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Benzodiazepines for anxiety disorders: maximising the benefits and minimising the risks

  • Vladan Starcevic

Summary

Benzodiazepines still play an important role in the management of anxiety disorders but dependence is associated with their therapeutic use. The key to effective and safe long-term use of benzodiazepines is: the careful selection of patients who might benefit from them; administration in clinical situations in which they are more likely to be beneficial; use of lower doses and in conjunction with an antidepressant, if possible; monitoring and managing their side-effects; and minimising the risk of withdrawal symptoms and relapse, mainly through tapering the dose and/or combining with effective psychological interventions.

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Copyright

Corresponding author

Dr Vladan Starcevic, Nepean Hospital, Department of Psychiatry, PO Box 53, Penrith NSW 2751, Australia. Email: vladan.starcevic@sydney.edu.au

Footnotes

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Declaration of Interest

V.S. has received honoraria for talks at meetings sponsored by Lundbeck, the Lundbeck Institute and AstraZeneca, and travel assistance from AstraZeneca, Boehringer Ingelheim and the Lundbeck Institute.

For a commentary on this article see pp. 259–262, this issue.

Footnotes

References

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Andersch, S, Hetta, J (2003) A 15-year follow-up study of patients with panic disorder. European Psychiatry 18: 401–8.
Balter, MB, Levine, J, Manheimer, D (1974) Cross-national study of the extent of anti-anxiety/sedative drug use. New England Journal of Medicine 290: 769–74.
Barbone, F, McMahon, AD, Davey, PG et al (1998) Association of road-traffic accidents with benzodiazepine use. Lancet 352: 1331–6.
Barker, MJ, Greenwood, KM, Jackson, M et al (2004) Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs 18: 3748.
Biondi, M, Picardi, A (2003) Increased probability of remaining in remission from panic disorder with agoraphobia after drug treatment in patients who received concurrent cognitive-behavioural therapy: a follow-up study. Psychotherapy and Psychosomatics 72: 3442.
Bruce, SE, Vasile, RG, Goisman, RM et al (2003) Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? American Journal of Psychiatry 160: 1432–8.
Busto, UE, Bremner, KE, Knight, K et al (2000) Long-term benzodiazepine therapy does not result in brain abnormalities. Journal of Clinical Psychopharmacology 20: 26.
Cowley, DS, Ha, EH, Roy-Byrne, PP (1997) Determinants of pharmacologic treatment failure in panic disorder. Journal of Clinical Psychiatry 58: 555–61.
Cross-National Collaborative Panic Study, Second Phase Investigators (1992) Drug treatment of panic disorder. Comparative efficacy of alprazolam, imipramine, and placebo. British Journal of Psychiatry 160: 191202.
Davidson, JRT, Petts, N, Richichi, E et al (1993) Treatment of social phobia with clonazepam and placebo. Journal of Clinical Psychopharmacology 13: 423–8.
Deckersbach, T, Moshier, SJ, Tuschen-Caffier, B et al (2011) Memory dysfunction in panic disorder: an investigation of the role of chronic benzodiazepine use. Depression and Anxiety 28: 9991007.
Demyttenaere, K, Bonnewyn, A, Bruffaerts, R et al (2008) Clinical factors influencing the prescription of antidepressants and benzodiazepines: results from the European study of the epidemiology of mental disorders (ESEMeD). Journal of Affective Disorders 110: 8493.
Freeman, SA (2009) The benzodiazepine stigma persists. Journal of Clinical Psychiatry 70: 1727–8.
Gelernter, CS, Uhde, TW, Cimbolic, P et al (1991) Cognitive-behavioral and pharmacological treatments of social phobia: a controlled study. Archives of General Psychiatry 48: 938–45.
Goddard, AW, Brouette, T, Almai, A et al (2001) Early coadministration of clonazepam with sertraline for panic disorder. Archives of General Psychiatry 58: 681–6.
Haefely, W (1986) Biological basis of drug-induced tolerance, rebound, and dependence: contribution of recent research on benzodiazepines. Pharmacopsychiatry 19: 353–61.
Healy, D (2002) Psychiatric Drugs Explained. Third Edition 142. Churchill Livingstone.
Lucki, I, Rickels, K, Geller, AM (1986) Chronic use of benzodiazepines and psychomotor and cognitive test performance. Psychopharmacology (Berlin) 88: 426–33.
Mol, AJJ, Gorgels, WJMJ, Voshaar, RCO et al (2005) Associations of benzodiazepine craving with other clinical variables in a population of general practice patients. Comprehensive Psychiatry 46: 353–60.
Nagy, LM, Krystal, JH, Woods, SW et al (1989) Clinical and medication outcome after short-term alprazolam and behavioral group treatment in panic disorder: 2.5 year naturalistic follow-up study. Archives of General Psychiatry 46: 993–9.
Noyes, R, Garvey, MJ, Cook, B (1991) Controlled discontinuation of benzodiazepine treatment for patients with panic disorder. American Journal of Psychiatry 148: 517–23.
O'Brien, CP (2005) Benzodiazepine use, abuse, and dependence. Journal of Clinical Psychiatry 66 (suppl 2): 2833.
Otto, MW, Pollack, MH, Sachs, GS et al (1993) Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder. American Journal of Psychiatry 150: 1485–90.
Pollack, MH, Otto, MW, Tesar, GE et al (1993) Long-term outcome after acute treatment with alprazolam or clonazepam for panic disorder. Journal of Clinical Psychopharmacology 13: 257–63.
Pollack, MH, Simon, NM, Worthington, JJ et al (2003) Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. Journal of Psychopharmacology 17: 276–82.
Pradel, V, Delga, C, Rouby, F et al (2010) Assessment of abuse potential of benzodiazepines from a prescription database using “doctor shopping” as an indicator. CNS Drugs 24: 611–20.
Rapoport, MJ, Lanctot, KL, Streiner, DL et al (2009) Benzodiazepine use and driving: a meta-analysis. Journal of Clinical Psychiatry 70: 663–73.
Rickels, K, Downing, R, Schweizer, E et al (1993) Antidepressants for the treatment of generalized anxiety disorder: a placebo-controlled comparison of imipramine, trazodone, and diazepam. Archives of General Psychiatry 50: 884–95.
Rickels, K, DeMartinis, N, Aufdembrinke, B (2000) A double-blind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder. Journal of Clinical Psychopharmacology 20: 12–8.
Rosenbaum, JF, Moroz, G, Bowden, CL (1997) Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. Journal of Clinical Psychopharmacology 17: 390400.
Rosenbaum, JF (2005) Attitudes toward benzodiazepines over the years. Journal of Clinical Psychiatry 66 (suppl 2): 48.
Rothschild, AJ, Shindul-Rothschild, J, Viguera, A et al (2000) Comparison of the frequency of behavioral disinhibition on alprazolam, clonazepam, or no benzodiazepine in hospitalized psychiatric patients. Journal of Clinical Psychopharmacology 20: 711.
Salzman, C (1991) The APA Task Force report on benzodiazepine dependence, toxicity, and abuse. American Journal of Psychiatry 148: 151–2.
Salzman, C, Miyawaki, EK, le Bars, P et al (1993) Neurobiologic basis of anxiety and its treatment. Harvard Review of Psychiatry 1: 197206.
Schweizer, E, Rickels, K, Weiss, S et al (1993) Maintenance drug treatment of panic disorder: I. Results of a prospective, placebo-controlled comparison of alprazolam and imipramine. Archives of General Psychiatry 50: 5160.
Shader, RI, Greenblatt, DJ (1993) Use of benzodiazepines in anxiety disorders. New England Journal of Medicine 328: 1398–405.
Smolders, M, Laurant, M, van Rijswijk, E et al (2007) The impact of comorbidity on GPs' pharmacological treatment decisions for patients with an anxiety disorder. Family Practice 24: 538–46.
Soumerai, SB, Simoni-Wastila, L, Singer, C et al (2003) Lack of relationship between long-term use of benzodiazepines and escalation to high dosages. Psychiatric Services 54: 1006–11.
Spiegel, DA, Bruce, TJ, Gregg, SF et al (1994) Does cognitive behavior therapy assist slow-taper alprazolam discontinuation in panic disorder? American Journal of Psychiatry 151: 876–81.
Stahl, SM (2002) Don't ask, don't tell, but benzodiazepines are still the leading treatments for anxiety disorder. Journal of Clinical Psychiatry 63: 756–7.
Starcevic, V (2011) Have anxiety disorders been disowned by psychiatrists? Australasian Psychiatry 19: 12–6.
Uhlenhuth, EH, Balter, MB, Ban, TA et al (1999) International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders. Journal of Clinical Psychopharmacology 19 (suppl 2): 23-29S.
Vasile, RG, Bruce, SE, Goisman, RM et al (2005) Results of a naturalistic longitudinal study of benzodiazepine and SSRI use in the treatment of generalized anxiety disorder and social phobia. Depression and Anxiety 22: 5967.
Wagner, AK, Ross-Degnan, D, Gurwitz, JH et al (2007) Effect of New York State regulatory action on benzodiazepine prescribing and hip fracture rates. Annals of Internal Medicine 146: 96103.
Worthington, JJ, Pollack, MH, Otto, MW et al (1998) Long-term experience with clonazepam in patients with a primary diagnosis of panic disorder. Psychopharmacology Bulletin 34: 199205.

Benzodiazepines for anxiety disorders: maximising the benefits and minimising the risks

  • Vladan Starcevic

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Benzodiazepines for anxiety disorders: maximising the benefits and minimising the risks

  • Vladan Starcevic
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eLetters

Re:Benzodiazepines and Cognition & Managing Inappropriate Prescribing in Clinical Practice

Vladan Starcevic, Associate Professor
09 November 2012

Issues in Benzodiazepine Use I thank Drs Devender Yadav and Sandeep Singh for their comments regarding my article on benzodiazepines (Starcevic 2012). They seem to be particularly concerned about cognitive side-effects of benzodiazepines. Asnoted in my article, this is a controversial area and research findings and opinions are divergent. Considering their potential adverse effects oncognitive functioning, caution is certainly needed when benzodiazepines are prescribed to elderly people.

There is still a lack of evidence that benzodiazepines cause dementia. A recently published prospective population-based study (de Gageet al 2012) reported that new use of benzodiazepines was associated with increased risk of dementia. This association needs to be better understoodand calls for further research. However, it is premature to conclude that there is an aetiological link between the two. Many possible confounding variables were not controlled for and the study had a number of limitations, as acknowledged by the authors. Furthermore, it was unclear whether a degree of exposure to benzodiazepines was related in any way to the risk of developing dementia, which also casts some doubt on the causalrelationship. Finally, benzodiazepines may first be used in the elderly for symptoms such as sleep disturbance and anxiety, which may represent prodromal features or early symptoms of dementia. In these cases, benzodiazepines should obviously not be implicated in the aetiology of dementia.

Drs Yadav and Singh also make an important point about various clinical effects of benzodiazepines in relation to their binding sites. Indeed, benzodiazepines exert their effects through GABA-A receptors, which have several subtypes and are located in different parts of the brain. These receptor subtypes are believed to mediate various effects of benzodiazepines, and the challenge for the future may be to develop what may be called "second-generation" benzodiazepines. These drugs might act selectively on alpha-2 subtype, thereby exhibiting anxiolytic effects (Lowet al 2000), whilst producing no activation of alpha-1 subtype, deemed to be responsible for sedation, unwanted cognitive effects and dependence (Rudolph et al 1999; Tan et al 2010). Such non-sedating and non-dependenceproducing anxiolytics, also devoid of cognitive side-effects, would represent a significant improvement in the pharmacological treatment of anxiety.

Discontinuing long-term use of benzodiazepines can be difficult, as noted in my article (Starcevic, 2012). Therefore, any innovative measure that can facilitate this process, including a stepped care approach, can only be welcome.

Referencesde Gage SB, Begaud B, Bazin F, et al (2012) Benzodiazepine use and risk of dementia: prospective population based study. BMJ 345: e6231.

Low K, Crestani F, Keist R, et al (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290: 131-4.

Rudolph U, Crestani F, Benke D, et al (1999) Benzodiazepine actions mediated by specific y-aminobutyric acidA receptor subtypes. Nature 401: 796-800.

Starcevic V (2012) Benzodiazepines for anxiety disorders: maximising the benefits and minimising the risks. Advances in Psychiatric Treatment 18: 250-8.

Tan KR, Brown M, Labouebe G, et al (2010) Neural bases for addictive properties of benzodiazepines. Nature 463: 769-74.

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Conflict of interest: None declared

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Benzodiazepines and Cognition & Managing Inappropriate Prescribing in Clinical Practice

Devender Singh Yadav, Specialty Doctor in Psychiatry
09 November 2012

Benzodiazepines and Cognition

Starcevic, V [1] highlights the importance of prescribing benzodiazepines to a highly selective group of patients, but sadly doesn’t comment a great deal on prescribing benzodiazepines to a vulnerable group of elderly people. These elderly patients are particularly prone to the side-effects of benzodiazepines, especially the effect of benzodiazepines on cognition.

It has been reported that benzodiazepines can cause anterograde amnesia [2], which Starcevic also highlights, but does long-term use of benzodiazepines cause reversible dementia and does it then progress to progressive dementia [3]? These questions remain unanswered and require further research.

The authors of a recent study published in the BMJ evaluated the association between use of benzodiazepines and incident dementia [4]. The authors quote and cross-refer to studies focusing on the association between benzodiazepine use and dementia or cognitive decline in elderly people (these quoted studies report conflicting results). In their prospective population-based cohort study, (mean age of participants being 78.2 years), the authors report that new use of benzodiazepines was associated with increased risk of dementia and results of a complementary nested case-control study showed that over-use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia.The authors reported several limitations in their study and recommend further research to explore whether long term use of benzodiazepines in people under 65 is also associated with an increased risk of dementia.

Also, further research on emerging therapies might be a way forward [5]. Both benzodiazepines and non-benzodiazepine Z-drugs (zolpidem, zopiclone and zaleplon) hypnotics act on the benzodiazepine binding site of the GABA A/Benzodiazepine receptor to enhance the effect of GABA. The GABA A/Benzodiazepine receptor has many subtypes, which mediate different functions. Preclinical studies show that a1 subtype is highly expressed in the cortex where it mediates sedation and zolpidem is the prototypical a1 selective agonist. a2 and a3 subtypes are predominantly found in sub cortical brain structures that mediate anxiety and sleep. Esozopiclone is relatively a 2/3 selective. a5 is particularly localized in the hippocampus where it is involved in memory. Newer a2/3 selective benzodiazepine receptor agonists are being developed as non-sedating anxiolytic agents, which will maximize the benefits and minimize the risks of the currently used benzodiazepines, especially the effect of benzodiazepines on cognition.

References:

1. Starcevic V. Benzodiazepines for anxiety disorders: maximising the benefits and minimising the risks. Advances in Psychiatric Treatment 2012; 18: 250-258 2. Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines, 10th edition. Informa healthcare. 2009; 241

3. Yadav DS. Dementia Classification Advances in Psychiatric Treatment 2012; 18: 315-316

4. de Gage SB, Bégaud B, Bazin F. Benzodiazepine use and risk of dementia: prospective population based study. BMJ 2012;345:e6231

5. Wilson S. Emerging therapies for sleep disorders. British Journal of Hospital Medicine 2009; 70(6): 327-331Managing Inappropriate Anxiolytic/Hypnotic Prescribing in Clinical Practice

Given the fact that hypnotics will sedate when given during the day and most anxiolytics (‘sedatives’) will induce sleep when given at night [1], the distinction between a hypnotic and an anxiolytic is merely of semantic value.

Inappropriate hypnotic prescribing is quite common in clinical practice and is a widespread problem. This may lead to difficulty in withdrawing the drug if the patient has taken it for more than a few weeks. The use of hypnotics is associated with the development of tolerance, dependence and withdrawal symptoms, which Starcevic, V also reports.

Starcevic [2] reports on talisman dependence and last dose dependence, which can be a problem in discontinuing long-term benzodiazepine use.

To help such patients, we wrote in an article on good clinical care [3], that evidence was found for the efficacy of stepped care in discontinuing long-term benzodiazepine use. Minimal intervention – giving simple advice in the form of a letter or meeting to a large group of people, followed by systematic discontinuation – defined as treatment programmes led by a physician or a psychologist. Augmentation of systematic discontinuation with imipramine or group cognitive-behaviour therapy for patients with insomnia was superior to systematic discontinuation alone [4].

References:

1. British National Formulary (BNF) 56 edition, September 2009, British Medical Association and Royal Pharmaceutical Society of Great Britain

2. Starcevic V. Benzodiazepines for anxiety disorders: maximising the benefits and minimising the risks. Advances in Psychiatric Treatment 2012; 18: 250-258

3. Yadav DS, Davies RH. Good Clinical Care, Benzodiazepines and Z drugs: Managing inappropriate hypnotic prescribing in clinical practice. Foundation Years Journal 2012; 6 (6): 6-9

4. Voshaar RCO et al. Strategies for discontinuing long-term benzodiazepine use: meta-analysis. Br J Psychiatry 2006; 189: 213-20

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Conflict of interest: None declared

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