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Increase in Suicidal Thoughts and Tendencies:
Association with Diazepam Therapy

Hewitt F. Ryan, MD; F. Bruce Merritt, MD;
George E. Scott, MD; Richard Krebs, MD;
and Betty L. Thompson, R.N.

JAMA, March 25, 1968 · Vol 203, No 13

From Denver General Hospital: (Drs. Ryan, Scott and Krebs and Mrs. Thompson), Mount Airy Hospital: (Drs. Ryan and Merritt), and Bethesda Hospital: (Dr. Ryan), Denver. Reprint requests to Denver General Hospital, W Sixth Ave and Cherokee St, Denver 80204 (Dr. Ryan).

Seven cases occurred in which there was an association in time between the institution of diazepam therapy and the onset of suicidal thoughts and tendencies, which tended to be concealed by patients who were at the time receiving psychiatric treatment. An additional patient demonstrated deepening of depression while receiving diazepam. Physicians should consider the possible adverse depressive effect of diazepam when prescribing it as an antianxiety agent.

DIAZEPAM, a benzodiazepine, is an analogue of chlordiazepoxide hydrochloride and oxazepam. Most clinical papers written in regard to diazepam have reported it to be a worthwhile antianxiety agent, and its use in patients with anxiety reactions and mild agitated depressions has been recommended. It has generally been considered to be a safe drug and well tolerated.

There have, however, been some reports in the literature of an increase in suicidal thoughts and tendencies in individuals who have been treated with diazepam. Rao(1) reported that in one patient out of the eight in the group receiving diazepam in his study depression developed with suicidal tendencies during trial diazepam therapy. With the administration of imipramine hydrochloride, the depression lifted. In a study reported by Gundlach et al,(2) emergent suicidal impulses and thoughts developed in nine patients, seven of whom were receiving diazepam, and two of whom were receiving placebo. In the study by McDowell et al,(3) two patients discontinued diazepam therapy, one because the drug made him feel ill and the other because the drug made him feel depressed. These reports are at variance with the enthusiasm expressed for diazepam by most writers. The major adverse side effects have been considered to be the possible development of ataxia and confusion. However, the report by Feldman(4) of the progressive development of dislike and hate in some patients, manifested in one by an overt act of violence, may, not be totally unrelated to the problem to which we here address ourselves. The problems which Kearney and Bonime(5) discuss are also pertinent.

The following cases are being reported due to the association in time between the institution of diazepam medication and the onset of suicidal thoughts and tendencies or of increased depression, which caused concern about the existence of a suicidal risk in the individual patient involved. In two cases, suicide did take place.

Report of Cases

CASE 1. A 28-year-old man with a history of sexual deviation was hospitalized with symptoms of depression and suicidal thoughts. He was tremulous and anxious. The diagnostic impression was psychoneurotic depressive reaction. He showed slight improvement following approximately two weeks of therapy with chlorpromazine hydrochloride and chlordiazepoxide hydrochloride, which were given to relieve anxiety. This therapy was discontinued, and treatment with diazepam, 5mg three times a day, was started. The patient became withdrawn, confused, and increasingly depressed. Ten days after onset of diazepam therapy, he left the hospital and, with the intention of killing himself, purchased a gun. He failed to commit suicide only because the gun was wrestled from him by friends as he started to shoot himself. Diazepam therapy was discontinued, and administration of imipramine hydrochloride, 50mg four times a day, was instituted. After three to four days, the patient was less depressed both objectively and subjectively.

CASE 2. A 60-year-old woman was admitted with the complaint of nervousness. She was withdrawn, tremulous, anxious, and depressed. The diagnosis on admission was agitated depression. She received phenothiazines and imipramine, but her condition did not improve. On the ninth day, therapy with these drugs was stopped, and administration of diazepam, 5mg three times daily, was started. The patient complained of worsening anxiety and depression over the next four days. Diazepam therapy was discontinued, chlorpromazine therapy was begun, and several days later, the patient was smiling and showed subjective improvement.

CASE 3. A 38-year-old man was admitted after an ingestion of sedatives. He had recently been treated at another hospital for a similar overdose. Following treatment of the acute results of the ingestion, the patient was depressed and withdrawn with much somatic concern. The diagnostic impression was psychoneurotic depressive reaction. He was placed on a regimen of diazepam, 5mg taken four times daily. On the third day of diazepam therapy, he left the hospital without permission and shot himself to death the following day.

CASE 4. A 32-year-old woman who had been treated as a psychiatric outpatient for two years at weekly intervals was considered to have an anxiety depression. There had been a steady decrease in depressive content to a point where depression was only a periodic symptom, usually following marital discord or illness of her children. Because of increased anxiety due to some family conflicts and a visit with her in-laws, she was placed on a regimen of diazepam, 5mg three times a day, with immediate lessening of her anxiety. At the end of one week of diazepam therapy, it was apparent that there was a rapidly increasing depression which could not be explained on a psychological basis. In addition to depression, the patient showed disturbance in her mentation with confusion, lapses of memory, and forgetfulness. Due to her subjective relief from anxiety, medication was not changed. She became psychotically depressed and planned suicide. She was hospitalized seven weeks after diazepam therapy was begun. This therapy was then discontinued. Administration of amitryptyline hydrochloride, 25mg three times daily, was begun. Three days later, the patient showed only mild depression, although there was some increase in her anxiety.

CASE 5. A 62-year-old woman with a five month history of chronic fatigue and depression became delirious during withdrawal of anileridine phosphate. The delirium cleared in a week's time. The patient was placed on a regimen of chlordiazepoxide hydrochloride, 5mg three times daily. After pneumoencephalography was performed, chlordiazepoxide therapy was discontinued by the neurosurgeon, who substituted administration of diazepam, 5mg four times a day. Nine days later, the patient had a return of her feeling of depression with spontaneous weeping. She also experienced impairment in her reality testing at night. This situation continued for four days, at which time therapy with imipramine hydrochloride, 25mg four times daily, was started. The following day, the patient's spirits were improved. Diazepam administration was then discontinued. On the next day, she reported that she was experiencing "an excellent day," that her appetite was good, and that her spirits were up. The improvement continued, and the patient was discharged from the hospital after another day.

CASE 6. A 30-year-old woman who had been in group psychotherapy for eight months due to a chronic anxiety depression was hospitalized with the diagnosis of psychotic depressive reaction. For the preceding five weeks, she had taken diazepam, 5mg four times a day, during which time she experienced sleep disturbance, loss of appetite, a 13 lb weight loss, spontaneous weeping, and finally, suicidal thoughts. On admission, diazepam therapy was discontinued, and the patient was placed on a regimen of imipramine. She was less depressed the following day, much less depressed the next day, and did not appear psychotically depressed at the end of the first week in the hospital. By this time, she had regained 4 lb of weight and was cheerful, bright, and capable of being reflective about herself. She was able to be discharged from the hospital two weeks after she was admitted.

CASE 7. A 53-year-old woman was seen for supportive psychotherapy as an outpatient. Chlordiazepoxide hydrochloride, 10mg four times a day, and desipramine hydrochloride, 25mg three times daily, were prescribed for symptoms of anxiety and depression. The patient responded with mood improvement, decrease in anxiety, and the ability to function in a realistic manner. Twelve weeks later, the patient was seen in consultation after a serious suicide attempt. History from the patient and others indicates that she had done fairly well but had had some recurrence of anxiety in the interim until five days prior to the suicide attempt. At that time, her internist placed her on a regimen of diazepam, 5mg four times daily. Immediately, the patient felt considerable decrease in anxiety but marked increase in depression. Friends noted that she suddenly became withdrawn but, as she presented a calm and somewhat smiling appearance, the suicidal state was not suspected. In the hospital, diazepam administration was stopped, and the previous drug therapy was reinstituted. Her condition improved dramatically, and the patient, in much better spirits, soon left the hospital. There has been no recurrence of a severe depressive reaction, and she is coping with her life situation reasonably well.

CASE 8. A 39-year-old woman was hospitalized with an anxiety depression two weeks after the death of a parent. Her depression was considered to be psychoneurotic in degree; she did not receive antidepressant medication but did receive chlordiazepoxide for anxiety. She was moved to the day care program, and from it was transferred to the outpatient department, where she was seen in group therapy. Eight weeks after admission to the hospital, while being followed up as an outpatient, she had her medication changed to diazepam, 5mg or 7.5mg twice a day. The prescription for sixty 5mg tablets was refilled after 14 days, indicating that the patient was taking approximately 5mg four times daily. One week later, she committed suicide by glutethimide ingestion. She had stooped attending group therapy but had not been considered to be suicidal.

Comment

As indicated, cases of an increase in suicidal thoughts and tendencies associated with the use of diazepam have previously been reported. In addition to further cases being presented, two actual suicides and two serious attempts are reported.

It should be noted that of these eight patients, two were considered to have a psychotic depressive illness initially. The condition of one of these quickly improved, and this patient was not regarded as having basically a psychotic illness. The six other patients were regarded as having psychoneurotic illnesses when they presented. The diagnostic impression in Case 1 was revised to a psychotic process after the patientís suicide attempt. This kind of revision in diagnostic thinking also occurred after patient 3 did commit suicide. The other individuals continued to be regarded as having had adequate ego strength and are not considered to have had underlying psychoses or borderline psychoses. This point is made because, while diazepam is no longer recommended as a useful drug in psychotic illness, it is recommended for the alleviation of anxiety in individuals suffering from psychoneurosis.

Five patients showed improvement in a matter of three or four days after the discontinuing of diazepam therapy and the institution of treatment with antidepressant drugs, either imipramine or amitryptyline. The improvement is considered to be associated in time with diazepam withdrawal rather than with the onset of antidepressant medication, as neither imipramine nor amitryptyline is believed to contribute to the lifting of depression in this short a time span.

We believe that in several of the cases presented there occurred the insidious onset of suicidal ideation and intent as seen in "smiling depressions" in association with the use of diazepam. A smiling depression is a facade manifested by some severely depressed individuals in which the use of denial tends to conceal the underlying depressed affect. This has been a cause for concern to us and, therefore, we are reporting our experience.

There has been no clear warning that diazepam may have this kind of adverse effect in psychiatric patients, only that it cannot be expected to do the job of the accepted antidepressants in patients with severe depression. It would seem that caution should be exercised in the use of diazepam in all patients in order to promptly detect adverse depressive effects. The use of diazepam in even mild depressions, in our view, requires consideration of the potential hazard of the onset of suicidal thoughts and tendencies which may not be readily recognized.

Generic and Trade Names of Drugs

Diazepam - Valium
Chlordiazepoxide hydrochloride - Librium
Oxazepam - Serax
Imipramine hydrochloride - Tofranil
Chlorpromazine hydrochloride - Thorazine Hydrochloride
Amitryptyline hydrochloride - Elavil hydrochloride
Anileridine phosphate - Leritine Phosphate
Glutethimide - Doriden
Desipramine hydrochloride - Norpramin, Pertofrane

References

  1. Rao, A.V.: A Controlled Trial With "Valium" in Obsessive Compulsive State. J Indian Med Assoc 42:564-567 (June 16) 1964.

  2. Gundlach, R., et el: A Double-Blind Outpatient Study of Diazepam (Valium) and Placebo. Psychopharmacologia 9:81-92, 1966.

  3. McDowall, A.; Owen, S.; and Robin, A.A.: A Controlled Comparison of Diazepam and amylobarbitone in Anxiety States, Brit J Psychiat 112:629-631 (June) 1966.

  4. Feldman, P.E.: An Analysis of the Efficacy of Diazepam, J Neuropsychiat 1(suppl 3):62-67 (Aug) 1962.

  5. Kearney, T., and Bonime, H.C.: Problems of Drug Evaluation in Outpatients, Dis Nerv Syst 27:604-606 (Sept) 1966.

From Denver General Hospital: (Drs. Ryan, Scott and Krebs and Mrs. Thompson), Mount Airy Hospital: (Drs. Ryan and Merritt), and Bethesda Hospital: (Dr. Ryan), Denver. Reprint requests to Denver General Hospital, W Sixth Ave and Cherokee St, Denver 80204 (Dr. Ryan).



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