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144 J Psychiatry Neurosci 2010;35(2)
© 2010 Canadian Medical Association
Tryptophan for refractory bipolar
spectrum disorder and sleep-phase
delay
A 45-year-old woman who worked in
an office was first seen in our clinic in
2000 at the age of 36. She received a
diag nosis of major depressive disorder
with atypical features and had one
suspected prior hypomanic episode.
Subsequent trials of nefazodone and
later venlafaxine were moderately ef-
fective in controlling her depressive
symptoms. However, at age 40, she
had another hypomanic or manic
episode, during which she made 2 im-
pulsive trips to gamble and accrued at
least $10 000 in debt through impul-
sive spending, excessive drinking and
online gambling at night. She did not
report an increase in socialization or
sexual activity during these episodes.
Divalproex was added as a mood
stabilizer, and venlafaxine was re-
placed with risperidone; however, the
latter drug was poorly tolerated.
Owing to a recurrence of her depres-
sive symptoms, venlafaxine (75 mg
daily) was added for about 6 months.
At that time, it became more apparent
that a longstanding sleep-phase delay
of several hours was a major concern.
Although her employer tolerated her
pattern of arriving after 11:00 am each
day, this caused ongoing stress and
conflict with her direct supervisor and
fellow workers. Because the sleep dis-
turbance was initially viewed as a
residual symptom of bipolar depres-
sion, venlafaxine was stopped, and a
trial of lamotrigine was undertaken
but had no clear benefit.
The patient noticed a dramatic im-
provement in her sleep-phase delay
during a 2-week work assignment in
Mexico, but this ended with her return
home. A sleep study obtained in Febru-
ary 2006 confirmed the phase-delay in
her sleep. Over the next 15 months tri-
als of zopiclone and light therapy were
ineffective in altering her sleep–wake
cycle or improving her mood. Dival-
proex was discontinued because of con-
cern about alopecia and lack of efficacy.
A trial of L-tryptophan, starting at a
dose of 1 g in the evening was begun
in June 2007, and withing 3 weeks she
began to report an improvement in her
ability to get to sleep and wake on
time in the morning. Over a few more
weeks, the dosage was increased to
3.5 g daily combined with over-the-
counter pyridoxine to limit the build-
up of potentially toxic metabolites of
tryptophan. After about 10 weeks of
treatment, she began to consistently
arrive at work at 9 am, and her depres-
sive symptoms cleared.
Two years after L-tryptophan was
initiated, she continued to show a nor-
mal sleep–wake pattern and remained
free of depressive and hypomanic
symptoms. She was taking no pre-
scribed medications except L-trypto-
phan and pyridoxine.
This case illustrates how sleep dis-
turbances can be important and un-
derappreciated contributors to the
burden of illness for patients with
mood disorders. In this patient, a
sleep-phase delay was the most dis-
abling feature, and treatment of this
symptom was associated with a major
improvement in her overall function-
ing and well-being.
Animal studies have demonstrated
that tryptophan is able to shift circad -
ian rhythms in various contexts.1,2 In
humans, tryptophan has been shown
to reduce sleep-onset latency while in-
creasing subjective sleepiness.3,4 Tryp-
tophan has also shown success in the
treatment of seasonal affective disor-
der,5which is characterized by hyper-
somnia and a delayed circadian phase
in many cases. These studies suggest
that a chronobiological mechanism is
most likely to explain the marked im-
provement in overall functioning ex-
perienced by this patient. Whereas
there is not yet systematic evidence for
the efficacy of tryptophan and other
phase-shifting strategies, they deserve
consideration in patients with other-
wise refractory bipolar disorder.
Robert G. Cooke, MD
Robert D. Levitan, MD
Mood and Anxiety Division
Centre for Addiction and Mental Health
Department of Psychiatry
University of Toronto
Toronto, Ont.
Competing interests: None declared for
Dr. Cooke. Dr. Levitan has previously re-
ceived research funds and was on the
speaker’s bureau for ICN Canada. He has
also received funding in the last 5 years
from Biovail, Janssen-Ortho, GlaxoSmith -
Kline, The Litebook Company, Wyeth and
Astra-Zeneca.
DOI: 10.1503/jpn.100009
References
1. Garau C, Aparicio S, Rial RV, et al. Age
related changes in the activity-rest circa-
dian rhythms and c-fos expression of
ring doves with aging. Effects of trypto-
phan intake. Exp Gerontol 2006;41:430-8.
2. Glass JD, Selim M, Srkalovic G, et al.
Tryptophan loading modulates light-
induced responses in the mammalian cir-
cadian system. J Biol Rhythms 1995; 10: 80-90.
3. Hartmann EL. Effect of L-tryptophan
and other amino acids on sleep. Nutr
Rev 1986;44(Suppl):70-3.
4. Schneider-Helmert D, Spinweber CL.
Evaluation of L-tryptophan for treat-
ment of insomnia: a review. Psychophar-
macology (Berl) 1986;89:1-7.
5. McGrath RE, Buckwald B, Resnick EV.
The effect of L-tryptophan on seasonal
affective disorder. J Clin Psychiatry 1990;
51: 162-3.
Psychopharmacology for the Clinician
The information in this column is not intended as a definitive treatment strategy but as a suggested approach for clinicians treating patients
with similar histories. Individual cases may vary and should be evaluated carefully before treatment is provided.
Psychopharmacology for the Clinician columns are usually based on a case report that illustrates a point of interest in clinical psychopharmacology.
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