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L-Tryptophan Augmentation of Light Therapy in Patients with Seasonal Affective Disorder

Raymond W Lam, MD¹, Robert D Levitan, MD², Edwin M Tam, MD³, Lakshmi N Yatham, MB⁴,
Sophie Lamoureux, BA⁵, Athanasios P Zis, MD⁶

Objective: Up to one-third of patients with seasonal affective disorder (SAD) do not have a full response to light therapy. Given the evidence for serotonergic dysregulation in SAD, we examined the possible role of l-tryptophan as an augmentation strategy for nonresponders and partial responders to light therapy.

Method: Eligible drug-free patients meeting DSM-IV criteria for SAD were treated for 2 weeks using a standard morning light therapy regimen (10 000 lux cool-white fluorescent light for 30 minutes). Partial and nonresponders were treated for 2 weeks with open-label l-tryptophan (1 g 3 times daily) while light therapy was continued. Ratings at baseline and follow-up included the 29-item Structured Interview Guide for the Hamilton Depression Rating Scale, SAD version (SIGH-SAD) and the Clinical Global Impression (CGI) scale.

Results: Sixteen patients began the l-tryptophan augmentation phase. Two patients discontinued medications within 3 days because of side effects. In the 14 patients completing treatment, the addition of l-tryptophan resulted in significant reduction of mean depression scores. Nine of 14 patients (64%) showed very good clinical responses to combined treatment and minimal side effects.

Conclusion:  This open-label study suggests that l-tryptophan may be an effective augmentation strategy for those patients with SAD who show limited or poor response to bright light therapy. Further placebo-controlled studies are warranted to demonstrate efficacy.

(Can J Psychiatry 1997;42:303–306)

Key Words: seasonal affective disorder, light therapy, tryptophan, serotonin, depressive disorders, antidepressants, augmentation

Recent critical reviews have concluded that bright light therapy is an effective treatment for SAD (1–3). Large data sets show that a good clinical response to light therapy is seen in approximately 65% of patients with SAD, with 22% of patients experiencing a partial response, and 13% showing little or no response (3). To date, there have been no studies of possible treatment strategies for the one-third of patients who are partial or nonresponders to light therapy.

The mechanism of action of light therapy for SAD is still unknown, but several studies have suggested that bright light may directly affect serotonergic neurotransmission. For example, patients with SAD who are in clinical remission after treatment with light therapy experience a transient clinical relapse following rapid depletion of the serotonin precursor, tryptophan (4,5). This suggests that light therapy acts via serotonergic pathways. Also of interest is that other studies have shown efficacy of serotonergic medications for SAD, including d-fenfluramine (6,7), fluoxetine (8), and sertraline (9). Additionally, one small crossover study found that l- tryptophan was superior to pill placebo and similar in effect to evening bright light exposure (10).

Given this evidence for a serotonergic mechanism in SAD, the goal of this study was to collect pilot data on the possible role of l-tryptophan as an augmentor of bright light treatment in patients with SAD.

Method

Patients were seen and assessed by experienced psychiatrists in mood disorders clinics at 2 teaching hospitals. Patients were diagnosed based on an unstructured clinical interview using DSM-IV criteria. To be eligible for light treatment, subjects had to: 1) meet DSM-IV criteria for recurrent major depressive disorder with a seasonal (winter) pattern, 2) have been drug-free for at least 2 weeks (at least 5 weeks for previous fluoxetine use), and 3) obtain a pretreatment 29-item SIGH-SAD score of greater than 20. Eligible patients were treated at home with a standard regimen of light therapy consisting of 2 weeks of daily exposure to a fluorescent light box. The light box used cool-white fluorescent light with an illumination of 10 000 lux at eye level. Each light box was fitted with an ultraviolet filter. Patients were instructed to sit with their eyes open under the light box for 30 minutes daily during the early morning (for example, between 07:00 and 08:00).

Patients were assessed at baseline and at follow-up visits with the SIGH-SAD (11). This scale generates the 21-item HDRS score, as well as an 8-item atypical symptom addendum that is widely used in SAD research. Patients were considered nonresponders or partial responders if they had less than 50% reduction in SIGH-SAD scores after 2 weeks of light therapy, or if their posttreatment SIGH-SAD score was greater than 14. The CGI Improvement scale was also rated at each follow-up visit.

Partial and nonresponders to light therapy were then treated with open-label l-tryptophan at a dose of 1 g 3 times daily with a carbohydrate snack for 2 weeks. The patients continued morning light therapy during l-tryptophan treatment. Side effects were recorded at each follow-up visit.

Results

A total of 16 patients began the l-tryptophan augmentation phase. All had a unipolar diagnosis. Two female patients experienced early side effects (nausea, gastrointestinal distress, headache) and discontinued the medication after 2 or 3 days. We report results on 14 patients who completed at least one week of treatment; 13 patients (11 women and 2 men) completed 2 weeks of treatment with l-tryptophan, while one female patient completed one week. The mean age ± SD of these patients was 39.6 years ± 8.5 years (range, 26 to 52 years).

Figure 1 shows the 29-item SIGH-SAD scores for individual patients at each assessment. The mean  ± SD SIGH-SAD scores at baseline and after 2 weeks of light therapy alone were 31.5 ± 7.1 and 26.4 ± 7.6, respectively. After light therapy, 10 of the 14 patients (71%) were considered nonresponders (less than 25% reduction in depression scores from baseline), while 4 patients (29%) were partial responders (between 25% and 50% reduction in depression scores).

Figure 1. Depression scores versus treatment condition (light therapy alone, light therapy plus l-tryptophan [TRP]) in 14 patients with SAD. Bars represent mean scores. *Represents a patient who received only one week of light therapy plus TRP.

After the addition of l-tryptophan, there was a significant reduction in SIGH-SAD score compared with before l-tryptophan use (mean: 15.4 ± 9.5; paired t test: t = 4.3, df 13, P < 0.001). The mean percentage improvement in SIGH-SAD scores from baseline after light therapy alone was 16%, compared with 51% improvement after l-tryptophan augmentation (paired t test: t = 4.2, df 13, P < 0.001).

Inspection of individual responses showed that 8 of 14 (57%) patients experienced a clinical remission with l-tryptophan augmentation, defined as a greater than 50% reduction in depression scores from baseline and a posttreatment SIGH-SAD score of less than 15. An additional patient had a clinical response (greater than 50% improvement), with a posttreatment score of 16. Four of these responders had less than 25% improvement after 2 weeks of light therapy alone. Similarly, 9 of 14 (64%) patients were rated as much improved or very much improved on the CGI following l-tryptophan augmentation.

Side effects reported by patients who completed the l-tryptophan phase included: 3 patients with headache, 2 patients with nausea or gastrointestinal distress, and 2 patients with flushing or sweating. All side effects were mild and did not affect treatment.

Discussion

This preliminary, open-label study found that l-tryptophan augmentation, at a dose of 3 g/day, produced marked responses in 9 of 14 (64%) patients with SAD who showed little or partial response to 2 weeks of light therapy alone. Two of the initial 16 patients (12.5%) had early side effects that resulted in discontinuation of l-tryptophan, so dose titration may be required in some patients. The 14 patients who completed the l-tryptophan trial had a few mild side effects to the medication. These results suggest that l-tryptophan augmentation may be a useful clinical strategy for patients with SAD who show limited response to light therapy alone.

This conclusion must be considered tentative, however, since we used an open-label study design, and therefore nonspecific or placebo effects cannot be ruled out. Nevertheless, significant improvement occurred even in patients showing little response to an open-design, 2-week trial of light therapy, that is, in patients less likely to exhibit marked placebo responses. Since we continued light therapy during l-tryptophan administration, it is also possible that the clinical improvement seen during the combined treatment resulted from the longer trial of light therapy. Most studies of light therapy have been only 1 to 2 weeks in duration (2,12). Of the 3 studies that used longer treatment periods, only one was placebo-controlled, but the very low response rate to light in that 4-week study makes it difficult to evaluate the week-by-week response (13). Another study, using an open design, showed increasing improvement in mean depression scores over the 4 weeks of light therapy, but most of the improvement occurred within the first 2 weeks, with a plateau in response at 3 weeks (14). The third study, a 5-week comparison of bright light therapy plus pill placebo against dim light therapy plus fluoxetine also found that the greatest benefit of bright light occurred during the first 2 weeks of treatment (15). Thus it appears unlikely that the marked improvement seen with l-tryptophan augmentation would be attributable solely to the longer duration of light therapy.

Finally, we cannot exclude the possibility that l- tryptophan alone would be effective in this sample. A previous small-sample study (n = 13) compared 3 one-week treatments with l-tryptophan (1.5 g 3 times daily), pill placebo, and evening bright light (2500 lux for 2 hours) in a cross-over design (10). Both light and active-drug conditions resulted in improvement, but only the l-tryptophan was significantly superior to pill placebo. Another preliminary report suggested that l-tryptophan alone was as effective as bright light therapy in SAD, but the l-tryptophan condition required 4 weeks of treatment to demonstrate significant clinical effects (16).

In conclusion, l-tryptophan augmentation appears to be a useful strategy for poor or partial response to light therapy alone. The l-tryptophan is well tolerated by the majority of patients using light therapy. Placebo-controlled studies are required, however, to conclusively demonstrate the efficacy of this potentially useful augmentation strategy.

Acknowledgements

This study was funded, in part, by an unrestricted research grant from ICN Canada. A modified version of this paper was presented at the 8th Annual Meeting of the Society for Light Treatment and Biological Rhythms (SLTBR), Bethesda, Maryland, June 2–4, 1996.

References

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Résumé

Objectif : Près du tiers des patients atteints de troubles affectifs saisonniers (TAS) ne répondent pas complètement à la photothérapie.  Étant donné la preuve de dérèglement sérotoninergique en cas de TAS, nous avons examiné le rôle éventuel du l-tryptophane en tant que stratégie d’augmentation lorsque la réponse à la photothérapie est nulle ou partielle.

Méthode : Les patients admissibles ne prenant aucun médicament et répondant aux critères du DSM-IV à l’égard des TAS ont été traités pendant 2 semaines grâce à un programme matinal standard de photothérapie (10 000 lux d’une lampe fluorescente à lumière blanche pendant 30 minutes).  Les patients dont la réponse était partielle ou nulle ont été traités pendant 2 semaines au l-tryptophane étiqueté en clair (1 g 3 fois par jour) tout en poursuivant la photothérapie.  Les évaluations de départ et de suivi comprenaient le guide d’entrevue dirigée à 29 items de l’échelle d’évaluation de la dépression de Hamilton, la version adaptée aux TAS (SIGH-SAD) et l’échelle d’impression clinique globale (CGI).

Résultats : Seize patients ont entrepris la phase d’augmentation au l-tryptophane.  Deux patients ont cessé de prendre le médicament en moins de 3 jours à cause d’effets secondaires.  Chez les 14 patients qui ont complété le traitement, l’ajout de l-tryptophane a provoqué une réduction significative des scores moyens de dépression.  Neuf des 14 patients (64 %) ont manifesté de très bonnes réponses cliniques au traitement en association et des effets secondaires minimes.

Conclusion : Cette étude ouverte laisse présager que le l-tryptophane peut constituer une stratégie d’augmentation efficace pour les patients atteints de TAS qui manifestent une réponse limitée ou faible à un traitement au moyen d’une lumière intense.  D’autres études contrôlées contre placebo sont justifiées afin de démontrer l’efficacité du traitement.

Manuscript received July 1996, revised December 1996.

¹Associate Professor, Division of Mood Disorders, Department of Psychiatry, University of British Columbia; Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia.

²Assistant Professor, Department of Psychiatry, University of Toronto; Clarke Institute of Psychiatry, Toronto, Ontario.

³Clinical instructor, division of Mood Disorders, Department of Psychiatry, University of British Columbia; Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia.

⁴Assistant Professor, Division of Mood Disorders, Department of Psychiatry, University of British Columbia; Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia.

⁵Research Assistant, Department of Psychiatry, University of Toronto; Clarke Institute of Psychiatry, Toronto, Ontario.

⁶Professor, Division of Mood Disorders, Department of Psychiatry, University of British Columbia; Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia.

Address for correspondence: Dr RW Lam, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1

e-mail: rlam@unixg.ubc.ca

Can J Psychiatry, Vol 42, April 1997