Journal Elsevier
ofAffective Disorders, 19 (1990) 125-132
125
JAD 00712
Tyrosine for depression: a double-blind trial Alan J. Gelenberg ‘, Joanne D. Wojcik 2, William E. Falk 2,3, Ross J. Baldessarini Steven H. Zeisel (j, David Schoenfeld ’ and Gloria S. Mok ’
2,3,4,5,
Departments of Psychiatry, ’ University of Arizona, Tucson, AZ, ,’ Massachusetts General Hospital, Boston, MA, ’ Harvard Medical School, Cambridge, MA, 4 McLean Hospital and Mailman Research Center, Boston, MA, 5 Neuroscience Program, Haruard Medical School, Cambridge, MA, 6 Department of Pediatrics, Boston University School of Medicine, Boston, MA and 7 Department of Medicine, Massachuseits General Hospital, Boston, MA, U.S.A. (Received 2 August 1989) (Accepted 13 December 1989)
Summary We treated 65 outpatients with RDC major depression in a randomized, prospective, double-blind comparison of oral L-tyrosine, 100 mg/kg/day, irnipramine, 2.5 mg/kg/day, or placebo for 4 weeks. Tyrosine increased and imipramine decreased 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion significantly, but there was no evidence that tyrosine had antidepressant activity. The only side effect to achieve statistical significance was greater dry mouth with imipramine. MHPG excretion and plasma amino acid concentrations failed to predict or correlate with clinical improvement.
Key words: L-Tyrosine; Amino acids; Major hydroxyphenylglycol (MHPG)
depression;
Introduction The catecholamine hypothesis of depression formulated by Schildkraut (1965) and since elaborated on by many authors - holds that, in at least some patients, depression reflects a central deficiency in availability or function of norepinephrine. In the light of experimental evidence that oral administration of the amino acid L-tyrosine, precursor of the catecholamines, can increase
Address for correspondence: Alan J. Gelenberg, Department of Psychiatry, University of Arizona Health ces Center, Tucson, AZ 85724, U.S.A. 0165-0327/90/$03.50
0 1990 Elsevier Science Publishers
M.D., Scien-
Catecholamine
hypothesis;
3-methoxy-4-
brain norepinephrine concentrations, we conducted a series of experiments administering tyrosine to depressed patients (Gelenberg et al., 1983). One depressed woman treated in a placebo-controlled, double-blind multiple cross-over experiment showed encouraging evidence of improvement (Gelenberg et al., 1980). Then, a small, double-blind pilot project compared tyrosine to placebo in 14 outpatients with major depression: of patients treated with tyrosine, 100 mg/kg/day p.o. for 4 weeks, four of six reached criteria (final Hamilton Depression Scale score I 10) of improvement versus only three of eight similarly treated with placebo. Five placebo non-responders were subsequently treated with open-label tyro-
B.V. (Biomedical
Division)
126
sine, and three reached improvement criteria. (Due to the small patient sample, statistical significance was not achieved.) Patients taking tyrosine showed an increased urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and increased fasting plasma levels of tyrosine. These encouraging results led to a larger outpatient trial comparing tyrosine both to placebo and to imipramine, which we report here. Methods
Subjects We enrolled men and women (without childbearing potential) outpatients, ages 18 to 75 years, with a definite diagnosis of major depressive disorder per Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) and an entry score of 2 20 on a modified Hamilton Depression Rating Scale (HAM-D), adapted to include symptoms of hypersomnia, hyperphagia, and weight gain (see Appendix). We excluded patients with a history of mania, symptoms of psychosis or a diagnosis of schizophrenia, those unable to give informed consent, or patients with a current diagnosis of alcoholism, other drug addiction, epilepsy or clinical evidence of serious suicidal risk with poor past response to antidepressant therapy or with medical illnesses that might interfere with treatment. Medications random numbers asComputer-generated, signed subjects to receive capsules containing either L-tyrosine, 500 mg, imipramine hydrochloride (in lactose), 12.5 mg, or lactose placebo. By study day 9, patients were to achieve a target dose (unless adverse reactions contravened) of 100 mg/kg/day of tyrosine or 2.5 mg/kg/day of imipramine in three divided doses, which they took for at least 4 weeks. Assessments Baseline examinations included an entry history, general physical and psychiatric examinations, and routine laboratory screening. Depression was rated on a modified HAM-D (see Appendix). A clinician also filled out a Clinical Global Impression (CGI), and patients rated their
depression on the Beck Depression Rating Scale (Beck). Before treatment and at the end of the experimental therapy, patients entered a clinical research center for three consecutive 24-h urine collections while they adhered to a strict low-monoamine diet. All patients had been free of medication for a minimum of 2 weeks. Each of these six 24-h urine collections was then analyzed for MHPG content by a high-performance liquid chromatographic (HPLC) assay with electrochemical detection (Alonso et al., 1981; Moleman et al., 1982). Blood was drawn at baseline and throughout the study for assays of plasma tyrosine concentration and the concentrations of other large neutral amino acids (Miller et al., 1980) analyzed by an HPLC with ultraviolet detection procedure of Fernstrom and Fernstrom (1981). Statistics The three treatment groups were compared using a mixed-model analysis of covariance for the first 4 weeks of treatment. If this test rejected the null hypothesis of no between-group differences (P > 0.05). individual planned post-hoc comparisons were made using a two-tailed Student’s t-test. Only subjects who completed at least 3 weeks of treatment were used in the efficacy analyses. An exact Kruskal-Wallis non-parametric test of frequency distribution was used to compare the risk of apparent side effects in each group. Toxicity was graded as 0 to 3: none, mild, moderate, and severe. Results
Subjects Sixty-five patients entered this study (n per group = 21-22). Males predominated (46 : 19) because of the childbearing potential exclusion. Patients ranged in age from 21 to 60 years (mean & SD = 39.5 k 10.7). Subject characteristics are summarized in Table 1. Intergroup differences in age (p = 0.2227) and baseline HAM-D totals (P = 0.9757) were non-significant. Seventeen subjects dropped out of the study before 3 weeks of treatment and thus were excluded from efficacy analyses. Four tyrosine subjects dropped out early: one due to side effects,
127 TABLE PATIENT
1
well as dichotomous outcome broken down by different definitions of ‘improved’ vs. ‘unimproved’, similarly failed to find any evidence for antidepressant efficacy of tyrosine.
CHARACTERISTICS
Males Females Total Mean age (years) Mean baseline HAM-D totals
Tyrosine
Imipramine
Placebo
16 5 21 36.2
16 6 22 41.6
14 8 22 40.5
24.3
24.3
24.5
one due to clinical worsening, two for administrative reasons. Eight imipramine patients were early dropouts: five because of side effects, one because of clinical worsening, two for administrative reasons. Five placebo-treated patients dropped out early: one due to side effects, two for clinical worsening, two because of administrative reasons. Efficacy Fig. 1 shows the mean HAM-D scores ( f SEM) by treatment group over 4 weeks of treatment. As evident, tyrosine failed to differ significantly from placebo. Imipramine showed a trend toward superiority. Analyses of Beck and CGI scores, as
5
-
, O
, I
Side effects The only side effect that occurred significantly more often with any of the three treatments was dry mouth - which was more prevalent in patients taking imipramine (P < 0.03). Seven patients dropped out of the trial because of side effects, five on imipramine treatment, one each with placebo and tyrosine. The five imipramine patients discontinued treatment because of severe sedation and anticholinergic effects and, in one case, loss of impulse control. The one placebo patient stopped because of nausea and vomiting and the tyrosine patient because of palpitations. MHPG secretion Fig. 2 shows the change in mean 24-h urinary MHPG (k SEM) excretion for the three treatment groups. Clearly, tyrosine was associated with a significant increase in MHPG excretion, imipramine with a decrease. Pre-treatment MHPG levels and on-treatment change in MHPG excretion
I 3
I 2
, I
WEEK DRUC
Fig, I,
-i
Mem Hamilton Depression
5-f-k t D-Q-0 p Scale score totals f SEM by week.
I5
128
0
n
failed to correlate with antidepressant any treatment group.
O 31
response
in
9
e
Plasma amino acid levels Fig. 3 demonstrates changes in mean fasting plasma tyrosine levels ( + SEM) for the three treatment groups. Patients receiving tyrosine had significantly increased tyrosine levels. Pre-treatment tyrosine levels or the ratio of tyrosine to the other large neutral amino acids failed to predict improvement on tyrosine therapy, and alterations in this level and ratio failed to correlate with improvement during tyrosine therapy.
2-
0 I ”
u
O.I-
H P G
0
0 --
L-l
E x c
-0
I-
-0
2-
r e I
I 0 ”
Discussion
-0.3n /p d -0.4
-
I
a
t
P
Y
DRUG =
P-Value Fig. 2. Change
in urinary
a.onn1
MHPG
excretion.
N ml
n I
-10
I 4
P
1
DRUG
P-Value
Fig. 3. Change
= 0.0084
in tyrosine
levels
Our earlier positive impressions about the antidepressant efficacy of tyrosine at comparable doses (Gelenberg et al., 1980, 1983) were not borne out by the present study, which we believe is the largest of its kind so far reported. Mouret et al. (1988) have reported positive results with tyrosine in what they termed ‘dopamine-dependent depression’, but their treatment was non-blind and uncontrolled. Van Praag (1983) similarly reported favorable results with tyrosine, but also uncontrolled and in a mixture with Shydroxytryptophan. Three studies of tyrosine in attention deficit disorder were generally negative (Nemzer et al., 1986; Reimherr et al., 1987; Eisenberg et al., 1988). A negative study that involves treatment of a heterogeneous disorder is highly vulnerable to a type-II error: failure to find a significant effect when one does, in fact, exist. Perhaps larger patient samples would have allowed us to achieve statistically significant results, although our data do not support that argument. Perhaps more cogent, although still speculative, would be the contention that a subgroup of depressed patients might be responsive to tyrosine. Even though we did not find that patients with lower pre-treatment tyrosine plasma levels or the ratio of tyrosine to other large neutral amino acids had a greater likelihood of response to oral tyrosine (Moller et al., 1980), it is conceivable that a study with larger numbers of such patients would show a positive finding.
129
As expected, imipramine suppressed urinary excretion of the norepinephrine breakdown product MHPG, presumably by inhibiting norepinephrine turnover. Consistent with our earlier report, tyrosine elevated urinary MHPG excretion, presumably by enhancing norepinephrine turnover - whether peripheral or central. Perhaps agents which enhance norepinephrine turnover may not be good antidepressant agents. Although this appears to contradict the catecholamine theory of depression, it is by now obvious that the catecholamine theory first advanced in the 1960s is far too simplistic to explain adequately pathology of mood. Or, maybe only a subset of depressed patients might benefit from such therapy, although if such a subtype of depression exists, it is obvious that we did not have a sufficient sample in our study. Conceivably bipolar depressives might be a better target population, a speculation for which we have no data. The idea that a natural product with negligible side effects would turn out to be an effective treatment for depression appeared too good to be true - and our data suggest that it was. Although in our work to date we have found no hazard from tyrosine therapy, and while it is conceivable that somewhere there are patients who will benefit from this amino acid (more than from placebo), our research lends no support to that line of thinking.
Acknowledgements The authors thank Richard J. Wurtman, M.D. and John H. Growdon, M.D. for inspiring this project and assisting in design; the Ajinomoto Company and CIBA-Geigy for supplying gratis, respectively, tyrosine and imipramine; Mrs. Linda Leahy, Mrs. Lillian Gerard, and the staff of the Massachusetts General Hospital General Clinical Research Center for assistance with patients; and Mrs. Jacqueline Lamkin for preparation of the manuscript. MHPG assays were performed by Mr. Dennis Francoeur. This study was funded by USPHS Grants MH36662, MH-47370, MH-31154, and MH-31224.
Appendix Modified 27-item Hamilton Depression Rating Scale 1. DEPRESSED MOOD (sadness, hopeless, helpless, worthless) 0 = Absent 1 = These feeling states indicated only on questioning 2 = These feeling states spontaneously reported verbally 3 = Communicates feeling states non-verbally; i.e., through facial expression, posture, voice and tendency to weep 4 = Patient reports virtually only these feeling states in his spontaneous verbal and nonverbal communication 2. FEELINGS OF GUILT 0 = Absent 1 = Self-reproach; feels he has let people down 2 = Ideas of guilt or rumination over past errors or sinful deeds 3 = Present illness is a punishment; delusions of guilt 4 = Hears accusatory or denunciatory voices and/or experiences threatening visual hallucinations 3. SUICIDE 0 = Absent 1 = Feels life is not worth living 2 = Wishes he were dead or any thoughts of possible death to self 3 = Suicide ideas or gesture 4 = Attempts at suicide (only serious attempt) 4. INSOMNIA EARLY 0 = No difficulty falling asleep 2 = Complains of occasional difficulty falling asleep; i.e., more than one-half hour 2 = Complains of nightly difficulty falling asleep 5. INSOMNIA MIDDLE 0 = No difficulty 1 = Patient complains of being restless and disturbed during the night 2 = Waking during the night; getting out of bed (except for purposes of voiding)
130
6. INSOMNIA LATE 0 = No difficulty 1 = Waking in early hours of the morning but goes back to sleep 2 = Unable to fall asleep again if leaves bed 7. WORK AND ACTIVITIES 0 = No difficulty 1 = Thoughts and feelings of incapacity, fatigue or weakness related to activities, work, hobbies 2 = Loss of interest in activity, work, hobbies - either directly reported by patient, or indirect in listlessness, indecision and vacillation (feels he has to push self to work or activity) 3 = Decrease in actual time spent in activities or decrease in productivity. In hospital, rate 3 if patient does not spend at least 3 h/day in activities (hospital job or hobbies) exclusive of ward chores 4 = Stopped working because of present illness. In hospital, rate 4 if patient engages in no activities except ward chores, or if patient fails to perform ward chores unassisted 8. RETARDATION 0 = Normal speech and thought 1 = Slight retardation at interview 2 = Obvious retardation at interview 3 = Interview difficult 4 = Complete stupor 9. AGITATION 0 = None 1 = Fidgetiness 2 = Playing with hands, hair, obvious restlessness 3 = Moving about; can’t sit still 4 = Hand-wringing, nail-biting, hair-pulling, biting of lips; patient is on the run 10. ANXIETY PSYCHIC 0 = No difficulty 1 = Subjective tension and irritability 2 = Worrying about minor matters 3 = Apprehensive attitude apparent in face or speech 4 = Fears expressed without questioning
11. ANXIETY SOMATIC Physiological concomitants of anxiety such as _ gastro-intestinal: dry mouth, wind, indigestion, diarrhea, cramps, belching - cardiovascular: palpitations, headaches - respiratory: hyperventilation, sighing - urinary frequency; sweating 0 = Absent 1 = Mild 2 = Moderate 3 = Severe 4 = Incapacitating SYMPTOMS GASTRO-IN12. SOMATIC TESTINAL 0 = None 1 = Loss of appetite but eating without staff encouragement; heavy feelings in abdomen 2 = Difficulty eating without staff urging; requests or requires laxatives or medicines for bowels or medicines for G.I. symptoms 13. SOMATIC SYMPTOMS GENERAL 0 = None 1 = Heaviness in limbs, back or head; backaches, headache, muscle aches; loss of energy and fatiguability 2 = Any clear-cut symptom 14. GENITAL SYMPTOMS Symptoms such as loss of libido disturbances 0 = Absent 1 = Mild 2 = Severe
or menstrual
15. HYPOCHONDRIASIS 0 = Not present 1 = Self-absorption (bodily) 2 = Preoccupation with health 3 = Frequent complaints, requests etc. 4 = Hypochondriacal delusions 16. LOSS OF WEIGHT (answer only A or B)
for help,
131
A. When rating by history: 0 = No weight loss 1 = Probable weight loss associated with present illness 2 = Definite (according to patient) weight loss B. On weekly ratings by ward psychiatrist - when actual weight changes are measured: 0 = Less than 1 lb weight loss in week 1 = Greater than 1 lb weight loss in week 2 = Greater than 2 lb weight loss in week 17. INSIGHT 0 = Acknowledges being depressed and ill 1 = Acknowledges illness but attributes cause to bad food, climate, overwork, virus, no rest, etc. 2 = Denies being ill at all 18. DIURNAL
VARIATION p.m. a.m. 2 ratings: rate for both a.m. and p.m.; If symptoms are worse either in morning evening, note WHICH, and rate severity variation 0 = Absent 1 = Mild 2 = Severe
or of
19. DEPERSONALIZATION AND DEREALIZATION such as: feelings of unreality, nihilistic ideas 0 = Absent 1 = Mild 2 = Moderate 3 = Severe 4 = Incapacitating 20. PARANOID SYMPTOMS 0 = None 1 = Suspicious 2 = Ideas of reference 3 = Delusions of reference 21. OBSESSIONAL COMPULSIVE 0 = Absent 1 = Mild 2 = Severe
and persecution
AND SYMPTOMS
22. FATIGUABILITY 0 = Does not get more tired than usual 1 = Gets tired more easily than before (from strenuous physical or mental tasks) 2 = Gets tired more easily than before (even from small tasks) 3 = Is tired most of the day 4 = Too tired to do any tasks except for basic daily functions 23. SOCIAL WITHDRAWAL 0 = Interacts with other people as usual 1 = Less interested in socializing with others but continues to do so 2 = Interacting less with other people in social (optional) situations 3 = Interacting less with others in work or family situations (i.e., where necessary) 4 = Marked withdrawal from others in family or work situations 24. APPETITE INCREASE 0 = No increase in appetite 1 = Eating somewhat more than usual 2 = Eating much more than usual 25. CARBOHYDRATE CRAVING 0 = No change in food preference 1 = Eating more carbohydrates (starches and sugars) than before 2 = Eating much more carbohydrates than before 3 = Irresistible craving for sweets or starches 26. WEIGHT GAIN 0 = No weight gain 1 = Probable weight gain associated with present illness 2 = Definite weight gain (according to patient) 27. HYPERSOMNIA compare sleep length to euthymic and NOT to hypomanic sleep lengths; if this cannot be established, use 8 h 0 = No increase in sleep length 1 = At least 1 h increase to sleep length 2 = 2 + h increase 3 = 3 + h increase
132
4 = 4 + h increase Was euthymic sleep length used? Yes No Was 8-h sleep length used? No Yes References Alonso, R., Gibson, C.J. and McGill, J. (1981) Determination of 3-methoxy-4-hydroxyphenylglycol in urine by high performance liquid chromatography with amperometric detection. Life Sci. 29, 1689-1696. Eisenberg, J., Asnis, G.M., van Praag, H.M. and Vela, R.M. (1988) Effect of tyrosine on attention deficit disorder with hyperactivity. J. Clin. Psychiatry 49, 193-195. Fernstrom, M.H. and Femstrom, J.D. (1981) Rapid measurement of free amino acids in serum and CSF using high-performance liquid chromatography. Life Sci. 29, 2119-2130. Gelenberg, A.J., Wojcik, J.D., Growdon, J.H., Sved, A.F. and Wurtman, R.J. (1980) Tyrosine for the treatment of depression. Am. J. Psychiatry 137, 662-663. Gelenberg, A.J., Wojcik, J.D., Gibson, C.J. and Wurtman, R.J. (1983) Tyrosine for depression. J. Psychiatr. Res. 17, 175180. Moleman, P. and Borstrok, J.J.M. (1982) Analysis of urinary 3-methoxy-4-hydroxyphenylglycol by high performance
liquid chromatography and electrochemical detection. J. Chromatogr. 227, 391-405. Moller, S.E., Kirk, L. and Honore, P. (1980) Relationship between plasma ratio of tryptophan to competing amino acids and the response to L-tryptophan treatment in endogenously depressed patients. J. Affect. Disord. 2, 47-59. Mouret, J., Lemoine, P., Minuit, M.-P. and Robelin, N. (1988) La L-tyrosine guerit immediatement et a long terme, les depressions dopamino-dependantes. C. R. Acad. Sci. Paris 306, 93-98. Nemzer, E.D., Arnold, L.E., Votolato, N.A. and McConnell, H. (1986) Amino acid supplementation as therapy for attention deficit disorder. J. Am. Acad. Child Psychiatry 4. 509-513. Rein&err, F.W., Wender, P.H., Wood, D.R. and Ward, M. (1987) An open trial of L-tyrosine in the treatment of attention deficit disorder, residual type. Am. J. Psychiatry 144, 1071-1073. Schildkraut, J.J. (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am. J. Psychiatry 122, 509-522. Spitzer, R.L., Endicott, J. and Robins, E. (1978) Research Diagnostic Criteria: rationale and reliability. Arch. Gen. Psychiatry 35, 733-738. van Praag, H.M. (1983) In search of the mode of action of antidepressants: 5-HTP/tyrosine mixtures in depression. Neuro-Pharmacology 22, 433-440.
ofAffective Disorders, 19 (1990) 125-132
125
JAD 00712
Tyrosine for depression: a double-blind trial Alan J. Gelenberg ‘, Joanne D. Wojcik 2, William E. Falk 2,3, Ross J. Baldessarini Steven H. Zeisel (j, David Schoenfeld ’ and Gloria S. Mok ’
2,3,4,5,
Departments of Psychiatry, ’ University of Arizona, Tucson, AZ, ,’ Massachusetts General Hospital, Boston, MA, ’ Harvard Medical School, Cambridge, MA, 4 McLean Hospital and Mailman Research Center, Boston, MA, 5 Neuroscience Program, Haruard Medical School, Cambridge, MA, 6 Department of Pediatrics, Boston University School of Medicine, Boston, MA and 7 Department of Medicine, Massachuseits General Hospital, Boston, MA, U.S.A. (Received 2 August 1989) (Accepted 13 December 1989)
Summary We treated 65 outpatients with RDC major depression in a randomized, prospective, double-blind comparison of oral L-tyrosine, 100 mg/kg/day, irnipramine, 2.5 mg/kg/day, or placebo for 4 weeks. Tyrosine increased and imipramine decreased 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion significantly, but there was no evidence that tyrosine had antidepressant activity. The only side effect to achieve statistical significance was greater dry mouth with imipramine. MHPG excretion and plasma amino acid concentrations failed to predict or correlate with clinical improvement.
Key words: L-Tyrosine; Amino acids; Major hydroxyphenylglycol (MHPG)
depression;
Introduction The catecholamine hypothesis of depression formulated by Schildkraut (1965) and since elaborated on by many authors - holds that, in at least some patients, depression reflects a central deficiency in availability or function of norepinephrine. In the light of experimental evidence that oral administration of the amino acid L-tyrosine, precursor of the catecholamines, can increase
Address for correspondence: Alan J. Gelenberg, Department of Psychiatry, University of Arizona Health ces Center, Tucson, AZ 85724, U.S.A. 0165-0327/90/$03.50
0 1990 Elsevier Science Publishers
M.D., Scien-
Catecholamine
hypothesis;
3-methoxy-4-
brain norepinephrine concentrations, we conducted a series of experiments administering tyrosine to depressed patients (Gelenberg et al., 1983). One depressed woman treated in a placebo-controlled, double-blind multiple cross-over experiment showed encouraging evidence of improvement (Gelenberg et al., 1980). Then, a small, double-blind pilot project compared tyrosine to placebo in 14 outpatients with major depression: of patients treated with tyrosine, 100 mg/kg/day p.o. for 4 weeks, four of six reached criteria (final Hamilton Depression Scale score I 10) of improvement versus only three of eight similarly treated with placebo. Five placebo non-responders were subsequently treated with open-label tyro-
B.V. (Biomedical
Division)
126
sine, and three reached improvement criteria. (Due to the small patient sample, statistical significance was not achieved.) Patients taking tyrosine showed an increased urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and increased fasting plasma levels of tyrosine. These encouraging results led to a larger outpatient trial comparing tyrosine both to placebo and to imipramine, which we report here. Methods
Subjects We enrolled men and women (without childbearing potential) outpatients, ages 18 to 75 years, with a definite diagnosis of major depressive disorder per Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) and an entry score of 2 20 on a modified Hamilton Depression Rating Scale (HAM-D), adapted to include symptoms of hypersomnia, hyperphagia, and weight gain (see Appendix). We excluded patients with a history of mania, symptoms of psychosis or a diagnosis of schizophrenia, those unable to give informed consent, or patients with a current diagnosis of alcoholism, other drug addiction, epilepsy or clinical evidence of serious suicidal risk with poor past response to antidepressant therapy or with medical illnesses that might interfere with treatment. Medications random numbers asComputer-generated, signed subjects to receive capsules containing either L-tyrosine, 500 mg, imipramine hydrochloride (in lactose), 12.5 mg, or lactose placebo. By study day 9, patients were to achieve a target dose (unless adverse reactions contravened) of 100 mg/kg/day of tyrosine or 2.5 mg/kg/day of imipramine in three divided doses, which they took for at least 4 weeks. Assessments Baseline examinations included an entry history, general physical and psychiatric examinations, and routine laboratory screening. Depression was rated on a modified HAM-D (see Appendix). A clinician also filled out a Clinical Global Impression (CGI), and patients rated their
depression on the Beck Depression Rating Scale (Beck). Before treatment and at the end of the experimental therapy, patients entered a clinical research center for three consecutive 24-h urine collections while they adhered to a strict low-monoamine diet. All patients had been free of medication for a minimum of 2 weeks. Each of these six 24-h urine collections was then analyzed for MHPG content by a high-performance liquid chromatographic (HPLC) assay with electrochemical detection (Alonso et al., 1981; Moleman et al., 1982). Blood was drawn at baseline and throughout the study for assays of plasma tyrosine concentration and the concentrations of other large neutral amino acids (Miller et al., 1980) analyzed by an HPLC with ultraviolet detection procedure of Fernstrom and Fernstrom (1981). Statistics The three treatment groups were compared using a mixed-model analysis of covariance for the first 4 weeks of treatment. If this test rejected the null hypothesis of no between-group differences (P > 0.05). individual planned post-hoc comparisons were made using a two-tailed Student’s t-test. Only subjects who completed at least 3 weeks of treatment were used in the efficacy analyses. An exact Kruskal-Wallis non-parametric test of frequency distribution was used to compare the risk of apparent side effects in each group. Toxicity was graded as 0 to 3: none, mild, moderate, and severe. Results
Subjects Sixty-five patients entered this study (n per group = 21-22). Males predominated (46 : 19) because of the childbearing potential exclusion. Patients ranged in age from 21 to 60 years (mean & SD = 39.5 k 10.7). Subject characteristics are summarized in Table 1. Intergroup differences in age (p = 0.2227) and baseline HAM-D totals (P = 0.9757) were non-significant. Seventeen subjects dropped out of the study before 3 weeks of treatment and thus were excluded from efficacy analyses. Four tyrosine subjects dropped out early: one due to side effects,
127 TABLE PATIENT
1
well as dichotomous outcome broken down by different definitions of ‘improved’ vs. ‘unimproved’, similarly failed to find any evidence for antidepressant efficacy of tyrosine.
CHARACTERISTICS
Males Females Total Mean age (years) Mean baseline HAM-D totals
Tyrosine
Imipramine
Placebo
16 5 21 36.2
16 6 22 41.6
14 8 22 40.5
24.3
24.3
24.5
one due to clinical worsening, two for administrative reasons. Eight imipramine patients were early dropouts: five because of side effects, one because of clinical worsening, two for administrative reasons. Five placebo-treated patients dropped out early: one due to side effects, two for clinical worsening, two because of administrative reasons. Efficacy Fig. 1 shows the mean HAM-D scores ( f SEM) by treatment group over 4 weeks of treatment. As evident, tyrosine failed to differ significantly from placebo. Imipramine showed a trend toward superiority. Analyses of Beck and CGI scores, as
5
-
, O
, I
Side effects The only side effect that occurred significantly more often with any of the three treatments was dry mouth - which was more prevalent in patients taking imipramine (P < 0.03). Seven patients dropped out of the trial because of side effects, five on imipramine treatment, one each with placebo and tyrosine. The five imipramine patients discontinued treatment because of severe sedation and anticholinergic effects and, in one case, loss of impulse control. The one placebo patient stopped because of nausea and vomiting and the tyrosine patient because of palpitations. MHPG secretion Fig. 2 shows the change in mean 24-h urinary MHPG (k SEM) excretion for the three treatment groups. Clearly, tyrosine was associated with a significant increase in MHPG excretion, imipramine with a decrease. Pre-treatment MHPG levels and on-treatment change in MHPG excretion
I 3
I 2
, I
WEEK DRUC
Fig, I,
-i
Mem Hamilton Depression
5-f-k t D-Q-0 p Scale score totals f SEM by week.
I5
128
0
n
failed to correlate with antidepressant any treatment group.
O 31
response
in
9
e
Plasma amino acid levels Fig. 3 demonstrates changes in mean fasting plasma tyrosine levels ( + SEM) for the three treatment groups. Patients receiving tyrosine had significantly increased tyrosine levels. Pre-treatment tyrosine levels or the ratio of tyrosine to the other large neutral amino acids failed to predict improvement on tyrosine therapy, and alterations in this level and ratio failed to correlate with improvement during tyrosine therapy.
2-
0 I ”
u
O.I-
H P G
0
0 --
L-l
E x c
-0
I-
-0
2-
r e I
I 0 ”
Discussion
-0.3n /p d -0.4
-
I
a
t
P
Y
DRUG =
P-Value Fig. 2. Change
in urinary
a.onn1
MHPG
excretion.
N ml
n I
-10
I 4
P
1
DRUG
P-Value
Fig. 3. Change
= 0.0084
in tyrosine
levels
Our earlier positive impressions about the antidepressant efficacy of tyrosine at comparable doses (Gelenberg et al., 1980, 1983) were not borne out by the present study, which we believe is the largest of its kind so far reported. Mouret et al. (1988) have reported positive results with tyrosine in what they termed ‘dopamine-dependent depression’, but their treatment was non-blind and uncontrolled. Van Praag (1983) similarly reported favorable results with tyrosine, but also uncontrolled and in a mixture with Shydroxytryptophan. Three studies of tyrosine in attention deficit disorder were generally negative (Nemzer et al., 1986; Reimherr et al., 1987; Eisenberg et al., 1988). A negative study that involves treatment of a heterogeneous disorder is highly vulnerable to a type-II error: failure to find a significant effect when one does, in fact, exist. Perhaps larger patient samples would have allowed us to achieve statistically significant results, although our data do not support that argument. Perhaps more cogent, although still speculative, would be the contention that a subgroup of depressed patients might be responsive to tyrosine. Even though we did not find that patients with lower pre-treatment tyrosine plasma levels or the ratio of tyrosine to other large neutral amino acids had a greater likelihood of response to oral tyrosine (Moller et al., 1980), it is conceivable that a study with larger numbers of such patients would show a positive finding.
129
As expected, imipramine suppressed urinary excretion of the norepinephrine breakdown product MHPG, presumably by inhibiting norepinephrine turnover. Consistent with our earlier report, tyrosine elevated urinary MHPG excretion, presumably by enhancing norepinephrine turnover - whether peripheral or central. Perhaps agents which enhance norepinephrine turnover may not be good antidepressant agents. Although this appears to contradict the catecholamine theory of depression, it is by now obvious that the catecholamine theory first advanced in the 1960s is far too simplistic to explain adequately pathology of mood. Or, maybe only a subset of depressed patients might benefit from such therapy, although if such a subtype of depression exists, it is obvious that we did not have a sufficient sample in our study. Conceivably bipolar depressives might be a better target population, a speculation for which we have no data. The idea that a natural product with negligible side effects would turn out to be an effective treatment for depression appeared too good to be true - and our data suggest that it was. Although in our work to date we have found no hazard from tyrosine therapy, and while it is conceivable that somewhere there are patients who will benefit from this amino acid (more than from placebo), our research lends no support to that line of thinking.
Acknowledgements The authors thank Richard J. Wurtman, M.D. and John H. Growdon, M.D. for inspiring this project and assisting in design; the Ajinomoto Company and CIBA-Geigy for supplying gratis, respectively, tyrosine and imipramine; Mrs. Linda Leahy, Mrs. Lillian Gerard, and the staff of the Massachusetts General Hospital General Clinical Research Center for assistance with patients; and Mrs. Jacqueline Lamkin for preparation of the manuscript. MHPG assays were performed by Mr. Dennis Francoeur. This study was funded by USPHS Grants MH36662, MH-47370, MH-31154, and MH-31224.
Appendix Modified 27-item Hamilton Depression Rating Scale 1. DEPRESSED MOOD (sadness, hopeless, helpless, worthless) 0 = Absent 1 = These feeling states indicated only on questioning 2 = These feeling states spontaneously reported verbally 3 = Communicates feeling states non-verbally; i.e., through facial expression, posture, voice and tendency to weep 4 = Patient reports virtually only these feeling states in his spontaneous verbal and nonverbal communication 2. FEELINGS OF GUILT 0 = Absent 1 = Self-reproach; feels he has let people down 2 = Ideas of guilt or rumination over past errors or sinful deeds 3 = Present illness is a punishment; delusions of guilt 4 = Hears accusatory or denunciatory voices and/or experiences threatening visual hallucinations 3. SUICIDE 0 = Absent 1 = Feels life is not worth living 2 = Wishes he were dead or any thoughts of possible death to self 3 = Suicide ideas or gesture 4 = Attempts at suicide (only serious attempt) 4. INSOMNIA EARLY 0 = No difficulty falling asleep 2 = Complains of occasional difficulty falling asleep; i.e., more than one-half hour 2 = Complains of nightly difficulty falling asleep 5. INSOMNIA MIDDLE 0 = No difficulty 1 = Patient complains of being restless and disturbed during the night 2 = Waking during the night; getting out of bed (except for purposes of voiding)
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6. INSOMNIA LATE 0 = No difficulty 1 = Waking in early hours of the morning but goes back to sleep 2 = Unable to fall asleep again if leaves bed 7. WORK AND ACTIVITIES 0 = No difficulty 1 = Thoughts and feelings of incapacity, fatigue or weakness related to activities, work, hobbies 2 = Loss of interest in activity, work, hobbies - either directly reported by patient, or indirect in listlessness, indecision and vacillation (feels he has to push self to work or activity) 3 = Decrease in actual time spent in activities or decrease in productivity. In hospital, rate 3 if patient does not spend at least 3 h/day in activities (hospital job or hobbies) exclusive of ward chores 4 = Stopped working because of present illness. In hospital, rate 4 if patient engages in no activities except ward chores, or if patient fails to perform ward chores unassisted 8. RETARDATION 0 = Normal speech and thought 1 = Slight retardation at interview 2 = Obvious retardation at interview 3 = Interview difficult 4 = Complete stupor 9. AGITATION 0 = None 1 = Fidgetiness 2 = Playing with hands, hair, obvious restlessness 3 = Moving about; can’t sit still 4 = Hand-wringing, nail-biting, hair-pulling, biting of lips; patient is on the run 10. ANXIETY PSYCHIC 0 = No difficulty 1 = Subjective tension and irritability 2 = Worrying about minor matters 3 = Apprehensive attitude apparent in face or speech 4 = Fears expressed without questioning
11. ANXIETY SOMATIC Physiological concomitants of anxiety such as _ gastro-intestinal: dry mouth, wind, indigestion, diarrhea, cramps, belching - cardiovascular: palpitations, headaches - respiratory: hyperventilation, sighing - urinary frequency; sweating 0 = Absent 1 = Mild 2 = Moderate 3 = Severe 4 = Incapacitating SYMPTOMS GASTRO-IN12. SOMATIC TESTINAL 0 = None 1 = Loss of appetite but eating without staff encouragement; heavy feelings in abdomen 2 = Difficulty eating without staff urging; requests or requires laxatives or medicines for bowels or medicines for G.I. symptoms 13. SOMATIC SYMPTOMS GENERAL 0 = None 1 = Heaviness in limbs, back or head; backaches, headache, muscle aches; loss of energy and fatiguability 2 = Any clear-cut symptom 14. GENITAL SYMPTOMS Symptoms such as loss of libido disturbances 0 = Absent 1 = Mild 2 = Severe
or menstrual
15. HYPOCHONDRIASIS 0 = Not present 1 = Self-absorption (bodily) 2 = Preoccupation with health 3 = Frequent complaints, requests etc. 4 = Hypochondriacal delusions 16. LOSS OF WEIGHT (answer only A or B)
for help,
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A. When rating by history: 0 = No weight loss 1 = Probable weight loss associated with present illness 2 = Definite (according to patient) weight loss B. On weekly ratings by ward psychiatrist - when actual weight changes are measured: 0 = Less than 1 lb weight loss in week 1 = Greater than 1 lb weight loss in week 2 = Greater than 2 lb weight loss in week 17. INSIGHT 0 = Acknowledges being depressed and ill 1 = Acknowledges illness but attributes cause to bad food, climate, overwork, virus, no rest, etc. 2 = Denies being ill at all 18. DIURNAL
VARIATION p.m. a.m. 2 ratings: rate for both a.m. and p.m.; If symptoms are worse either in morning evening, note WHICH, and rate severity variation 0 = Absent 1 = Mild 2 = Severe
or of
19. DEPERSONALIZATION AND DEREALIZATION such as: feelings of unreality, nihilistic ideas 0 = Absent 1 = Mild 2 = Moderate 3 = Severe 4 = Incapacitating 20. PARANOID SYMPTOMS 0 = None 1 = Suspicious 2 = Ideas of reference 3 = Delusions of reference 21. OBSESSIONAL COMPULSIVE 0 = Absent 1 = Mild 2 = Severe
and persecution
AND SYMPTOMS
22. FATIGUABILITY 0 = Does not get more tired than usual 1 = Gets tired more easily than before (from strenuous physical or mental tasks) 2 = Gets tired more easily than before (even from small tasks) 3 = Is tired most of the day 4 = Too tired to do any tasks except for basic daily functions 23. SOCIAL WITHDRAWAL 0 = Interacts with other people as usual 1 = Less interested in socializing with others but continues to do so 2 = Interacting less with other people in social (optional) situations 3 = Interacting less with others in work or family situations (i.e., where necessary) 4 = Marked withdrawal from others in family or work situations 24. APPETITE INCREASE 0 = No increase in appetite 1 = Eating somewhat more than usual 2 = Eating much more than usual 25. CARBOHYDRATE CRAVING 0 = No change in food preference 1 = Eating more carbohydrates (starches and sugars) than before 2 = Eating much more carbohydrates than before 3 = Irresistible craving for sweets or starches 26. WEIGHT GAIN 0 = No weight gain 1 = Probable weight gain associated with present illness 2 = Definite weight gain (according to patient) 27. HYPERSOMNIA compare sleep length to euthymic and NOT to hypomanic sleep lengths; if this cannot be established, use 8 h 0 = No increase in sleep length 1 = At least 1 h increase to sleep length 2 = 2 + h increase 3 = 3 + h increase
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4 = 4 + h increase Was euthymic sleep length used? Yes No Was 8-h sleep length used? No Yes References Alonso, R., Gibson, C.J. and McGill, J. (1981) Determination of 3-methoxy-4-hydroxyphenylglycol in urine by high performance liquid chromatography with amperometric detection. Life Sci. 29, 1689-1696. Eisenberg, J., Asnis, G.M., van Praag, H.M. and Vela, R.M. (1988) Effect of tyrosine on attention deficit disorder with hyperactivity. J. Clin. Psychiatry 49, 193-195. Fernstrom, M.H. and Femstrom, J.D. (1981) Rapid measurement of free amino acids in serum and CSF using high-performance liquid chromatography. Life Sci. 29, 2119-2130. Gelenberg, A.J., Wojcik, J.D., Growdon, J.H., Sved, A.F. and Wurtman, R.J. (1980) Tyrosine for the treatment of depression. Am. J. Psychiatry 137, 662-663. Gelenberg, A.J., Wojcik, J.D., Gibson, C.J. and Wurtman, R.J. (1983) Tyrosine for depression. J. Psychiatr. Res. 17, 175180. Moleman, P. and Borstrok, J.J.M. (1982) Analysis of urinary 3-methoxy-4-hydroxyphenylglycol by high performance
liquid chromatography and electrochemical detection. J. Chromatogr. 227, 391-405. Moller, S.E., Kirk, L. and Honore, P. (1980) Relationship between plasma ratio of tryptophan to competing amino acids and the response to L-tryptophan treatment in endogenously depressed patients. J. Affect. Disord. 2, 47-59. Mouret, J., Lemoine, P., Minuit, M.-P. and Robelin, N. (1988) La L-tyrosine guerit immediatement et a long terme, les depressions dopamino-dependantes. C. R. Acad. Sci. Paris 306, 93-98. Nemzer, E.D., Arnold, L.E., Votolato, N.A. and McConnell, H. (1986) Amino acid supplementation as therapy for attention deficit disorder. J. Am. Acad. Child Psychiatry 4. 509-513. Rein&err, F.W., Wender, P.H., Wood, D.R. and Ward, M. (1987) An open trial of L-tyrosine in the treatment of attention deficit disorder, residual type. Am. J. Psychiatry 144, 1071-1073. Schildkraut, J.J. (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am. J. Psychiatry 122, 509-522. Spitzer, R.L., Endicott, J. and Robins, E. (1978) Research Diagnostic Criteria: rationale and reliability. Arch. Gen. Psychiatry 35, 733-738. van Praag, H.M. (1983) In search of the mode of action of antidepressants: 5-HTP/tyrosine mixtures in depression. Neuro-Pharmacology 22, 433-440.
