International Journal of Psychiatry in Clinical Practice, 2008; 12(1): 8588

COMMENTARY

Still no evidence that benzodiazepines cause depression

SCOTT B. PATTEN

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Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

Abstract A large number of drugs have been implicated in causing depression by case reports and case series. For a few specific drugs, the association has subsequently been confirmed by appropriately designed studies. In other instances, a lack of substantiating evidence has lead to a gradual disappearance of concern about a potential association. The benzodiazepines represent a deviation from this pattern: they are widely believed to cause depression, but there is a lack of evidence to substantiate this claim. In DSM-IV, there is a category of mood disorder for drug-induced depression (substance-induced mood disorder), and the text of the manual specifically refers to benzodiazepines as a potential cause. Despite the apparently entrenched nature of this belief, there continues to be a lack of credible evidence that benzodiazepines can cause depression as a side effect.

Key Words: Depressive disorder, chemically induced, benzodiazepines, substance induced mood disorder

Standards of evidence in pharmacoepidemiology have become increasingly rigorous in recent decades. However, there are situations where apparently unsubstantiated beliefs continue to be held with surprising tenacity. An example is the belief that benzodiazepines can cause depression. Smith and Salzman [1] published a commentary on this topic in the journal Hospital and Community Psychiatry 15 years ago. Their commentary highlighted an inconsistency between the widely held clinical belief that benzodiazepines cause depression and the absence of clear evidence that they do. It appears that little has changed since then. Benzodiazepines apparently continue to be widely believed to cause depression. Expressions of opinion in the literature [2] and less formal reference sources1 provide evidence of continuation of this belief. The current edition of the Diagnostic and Statistical Manual of Mental Disorders [3] includes a diagnostic category for drug-induced depression called substance-induced mood disorder. The category is reserved for circumstances in which a prominent and persistent mood disturbance is judged (based on ‘‘evidence from the history, physical examination or laboratory findings’’) to be due

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For example: http://www.psychnet-uk.com/dsm_iv/major_depression. htm, and the popular American site ‘‘WebMD’’ http://www.webmd. com/content/article/45/1663_51214.htm

to a drug exposure or withdrawal. Among the potentially depressogenic drugs listed in the text of the manual are the benzodiazepines. Although case reports associating benzodiazepines and depression can be found in the early literature, e.g. Ref. [4], the most influential case series was reported by Hall in the American Journal of Psychiatry in 1972 [5]. Hall et al. subsequently authored a 1981 paper called ‘‘Paradoxical reactions to benzodiazepines’’ which included a section on depression [6]. This section encouraged caution in the interpretation of their (and others’) earlier case reports: ‘‘In the majority of cases, it is extremely difficult to determine whether the depression represents a worsening of an already existing depressive process or whether it is a de novo condition associated with the use of benzodiazepines’’. Nathan reported three cases of major depression among respondents to a newspaper advertisement for a benzodiazepine withdrawal program [7]. Lydiard et al. described the emergence of major depression in 15 patients being treated with alprazolam for panic disorder in their clinic [8], and subsequently reported similar occurrences in relation to lorazepam treatment [9]. Caseseries such as these do not contain sufficient methodological rigour to substantiate an association. Perhaps the most daunting methodological barriers towards confirming an association between benzodiazepines and depression are the issues of

Correspondence: Professor Scott B. Patten, Department of Community Health Sciences, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Tel.: 1 403 220 8752. Fax: 1 403 270 7307. E-mail: [email protected]

(Received 13 December 2006; accepted 5 April 2007) ISSN 1365-1501 print/ISSN 1471-1788 online # 2008 Taylor & Francis DOI: 10.1080/13651500701419644

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confounding by indication, confounding by severity and protopathic bias. Distinctions between these categories of bias have been described by Salas et al. [10]. Confounding by indication refers to a situation in which the reason for use of a drug (its indication) is associated with an outcome in a way that can create a false impression that the drug has caused the outcome. Confounding by indication implies that the indication is an independent risk factor for the outcome, not just a link on a causal chain, and therefore that the indication is a risk factor for outcome even in the absence of (in this case, benzodiazepine) exposure. For example, in studies of the association between infertility and antidepressant drugs, Salas et al. argued that depression should be considered a confounder since it may be an independent risk factor for infertility and is likely to be associated with antidepressant exposure [10]. If not only the indication for use of a drug but also its severity are associated with an outcome, then confounding by severity can occur because more severe conditions are more likely to be treated. An example provided by Salas et al. involves research into whether treatment of rheumatoid arthritis with gold salts is associated with increased mortality. In addition to confounding by indication (rheumatoid arthritis), confounding by severity is possible because gold salts are likely to be used in the most severe stages of rheumatoid arthritis [10]. Protopathic bias refers to a situation whereby early manifestations of a disease lead to changes in exposure to a potential risk factor. For example, a drug given for abdominal pain may be erroneously associated with hepatic injury because abdominal pain may be a prodromal symptom of hepatic disease [10]. Anxiety disorders are an indication for benzodiazepine treatment and accompany depressive disorders approximately 60% of the time [11]. Since anxiety disorders are associated with mood disorders even in the absence of benzodiazepine exposure (i.e. are independently associated), confounding by indication can occur. Sleep disturbances, another set of indications for benzodiazepine treatment, are a symptomatic and potentially prodromal manifestation of depressive disorders [3]. If sleep disturbances are prodromal, protopathic bias could result. Primary insomnia may be an independent risk factor for depression, see a review of epidemiological studies by Riemann and Voderholzer [12], so confounding by indication is also a possibility. To the extent that the severity of sleep disturbance may be associated with the probability of benzodiazepine use and with the risk of depression, confounding by severity could also occur. Stressful life events and ‘‘sub-clinical’’ depressive symptoms may lead to the use of benzodiazepines for short-term relief of distress, but are themselves risk factors for subsequent depressive disorders [13]. As such, confounding by indication

by this mechanism is a possibility. Also, since severe and threatening life events tend to be those most strongly associated with depressive disorders, confounding by severity may occur. Because of confounding by indication, confounding by severity and protopathic biases, associations between benzodiazepine exposure and depression are expected in observational studies. This has indeed been the case [14,15]. In view of the various methodological considerations described above, it is clear that certain types of evidence cannot answer to the question of whether benzodiazepines can cause depression. The evidence must come from studies employing specific methodological features. First, random allocation of exposure to benzodiazepines should be employed to deal with confounding and protopathic biases. Second, valid measurement strategies for depression should be employed. A systematic literature review using these standards of evidence found evidence that several drugs, but not benzodiazepines, are associated with depression [16]. Why does the belief that benzodiazepines can cause depression persist? One possible explanation is a linguistic one. Benzodiazepines are CNS depressants. The word depression means ‘‘lowering’’ (as can be more fully appreciated from the use of the word in disparate disciplines such as economics and geography). However, a lowering of mood, as occurs in mood disorders, is a different concept from the lowering of alertness and/or suppression of respiration implied by a term found frequently in the benzodiazepine literature: CNS depression. Additional potential explanations may be found in the historical literature about drug-induced depression. The first drug to be implicated in causing depression, reserpine (a treatment for high blood pressure) was implicated on the basis of case reports and observations made during early clinical trials [17 19]. However, it has subsequently been suspected that reserpine simply causes fatigue at high dosages which, in the absence of formal measurement, was mistaken for depression [2023]. It is possible that the term depression was used correctly as a descriptor of lowered activity or energy levels, but in a way that was subsequently not distinguished from emotional depression or the concept of a depressive disorder as currently defined. Another family of drugs that have been implicated in causing depression by case reports [2431] are the b-adrenergic blockers. However, the apparent association may have been due to a similar form of measurement or misclassification bias, as several studies using formal assessment strategies for depression failed to confirm that an association exists [3237]. It should be noted that depression may be a feature of benzodiazepine withdrawal. Ashton followed a series of 50 patients being withdrawn from long-term treatment and reported that depression

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Benzodiazepines and depression was ‘‘common’’ during a protracted period after withdrawal [38]. During studies leading to the development of the Benzodiazepine Withdrawal Symptom Questionnaire, Tyrer et al. [39] noted that depression was among the most common withdrawal symptoms. However, it was also a nonspecific symptom in the sense that it did not reliably peak during the withdrawal period. Some authors have concluded that benzodiazepines may have antidepressant activity. According to a meta analysis by Petty et al., the evidence is restricted largely to a single triazolobenzodiazepine (alprazolam) and only for mild depression [40]. The absence of evidence that benzodiazepines cause depression cannot logically be interpreted as evidence that an effect does not exist. The principle of refutability in medical research means that it may be impossible ever to ‘‘prove’’ that benzodiazepines never cause depression. This does not mean, however, that unsubstantiated beliefs should remain unchanged forever. After many decades of entrenchment, the idea that benzodiazepines cause depression seems increasingly unsustainable in the absence of any evidence in support of it. This belief should probably be assigned to the category of ‘‘medical myth’’ until evidence to the contrary surfaces.

[3] American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000. [4] Ryan HF, Merril B, Scott GE, Krebs R, Thompson BL. Increase in suicidal thoughts and tendencies. Association with diazepam therapy. J Am Med Assoc 1968;203:1357. [5] Hall RCW, Joffe JR. Aberrant response to diazepam: a new syndrome. Am J Psychiatry 1972;129:1148. [6] Hall RCW, Zisook S. Paradoxical reactions to benzodiazepines. Br J Clin Pharm 1981;11:99104S. [7] Nathan RG, Robinson D, Cherek DR, Davison S, Sebastian S, Hack M. Long-term benzodiazepine use and depression. Am J Psychiatry 1985;142:1445. [8] Lydiard RB, Laraia MT, Ballenger JC, Howell EF. Emergence of depressive symptoms in patients receiving alprazolam for panic disorder. Am J Psychiatry 1987;144:6645. [9] Lydiard RB, Howell EF, Laraia MT, Fossey M, Ballenger JC. Depression in patients receiving lorazepam for panic. Am J Psychiatry 1989;146:12301. [10] Salas M, Hofman A, Stricker BH. Confounding by indication: An example of variation in the use of epidemiological terminology. Am J Epidemiol 1999;149:9813. [11] Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). J Am Med Assoc 2003;289:3095105. [12] Riemann D, Voderholzer U. Primary insomnia: a risk factor to develop depression? J Affect Disord 2003;76:2559. [13] Lewinsohn PM, Hoberman HM, Rosenbaum M. Prospective study of risk factors for unipolar depression. J Abnorm Psychol 1988;97:25164. [14] Craig TJ, van Natta PA. Current medication use and symptoms of depression in a general population. Am J Psychiatry 1978;135:10369. [15] Patten SB, Lavorato DH. Medication use and major depressive syndrome in a community population. Comp Psychiatry 2001;42:12431. [16] Patten SB, Barbui C. Drug-induced depression: a systematic review to inform clinical practice. Psychother Psychosom 2004;73:20715. [17] Fries ED. Mental depressions in hypertensive patients treated for long periods with large doses of reserpine. New Engl J Med 1954;251:10068. [18] Muller JC, Pryor WW, Gibbons JE, Orgain ES. Depression and anxiety occurring during rauwolfia therapy. J Am Med Assoc 1955;159:8369. [19] Lemieux G, Davignon A, Genest J. Depressive states during rauwolfia therapy for arterial hypertension. Can Med Assoc J 1956;74:5226. [20] Fraser HS. Reserpine: A tragic victim of myths, marketing, and fashionable prescribing. Clin Pharm Ther 1996;60:368 73. [21] Healy D, Savage M. Reserpine exhumed. Br J Psychiatry 1998;172:3768. [22] Lavorato DH, Patten SB. Antihypertensive medications and depression, an historical perspective. Pharmacoepidemiol Drug Safety 1999;8:3559. [23] Widmer RB. Reserpine: the maligned antihypertensive drug. J Fam Pract 1985;20:813. [24] Nolan BT. Acute suicidal depression associated with use of timolol. J Am Med Assoc 1982;247:1567. [25] Kalayam B, Shamoian CA. Propranolol, psychoneuroendocrine changes, and depression. Am J Psychiatry 1982; 139(10):13745. [26] McNeil GN, Shaw PK, Dock DS. Substitution of atenolol for propranolol in a case of propranolol-related depression. Am J Psychiatry 1982;139:11878. [27] Russell JW, Schuckit MA. Anxiety and depression in patient on nadolol. Lancet 1982;ii:19823. [28] Oppenheim G. Propranolol-induced depression: mechanism and management. Aust NZ J Psychiatry 1983;17:4002. /

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. Benzodiazepines continue to be regarded as causes of depression, but evidence substantiating this belief has failed to appear in the literature . The entrenchment of the belief that benzodiazepines can cause depression, especially in North America, may be due to statements to this effect in DSM-IV Acknowledgements

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Statement of interest

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The author has no commercial or other associations that might pose a conflict of interest in association with this article.

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Dr Patten is a Health Scholar with the Alberta Heritage Foundation for Medical Research, and a Research Fellow with the Institute of Health Economics.

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Key points

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References

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[1] Smith BD, Salzman C. Do benzodiazepines cause depression? Hosp Comm Psychiatry 1991;42:11012. [2] Anonymous. Drugs that may cause psychiatric symptoms. Medical Lett 2002;44. /

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[29] Cremona-Barbaro A. Propranolol and depression. Lancet 1983;i:185. [30] Pollack MH, Rosenbaum JF, Cassem NH. Propranolol and depression revisited: three cases and a review. J Nerv Ment Dis 1985;173:1189. [31] Orlando RG. Clinical depression associated with betaxolol. Am J Ophthalmol 1986;102:275. [32] Schleifer SJ, Slater WR, Macari-Hinson MM, et al. Digitalis and B-blocking agents: effects on depression following myocardial infarction. Am Heart J 1991;121(5):1397402. [33] Ried LD, Johnson RE, McFarland BH, Brody KK. Antihypertensive drug use and the risk of depression among older hypertensives in an HMO. J Pharmacoepidemiol 2000;8: 128. [34] Prisant LM, Spruill WJ, Fincham JE, Wade WE, Carr AA, Adams MA. Depression associated with antihypertensive drugs. J Fam Pract 1991;33:4815. /

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[35] Stoudemire A, Brown JT, Harris RT, et al. Propranolol and depression: a reevaluation based on a pilot clinical trial. Psychiatric Medicine 1984;2(2):2118. [36] Bartels D, Glasser M, Wang A, Swanson P. Association between depression and propranolol use in ambulatory patients. Clin Pharm 1988;7:14650. [37] Carney RM, Rich MW, teVelde A, Saini J, Clark K, Freedland KE. Prevalence of major depressive disorder in patients receiving beta-blocker therapy versus other medications. Am J Med 1987;83:2236. [38] Ashton H. Benzodiazepine withdrawal: outcome in 50 patients. Br J Addict 1987;82:66571. [39] Tyrer P, Murphy S, Riley P. The Benzodiazepine Withdrawal Symptom Questionniare. J Affect Disord 1990;19:5361. [40] Petty F, Trividi MH, Fulton M, Rush AJ. Benzodiazepines as antidepressants: does GABA play a role in depression? Biol Psychiatry 1995;38:57891. /

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Still no evidence that benzodiazepines cause depression.

A large number of drugs have been implicated in causing depression by case reports and case series. For a few specific drugs, the association has subs...
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