905

DEPRESSION ASSOCIATED WITH ORAL CHOLINE

SIR,-Recent interest in the use of oral choline in the inves-tigation and treatment of tardive dyskinesia has developedfrom a number of convergent lines of research. It has been sug-gested that tardive dyskinesia, as a long-term side-effect ofneuroleptic treatment, is an iatrogenic choreiform motor dis-order caused by dopaminergic activity in the stnatum resultingfrom a chemical (neuroleptic) denervation supersensitivity. Anumber of lines of evidence suggest that movement is regulatedbv a dopamine/acetylcholine balance in the nigrostriataltract.’ The evidence suggests that dopamine predominanceresults in choreiform disorders, whereas acetylcholine pre-dominance produces rigidity and akinesia. A resultant corre-late is that re-establishing dopamine/acetylcholine balance

either lowering the high or raising the low transmitter system)wil! reduce the motor symptoms. In animals oral choline in-creases brain-tissue levels of acetylcholine, and the samemechanism probably increases central cholinergic tone in man.A noradrenaline/acetylcholine balance has been proposed formood regulation.4 Since physostigmine reverses mania and

pushes normal mood into severe transient depression,5 it is pos-tulated that in depression there is a relative or actual choliner-gic hyperactivity. Increasing cholinergic load would increasethe likelihood of depression, and depression would therefore bean expected side-effect of oral choline treatment. We reporthere two patients who became clinically depressed while takingcholine for tardive dyskinesia:Case 1.-This 29-year-old man has been treated with neuro-

leptics for 3 y, and tardive dyskinesia has developed over thepast 10 mo. Durmg the drug evaluation of his movement dis-order, he was given intravenous physostigmine (2.5 mg over20 min) which reduced his movement by 30-45% and changedhis mood to painfully severe transient depression; the amphe-tamine he received as part of the tardive-dyskinesia evaluationintensified his movements and caused euphoria. He receivedoral choline for the proposed treatment of his movement dis-order, beginning at 3 g a day, increasing to 9 g over 1½ wk.His symptom development paralleled the dose increase until, at9 g, he became highly agitated, paranoid, and even more severe-ly depressed, with feelings of worthlessness and hopelessness.Chohne was withdrawn and restarted 2 wk later. The patient’smood changes were carefully observed. When the choline wasincreased to 9 g per day, he again developed feelings of hope-lessness, worthlessness, paranoia, and suicidal thoughts. Intra-venous atropine (24 mg given over 30 min) relieved the symp-toms of depression over the next 20-30 min. The Hamiltondepression score increased from 31 (at 3 g choline) to 46 (at9 g). At that dose level he made an unsuccessful suicide

attempt. After the drug was stopped, the symptoms remittedover 4-5 days.Case 2.-This 57-year-old woman has been treated with

neuroleptics for 15 yr, and tardive dyskinesia has developedover the past 3 years. During neuroleptic-drug use her conver-sation was psychotic, and it became worse with drug with-drawal. She began on 3 g per day of choline, increasing to 9g over 2 wk. Although choline produced a modest reduction ofher dyskinesia symptoms, she developed severe depressivesymptoms. Initially motor retardation with weakness occurred,accompanied by delusional talk of death, hopelessness, anddespair. She began to talk of dying and never leaving hospital.After drug withdrawal the weakness and the depressive delu-sional talk remitted over 7-8 days.

Since choline will certainly continue to be used in the eva-luation of movement disorders, awareness of depression as apossible side-effect of choline is warranted. Our observation isaiso important in that it supports the adrenergic/cholmergic

1. Rubovits, R., Klawans, H Archs gen Psychiat 1972, 27, 502.2. Barbeau, A. Adv. Neurol. 1973, 1, 473.

3. Cohen, E., Wurtman, R. Life Sci. 1975,16, 1095.4. Davis J. M., Janowsky, D. in Neurotransmitter Balances Regulating Beha-

vior (edited by E. R. Domino and J. M. Davis, p. 135 Ann Arbor, 1975.5. Janowsky, D., El-Yousef, M. K., Davis, J. M. , Sekerke, H. J. Archs gen Psy-

chiat. 1973, 28, 542.

concept of mood changes and demonstrates a correlationbetween increased cholinergic tone and depression.

CAROL TAMMINGAROBERT C. SMITHSIDNEY CHANG

JOSEPH S. HARASZTIJOHN M. DAVIS

Department of Psychiatry,University of Chicago,Chicago, Illinois 60637, U.S.A.

SPIRONOLACTONE-INDUCED GYNÆCOMASTIARELATED TO ALLERGIC REACTION TO ’DARVON

COMPOUND’

SIR,—A major side-effect of spironolactone is gynxcomas-tia.1 Although the specific cause of this effect is not known, itmay be related to alteration of the drug-metabolising oxidaseP-450.2 Whether the alteration of this enzyme activity changestestosterone metabolism and thereby contributes to gynaeco-mastia is a matter of controversy.3 The frequency of spirono-lactone-induced gynxcomastia is 1.2%; it occurs soon after thedrug is first given.’ We report here an episode of transientgynsecomastia which developed four years after treatment withspironolactone had been started and was temporally related toan allergic reaction provoked by the analgesic ’Darvon Com-pound’ (aspirin 230 mg, caffeine 30 mg, phenacetin 150 mgpropoxyphene hydrochloride 65 mg).A 58-year-old White man who had been treated for 5 years

for hypertension and hypoparathyroidism and atheroscleroticvascular heart-disease was seen in the outpatient clinic for lowback pain after a fall on ice. Because of persistent musculoske-letal aches without physical or radiological evidence of skeletalabnormality, darvon compound (65 mg four times a day) wasprescribed in addition to his other medications: spironolactone(150 mg a day), vitamin D (1 mg a day), digoxin (0-25 mg aday), calcium glubionate (30 ml a day), nitroglycerin as

needed, and isosorbide dinitrate (5 mg four times a day). Hewas seen in the clinic about 2 weeks later for swollen tenderbreasts and a pruritic rash on his chest and neck. On examina-tion, both breasts were tender to palpation and measured 6 cmin diameter. A macular, erythematous eruption covered thethorax and cervical region. Darvon and spironolactone werediscontinued, with resolution of the rash and a decrease inbreast swelling (2 cm). A month later the patient was chal-lenged with darvon compound, and a pruritic rash developedover the thorax. The medication was again stopped. Spirono-lactone was then given for 10 days, without any sign of furtherbreast changes. After 10 days, darvon compound was givenagain but was stopped by the patient when the pruritic rashreappeared and breast swelling and tenderness began to de-velop. Despite continued treatment with spironolactone, thegynoccomastia has resolved.

It is unusual for spironolactone to produce gynaecomastiafor the first time after many years of use. The allergic reactionto darvon compound was considered a precipitating cause.Although this patient had previously taken propoxyphene hyd-rochloride without an allergic reaction, we cannot be sure

which of the other components in the darvon compound is re-sponsible for the allergy. Because the patient developed symp-toms similar to those of his original reaction when he was chal-lenged with darvon while he was taking spironolactone, theredoes seem to be a relation. Whether darvon specifically or theallergic reaction it provoked increased the sensitivity to spir-onolactone is uncertain.

Hypertension-Endocrine Branch,National Heart, Lung and Blood Institute,National Institutes of Health,Bethesda, Maryland 20014, U.S.A

A. A. LICATAF. C. BARTTER

1. Bridgman, J. F., Buckler, J M Br. med. J 1974, iii, 5202. Stripp, B , Menard, R , Zampaglione, N E , Hamrick, M E., Gllette, J. R.

Drug Metab. Distrib. 1973, 1, 2163. Stripp, B. , Taylor, A. A., Bartter, F. C., Gillette, J. R., Loriaux, D. L., Eas-

ley, R., Menard, R H J clin. Endocr. Metab. 1975, 41, 777.4. Walsh, P. C., Siteri, P. K J. Urol 1975, 114, 254.5. Greenblatt, D. J., Koch-Weser, J J. Am med. Ass 1973, 225, 40.