Jan 12, 1992 - peutic is strengthened by the finding that d-fenfluramine, which causes release of serotonin, was better than placebo in relieving depression in ...
Tryptophan in the Treatment of Late Luteal Phase Dysphoric Disorder: A Pilot Study Susanne Steinberg' 2, Lawrence Annable2, Simon N. Young2'3, Marie-Claire B6langer2 'St. Mary's Hospital, Montreal, Quebec, Canada 2Department of Psychiatry, McGill University, Montreal, Quebec, Canada 3School of Dietetics and Human Nutrition, McGill University, Montreal, Quebec, Canada Submitted: January 12, 1992 Accepted: September 20, 1993
Thirteen patients diagnosed during two menstrual cycles as suffering from late luteal phase dysphoric disorder were then followed in an open pilot study for a further three cycles. During one complete cycle, baseline levels of symptoms were obtained. During the next three cycles, the patients were treated with L-tryptophan, six grams per day. L-tryptophan treatment was associated with a significant amelioration of symptoms with only mild side effects. These data suggest that L-tryptophan should be tested at a dose of six grams of L-tryptophan per day in a placebo-controlled study in patients with late luteal phase dysphoric disorder who suffer from symptoms such as depression, irritability, insomnia and carbohydrate craving, which may respond to potentiation of serotonin function. Key words: premenstrual depression, late luteal phase dysphoric disorder, tryptophan
INTRODUCTION
Premenstrual depression, now referred to in the phoric disorder (Brzezinski et al 1990). The symptoms of late DSM-m-R as late luteal phase dysphoric disorder, is a luteal phase dysphoric disorder include, in addition to depressyndrome for which, until recently, no clearly effective treat- sion, cravings for foods rich in carbohydrates, insomnia, ment had been demonstrated (Steinberg 1991). However, emotional lability and hostility. Low serotonin levels may be recently one study with the tricyclic antidepressant one ofthe factors involved in the etiology of these symptoms. The serotonin precursor, L-tryptophan, has some antidepressant action, although it is probably not as effective as standard antidepressants in severe depression (Young 1986). L-tryptophan is also a useful hypnotic in cases of mild to moderate insomnia (Young 1986). In two studies L-tryptophan was effective in reducing aggression in pathologically aggressive patients (Morand et al 1983; Volavka et al 1990). An open-label comparison of the combination of L-tryptophan and pyridoxine to placebo in late luteal phase dysphoric disorder has been published (Harrison et al 1984). The combination was found to be no better than placebo. However, Address reprint requests to: Susanne Steinberg, M.D., M.Sc., the dose of L-tryptophan used was from 1.5 grams to six St. Mary's Hospital, 3830 Lacombe, Montreal, Quebec, Canada grams with a mean of 3.7 grams. The normal intake of H3T 1M5 L-tryptophan is one to two grams per day, and doses of six
clomipramine which acts preferentially on serotonin reuptake, and two studies with fluoxetine which is a selective inhibitor of serotonin reuptake, demonstrated a significant therapeutic effect of the relevant drug compared to placebo (Sundblad et al 1992; Menkes et al 1992; Wood et al 1992). The possibility that potentiation of serotonin might be therapeutic is strengthened by the finding that d-fenfluramine, which causes release of serotonin, was better than placebo in relieving depression in patients with late luteal phase dys-
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1961) and the Self-Report Symptom Inventory of 90 items (SCL-90) (Guy 1976). The principal investigator carried out weekly psychiatric interviews with the patients and completed the Steiner Observer Rating Scale (SORS) (Steiner et al 1980) and a side-effect checklist. The physical examination and laboratory tests were repeated at the final visit. Blood samples were drawn for the measurement of plasma L-tryptophan (bi-monthly), once at ovulation and once during the premenstrual week, and for plasma prolactin (weekly). Plasma prolactin concentrations were measured by METHOD the double antibody radioimmunoassay technique of Sinha et al. (1973). The measurement of plasma L-tryptophan reSubjects quired that the blood be taken from fasting patients before their morning dose of medication, collected in heparinized Seventeen patients were recruited from the Premenstrual vacutainers and centrifuged within 0.5 hours. Free (non-alSyndrome Clinic at the Royal Victoria Hospital in Montreal. bumin bound) plasma L-tryptophan was taken as the L-trypInclusion criteria required that they be between 21 to 45 years tophan concentration in an ultra-filtrate of plasma. of age, have regular menstrual cycles, be in good physical Immediately after centrifugation of the blood, the plasma was health, use a contraceptive method other than the birth con- equilibrated with five percent carbon dioxide to maintain the trol pill and meet the proposed DSM-llI-R criteria for late pH at 7.4 and then ultra-filtrated at 250C using an Amicon luteal phase dysphoric disorder. The patients also needed to ultrafilter and YMT membranes. The have moderate to severe premenstrual syndrome as deter- MPS-l-centrifugal was then frozen at -200C and L-tryptophan ultra-filtrate mined by a score of at least 30 on the Steiner Observer Rating levels were determined within one month by the method of Scale, and have more positive than negative responses on the Denckla and Dewey (1967). Steiner Self Rating Scale (Steiner et al 1980). The Steiner Observer Rating Scale was modified so that each of the Treatment 16items was evaluated on a nine point scale of severity ranging from one to nine, The symptoms had to be clearly During the treatment phase, the patients were prescribed cyclical and occur in the luteal phase as indicated by the Daily a total of six grams of L-tryptophan, two grams three times Rating Scale (Halbreich et al 1985). Patients were excluded per day, after breakfast, after lunch and before bed, for from the study if they had a current DSM-HI-R Axis I 14days, from ovulation to the onset of menses during the first diagnosis or treatment of such an illness in the preceding two cycle. Shortly after the study commenced, it became apparent years, a history of alcohol or drug abuse in the past five years, that most of the clients continued to suffer symptoms during a plan to become pregnant in the following six months or a the first three days of their menstruation. Consequently, need to take concomitant medications. All patients gave during the next cycles the L-tryptophan was prescribed for written informed consent to participate in the study, which 17 days. Patients who complained of nausea, despite ingeswas approved by the Research Ethics Board of the Royal tion of L-tryptophan after meals, responded better if the Victoria Hospital in Montreal. majority of the dose was given at night. In the second and third cycles these women received two grams after breakfast Measures and four grams before retiring. All but one patient continued on total dosage of six grams per day. The latter continued The patients were first assessed without study medication on areduced (three grams) due to side-effects in the during the two months prior to entering the twelve-week second and dosages third cycle. Compliance was monitored on a treatment period. The initial visit included a medical history, weekly basis a by pill count carried out by the research physical examination and a complete psychiatric evaluation. assistant. The brand of L-tryptophan used was TryptanTm The following laboratory tests were done: biochemistry from ICN Canada. This brand of L-tryptophan has not been (SMA 16), hematology (CBC and differential), thyroid func- associated with any cases of eosinophilia myalgia syndrome tions (T3RU, FT4I, TSH, T3RIA), plasma L-tryptophan, pro(Wilkins 1990). lactin, magnesium, a urinalysis and an electrocardiogram The Daily Rating Scale of Halbreich et al (1985) was com- RESULTS pleted daily for two months prior to the trial to establish the cyclical nature of the disorder. The following rating scales Early terminations were completed weekly by the patient during the entire study period: the Steiner Self Rating Scale (SSRS) (Steiner et al Of the 17 patients who entered the study, 13 completed 1980), the Menstrual Distress Questionnaire (MDQ) (Moos the 12 week treatment period. Three patients withdrew from 1968), the Beck Depression Inventory (BDI) (Beck et al the study during the first month before receiving L-tryptoday are recommended to ensure that serotonin synthesis is maximized throughout each 24 hour period (Young 1986). Because of the clinical efficacy of fluoxetine, clomipramine and d-fenfluramine, drugs which are thought to potentiate serotonin function, and because tryptophan, the precursor of serotonin, is useful in the treatment of some of the symptoms of late luteal phase dysphoric disorder, we have now tested tryptophan (in an open-label pilot study) at a more appropriate dose for this condition. grams per
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results of Schmidt et al (1990) whose patient group reported significantly more negative life events than the controls.
Premenstrual symptoms MDQ Total Score
100!.
p=0.002
80: 601 N.S.
N.S
I
40
20Kmo0--E.Days 4-14
Days 15-24
_ No Treatment
Fig. 1
Days 25-33
L-Tryptophan
Comparison of total scores on the Menstrual Distress Questionnaire (MDQ) by phase of menstrual cycle for subjects on and off L-trytophan treatment; p value obtained by repeated measures analysis of variance on data averaged over three to four cycles.
phan; one was lost to follow-up, one had a language barrier that was more serious than initially recognized and the third withdrew because of fears associated with a previous allergic reaction to an unrelated drug. The fourth patient who withdrew from the study finished the first cycle without incident, but then suffered a severe panic attack requiring a visit to the emergency room on the first day of the second cycle. Because this was a preliminary study to determine whether or not there is any evidence that L-tryptophan has a therapeutic effect in LLPDD, we excluded this patient from the efficacy analysis on the grounds that she did not complete a sufficient period of time on the investigational drug to be able to assess its therapeutic potential. Thus, the efficacy analysis was based on 13 patients, and the safety analysis on 14.
Demographic data The ages of the 13 patients included in the efficacy analysis ranged from 23 to 41 years with a mean age of 35.3years and a standard deviation of 6.0 years. Seven of the women were married, two were divorced and four were single; eight had children; twelve were employed; six had a previous history of psychiatric treatment (but met the study entry requirements specified earlier), four for depression, one for drug abuse and one for drug and alcohol abuse with a suicide attempt; four reported dysmenorrhoea during their menses, which was already effectively treated with anti-inflammatory drugs. Finally, 11 of the 13 women were rated as having important life stresses. This is consistent with the
The first analysis carried out was a comparison of the maximum score obtained for each patient on the modified Steiner Observer Rating Scale during the L-tryptophan treatment period (days 15 to 28 of the first treatment cycle and days 15 to 3 of the second and third treatment cycles) with the pretreatment score during the late luteal phase, by means of a paired t-test (two-tailed). This revealed a highly significant (t = 8.14, df = 12, p < 0.001) reduction in SORS scores from a mean of 90.4 (sd = 19.4) at untreated baseline to an average maximum of 52.5 (sd = 16.3) during treatment, which represents a 42% reduction. An analysis of the frequency of response on this measure indicated that three of the 13 patients (23.1%) had a 50% or greater reduction in SORS scores, seven (53.9%) had a 25 to 49% reduction, and three (23.1%) had a 15 to 24% reduction. Examination of the average scores on the Menstrual Distress Questionnaire for each day of the menstrual cycle confirmed that the latter could be divided into three distinct phases with respect to symptomatology: days four to 14 with minimal distress corresponding to the follicular phase; days 15 to 24 with moderate distress following the surge in hormone levels after ovulation; and days 25 to three with severe distress. Some of the patients were occasionally noncompliant with respect to L-tryptophan treatment, either taking L-tryptophan during days four to 14 when it was not prescribed (seven instances reported) or failing to take L-tryptophan when it was prescribed during days 15 to three (seven instances), so that for each of the three menstrual phases there were observations both on and off L-tryptophan. The patients' reports of when they took the L-tryptophan were supported by the plasma tryptophan measurements and the pill count. We took advantage of the noncompliance to compare the symptoms in patients during the periods when they took L-tryptophan to those when they did not by means of repeated measures analysis of variance. The results of this analysis for the total score of the MDQ averaged over three or four cycles are shown in Figure 1. Ingestion of L-tryptophan during the late luteal phase was associated with a significant decline in the MDQ total score (39%, t = 3.25, df = 45, p = 0.002), but no effect of tryptophan was seen at other phases of the cycle. L-tryptophan also caused a decline in the total scores of the SORS (p < 0.001) and the SCL-90 (p = 0.03), but not on the SSRS or the BDI, during the late luteal phase. Repeated measures analyses of variance were also carried out on the factors of the MDQ to investigate which symptoms improved with L-tryptophan during the late luteal phase (Table 1). These analyses were exploratory so no attempt was made to adjust the p-values to take into account the fact that eight separate tests were done. Ingestion of L-tryptophan was
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Table 1
Effect of L-tryptophan on the Menstrual Distress Questionnaire (MDQ) factor scores in the late luteal phase: results of repeated measures analysis of variance (values based on six-point scale ranging from 0 to 5) Untreated (n = 9) Standard deviation Meana MDQ Factor 1.27 1.59 Pain 1.04 Water retention 1.86 0.91 1.74 Autonomic reactions 1.51 2.20 Negative affect 1.41 Impaired concentration 1.65 1.13 Behavior changes 1.30 Arousal 1.32 0.90 Control 0.95 0.81 aLeast squares estimate of mean adjusted for imbalance in cell sizes
associated with reductions in the mean scores for water retention (p = 0.01), autonomic reactions (p = 0.005), negative affect (p = 0.008), impaired concentration (p = 0.001), control (p), and pain (p = 0.07), but not for behavior change (p = 0.13) or arousal (p = 0.17). L-tryptophan was also associated with a reduction in the mean score for change in eating habits (p < 0.05), the only item in the MDQ not included in any of the factors. Plasma L-Tryptophan Concentrations The geometric means and 95% confidence intervals for the total and free plasma L-tryptophan concentrations during and without L-tryptophan treatment are shown in Table 2. The geometric mean (i.e., the mean of log-transformed values converted back to the original units of measurement) was used rather than the arithmetic mean because of a tendency for the standard deviation of the L-tryptophan concentrations to increase in proportion to the mean value (Fleiss 1986). During L-tryptophan treatment, the mean total and free plasma L-tryptophan concentrations increased by 123% and 171%, respectively. There were no significant (p < 0.05) differences between cycles nor any effect of the menstrual phase on the L-tryptophan concentrations. Also, there was no consistent correlation between plasma L-tryptophan concentration and degree of improvement on the rating scales.
L-Tryptophan (n = 13) Standard deviation Meana 0.89 1.20 0.91 1.12 0.28 0.28 1.06 1.39 0.83 0.86 0.83 0.95 0.67 1.03 0.43 0.27
Difference t
1.84 2.70 2.96 2.77 3.40 1.55 1.38 4.85
p
0.07 0.01 0.005 0.008 0.001 0.13 0.17 < 0.001
in one patient. Finally, one patient described symptoms suggesting hypomania: insomnia without fatigue, elation, hyperactivity, decreased appetite, distractibility. The symptoms were such that the L-tryptophan dosage was decreased (three grams per day) until they remitted. Another phenomenon noted by three of the women in the study was a withdrawal syndrome following abrupt cessation of L-tryptophan: one woman complained of middle insomnia, nightmares and increased appetite for one day, another suffered three nights ofinsomnia with associated hyperactive behavior during the day and a third complained of fatigue and headache for a few days when the amino acid was stopped. In all three patients the symptoms resolved spontaneously.
Routine laboratory test results, plasma prolactin and magnesium Routine laboratory work including EKG, urinalysis, SMA 16, CBC and differential, and thyroid functions were within normal limits before and after treatment with L-tryptophan. Plasma prolactin levels, done weekly, were unchanged by L-tryptophan treatment and showed no variations with the cycles. Plasma magnesium levels remained stable in all 13 patients. Follow-up
Although all 13 patients who completed the trial were offered follow-up treatment with L-tryptophan and/or psyThe side-effects were essentially mild in character and chotherapy, eight did not take advantage of this option. The predominantly involve the gastrointestinal tract and the cen- main reason the eight patients did not continue to take tryptral nervous system. The most common side effect was tophan was the cost of the drug. Of the five who accepted anorexia which was mild in six patients and moderate in one follow-up treatment all accepted both L-tryptophan and psypatient. Dizziness was mild in one patient and moderate in a chotherapy. One patient discontinued L-tryptophan after six further two patients. A severe panic attack occurred on the months in order to become pregnant, but the other four all first day of the second cycle of L-tryptophan administration continued for more than a year. Four of the women had Side-effects
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Table 2
Total and free plasma L-tryptophan concentrations (ng/ml) during and without treatment with L-tryptophan: geometric means and 95% confidence intervala Untreated L-tryptophan Difference Geometric confidence Geometric Confidence Plasma Tryptophan n mean intervalb n mean interval F p Total 53 10.62 9.06 to 12.46 47 23.70 19.96 to28.13 46.17
