1 Selective serotonin reuptake inhibitors (SSRI) – sales, withdrawal ...

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REVIEW
doi:10.1111/j.1360-0443.2011.03686.x
What is the difference between dependence
and withdrawal reactions A comparison of
benzodiazepines and selective serotonin
re-uptake inhibitorsadd_3686 900..908
Margrethe Nielsen 1 , Ebba Holme Hansen 2 & Peter C. Gøtzsche 1
The Nordic Cochrane Centre, Department 3343, Copenhagen, Denmark 1 and University of Copenhagen, Faculty of Pharmaceutical Sciences, Copenhagen,
Denmark 2
ABSTRACT
Aims To explore the rationale for claiming that benzodiazepines cause dependence while selective serotonin
re-uptake inhibitors (SSRIs) do not. Methods We analysed the definitions of dependence and withdrawal reactions as
they had appeared over time in the Diagnostic Statistical Manual of Mental Diseases (DSM) and the International Classification
of Diseases (ICD). We also compared the discontinuation symptoms described for the two drug groups in a
systematic review. Results The definition of substance dependence has changed over time in both the DSM and ICD.
In the most recent classifications several criteria, including behavioural, physiological and cognitive manifestations,
must be fulfilled. This change was published with the revision of the DSM-III revision in 1987 (DSM-IIIR), after the
recognition of benzodiazepine dependence and just before the SSRIs were marketed in 1987–88. We found that
discontinuation symptoms were described with similar terms for benzodiazepines and SSRIs and were very similar for
37 of 42 identified symptoms described as withdrawal reactions. Conclusions Withdrawal reactions to selective
serotonin re-uptake inhibitors appear to be similar to those for benzodiazepines; referring to these reactions as part
of a dependence syndrome in the case of benzodiazepines, but not selective serotonin re-uptake inhibitors, does
not seem rational.
Keywords
Benzodiazepine, dependence, DSM, ICD, SSRI, withdrawal reactions.
Correspondence to: Margrethe Nielsen, The Nordic Cochrane Centre, Department 3343, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
E-mail: marn@phmetropol.dk
Submitted 29 January 2011; initial review completed 29 March 2011; final version accepted 10 October 2011
INTRODUCTION
In a historical perspective, it has been well described that
psychotropic drugs may cause withdrawal reactions.
Benzodiazepines were marketed at the beginning of the
1960s, primarily for the treatment of anxiety and insomnia.
Already in 1961, a study documented dependence
with benzodiazepines [1]. Two decades later, in 1980, the
addictive characteristics of benzodiazepines were recognized
by the authorities, although at the beginning as
only a minor problem, because they had received few
spontaneous reports on dependence [2]. In 1988, after
publication of many studies, the true extent of the
problem was acknowledged by the authorities [3]. The
usage increased dramatically until the 1980s, and then
decreased because of their dependence potential [4].
For antidepressants, withdrawal reactions were first
reported with imipramine, a tricyclic antidepressant
(TCA), in 1959 and were described in detail in 1961 [5].
Subsequent studies reported that withdrawal reactions
also occur with other TCAs and with the monoamine
oxidase inhibitors (MAOIs) [6]. The selective serotonin
re-uptake inhibitors (SSRIs) were launched in the late
1980s and were marketed for some of the same indications
as benzodiazepines; for example, anxiety and
phobia. From 1991 and onwards, case reports [7–11]
about withdrawal reactions following use of SSRIs were
published and concern was raised that these drugs might
© 2011 The Authors, Addiction © 2011 Society for the Study of Addiction Addiction, 107, 900–908