Psychopharmacology
Do Benzodiazepines Cause Depression? Blake
D.
Smith,
Carl Salzman,
M.D.
M.D.
It is not uncommon in everyday clinical practice to hear the suggestion of a causal link between the use of benzodiazepines and the emergence ofdepressive symptoms. However, the standard reference manuals are far from clear on this issue. One recent pharmacologic text states that “occasional patients become depressed during chronic benzodiazepine therapy, but whether there is a causal association remains in doubt” (1). Another does not mention depression in the list of potential side effects of benzodiazepines (2). However, the report ofthe American Psychiatric Association’s task force on benzodiazepine toxicity states that although depression is not a frequent side effect, “Benzodiazepines have been reported to cause or exacerbate symptoms ofdepression” (3). In a standard pharmacologic textbook, depression is noted to be an occasional side effect of benzodiazepine use (4). The purpose of this column is to review the relationship between benzodiazepines and depression.
pression and the development of suicidal ideation after institution of diazepam therapy forpatients diagnosed as having depressive disorders (5). There were two cases ofactual suicide and two serious attempts. The survivors improved within three to four days after discontinuing diazepam. Several years later, another report described six patients on diazepam who developed a cluster of symptoms that included tremulousness, apprehension, insomnia, depression, and ego-alien suicidal ideation (6). All six were considered previously emotionally stable, and all symptoms cleared within seven days after the patients discontinued the diazepam. It should be noted that all the patients were receiving a minimum of 40 mg ofdiazepam daily and that all had significant medical conditions. These accounts were supported by other early reports of an association between diazepam use and the development of depression (7-9). Two of these reports were of clinical trials
Dr. Smith is a resident in psychiatry and Dr. Salzman, the editor of this column, is director of psychopharmacology at Massachusetts Mental Health Center, 74 Fenwood Road, Boston, Massachusetts 02115.
using diazepam (7,8). In one trial, one of eight patients receiving diazepam for treatment of obsessivecompulsive neurosis developed depression (7). In the other trial, a double-blind study of diazepam and placebo for treatment of anxiety in a heterogeneous group of psychiatric patients, seven of 50 patients (14 percent) developed suicidal impulses, and four patients (8 percent) showed an increase in depressive symptoms (8). In the latter trial, two subjects receiving placebo also developed suicidal impulses. All seven of the diazepam-treated subjects who developed suicidal impulses were diagnosed as previously having psychotic illnesses. More recent clinical trials of ben-
Hospital
November
Reports in the literature One of the earliest and most frequently cited reports of an association between benzodiazepine use and depression, published in 1968, presented seven cases of worsening de-
and Community
Psychiatry
1991
Vol.42
No.
11
zodiazepines for the treatment of various anxiety disorders have reported depression as a potential adverse effect (10-14). Unfortunately, the term “depression” is often ill defined in these studies, making it difficult to assess the clinical significance ofthe side effect. However, the development of major depressive episodes (meeting DSM-III criteria) by patients receiving benzodiazepines for panic disorder has been discussed in two separate clinical studies (10,1 1). Lorazepam was reported to have caused major depressive episodes in eight of 30 subjects (26.7 percent), with another three developing mild depression (10). In a similar trial using alprazolam, 1 5 of46 subjects (33 percent) developed symptoms consistent with a major depressive episode (1 1 No patients in these two trials developed suicidal ideation, and the symptoms often diminished with decreased doses of the benzodiazepine. However, some patients did require treatment with tricyclic antidepressants. Depressive symptoms have been discovered in clinical trials comparing bromazepam with lorazepam (12) and with diazepam (13) in the treatment of generalized anxiety. In the bromazepam-diazepam trial, the depression remitted when the drug was withdrawn or the dosage was decreased by one-third. In this trial, depression tended to occur in patients with lower mean scores on the Hamilton Anxiety Rating Scale, a finding consistent with another study in which subjects with low trait anxiety reported increased depression after the administration of 10 mg ofdiazepam (1 5). However, in the latter study the depressive symptoms emerged almost immediately after the administration of diazepam, whereas in the other studies depressive symptoms emerged two to four weeks into the trial. An uncontrolled, retrospective analysis of patients suffering from panic disorder and agoraphobia added clonazepam to the list of benzodiazepines associated with the emergence of depression (14). Three of 31 subjects (10 percent) treated with clonazepam developed depression. Finally, a recent review of alpra).
1101
zolam found that when aiprazopam was compared with placebo, depression was an uncommon and insignificant adverse effect (16). The incidence of depression with aiprazolam was 11.9 percent (204 in 1,717 cases); subjects receiving placebo reported a 19.1 percent incidence (229 in 1 1 99 cases). This review also found a 1 7 percent incidence of depression with diazepam (107 in 629 cases), and a 7.3 percent incidence with imipramine (107 in 629 cases).
1 . Ge!enberg SC: The
2.
,
.
Discussion There are no data to support the view that depression is a regular or even a frequent concomitant of therapeutic benzodiazepine use. However, given the number of reports in the literature noting an association between benzodiazepine use and the emergence of depressive symptoms, it seems prudent to assume that benzodiazepine treatment occasionally leads to significant depression and even suicide. The mechanism by which the benzodiazepines may cause depressive symptoms is unclear, and there is no evidence that any particular class of benzodiazepine or individual benzodiazepine taken at therapeutic doses is more likely to cause depression. Some evidence indicates that higher doses are associated with increased risk and that lowering the dose may resolve the depression. Besides lowering the dose, discontinuing the drug, switching to a different benzodiazepine, or treating with an antidepressant agent will likely resuit in resolution of the symptoms. Some evidence supports the advisability of being more vigilant when treating patients with low trait anxiety, as they may be more susceptible to depression. Because benzodiazepines are so widely used, further careful epidemiologic data about the drugs’ association with depression are needed. Until such data are available, clinicians should keep in mind the possibility that their benzodiazepinetreated patients may occasionally develop depressive symptoms and that in most cases these symptoms are quite responsive to treatment.
1102
Social
References
3-
4.
5-
6.
7.
8.
9.
10.
11.
12.
13.
AJ, Bassuk Practitioner’s
15.
16.
Schoonover to Psycho-
active Drugs, 3rd ed. New York, Pienum, 1991 Schatzberg AF, Cole JO: Manual of Clinical Psychopharmacology. Washington, DC, American Psychiatric Press, l986,pp 151-152 Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990 Gilman AG, Goodman LS, Rail TW, et xi: Goodman and Gilman’s Pharmacological Basis of Therapeutics, 7th ed. New York, Macmillan, 1985, pp 349350 Ryan HW, Merrill FB, Scott GE, et ai: Increase in suicidal thoughts and tendencies.JAMA 203:135-137, 1968 Hall RCW, Joffe JR: Aberrant response to diazepam: a new syndrome. American Journal ofPsychiatry 129:738-742, 1972 Rao AV: A controlled trial with “Va!ium’ in obsessive compulsive state.Journal ofthe Indian Medical Association 42: 564-567, 1967 Gundlach R, Engelhardt DM, Hankoff L, et a!: A double-blind outpatient study ofdiazepam (Valium) and placebo. Psychopharmacologia 9:81-92, 1966 McDowall A, Owen 5, Robin AA: A controlled comparison of diazepam and amylobarbitone in anxiety states. British Journal of Psychiatry 112:629-631, 1966 Lydiard RB, Hosell EF, Laraia MT, et a!: Depression in patients receiving ionizepam for panic. American Journal of Psychiatry 146:629-631, 1989 Lydiard RB, Laraia MT. BailengerJC, et a!: Emergence ofdepressive symptoms in patients receiving aiprazolam for panic disorder. Americanjournal of Psychiatry 144:664-665, 1987 Fontaine R, Mercier P, Beaudry P, et a!: Bromazepam and lorazepam in generalized anxiety: a placebo-controlled study with measurement of drug plasma concentrations. Acta Psychiatrica Scandinavica 74:451-458, 1986 Fontaine R, Annable L, Chouinard G, et a!: Bmmazepam and diazepam in generalized anxiety: a placebo-controlled study with measurement ofdrug plasma concentrations. Journal of Clinical Psychopharmacology
14.
EL, Guide
3:80-87,
November
1991
Vol.42
(Continuedfrom
4.
5.
No. 11
Update
page
1096)
Md, National Association of Social Workers, June 1988, p97 National Health Care Proposal. Silver Spring, Md, National Association of Social Workers, Legislative Affisirs Office, May 1991 Sen Daniel Inouye on NASW national health care proposal, May 22, 1990. Congressional Record (daily ed) 136(66): S6709-6711,
6.
1990
Cost Analysis of the NASW National Health Care Proposal. Columbia, Md, Center for Health Policy Studies, Oct 26, 1990
DSM-IV
in Progress from page 1100)
(Continued
ant disorder The September the DSM-JV information alternatives available to searchers in may comment.
and
conduct disorder. 1991 publication of Options Book (4) makes on the current DSM-IV for these two disorders practitioners and rethe community so they
Acknowledgments The
author
is indebted
the
subgroup
on
disorders,
which
Garfinkel,
to members
disruptive
includes
Russell
of
behavior
Drs.
Barkley,
Barry Joseph
Biederman, Magda Campbell, Laurence Greenhill, Lily Hechtman, Benjamin Lahey, Jeffrey Newcorn, Herbert Quay, Bennett Shaywitz, and David Shaffer, for
their
comments
on
the
options
and
to Dr. Benjamin Lahey, Dr. Christopher Thomas, and Joyce Thompson for their comments
on
an earlier
draft.
References 1.
1983
Pollack MH, Tesar GE, Rosenbaum JF, et a!: Clonazepam in the treatment of panic disorder and agoraphobia: a oneyear follow-up. Journal of Clinical Psychopharmacology 47:475-476, 1986 Wilkinson CJ: Effects of diazepam (Valium) and trait anxiety on human physical aggression and emotional state. Journal of Behavioral Medicine 8:10 1114,1985 Fawcett JA, Kravitz HM: Alprazoiam: pharmacokinetics, clinical efficacy, and mechanism of action. Pharmacotherapy 2:243-254, 1982
Work
2.
3.
4.
Loeber R, Lahey BB, Thomas C: The diagnostic conundrum of oppositional defiant disorder and conduct disorder. Journal of Abnormal Psychology, in press Kazdin AE: Treatment of antisocial behavior in children: current status and fucure directions. Psychological Bulletin 102:187-203, 1987 Loeber R: Antisocial behavior: more enduring than changeable? Journal of the American Academy of Child and Adolescent Psychiatry, in press Task Force on DSM-W: The DSM-IV Options Book: Work in Progress. Washington, DC, American Psychiatric Press, 1991
Hospital
and
Community
Psychiatry
Do Benzodiazepines Cause Depression? Blake
D.
Smith,
Carl Salzman,
M.D.
M.D.
It is not uncommon in everyday clinical practice to hear the suggestion of a causal link between the use of benzodiazepines and the emergence ofdepressive symptoms. However, the standard reference manuals are far from clear on this issue. One recent pharmacologic text states that “occasional patients become depressed during chronic benzodiazepine therapy, but whether there is a causal association remains in doubt” (1). Another does not mention depression in the list of potential side effects of benzodiazepines (2). However, the report ofthe American Psychiatric Association’s task force on benzodiazepine toxicity states that although depression is not a frequent side effect, “Benzodiazepines have been reported to cause or exacerbate symptoms ofdepression” (3). In a standard pharmacologic textbook, depression is noted to be an occasional side effect of benzodiazepine use (4). The purpose of this column is to review the relationship between benzodiazepines and depression.
pression and the development of suicidal ideation after institution of diazepam therapy forpatients diagnosed as having depressive disorders (5). There were two cases ofactual suicide and two serious attempts. The survivors improved within three to four days after discontinuing diazepam. Several years later, another report described six patients on diazepam who developed a cluster of symptoms that included tremulousness, apprehension, insomnia, depression, and ego-alien suicidal ideation (6). All six were considered previously emotionally stable, and all symptoms cleared within seven days after the patients discontinued the diazepam. It should be noted that all the patients were receiving a minimum of 40 mg ofdiazepam daily and that all had significant medical conditions. These accounts were supported by other early reports of an association between diazepam use and the development of depression (7-9). Two of these reports were of clinical trials
Dr. Smith is a resident in psychiatry and Dr. Salzman, the editor of this column, is director of psychopharmacology at Massachusetts Mental Health Center, 74 Fenwood Road, Boston, Massachusetts 02115.
using diazepam (7,8). In one trial, one of eight patients receiving diazepam for treatment of obsessivecompulsive neurosis developed depression (7). In the other trial, a double-blind study of diazepam and placebo for treatment of anxiety in a heterogeneous group of psychiatric patients, seven of 50 patients (14 percent) developed suicidal impulses, and four patients (8 percent) showed an increase in depressive symptoms (8). In the latter trial, two subjects receiving placebo also developed suicidal impulses. All seven of the diazepam-treated subjects who developed suicidal impulses were diagnosed as previously having psychotic illnesses. More recent clinical trials of ben-
Hospital
November
Reports in the literature One of the earliest and most frequently cited reports of an association between benzodiazepine use and depression, published in 1968, presented seven cases of worsening de-
and Community
Psychiatry
1991
Vol.42
No.
11
zodiazepines for the treatment of various anxiety disorders have reported depression as a potential adverse effect (10-14). Unfortunately, the term “depression” is often ill defined in these studies, making it difficult to assess the clinical significance ofthe side effect. However, the development of major depressive episodes (meeting DSM-III criteria) by patients receiving benzodiazepines for panic disorder has been discussed in two separate clinical studies (10,1 1). Lorazepam was reported to have caused major depressive episodes in eight of 30 subjects (26.7 percent), with another three developing mild depression (10). In a similar trial using alprazolam, 1 5 of46 subjects (33 percent) developed symptoms consistent with a major depressive episode (1 1 No patients in these two trials developed suicidal ideation, and the symptoms often diminished with decreased doses of the benzodiazepine. However, some patients did require treatment with tricyclic antidepressants. Depressive symptoms have been discovered in clinical trials comparing bromazepam with lorazepam (12) and with diazepam (13) in the treatment of generalized anxiety. In the bromazepam-diazepam trial, the depression remitted when the drug was withdrawn or the dosage was decreased by one-third. In this trial, depression tended to occur in patients with lower mean scores on the Hamilton Anxiety Rating Scale, a finding consistent with another study in which subjects with low trait anxiety reported increased depression after the administration of 10 mg ofdiazepam (1 5). However, in the latter study the depressive symptoms emerged almost immediately after the administration of diazepam, whereas in the other studies depressive symptoms emerged two to four weeks into the trial. An uncontrolled, retrospective analysis of patients suffering from panic disorder and agoraphobia added clonazepam to the list of benzodiazepines associated with the emergence of depression (14). Three of 31 subjects (10 percent) treated with clonazepam developed depression. Finally, a recent review of alpra).
1101
zolam found that when aiprazopam was compared with placebo, depression was an uncommon and insignificant adverse effect (16). The incidence of depression with aiprazolam was 11.9 percent (204 in 1,717 cases); subjects receiving placebo reported a 19.1 percent incidence (229 in 1 1 99 cases). This review also found a 1 7 percent incidence of depression with diazepam (107 in 629 cases), and a 7.3 percent incidence with imipramine (107 in 629 cases).
1 . Ge!enberg SC: The
2.
,
.
Discussion There are no data to support the view that depression is a regular or even a frequent concomitant of therapeutic benzodiazepine use. However, given the number of reports in the literature noting an association between benzodiazepine use and the emergence of depressive symptoms, it seems prudent to assume that benzodiazepine treatment occasionally leads to significant depression and even suicide. The mechanism by which the benzodiazepines may cause depressive symptoms is unclear, and there is no evidence that any particular class of benzodiazepine or individual benzodiazepine taken at therapeutic doses is more likely to cause depression. Some evidence indicates that higher doses are associated with increased risk and that lowering the dose may resolve the depression. Besides lowering the dose, discontinuing the drug, switching to a different benzodiazepine, or treating with an antidepressant agent will likely resuit in resolution of the symptoms. Some evidence supports the advisability of being more vigilant when treating patients with low trait anxiety, as they may be more susceptible to depression. Because benzodiazepines are so widely used, further careful epidemiologic data about the drugs’ association with depression are needed. Until such data are available, clinicians should keep in mind the possibility that their benzodiazepinetreated patients may occasionally develop depressive symptoms and that in most cases these symptoms are quite responsive to treatment.
1102
Social
References
3-
4.
5-
6.
7.
8.
9.
10.
11.
12.
13.
AJ, Bassuk Practitioner’s
15.
16.
Schoonover to Psycho-
active Drugs, 3rd ed. New York, Pienum, 1991 Schatzberg AF, Cole JO: Manual of Clinical Psychopharmacology. Washington, DC, American Psychiatric Press, l986,pp 151-152 Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990 Gilman AG, Goodman LS, Rail TW, et xi: Goodman and Gilman’s Pharmacological Basis of Therapeutics, 7th ed. New York, Macmillan, 1985, pp 349350 Ryan HW, Merrill FB, Scott GE, et ai: Increase in suicidal thoughts and tendencies.JAMA 203:135-137, 1968 Hall RCW, Joffe JR: Aberrant response to diazepam: a new syndrome. American Journal ofPsychiatry 129:738-742, 1972 Rao AV: A controlled trial with “Va!ium’ in obsessive compulsive state.Journal ofthe Indian Medical Association 42: 564-567, 1967 Gundlach R, Engelhardt DM, Hankoff L, et a!: A double-blind outpatient study ofdiazepam (Valium) and placebo. Psychopharmacologia 9:81-92, 1966 McDowall A, Owen 5, Robin AA: A controlled comparison of diazepam and amylobarbitone in anxiety states. British Journal of Psychiatry 112:629-631, 1966 Lydiard RB, Hosell EF, Laraia MT, et a!: Depression in patients receiving ionizepam for panic. American Journal of Psychiatry 146:629-631, 1989 Lydiard RB, Laraia MT. BailengerJC, et a!: Emergence ofdepressive symptoms in patients receiving aiprazolam for panic disorder. Americanjournal of Psychiatry 144:664-665, 1987 Fontaine R, Mercier P, Beaudry P, et a!: Bromazepam and lorazepam in generalized anxiety: a placebo-controlled study with measurement of drug plasma concentrations. Acta Psychiatrica Scandinavica 74:451-458, 1986 Fontaine R, Annable L, Chouinard G, et a!: Bmmazepam and diazepam in generalized anxiety: a placebo-controlled study with measurement ofdrug plasma concentrations. Journal of Clinical Psychopharmacology
14.
EL, Guide
3:80-87,
November
1991
Vol.42
(Continuedfrom
4.
5.
No. 11
Update
page
1096)
Md, National Association of Social Workers, June 1988, p97 National Health Care Proposal. Silver Spring, Md, National Association of Social Workers, Legislative Affisirs Office, May 1991 Sen Daniel Inouye on NASW national health care proposal, May 22, 1990. Congressional Record (daily ed) 136(66): S6709-6711,
6.
1990
Cost Analysis of the NASW National Health Care Proposal. Columbia, Md, Center for Health Policy Studies, Oct 26, 1990
DSM-IV
in Progress from page 1100)
(Continued
ant disorder The September the DSM-JV information alternatives available to searchers in may comment.
and
conduct disorder. 1991 publication of Options Book (4) makes on the current DSM-IV for these two disorders practitioners and rethe community so they
Acknowledgments The
author
is indebted
the
subgroup
on
disorders,
which
Garfinkel,
to members
disruptive
includes
Russell
of
behavior
Drs.
Barkley,
Barry Joseph
Biederman, Magda Campbell, Laurence Greenhill, Lily Hechtman, Benjamin Lahey, Jeffrey Newcorn, Herbert Quay, Bennett Shaywitz, and David Shaffer, for
their
comments
on
the
options
and
to Dr. Benjamin Lahey, Dr. Christopher Thomas, and Joyce Thompson for their comments
on
an earlier
draft.
References 1.
1983
Pollack MH, Tesar GE, Rosenbaum JF, et a!: Clonazepam in the treatment of panic disorder and agoraphobia: a oneyear follow-up. Journal of Clinical Psychopharmacology 47:475-476, 1986 Wilkinson CJ: Effects of diazepam (Valium) and trait anxiety on human physical aggression and emotional state. Journal of Behavioral Medicine 8:10 1114,1985 Fawcett JA, Kravitz HM: Alprazoiam: pharmacokinetics, clinical efficacy, and mechanism of action. Pharmacotherapy 2:243-254, 1982
Work
2.
3.
4.
Loeber R, Lahey BB, Thomas C: The diagnostic conundrum of oppositional defiant disorder and conduct disorder. Journal of Abnormal Psychology, in press Kazdin AE: Treatment of antisocial behavior in children: current status and fucure directions. Psychological Bulletin 102:187-203, 1987 Loeber R: Antisocial behavior: more enduring than changeable? Journal of the American Academy of Child and Adolescent Psychiatry, in press Task Force on DSM-W: The DSM-IV Options Book: Work in Progress. Washington, DC, American Psychiatric Press, 1991
Hospital
and
Community
Psychiatry
