"Benzodiazepines, antidepressants and addiction: A plea for conceptual rigor..."

[[La...]]

The full title of this letter to the editor at the Journal of Psychopharmacology (Sept./19) is "Benzodiazepines, antidepressants and addiction: A plea for conceptual rigor  and consistency".

 

https://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/31556796 

[[lo...]]

Thanks for posting, very interesting.  I follow Jahuar on Twitter and he follows me.

[[La...]]

I do wish the article included a clear and concise explanation of physiological dependency, which happens with many different kinds of medications. Benzos and SSRIs are included on the list, of course, but so are others. Awhile back, I shared an article on this topic by Dr. David Juurlink, and it was very clear and accessible, unlike this one.

 

 

[[La...]]

For anyone who couldn't read the article using the link above, I'm going to try to copy and paste the article here:

 

The editorial by Jauhar et al. (2019) discusses the recently published  concerns  about  “addiction”  to  antidepressants  (mainly  serotonin  reuptake  inhibitors  and  serotonin  and  noradrenaline  reuptake inhibitors) in light of an increasing number of publications  addressing  antidepressant  withdrawal  symptoms.  They  (Jauhar et al., 2019) ask a crucial question (“Are antidepressants addictive?”),  examine  conceptual  and  methodological  issues  and arrive at a conclusion that “there is minimal evidence, using established classification systems and concepts, that antidepressants should be classified as addictive substances” (p.657). We agree with their conclusion that antidepressants are not addictive and  that  the  main  argument  invoked  in  support  of  addiction  to  antidepressants – the presence of withdrawal symptoms – is not valid.  However,  we  would  like  to  point  that  the  same  standard  used for antidepressants in this regard should also be applied to other pharmacological agents – in particular to benzodiazepines. We are concerned that benzodiazepines (positive allosteric mod-ulators of gamma aminobutyric acid [GABA-A] receptor, ben-zodiazepine site) are frequently labelled as “addictive” and are included  in  the  Diagnostic  and  Statistical  Manual  of  Mental  Disorders,    Fifth    Edition    (DSM-5;    American    Psychiatric    Association, 2013) among addictive substances. Unfortunately, this DSM-5 listing of benzodiazepines has been used by Jauhar et  al.  (2019)  as  an  example  in  their  argument  against  putative  addiction to antidepressants.We would like to address two main issues here. The first is the looseness with which the terms “addiction” and “addictive” are used.  The  second  is  the  erroneous  portrayal  of  benzodiazepine  dependence and abuse in much of the literature and as exemplified by Jauhar et al. (2019).

What is addiction and what makes a substance addictive?

 

Jauhar et al. (2019) correctly note that withdrawal symptoms that occur  upon  discontinuation  of  medications  prescribed  for  valid  medical  reasons  do  not  suggest  a  substance-related  disorder.  However, they provide Leshner’s (1997: 45) definition of addic-tion as “compulsive drug seeking and use” and contrast antidepressants  with  benzodiazepines  by  stating  that  benzodiazepine  dependence  is  characterized  by  “compulsion.  .  .  in  those  who  abuse  them.”  “Compulsion”,  like  “dependence”  and  “abuse”  is  not  well  defined  by  Jauhar  et  al.  (2019).  This  entire  discussion 

also correctly implies that antidepressant dependence itself does not exist, despite withdrawal symptoms upon discontinuation of these  agents.  If  this  implication  is  accurate,  withdrawal  symp-toms that occur upon cessation of any substance, including ben-zodiazepines,  should  not  be  construed  to  reflect  dependence  on  or abuse of that substance.It  is  important  to  note  that  “addiction”  is  not  a  term  clearly  endorsed  by  the  DSM-5  (American  Psychiatric  Association,  2013). Addiction does not appear in its glossary of technical terms and is not defined elsewhere in the DSM–5. The only mention of addiction is via the name of the nosological group of “substance-related  and  addictive  disorders”,  but  the  DSM-5  (American  Psychiatric  Association,  2013)  does  not  define  “addictive  disor-ders.”  In  the  introductory  description  of  substance-related  and  addictive disorders, the DSM-5 states that the substances in ques-tion “produce such an intense activation of the reward system that normal activities may be neglected” and that these “drugs of abuse directly  activate  the  reward  pathways”  producing  “feelings  of  pleasure”  (p.481).  It  follows  that  all  10  classes  of  substances  encompassed  by  this  nosological  group,  including  benzodiaz-epines, are effectively considered “drugs of abuse” and that they all  produce  a  “high.”  However,  plenty  of  evidence  suggests  that when it comes to benzodiazepines, this is not true. Unfortunately, the  mere  fact  that  benzodiazepines  are  listed  among  the  DSM-5  substance-related and addictive disorders is often interpreted as an official  endorsement  of  the  position  that  benzodiazepines  are  “addictive.”Interestingly, the DSM-5 (American Psychiatric Association, 2013) does include a diagnostic category of “antidepressant dis-continuation  syndrome,”  which  is  placed  in  the  nosological  group  of  “medication-induced  movement  disorders  and  other  adverse effects of medication.” Besides avoiding the term “anti-depressant withdrawal symptoms,” the DSM-5 is also careful not to  attribute  these  “discontinuation  symptoms”  to  antidepressant  dependence  or  to  a  hypothetical  “antidepressant  use  disorder”  and  indeed,  the  term  “antidepressant  dependence”  does  not  appear in the DSM-5 text. The DSM-5 also makes this puzzling assertion: “The antidepressant discontinuation syndrome is based solely on pharmacological factors and is not related to the rein-forcing  effects  of  an  antidepressant”  (p.713).  Such  an  approach  begs the question of the explanation for “antidepressant discontinuation  syndrome:”  what  causes  it,  where  does  it  come  from,  how does it differ from the symptoms of withdrawal from other substances, and are antidepressants really devoid of “reinforcing effects?” This is in contrast to the DSM-5 portrayal of the withdrawal  symptoms  associated  with  the  cessation  of  benzodiazepines, where benzodiazepines are assumed to have “reinforcing effects.”  Moreover,  although  benzodiazepine  withdrawal  symptoms do not have to be present for making the DSM-5 diagnosis of sedative, hypnotic, or anxiolytic use disorder, their presence is often considered a manifestation of this disorder.We  also  question  whether  “compulsion”  should  be  the  key  criterion for making a substance addictive, an argument made by Jauhar  et  al.  (2019)  following  Leshner’s  (1997)  definition.  Compulsivity is usually defined as a repetitive behavior (regard-less of whether it pertains to using a substance or engaging in an activity) that is motivated by avoidance of the perceived negative consequences (e.g. withdrawal symptoms, distress, or feeling of anxiety) of ceasing the substance or activity. However, compulsivity is not sufficient for the definition of addiction because peo-ple  who  continue  taking  antidepressants  or  benzodiazepines  mainly to avoid the anticipated withdrawal symptoms (or return of primary symptoms of their disorder) should not be considered addicted only on that basis. Other criteria for substance addiction include an urge or a craving that immediately precedes substance use,  poor  self-control  over  substance  use,  and  continued  sub-stance  use  despite  its  adverse  consequences  (Potenza,  2006;  Shaffer, 1999). Only the presence of all these criteria may war-rant use of the term “addiction.” In our opinion, the DSM should define  addiction  clearly  in  its  future  iterations  if  it  continues  to  use the label “addictive disorders.” The DSM should also stipu-late the criteria that allow substances or behaviors to be considered addictive on the basis of this definition.For now, we believe that when using the terms “addiction” or  “compulsion  in  this  context,  it  should  always  be  stipulated  what these terms encompass, i.e. how they are defined. Failure to do so opens the floodgates to a chaotic situation where arbitrariness  reigns  and  where  the  presence  of  any  component  of  addiction,  or  only  the  presence  of  withdrawal  symptoms,  is  deemed sufficient to conclude that it is indicative of addiction or substance use disorder. Likewise, a disregard for the criteria for addiction would allow countless substances to be regarded as  addictive  –  a  dangerous  situation  with  conceptually  disastrous consequences for medicine.

 

Erroneous portrayal of benzodiazepine dependence and abuse

 

With  regards  to  the  issue  of  dependence,  Jauhar  et  al.  (2019)  state that “Repeated studies have indicated that around 35% of people will develop dependence, and these people appear more likely  to  had  been  taking  benzodiazepines  for  longer  periods  (>5 years) and have dependence-prone personalities (Murphy and Tyrer, 1991)” (pp.655–656). Although Jauhar et al. (2019) mention “repeated studies,” they only cite the article by Murphy and  Tyrer  (1991).  However,  this  article  does  not  address  the  issue of dependence, though its title includes the term “benzo-diazepine  dependence.”  In  fact,  Murphy  and  Tyrer  (1991)  address  benzodiazepine  withdrawal  and  conclude  somewhat  differently that “withdrawal symptoms were greater in patients who  had  taken  a  benzodiazepine  for  >5  years  and  were  most  marked  in  those  with  personality  disorders,  predominantly  dependent ones” (p.511). The putative definition of dependence by Murphy and Tyrer (1991, p.511) was “apparent withdrawal symptoms on reduction” (presumably, a reduction in the benzo-diazepine  dose).  There  were  no  other  signs  of  dependence,  addiction, or abuse in their patients. Patients in this study were actually  people  taking  a  prescribed  benzodiazepine  in  regular  dosage for six months or longer; unable to reduce or stop their drug because of apparent withdrawal symptoms; were taking no other psychotropic drugs; were taking their benzodiazepine in a daily dosage of 2–16 mg of diazepam or equivalent; were tak-ing their drugs (sic) for anxiety or insomnia or related neurotic symptomatology; and wished to stop benzodiazepines and participate  in  this  study.  Thus,  the  presence  of  withdrawal  symptoms  was  the  only  criterion  of  dependence  which  per  se,  as  noted  and  acknowledged  above,  is  not  enough  to  establish  a  diagnosis of substance use disorder and may not be enough to denote  the  kind  of  dependence  that  is  associated  with  actual  substance abuse. In addition, the DSM-5 (American Psychiatric Association, 2013, p.551) notes that the criterion of withdrawal is  not  considered  to  be  met  for  individuals  taking  sedatives,  hypnotics,  or  anxiolytics  (including  benzodiazepines)  under  medical  supervision.  Furthermore,  Murphy  and  Tyrer  (1991)  wrote about dependent or passive-dependent personality disor-der, not about dependence-prone personalities. This distinction is important because the latter term might erroneously suggest that some people are inherently more likely to become depend-ent on certain substances.

 

Why  have  benzodiazepines  been  mentioned  in  this  and  in  similar  arguments  by  others?  Because  benzodiazepines  are  perfectly set up to become victims of muddled thinking about addic-tion: they produce prompt relief, they are prescribed for patients who are anxious about control, they have a withdrawal syndrome, they  are  commonly  abused  by  polysubstance  abusers,  and  they  have had nobody to stand up for them since "Big Pharma" abandoned  them  in  favor  of  antidepressants.  If  not  for  assuming  a  conclusion about benzodiazepines, one could just as easily present an analogy between benzodiazepines and antidepressants as being reassuring about their abuse potential, rather than suggesting possible abuse of benzodiazepines.

 

Balon et al. 3The most informative question to ask about a drug’s potential for abuse is not whether anyone abuses it, but whether those with  no  substance  abuse  history  are  likely  to  do  so.  People  in  the throes of addiction may find ways to abuse a great variety of substances,  including  antidepressants,  anticonvulsants,  benzodiazepines, and atypical neuroleptics. For instance, quetiapine is known by street names such as “Susie Q” or “baby heroin,” gabapentin by “gabbies” or “johnnies,” and both are recognized to have street value (Buttram et al., 2017; Theremissine, 2008); gabapentin has been added to the list of controlled substances in some US states. These substances are alike in that they produce fairly  prompt  subjective  soothing  effects,  but  little  else.  The  way to gauge the risk of the true addictive potential of a drug is to measure the degree to which it reinforces its own administra-tion  or  induces  subjective  euphoria.  It  is,  in  fact,  difficult  to  induce  animals  to  self-administer  benzodiazepines  (Ator  and  Griffiths,  1987),  and  people  with  no  substance  abuse  history  have been found unable to distinguish these medications from placebo  (e.g.  de  Wit  et  al.,  1986;  Johansen  and  Uhlenhuth,  1980).  Further,  there  is  no  scientific  evidence  that  legitimate  prescription of benzodiazepines to non-substance abusers leads either to their abuse or to the abuse of other substances.The endless and seemingly unresolved debate about abuse, dependence,  and  addiction  of  various  medications,  especially  benzodiazepines,  is  frequently  ideological  and  stigmatizing,  forgetting patients and their illness. It is clear that just because a patient has symptoms of withdrawal and anxiety after benzodiazepine  is  stopped  does  not  constitute  a  reason  to  diagnose  abuse, addiction, or dependence. As noted by Greenblatt et al. (1983) almost four decades ago, “Since benzodiazepines cure neither  anxiety  nor  insomnia,  symptom  recurrence  can  be  anticipated after discontinuation of the drug” (p.357). Anxiety and insomnia are chronic disorders which do not get cured by a period of treatment with benzodiazepines or antidepressants. Long-term treatment should always be considered. In their systematic  review  and  meta-analysis  of  the  risk  of  relapse  after  discontinuation  of  long-term  treatment  with  antidepressants,  Batelaan and colleagues (2017) pointed out that such discontinuation increased the odds of relapse compared with continuation of antidepressant treatment. Summary relapse prevalence rates  for  continuation  treatment  were  36.4%  (30.8–42.1%,  n=28 studies) for the placebo group and 16.4% (12.6–21.1%, n=28  studies)  for  the  antidepressant  group.  There  is  also  evi-dence of lower relapse rates in panic disorder patients treated with  a  benzodiazepine  (clonazepam)  (34.1%  after  one-year  follow-up) compared to those in patients treated with a serotonin reuptake inhibitor (paroxetine) (61.8% after one-year fol-low-up)  (Freire  et  al.,  2017).  These  findings  raise  the  old  question:  why  do  we  label  as  dependent  only  patients  who  become  anxious  after  cessation  of  treatment  with  benzodiazepines and not patients with the same outcome after cessation of  treatment  with  antidepressants?  In  relation  to  benzodiazepines,  Marjot  (2012)  asked  how  we  can  know  whether  such  anxiety  is  symptom  recurrence,  symptom  emergence  (new  symptom emerging once the dose was reduced or stopped), or symptom misattribution (i.e. patients blaming benzodiazepines for their current distress). In this context, Marjot (2012) warned of the post hoc ergo propter hoc ("after this, therefore because of this") logical fallacy, whereby it is assumed that dependence precedes and therefore causes withdrawal symptoms. Finally, if we consider the study by Batelaan et al. (2017) and its recommendation  of  chronic  treatment  of  anxiety  disorders,  why  should  such  treatment  be  justified  only  with  antidepressants  (which  have  their  own  issues)  and  not  with  benzodiazepines,  when they are both associated with withdrawal symptoms upon their cessation?

 

Conclusion

 

In summary, we agree with Jauhar et al. (2019) that antidepressants are not addictive. This is based on the concept of addiction that  does  not  include  withdrawal  symptoms,  but  encompasses  craving  for  a  substance,  poor  self-control  over  substance  use,  continued  substance  use  despite  its  adverse  consequences,  and  compulsive  substance  use.  Espousing  the  consistency,  while  using  the  same  criteria  for  addiction,  we  also  emphasize  that  there  are  no  reasons  to  consider  benzodiazepines  addictive.  What is sorely needed is better understanding of the withdrawal symptoms, and of the pharmacological dependence that is often assumed  to  cause  these  symptoms,  while  resisting  attempts  to  equate them with addiction.