patients with depression at the beginning of treatment with fluoxetine. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Thirty individuals with major depressive disorder. INTERVENTIONS: Treatment over 8 weeks with 20 mg of fluoxetine per day and either tryptophan (2 to 4 g per day) or placebo. OUTCOME MEASURES: Mood was assessed using the 29-item Hamilton Depression Rating Scale (HDRS-29) and the Beck Depression Inventory (BDI). Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using standard procedures. RESULTS: During the first week of treatment, there was a significantly greater decrease in HDRS-29 depression scores, and a similar trend in BDI scores, in the tryptophan/fluoxetine group than in the placebo/fluoxetine group. No significant differences were noted at later time points. With respect to sleep measures, there was a significant group-by-time interaction for slow-wave sleep at week 4. Further analysis revealed a significant decrease in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group, but not in the tryptophan/fluoxetine group. No cases of serotonin syndrome occurred, and the combination was well tolerated, although the 4 g per day dosage of tryptophan produced daytime drowsiness. CONCLUSIONS: Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep. Further large-scale studies are needed to confirm these initial findings.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.5M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hamilton M. Frequency of symptoms in melancholia (depressive illness) Br J Psychiatry. 1989 Feb;154:201–206. [PubMed]
  • Benca RM, Obermeyer WH, Thisted RA, Gillin JC. Sleep and psychiatric disorders. A meta-analysis. Arch Gen Psychiatry. 1992 Aug;49(8):651–670. [PubMed]
  • Van Moffaert MM. Sleep disorders and depression: the 'chicken and egg' situation. J Psychosom Res. 1994;38 (Suppl 1):9–13. [PubMed]
  • Beasley CM, Jr, Sayler ME, Weiss AM, Potvin JH. Fluoxetine: activating and sedating effects at multiple fixed doses. J Clin Psychopharmacol. 1992 Oct;12(5):328–333. [PubMed]
  • van Bemmel AL, van den Hoofdakker RH, Beersma DG, Bouhuys AL. Changes in sleep polygraphic variables and clinical state in depressed patients during treatment with citalopram. Psychopharmacology (Berl) 1993;113(2):225–230. [PubMed]
  • Sandor P, Shapiro CM. Sleep patterns in depression and anxiety: theory and pharmacological effects. J Psychosom Res. 1994;38 (Suppl 1):125–139. [PubMed]
  • COPPEN A, SHAW DM, FARRELL JP. Potentiation of the antidepressive effect of a monoamine-oxidase inhibitor by tryptophan. Lancet. 1963 Jan 12;1(7272):79–81. [PubMed]
  • Glassman AH, Platman SR. Potentiation of a monoamine oxidase inhibitor by tryptophan. J Psychiatr Res. 1969 Dec;7(2):83–88. [PubMed]
  • Ayuso Gutierrez JL, Aliño JJ. Tryptophan and an MAOI (nialamide) in the treatment of depression. A double-blind study. Int Pharmacopsychiatry. 1971;6(2):92–97. [PubMed]
  • Walinder J, Skott A, Carlsson A, Nagy A, Bjorn-Erik R. Potentiation of the antidepressant action of clomipramine by tryptophan. Arch Gen Psychiatry. 1976 Nov;33(11):1384–1389. [PubMed]
  • Hale AS, Procter AW, Bridges PK. Clomipramine, tryptophan and lithium in combination for resistant endogenous depression: seven case studies. Br J Psychiatry. 1987 Aug;151:213–217. [PubMed]
  • Shaw DM, Macsweeney DA, Hewland R, Johnson AL. Tricyclic antidepressants and tryptophan in unipolar depression. Psychol Med. 1975 Aug;5(3):276–278. [PubMed]
  • Chouinard G, Young SN, Annable L, Sourkes TL. Tryptophan-nicotinamide, imipramine and their combination in depression. A controlled study. Acta Psychiatr Scand. 1979 Apr;59(4):395–414. [PubMed]
  • Wyatt RJ, Engelman K, Kupfer DJ, Fram DH, Sjoerdsma A, Snyder F. Effects of L-tryptophan (a natural sedative) on human sleep. Lancet. 1970 Oct 24;2(7678):842–846. [PubMed]
  • Hartmann E, Cravens J, List S. Hypnotic effects of L-tryptophan. Arch Gen Psychiatry. 1974 Sep;31(3):394–397. [PubMed]
  • Brown CC, Horrom NJ, Wagman AM. Effects of L-tryptophan on sleep onset insomniacs. Waking Sleeping. 1979 Apr;3(2):101–108. [PubMed]
  • Hartmann E, Spinweber CL. Sleep induced by L-tryptophan. Effect of dosages within the normal dietary intake. J Nerv Ment Dis. 1979 Aug;167(8):497–499. [PubMed]
  • KOELLA WP, CZICMAN JS. Influence of serotonin upon optic evoked potentials, EEG, and blood pressure of cat. Am J Physiol. 1963 May;204:873–880. [PubMed]
  • Hajak G, Huether G, Blanke J, Blömer M, Freyer C, Poeggeler B, Reimer A, Rodenbeck A, Schulz-Varszegi M, Rüther E. The influence of intravenous L-tryptophan on plasma melatonin and sleep in men. Pharmacopsychiatry. 1991 Jan;24(1):17–20. [PubMed]
  • Adam K, Oswald I. One gram of L-tryptophan fails to alter the time taken to fall asleep. Neuropharmacology. 1979 Dec;18(12):1025–1027. [PubMed]
  • Cooper AJ. Tryptophan antidepressant 'physiological sedative': fact or fancy? Psychopharmacology (Berl) 1979 Mar 14;61(1):97–102. [PubMed]
  • Linnoila M, Viukari M, Numminen A, Auvinen J. Efficacy and side effects of chloral hydrate and tryptophan as sleeping aids in psychogeriatric patients. Int Pharmacopsychiatry. 1980;15(2):124–128. [PubMed]
  • Belongia EA, Hedberg CW, Gleich GJ, White KE, Mayeno AN, Loegering DA, Dunnette SL, Pirie PL, MacDonald KL, Osterholm MT. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med. 1990 Aug 9;323(6):357–365. [PubMed]
  • Wilkins K, Wigle D. Eosinophilia-myalgia syndrome. CMAJ. 1990 Jun 1;142(11):1265–1266. [PMC free article] [PubMed]
  • Steiner W, Fontaine R. Toxic reaction following the combined administration of fluoxetine and L-tryptophan: five case reports. Biol Psychiatry. 1986 Sep;21(11):1067–1071. [PubMed]
  • BECK AT, WARD CH, MENDELSON M, MOCK J, ERBAUGH J. An inventory for measuring depression. Arch Gen Psychiatry. 1961 Jun;4:561–571. [PubMed]
  • Agnew HW, Jr, Webb WB, Williams RL. The first night effect: an EEG study of sleep. Psychophysiology. 1966 Jan;2(3):263–266. [PubMed]
  • Buysse DJ, Kupfer DJ. Diagnostic and research applications of electroencephalographic sleep studies in depression. Conceptual and methodological issues. J Nerv Ment Dis. 1990 Jul;178(7):405–414. [PubMed]
  • Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci. 1994 Jul;15(7):220–226. [PubMed]
  • Bronzino JD, Morgane PJ, Stern WC. EEG synchronization following application of serotonin to area postrema. Am J Physiol. 1972 Aug;223(2):376–383. [PubMed]
  • Joseph MH, Risby D. The determination of kynurenine in plasma. Clin Chim Acta. 1975 Sep 1;63(2):197–204. [PubMed]

Articles from Journal of Psychiatry & Neuroscience : JPN are provided here courtesy of Canadian Medical Association