University of Oxford, Warneford Hospital, Oxford, UK
Correspondence: Dr A. Scarnà, Neurosciences Building, University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. Tel: 01865 226492; e-mail: anna.scarna{at}psych.ox.ac.uk
Declaration of interest This study was funded by the Wellcome Trust; P.J.C. is a Medical Research Council (MRC) Clinical Scientist, S.F.B.M. is an MRC Clinician Scientist Fellow and C.J.H. is an MRC Training Fellow.
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ABSTRACT |
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Aims To assess whether a simple, branched-chain amino acid (BCAA) drink diminishes manic symptoms acutely and following repeated administration.
Method Twenty-five patients with mania were randomly and blindly allocated to treatment with BCAA (60 g) or placebo daily for 7 days.
Results Relative to placebo, the BCAA drink lowered mania ratings acutely over the first 6 h of treatment. In protocol completers there was a persistent advantage to the BCAA group 1 week after the end of treatment.
Conclusions A nutritional intervention that decreases tyrosine availability to the brain acutely ameliorates manic symptoms. Further studies are required to assess whether this approach has longer-term efficacy.
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INTRODUCTION |
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In our study we used a simpler amino acid mixture containing only three branched-chain amino acids (BCAAs): leucine, isoleucine and valine. These amino acids compete with phenylalanine and tyrosine for brain entry, and studies in healthy volunteers indicate that BCAAs produce cognitive and endocrine effects consistent with attenuation of central dopamine neurotransmission (Gijsman et al, 2002). In addition, the BCAA drink is palatable, safe and well tolerated during longer-term ingestion (Richardson et al, 1999). The effect of the BCAA drink on manic symptoms was assessed both acutely and after repeated administration.
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METHOD |
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Participants
Patients participating in the study fulfilled DSM-IV criteria for bipolar I
disorder with a current manic episode
(American Psychiatric Association,
1994) and were assessed to have a score of 20 or more on the Young
Mania Rating Scale (YMRS; Young et
al, 1978). These patients were recruited from five acute
wards within the Oxfordshire Mental Healthcare National Health Service Trust.
The main exclusion criteria were serious physical illness and the inability to
give informed consent in the opinion of either the ward consultant or the
investigators. We also excluded patients who were taking sodium valproate,
because both valproate and BCAA may have hepatotoxic effects and we did not
wish to risk a possible interaction.
Intervention
Each patient received a drink containing 60 g amino acid or a seemingly
identical placebo. The experimental mixture consisted of valine, isoleucine
and leucine in the ratio 3:3:4. The control drink contained fatty flakes to
simulate the texture of the experimental mixture. Both drinks also contained
flavouring, peanut oil and water, as described elsewhere
(Gijsman et al, 2002;
Scarnà et al,
2002). All drinks were prepared and administered by a research
nurse not involved in the further execution of the study. Prescribed
medication and food were not withheld during the study period. The drink was
administered once daily in the morning.
Objectives
To assess the tolerability and effect of a drink containing BCAAs compared
with placebo on the symptoms of acute mania, specifically over 6 h after the
first drink as well as during and after a treatment period of 7 days.
Outcomes
The YMRS was used as the sample selection tool. Our outcome measure was the
Beigel Manic State Rating Scale, which is sensitive to clinical changes over
short periods and reflects a wider spectrum of symptoms
(Beigel & Murphy, 1971;
McTavish et al, 2001). Participants were assessed immediately before administration of the first
drink and then hourly for 6 h. Subsequent ratings were carried out on days 4
and 8, and 1 week after the end of treatment on day 15, after a 1-h
observation period and interview.
Sample size
A single dose of a tyrosine-free amino acid drink reduced manic symptoms by
35% in a similar study with group size of 10
(McTavish et al,
2001). For the study described here we aimed at a similar effect
after a single dose and therefore required a group size of at least 10. For
the 15-day follow-up we aimed at 10 completers in each group.
Randomisation
An independent investigator generated a randomisation sequence on a
computer. Randomisation was calculated in blocks of four. Allocation was
concealed by using numbered and weight-balanced boxes containing all the
ingredients for the treatment of one patient. The independent supplier of the
ingredients prepared these boxes. Patients included in the study were given a
sequential number and the corresponding box was opened by the independent
research nurse when preparing the first drink.
Masking
Participants and investigators were masked to group assignment. The success
of masking was not separately assessed.
Statistical methods
For the single dose study, Beigel scores were analysed as change from
baseline and compared using a repeated-measures analysis of variance (ANOVA)
with time (time of rating) as the within-subject factor and
drink (BCAA or placebo) as the between-subject factor. For the
15-day follow-up the Beigel scores were also analysed as change from baseline.
Repeated-measures ANOVAs were conducted with day (day of rating)
as the main within-subject factor and drink (BCAA or placebo) as
the between-subject factor. For all ANOVAs, uncorrected degrees of freedom are
reported for reasons of clarity, but HuynhFeldt correction was used.
All t-tests are reported with equal variances not assumed.
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RESULTS |
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Baseline data
Patients were aged 19-62 years (mean 41 years). Three patients were
experiencing a first episode of mania; the others had a mean of 2 previous
hospital admissions for manic illness (range 1 to 4). The medication used for
each patient was left to the discretion of the psychiatrist. Twenty-two
patients were receiving antipsychotic medication during the study. Nine of
these participants were also receiving treatment with a mood stabiliser: 5
were receiving carbamazepine, and 4 were receiving lithium. Mood stabiliser
monotherapy had not failed in this group of patients; rather, the standard
treatment for most of the consultant psychiatrists was an antipsychotic plus a
benzodiazepine. Of the remaining 3 participants, 1 was taking lithium only, 1
carbamazepine only and 1 both drugs combined.
Fifteen of the participants received intermittent treatment with benzodiazepines. In the placebo group, 5 patients were taking lorazepam and 1 patient was taking zopiclone. One patient had taken lorazepam on one occasion before being changed to zopiclone. In the BCAA group, 5 patients were taking lorazepam, 2 clonazepam and 1 diazepam. When converted to diazepam equivalents, there was little difference between the average amounts taken at the start of the study (5.4 mg for the placebo group, 6.5 mg for the BCAA group) and this did not differ significantly throughout the duration of the study.
The mean score on the YMRS was 29 (range 21-42), within the range of that seen in drug treatment studies of mania (Tohen et al, 2000). The two groups (BCAA v. placebo) were well matched for baseline severity of manic symptoms on the YMRS: 29.3 (s.d. 5.2) v. 29.2 (s.d. 7.2); age: 41.3 (s.d. 12.4) v. 40.3 (s.d. 12.4) years; and gender: 6/13 v. 4/12 female.
Numbers analysed
All 25 participants received the allocated intervention on day 1 of the
study. These participants completed all follow-up measurements and were
included in the intention-to-treat analysis. Additionally, we analysed data
from the 18 participants who received the full 7 days of treatment.
Outcomes
Administration of the BCAA drink on day 1 significantly reduced clinical
ratings of mania as measured by change from baseline on the Beigel scale
relative to the placebo drink (Fig.
1). A two-way ANOVA showed significant effects of time
(F=10.21, d.f.=6,138, P<0.01) and of drink
(F=9.81, d.f.=1,23, P=0.01) and a significant interaction
(F=2.84, d.f.=6,138, P=0.02). Post hoc testing
showed significant differences between BCAA and control drinks at three time
points (Fig. 1).
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Over the subsequent 2 weeks both treatment groups showed a fall in clinical ratings of mania on the intention-to-treat analysis (Fig. 2). The ANOVA showed a significant effect of day (F=13.81, d.f.=3,69, P<0.01) but no significant effect of drink (F=1.67, d.f.=1,23, P=0.21) and no significant interaction (F=1.35, d.f.=3,69, P=0.27). The analysis of treatment completers showed significant effects of day (F=10.62, d.f.=3,48, P<0.01) and of drink (F=41.52, d.f.=1,16, P<0.01) and a significant interaction (F=10.16, d.f.=3,48, P<0.01). Pairwise comparisons showed only a trend in difference between groups on day 4 (t1,16=1.84, P=0.09), no difference on day 8 (t1,16=0.89, P=0.39), and a significant difference between groups on day 15 (t1,16=7.5, P<0.01). The placebo effect diminished during the week of treatment, whereas the BCAA group continued to improve (Fig. 3).
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Adverse events
The BCAA drink was generally well tolerated over the period of the study
and the majority of the patients had no problem in swallowing it. The only
substantial adverse effects were reported by the two participants in the BCAA
group who discontinued the treatment because of nausea or tiredness.
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DISCUSSION |
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In fact, it is possible that the BCAA drink is less effective than the full tyrosine-free amino acid mixture in acutely reducing the symptoms of mania. In the current study the people treated with BCAA showed a decrease in ratings on the Beigel scale that was about 20% greater than that of the placebo group. This is somewhat less than the 35% reduction in symptoms seen in our previous study (McTavish et al, 2001). One possible explanation for this lesser effect is that the BCAA drink used by McTavish et al might have been less active at lowering brain tyrosine availability, because the full tyrosine-free amino acid mixture lowers plasma tyrosine concentrations as well as decreasing its brain entry by competition at the bloodbrain barrier. In contrast, the BCAA drink used in the current study would be expected to lower brain tyrosine by competition only (Gijsman et al, 2002). Another possibility is that the tyrosine-containing control amino acid mixture used in our previous study could have caused some activation (Grevet et al, 2002), lowering the placebo response and inflating the apparent effect of the tyrosine-free mixture.
Longer-term effects
Both patient groups showed an amelioration of symptoms over the 2-week
period, with most measures yielding significant effects of day, but not of
drink. This is not surprising since routine treatment was not controlled and
patients continued to receive both routine and as required
medication on the usual basis of perceived clinical need. An
intention-to-treat analysis failed to differentiate placebo from the BCAA
treatment, but despite the power limitations of such a small study, there were
hints of additional benefit in the BCAA group. For example, 4 of the 8 BCAA
patients were discharged before day 15, compared with only 2 from the 10 in
the placebo group.
When the results from the study completers (participants who accepted the full treatment protocol) were assessed, there appeared to be a waning of the symptomatic improvement in the placebo group after treatment cessation, but a continued improvement in the BCAA group participants which was statistically significant on day 15. The reason why the BCAA group should have continued to improve after the end of treatment is not clear. It is possible that an adjunctive effect of the drink for 1 week allowed a more rapid resolution of the manic syndrome even after BCAA treatment ended. In contrast, the placebo improvement seemed to wane as would be expected.
Mechanism of action of branched-chain amino acids
Acute BCAA treatment increases plasma prolactin levels and impairs
performance on a spatial recognition task, effects consistent with attenuation
of dopamine neurotransmission (Gijsman
et al, 2002). In addition, using positron emission
tomography we have found that a full tyrosine-free amino acid mixture
increases striatal binding of the dopamine receptor ligand
[11C]raclopride in healthy volunteers, an effect consistent with
lowered presynaptic dopamine release
(Montgomery et al,
2002).
Although we believe that there is now strong evidence that the BCAA mixture impairs dopamine release for the first few hours after administration, we do not know for how long this effect persists and whether it is maintained after repeated treatment. We decided to administer the BCAA drink once daily to increase compliance, but it is possible that more-frequent daily treatment would have produced a better effect. However, administration of BCAAs at high dosage carries potential risks such as increased plasma ammonia concentration hepatotoxicity. In a study in healthy volunteers we monitored plasma ammonia levels after a drink containing 60 g BCAA, and found that although plasma ammonia concentrations were elevated over 6 h, the average maximum elevation (52 µmol/l) was below toxic plasma levels (> 80 µmol/l) (Scarnà et al, 2001). However, higher doses or longer-term use of BCAA treatment might require liver function test monitoring.
Possible therapeutic utility
Taken together, our findings suggest that the BCAA drink is a useful and
well-tolerated tool for modifying dopaminergic function. Although it may be
unrealistic to expect such a dietary manipulation to be as potent as an
antipsychotic drug, the BCAA drink does appear to achieve an acute reduction
in symptoms in patients with mania. Indications of a more persistent effect in
speeding symptom resolution will need to be explored in future longer-term
trials.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication May 17, 2002. Revision received September 27, 2002. Accepted for publication October 10, 2002.
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