L-Tryptophan for Premenstrual Depression

abstract & commentary

Synopsis: This study compares the efficacy of L-tryptophan vs. placebo in the treatment of premenstrual dysphoric disorder (PMDD). L-tryptophan was significantly superior to placebo in relieving mood and physical symptoms associated with PMDD.

Source: Steinberg S, et al. A placebo-controlled clinical trial of L-tryptophan in premenstrual dysphoria. Biol Psychiatry 1999;45:313-320.

In this study, the dietary supplement l-tryptophan was compared to placebo in the treatment of premenstrual dysphoric disorder (PMDD). Eighty women were recruited by referral from the obstetrics and gynecology department or by self-referral from a newspaper advertisement. Following a two-month evaluation period, eligible patients received randomized treatment for three months. The active treatment consisted of 2 mg of L-tryptophan three times a day for 17 days, from the time of ovulation to the third day of menstruation. A self-rating visual analog scale (VAS) was used to assess irritability, tension, dysphoria, mood swings, headache, bloating/edema, and breast tenderness. Other self-rating scales were used to assess effect, life events, and adjustment. A psychiatrist completed an observer rating scale. The maximum luteal phase VAS-mood score over the three treatment cycles was used as the principal outcome measure. This was felt to capture the most extreme disturbance of mood over the three cycles.

Of the original 80 women recruited, 63 completed the study, 32 in the L-tryptophan group and 31 in the placebo group. Analysis of the data showed a significant difference (P = 0.004) for the patient-rated VAS-mood scores for symptoms of dysphoria, mood, tension, and irritability for the group treated with L-tryptophan compared to placebo. The mean reduction from baseline in the VAS-mood score was 34.5% for L-tryptophan compared to 10.4% for placebo. The significant reduction in the mood scores occurred in the first month with no further improvement in successive treatment months. L-tryptophan did not show significant benefit for the symptoms of headache, edema, or breast sensitivity. However, no significant difference was found between the two treatment groups when assessed by a clinician.

No symptoms of eosinophilia myalgia syndrome were noted in the current study. Previous use of a presumably contaminated batch of L-tryptophan has been associated with the eosinophilia myalgia syndrome.

Comment by Lucy J. Puryear, MD

Premenstrual dysphoric disorder (PMDD) affects between 3-5% of women during their reproductive years. Symptoms include irritability, dysphoria, and sleep disturbance along with physical symptoms including breast tenderness, headache, and bloating. Symptoms begin in the late luteal phase of the menstrual cycle and remit with the onset of menses. Symptoms are severe enough that they interfere with daily functioning and cause difficulty in relationships and social and occupational functioning. During the rest of the menstrual cycle, there are no mood or physical symptoms and functioning returns to normal baseline.

Treatment for PMDD has included exercise, diet, and nutritional supplementation, gonadotropin-releasing hormone agonists, and antidepressants. Studies have demonstrated a greater efficacy with the serotonergic antidepressants, including fluoxetine, sertraline, paroxetine, citalopram, and clomipramine, compared to noradrenergic agents. This study is useful in that it uses a serotonin precursor, L-tryptophan, providing additional evidence for the importance of serotonin in the treatment of PMDD.

When evaluating women for PMDD it is important to rule out other psychiatric disorders, such as unipolar depression, bipolar depression, dysthymia, and anxiety disorders, all of which can worsen premenstrually. First line treatment for PMDD continues to be the serotonergic antidepressants. GNRH agonists have difficult side effects and can not be taken long term due to their causing a hypoestrogenergic state.1 Other non-pharmacologic treatments such as calcium, caffeine reduction, diet, and exercise show efficacy in some women and may be useful as adjunctive agents or for women with mild to moderate symptoms. This study supports the serotonergic hypothesis for PMDD and L-tryptophan may be a useful treatment for some women with mild to moderate symptoms.

1. Halbreich U. Gonadal hormones and antihormones, serotonin and mood. Psychopharmacol Bull 1990; 26(3):291-295.