MENTAL DEPRESSION IN HYPERTENSIVE PATIENTS TREATED FOR LONG PERIODS WITH LARGE DOSES OF RESERPINE* EDWARD D. FREIS, M.D.+ WASHINGTON, D. C. T HE introduction of Rauwolfia serpentina into this country by Wilkins and Judsonl and the purifica- tion of an active alkaloid, reserpine (Serpasil), has led to the widespread clinical IIS~ of the iatter drug not only in hypertension2,3 but also in neuropsychi- atric conditions." The purpose of this report is to describe the development of psychiatric complications in hypertensive patients treated with large doses of reserpine for long periods. CASE REPORTS CASE 1. Mrs. I.K., a 54-year-old widow, had mild hyper- tension for 1 year associated with headache and substernal pain. Since the death of her husband 2 years previously she had been more emotional and easily upset than formerlv. The blood pressure was 190/105. The fundi showed Grade 1 changes; the heart was normal in size, and examination of the urine was negative. The patient was treated with reserpine, 0.5 mg. twice daily, and alkavervir (Veriloid), 4 mg. 3 times daily, the average blood pressure falling to 165/100. There was no change in symptomatology until 4 months after treatment was instituted, when, after a vacation trip to visit her mother, she began to feel extremely depressed. She was conscious of "everything in her body" and was worried about her blood pressure. She did not believe that life was worth living. She wanted to remain at home and was in- capable of enjoying any of the pursuits that had formerly given her pleasure. Reserpine and alkavervir were withdrawn, and pheno- barbital, 60 mg. 4 times daily, was substituted. She im- proved slowly for the succeedmg 2 months and had re- mained free of depression when last seen six months later. CASE 2. Severe hypertension developed in W.H., a 44- year-old college professor, over a period of 3 years. When he was first seen in 1950 the blood pressure was 240/140, the fundi showed Grade 3 changes, with hemorrhages and exudates, and the heart was greatly enlarged; the urine gave a + f test for albumin. He was treated with alkavervir for 6 months, and then parenteral administration of hexamethonium was substituted. There was remarkable improvement, with reduction of aver- age blood pressure to 160/100. regression of changes in the optic fundi to Grade 1, decrease in the heart size and clear- ing of the albuminuria. He returned to a full-time schedule of teaching, feeling better than at any time in the past 5 years. In September, 1953, the treatment was changed to pen- tolinium tartrate (pentapyrrolidinium, or M&B 2050)) 100 mg. orally 3 times daily, and reserpine, 0.5 mg. 3 times daily. Sleepiness and lethargy developed so that after 2 weeks the dosage was reduced to 0.5 mg. twice daily. The patient continued to feel extremely well until Jan- *From the Cardiovascular Research Laboratory, Georgetown Univer- sity Has ital, the School o Medicine and the Veterans AdminIstration Hospital. stitute 0: the' l? `. Department of Medicine,, Georgetown University Supported III art by research grants from the National Heart In- atmnal Institutes of Health,, Public Health Service (Grant H-720), the Squibb Institute for Medicme Research, New ~runs. wick, New Jersey, and Irwin, Neisler and Company,, Decatur, Illinois, Sponsored (m part/, by the Veterans Admimstratlon and published with the approval of t e Chief Medical Director. The statements made and conclustons drawn by the author ZWP a result of his own study and do not necessarily reflect the opinion or policy of the Veterans Ad- ministration. tAdjunct clinical professor of medicine, Georgetown University School of .Medicine; chief, Medical Service, Veterans Administration Hospital; chief, Cardlov~cular Research Laboratory, Georgetown University Has- pital. uary, 1954, when he became severely depressed. He lost all self-confidence and became fearful of meeting people SO- cially, including his close friends, and excessively introspec- tive and lost all enthusiasm for his work. He debated whether to escape into alcoholism but did not do so. He did not want to leave his room or to meet anyone. He wished for death but did not contemplate suicide. He did not manifest anxiety so much as inertia of intel- lect and loss of capacity to enjoy life. His appetite remained good during this period, and he gained weight despite his depressed outlook. His ability to concentrate was markedly retarded in that he fumbled for words during lectures and was unable to digest the current literature in his field. He lived in another city and did not communicate his intellectual and emotional change to this clinic. Neverthe- less, there was a slight improvement in the spring of 1954 despite the fact that he continued to take reserpine. In June, when he was readmitted to the hospital for a checkup, reserpine was withdrawn, but pentolinium tartrate was con- tinued. He began to improve dramatically after 48 hours and within a week was restored to his usual mental and emotional vigor. C+E 3. Mrs. R.K., a 41,-year-old housewife, had hyper- t2e2nsyl;5 of 5 years' duration. The blood pressure was and the fund1 showed Grade 3 changes, with hemorrhages but no exudates. Cardiac and renal findings were not significantly abnormal. She was hospitalized and treated with alkavervir, 4 mg. 3 times daily, and reserpine, 0.5 mg. twice daily. After 1 week the dosage of reserpinc was reduced to 0.25 mg. once daily. After discharge from the hospital the home recordings of blood pressure averaged 150/100. The patient felt well until 4 months after treatment was instituted, when she became "chronically unhappy" and "nothing pleased her" and yet she could find no external reason for her dissatis- faction. Whereas previously she had always been extremely active and enjoyed shopping tours and club visits with her friends, she did not want to leave the house and did not enjoy her friends. Ordinary household duties were accom- plished with great effort. There was no loss of appetite and little anxiety associated with this depression. The dosage of reserpine was reduced to 0.1 mg. a day for 2 weeks, but the symptoms persisted. Reserpine, but not alkavervir, was then discontinued, and within 1 week she returned to her previously happy emotional and vigorous physical state, CASE 4.* J.J., a 60-year-old executive, had had hyper- tension for 10 years. In the past year the blood pressure had been about 200/120, but he had no hypertensive symptoms. He always had been rather tense and anxious and suffered from a moderate degree of claustrophobia. The fundi showed Grade 1 changes; the heart was not enlarged, and urinalysis was negative. The office recording of blood pres- sure was 210/115, but several recordings at home averaged 180/105. He was treated with an extract of Rauwolfia (Rauwiloid) 4 mg. twice daily for 1 month, and since there was nd change in blood pressure alkavervir, 5 mg. twice daily, and reserpine, 0.5 mg. twice daily, were substituted. On this regimen the blood pressure at home varied between 140/90 and 180/100. Because of continued feeling of emotional tension the dosage of reserpine was increased to 1.0 mg. twice daily after 1 month. The patient felt calmer and was quite well for the ensuing 2 months, when, immediately after his daughter's marriage, an acute depression with agitation developed. He was afraid to leave the house with- out his wife. His claustrophobia became so severe that he would not step into an elevator. He thought that he had become a burden to everyone and lay awake at night con- templating suicide. Reserpine, but not alkavervir, was discontinued but be- cause of the severity of the symptoms the consuiting psy- chiatrist decided to give him electroshock therapy without delay. After a short course of treatment the patient began to improve slowly and was soon back at work. CASE 5. H.B., a 52-year-old retired policeman, first had malignant hypertension in 1950. When he was seen in the hospital in 1950 the blood pressure was 230/140, the fundi showed Grade 4 changes, and the heart was enlarged, with pulmonary congestion; there was impairment of renal function without nitrogen retention. He responded well to treatment with hexamethonium subcutaneously and I-hydrazinophthalazine (Apresoline) orally and remained on that regimen until May, 1953, when pentolinium tartrate by mouth was substituted for the subcutaneous administration of hexamethonium. At this time reserpine, 0.25 mg. 3 times daily, was also given, this regimen being continued for approximately 1 year, dur- ing which the average blood pressure was 165/95. He felt quite well. On April 4, 1954, because of the development of easy fatigability and lassrtude, the dosage of reserpine was re- duced to 0.25 mg. once daily. Nevertheless, he continued to feel tired and also became depressed. He did not wish to leave the house, but at home he did not enjoy television, working in the garden or any of the other pursuits in which he had formerly taken pleasure. He woke up in the early hours of the morning and during this time considered various methods of committing suicide. Whereas he had previously been affably aggressive and talkative he now ap- peared quiet, uncertain and depressed. Reserpine was dis- continued, and he was followed by a psychiatrist. He im- proved slowly for several weeks but, when last seen, had still not returned completely to hrs previous personality state. DISCUSSION Although several drugs were used in these cases the evidence as a whole strongly suggests that the emo- tional disorders reported were brought on by reser- pine. Reserpine was the only agent used in all the patients, some receiving veratrum alkalaids and others *We are indebted to Dr. Robert Nenno, assistant chief of the De- partment of Psychiatry, Georgetown University Hospital, for diagnosis and treatment of the psychiatric complications that developed in this and the subsequent case. pentolinium bitartrate with or without l-hydrazin- ophthalazine. Furthermore, no psychiatric complica- tions of the kind described in these case reports were observed in patients taking any of the other antihy- pertensive agents without reserpine. Finally, in 4 cases the depression cleared after reserpine had been discontinued. Thus, it appears that reserpine rather than any of the other drugs was the most important contributing factor in the development of the de- pressed state. The emotional reaction of several patients did not appear to be that of a true anxiety depression. They manifested withdrawal from the environment, leth- argy and unhappiness but not anxiety. In addition, anorexia and weight loss did not occur. Neverthe- less, all considered life not worth living, and 2 of them contemplated suicide. Lesser degrees of depression have frequently been encountered in other patients in this clinic. Com- mon symptoms, often so mild as to pass without com- ment unless specifically asked for, were lack of am- bition, crying spells, introspection and lethargy. It is worthy of note that the dosage of reserpine in all cases except 1 was maintained at a higher level than that advised customarily, being 1.0 mg. a day in 2 and 1.5 and 2.0 mg. a day, respectively, in 2, only 1 of the patients being maintained on a dose of 0.25 mg. a day. It is also noteworthy that in every case the drug had been administered continuously for two months or longer before the symptoms of mental de- pression appeared. In 1 case the appearance of the syndrome was delayed for approximately a year after the institution of treatment. Once depression de- veloped, however, reductiun of the daily dosage from 0.25 to 0.1 mg. (Case 3) and from 1.0 mg. to 0.25 (Case 5) failed to relieve the symptoms, and com- plete withdrawal of the drug was necessary. It is also apparent that disturbing environmental factors may have played a part in the development of the syndrome. In Case 1 depression developed after the patient visited her mother, and in Case 4 it followed the marriage of the patient's daughter. In the remaining cases, however, no obvious precip- itating factors were evident. Since reserpine is being used widely at present for the treatment of mental illness, as well as hyperten- sion, it seems appropriate to call these cases to the attention of the medical profession, so that accumu- lated experience can confirm or reject the implica- tion of this report that reserpine caused the psychi- atric condition described. Although similar psychi- atric complications were not observed in patients treated with other Rauwolfia preparations it must be emphasized that the great majority of the patients in this clinic were treated with reserpine rather than with other extracts. Therefore, the experience with other drugs containing Rauwolfiu is too limited for one to pass judgment on whether they are also apt to produce this syndrome. SUMMARY AND CONCLUSIONS Five cases of mental depression are described. These developed in hypertensive patients after sev- eral months of continued treatment with reserpine in dosage varying from 1.0 to 2.0 mg. a day in 4 and 0.25 mg. a day in 1 of the cases. Maintenance doses of this agent should be kept as low as possible, prefer- ably below 0.25 mg. a day, to minimize the develop- ment of this syndrome. REFERENCES Wilkins, R. W., and Judson, W. E. Use of Rauwolfia scrpenfina in hypertensive patients. Ncur Eng. J. Med. 248:48-53, 1953. Wilkins,. R. W., et al. Reserpine in treatment of h ertension: note on relatrve dosage and effects. New Eng. J. Med.%0:477, 1954. Freis, E. D., and Ari, R. Clinical and experimental effects of re- serp~ne in patients with essential hypertension. Acad. SC. 59:45-53, 1954. Ann. New York Kline, N. S. Use of Rauwolfio rerpentino Bath. in neuropsychiatric conditions. Ann. New York Acad. SC. 59:107-132, 1954. C~~py~ight, 1954 by the Massacl~usctts Medical Society Prirlted ill the U. S. A.