Volume 2 Number 1


Alan Eppel & Farid Ahmad




Benzodiazepines and “Z-drugs”  are GABA-receptor modulators and are among  the most frequently prescribed drugs in psychiatry and primary care despite concerns about the potential for addiction.

Benzodiazepines are are widely used for the  treatment of anxiety symptoms, as hypnotics and as adjunctive treatment in depression.

The advantages of benzodiazepines are their overall medical safety compared to most other groups of psychotropic medications; their effectiveness in alleviating symptoms of anxiety and panic and their rapidity of onset.

Concerns about addiction are often misplaced for patients with anxiety and depressive disorders who are maintained on steady dosages.

Physiological dependence does develop but not addictive cravings so that it is possible to be gradually withdrawn from benzodiazepines after a period of therapeutic use.

Short-acting benzodiazepines such as alprazolam and lorazepam are more likely to lead to physiological dependence.

Longer acting drugs such as diazepam and clonazepam can be withdrawn more easily.

Individuals with a history of substance abuse and particularly alcoholism are more prone to develop both psychological and physiological dependence on benzodiazepines. They are more likely to take these drugs in order to produce a euphoric effect. This results in the development of tolerance with need for escalating dosages.

Benzodiazepines should be generally avoided as hypnotics because of the physiological dependence that develops resulting in rebound insomnia when attempts are made to discontinue the medication.

The “Z” drugs (e.g. zopiclone; zolpidem) act on the same receptors as benzodiazepines and induce the same problems with tolerance and rebound insomnia.



Benzodiazepines can cause impairment of memory and levels of alertness. This applies also to the Z drugs. This is particularly problematic in the elderly or those who already have some cognitive compromise.

The cognitive impact can be quite subtle with impairments in short-term memory and impaired ability to recall or retain new information.

Benzodiazepines may interfere with new learning. This may reduce the effectiveness of psychotherapy particularly cognitive behaviour therapy that depends on state learning e.g. exposure therapy.

Benzodiazepines have also been shown to worsen treatment response in PTSD.



More insidious is the fact that benzodiazepines may cause depression. This is of particular significance because benzodiazepines are frequently co-prescribed with antidepressants to enhance sleep, reduce anxiety and agitation.

Clinical and basic science research indicate that benzodiazepines may interfere with neurogenesis in the hippocampus. Neurogenesis is related  to antidepressant response.

This problem is particularly important in cases of treatment resistant depression when the possibility that the benzodiazepines are in fact perpetuating the problem go unrecognized. This may result in patients remaining depressed over many years because the negative impact of benzodiazepines has not been considered.


Case reports associating benzodiazepine use and depression have been published as early as the 1960’s.  However, these reports were subsequently criticized for having sub-standard methodological features (i.e., an absence of randomization, poor definitions for measurement of depression).  More importantly, however, with these studies it is difficult to determine if the depression described represents a worsening of an already existing depression, or new onset depression associated with the use of benzodiazepines.

Depression and anxiety disorders coexist approximately 60% of the time, even in the absence of benzodiazepine use. In addition, insomnia, for which benzodiazepines are commonly prescribed, may be symptomatic of an already existing depressive disorder.

A recent study identified a striking link between regular benzodiazepine use and treatment resistant depression.  Several possible explanations for the association were proposed.

First, the presence of co-morbid anxiety (for which benzodiazepines are often prescribed) may be a marker of treatment resistance, as “anxious depression” is associated with poorer response to antidepressant medication.

Second, results from the study indicated that those regularly using benzodiazepines had significantly higher scores on personal reserve and interpersonal sensitivity.  According to the authors, such individuals may be more likely to engage in avoidant coping skills and show constricted feelings and detachment from others.  By their very action benzodiazepines supress feelings, which may worsen depression and the effectiveness of any treatment.

The authors also cite evidence that benzodiazepines may interfere with psychotherapy due to induction of avoidance of feelings, cognitive inhibition, or by having more direct depressogenic effects.

The mechanism by which benzodiazepines may cause depressive symptoms is unclear, and further research pursuing possible explanations is warranted.


As a rule of thumb, if the patient has not responded to several trials of antidepressant treatment as expected one of the next steps should be to withdraw them from any co-prescribed benzodiazepines.




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