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

SSRi and dependence 903
Table 2 Criteria for substance withdrawal (source: DSM-IV).
(A) The development of a substance-specific syndrome due to
the cessation of (or reduction in) substance use that has
been heavy and prolonged
(B) The substance-specific syndrome causes clinically
significant distress or impairment in social, occupational or
other important areas of functioning
(C) The symptoms are not due to a general medical condition
and are not better accounted for by another mental
disorder
described dependence or withdrawal reactions and were
not case reports (Fig. 1).
We identified a range of symptoms (Table 3 and
Appendix S2), many of them described in several ways,
using different words. We adopted a categorization, which
has been used previously for antidepressant discontinuation
symptoms [6,22]:
• general symptoms
• gastrointestinal symptoms
• sleep-related symptoms
• balance-related symptoms
• sensory-related symptoms
• movement-related symptoms
• affective-related symptoms
• psychosis
According to this classification, we identified 42
symptoms, 37 of which were described for both benzodiazepines
and for SSRIs. Three symptoms (palpitations,
skin rash/itching and constipation) were described only
for benzodiazepines and two (bouts of crying and parkinsonism)
were described only for SSRIs. Symptoms for both
drug groups appeared in all the above-mentioned categories,
but for the benzodiazepines, the problem was categorized
as dependence in accordance with DSM-III, and for
the SSRIs as a withdrawal syndrome in accordance with
DSM-IV and ICD-10.
DISCUSSION
The withdrawal reactions to SSRIs were very similar to
those for benzodiazepines. It therefore makes no sense to
describe only the latter as dependence symptoms.
The reluctance towards accepting that psychoactive
drugs cause dependence can have serious clinical consequences.
In 2008 approximately 100 000 patients in
Denmark, in a population of only 5.5 million, were in
long-term treatment with benzodiazepines, and many of
them will require tapering of the doses over long timeperiods
if these drugs are ever to be discontinued [23].
It is remarkable that the bar for diagnosis of dependence
was raised at about the same time as it became
widely accepted that benzodiazepines lead to dependence,
namely with the revision of the DSM-III in 1987
(DSM-IIIR). This change happened just before the SSRIs
were marketed in 1987–1988.
Lack of validity of the change in definition
The change in definition of dependence in the DSM-IIIR
was based on literature about alcohol, opiates and narcotics,
and not about psychoactive medicine, although
the symptoms are not the same [24]. It is also unfortunate
that it gave rise to a new autonomous diagnosis
of withdrawal reactions for those who did not fulfil the
criteria for dependence.
Benzodiazepine dependence was based on the physical
criteria described in DSM-III, tolerance and withdrawal
reactions. The development of tolerance was described in
1980 [2], but this was later questioned with respect to the
anxiolytic effect [25], and clinical evidence supports the
idea that tolerance develops selectively to different drug
effects [26,27]. This means that benzodiazepines do not
always fulfil the two criteria of tolerance and withdrawal
reactions described in DSM-III.
It has also been suggested that SSRIs lose efficacy
during maintenance treatment [28–30]. Some have suggested
a pharmacokinetic tolerance reducing the concentration
of the drug or its duration of action, while others
have suggested pharmacodynamic processes changing
the sensivity to the drug [31]. Thus, in some cases SSRIs
fulfil the criteria of tolerance and if they had been marketed
8 years earlier they would therefore have fulfilled
the dependence criteria existing at the time. An additional
similarity is that not only benzodiazepines can
cause dependence at therapeutic doses; we found that
this is also the case for SSRIs.
The validity of the dependence criteria in DSM-IV and
ICD-10 is also questionable, as they are the same for
substances as diverse as alcohol, amphetamine, opiates,
cannabis, cocaine, caffeine, inhalant substances, nicotine
and sedative, hypnotic and anxiolytic drugs. There is also
room for some flexibility. According to DSM-IV, three out
of seven criteria must be met, but in the introduction
to the DSM-IV it is recommended to use one’s clinical
judgement about the number of criteria [32].
The general lack of a research and evidence-based
approach in the development of the DSM has been
described by Caplan [32], Kutchins & Kirk [33] and Lane
[34]. This deficiency has resulted in inclusion and exclusion
of diagnoses based on subjective, political or other
reasons than scientific ones. For example, the criteria for
the various diagnoses in the DSM-III and III-R were built
on questions to psychiatrists about which criteria for a
given category they found useful and whether they had
other suggestions. This process was rather subjective
and not evidence-based [32]. Concern about the dependence
criteria has also been raised by Voyer [35,36]. He
© 2011 The Authors, Addiction © 2011 Society for the Study of Addiction Addiction, 107, 900–908