Do antidepressants cause dependence?

 

"'When I use a word,' Humpty Dumpty said in a rather scornful tone, 'it means just what I chose it to mean - neither more nor less.'
'The question is,' said Alice, 'whether you can make words mean so many different things.'
'The question is,' said Humpty Dumpty, 'which is to be master - that's all.'"  Carroll (1871)

The word "dependence" is a construct of several different ideas, readily confused. The main ones are to do with the perceived strength and nature of the bonds between drug and user, and with (mainly medical) understandings of the harm thought to result from the bonds that exist.

The complexities of meaning are boundless, as are parameters of understanding. Is the bonding characteristically like some fettering with chains, or more like the hook-and-tangle grip of a patch of Velcro ? Is the dependence more of a physical or psychological thing, driven more by user or drug? Is it something which affects all drug users, or only some? Does the drug steer toward escalation of dosage, and how pleasing is it to take?

Questions like these help to define the risk of loss of personal autonomy and dignity, but other questions come to the potential for good or harm. Does the drug intoxicate, disable or damage others, and can illicit use be controlled? What are the known properties and effects of the drug and does it have therapeutic applications? And might dependence sometimes be benign - if a drug were deemed essential, or if compliance were a problem, for example? Here, meanings are defined more by different perspectives and context. The difference between a therapeutic dependence on insulin and persistent "recreational" use of an opiate is the difference between a footnote and a headline - though the same word, "dependence" might apply. The word 'dependence' is full of meanings and, in practice, they never seem quite the same.

And then there is the question of who speaks for and against the drug - and when they do. One reason for asking if antidepressants are drugs of dependence is that virtually every favoured remedy for psychic distress has belatedly turned out to be a drug of dependence - right back to the days when alcohol, opium and cocaine were liberally prescribed. Heroin was introduced into medicine in 1898, but the first published report of heroin dependence dates from 1913.

If I had asked, 20 years ago, "Are benzodiazepines drugs of dependence?" the resounding answer would have been NO. Two earlier decades of extensive use of benzodiazepine (BDZs) seemed to have established the risk was minimal, and the best available evidence confirmed it:

" … following an extensive review of all available data the Committee concluded that, on the present available evidence, the true addiction potential of benzodiazepines was low. The number dependent on the benzodiazepines in the UK from 1960 to 1977 has been estimated to be 28 persons. This is equivalent to a dependence rate of 5 - 10 cases per million patient months. Such cases of addiction were observed to occur most frequently in drug misusers, particularly in patients with a history of psychological or social inadequacy" Committee on the Review of Medicines (1980).

The rest is history, and the error was gross. Medawar (1992). Shortly after, it was estimated that a few hundred thousand people in the UK might be pharmacologically dependent on BDZs. Drug and Therapeutics Bulletin (1985). But significantly, the change mainly came, not because doctors recognised much of a problem, but because the public had complained:

" … if the popular press and more recently the legal profession had not taken up arms against the overprescription of tranquillisers, the issue of benzodiazepine dependence would still remain a medical curio only for the pages of medical journals. The media and lawyers have undoubtedly altered prescribing practices, mostly for the better." Hallstrom (1991)

I spent much of 1987-1989 (as researcher for the Plaintiff's legal team) studying how BDZ dependence came to light, and why it took so long - and more recently (quite independently), I have been researching the same about antidepressants, Medawar (1994, 1997, 1998-1999). The main focus has been on the newer SSRIs (selective serotonin reuptake inhibitors), and notably fluoxetine, paroxetine, sertraline and the closely-related drug, venlafaxine. The demand/supply for these Prozac-like drugs has led to a doubling of NHS prescriptions for antidepressants (ADs) in the past six years, and prescriptions for them now outnumber those for BDZs. Department of Health (1997).

The parallels between ADs and BDZs are such that it no longer seems credible to argue that the nature and strength of the bond that develops between drug and user is very different in either case. Indeed, reports of withdrawal reactions from ADs long predate and greatly outnumber the few reports there ever were about BDZs, Dilsaver (1984- 1994) - though they soared in the 1990s, as SSRIs became more widely used. By 1998, the UK authorities had received over 1,000 reports about paroxetine withdrawal reactions alone - many more than for all BDZs combined. MCA/CSM (1998). Even so, The UK Committee on Safety of Medicines and the Medicines Control Agency have hugely underestimated the risk - because again their calculations are mainly based on the numbers of spontaneous reports sent in:

"The absolute risk of a withdrawal reaction with any of the SSRIs may be so low that differences are undetectable except through spontaneous reporting where drug exposure is high." Price et al., (1996)

Spontaneous reports to the MCA/CSM suggest an incidence of three paroxetine withdrawal reactions per 10,000 prescriptions but, if treatment were interrupted, probably 30% of established users might experience them. Rosenbaum et al (1998)

In relation to dependence, there are several perceived differences between BDZs and ADs. One is that doctors know that many patients find antidepressants unpalatable - and because of this and the delayed onset of action, there is apparently not much of a street market for such drugs. However, another important factor is that recently the goalposts were dramatically but quietly moved: since 1994, the word "dependence" has acquired a brand-new meaning, and iatrogenic dependence has now, officially, pretty much ceased to exist. Briefly, "dependence" today is officially described in terms in terms of frank 'addiction', including hallmark features such as marked drug-seeking or self-destructive behaviour, and dosage escalation. APA (1994) - when only a few years back it simply meant that some people found it very hard to quit:

"Historically, long-term, high-dose, physiological dependence has been called addiction, a term that implies recreational use. In recent years, however, it has become apparent that physiological adaptation develops and discontinuance symptoms can appear after regular daily therapeutic dose administration (of BDZs) ... in some cases after a few days or weeks of administration. Since therapeutic prescribing is clearly not recreational abuse, the term dependence is preferred to addiction, and the abstinence syndrome is called a discontinuance syndrome." (APA, 1990)

In this sense, antidepressants (SSRIs in particular) undoubtedly seem drugs of dependence - though doctors and users have repeatedly been assured they are not. Royal Colleges of Psychiatry and General Practice (1992-1997) The point here is not that some people get bad withdrawal symptoms - but that the type of abstinence reaction means that many others continue to take medicine mainly because they suffer when they try to stop. This would be another reason why dependence on these mainstay drugs has not caused more concern:

"The probable reason is that patients (on BDZs) abort these reactions early on because they think their original symptoms are returning, and they get back on the drug. So we rarely see the full blown picture (Hollister, 1977)

"The withdrawal syndrome (with imipramine) complicates the evaluation of patients after drug discontinuation since both patients and physicians often interpret the onset of symptoms as an upsurge of 'anxiety' related to incipient relapse, and resume treatment with the gratifying subsidence of the 'anxiety'. This may cause both patients and physicians to overvalue the importance of the medication to the patient's stability" Kramer et al. (1961).

With the belated realisation that dependence on BDZs was a problem came also the recognition that they didn't really go on working. Long-term effectiveness was an illusion, the result of mistaking withdrawal symptoms for signs of relapse. Yet just as about one-third of long term BDZ users got stressed and anxious on withdrawal, so about the same proportion become measurably depressed when SSRIs are withdrawn Rosenbaum et al (1998) - not that most prescribers are aware of this. Young & Currie (1997). The only real difference with antidepressants is that the manufacturers and most experts persist in labelling this 'relapse', in spite of clear indications this is not so:

"The probability of depressive relapse is low in the days and weeks after the discontinuation of antidepressants, and the cumulative probability of relapse increases as a function of time when the patient is medication free." Drug & Therapeutics Bulletin (1988).

Severe depression is a truly miserable state to be in, and often very hard to treat, so one can only sympathise with the individual clinician (or patient) who believes in continuing treatment when a drug appears to help. Nor is it surprising this happens, when there are many (often industry-sponsored) consensus statements and treatment guidelines to encourage it. However, it does seem intensely worrying that the widespread belief that ADs are effective in the long term is based on the conclusions of clinical trials that have consistently defined withdrawal depression as "relapse". If the main treatment for this dominant antidepressant withdrawal symptom is more of the drug, the risk is that the bond will tighten - and that we may soon need to redefine 'dependence' all over again.

The wealth of evidence now on the Social Audit website - including scores of letters to and from the authorities - leave me in very little doubt that history is repeating itself even now. Medawar (1998-1999). Here it seems is another example of honest individuals once again getting into a collective mess. See for yourself the evidence the authorities have relied on to claim there is no problem - and how much of it seems tainted by abuse of secrecy, conflicts of interest, poor judgement, incompetent analyses, sloppy science, heavy commercial pressure, and indifference to the truth. Humpty Dumpty was surely right. The outstanding question has to be: "which is to be master - that's all".

 

REFERENCES

L. Carroll, Alice through the Looking-Glass (1871) (London: Puffin, 1997, 237.

Committee on the Review of Medicines, Systematic review of the benzodiazepines, Brit. Med. J., 1980, 29 March, 910-912.

Department of Health (Statistics Division, Branch SD1E). Prescription Cost Analysis, England, London: Department of Health, 1989 - 1997.

S. C. Dilsaver, J.F. Greden, Antidepressant withdrawal phenomena, Biological Psychiatry, 1984, 19, 2, 237-256.

S. C. Dilsaver, Antidepressant withdrawal syndromes: phenomenology and pathophysiology, Acta Psychiatr. Scand., 1989, 79, 113-117.

- Withdrawal phenomena associated with antidepressant and antipsychotic agents, Drug Safety, 1994, 10 (2), 103-114.

Drug & Therapeutics Bulletin, Some problems with benzodiazepines, 1985, March 25, 23, 21-23.

- Problems when withdrawing antidepressives, 1986, 21 April, 24, 29-30.

American Psychiatric Association Task Force on Benzodiazepine Dependency. Benzodiazepine Dependence, Toxicity, and Abuse. Washington DC: APA, 1990.)

- Diagnostic and Statistical Manual (DSM IV), 1994

 C. Hallstrom, Benzodiazepine dependence: who is responsible? J Forensic Psychiatry, 1991, 2, 1, 5-7.

L. E. Hollister, (Chairman, proceedings of a roundtable discussion on diazepam held in Chicago, 20 May, 1976), Valium: a discussion of current issues. Psychosomatics 1977, 18 (1), 44-58.

J.C. Kramer, D.F. Klein, M. Fink, Withdrawal symptoms following discontinuation of imipramine therapy, Am. J Psychiatry, 1961, 118, 549-550).

C. Medawar, Power and Dependence: Social Audit on the safety of medicines. London: Social Audit, 1992.

- Through the doors of deception? Nature 24 March 1994, 368, 369-370.

- The Antidepressant Web, Int J Risk & Safety in Medicine 1997, 10, 2, 75-126

- The Antidepressant Web Online, 1998-1999): http://www.socialaudit.org.uk

MCA/CSM, Adverse Drug Reaction Online Information Tracking (ADROIT) Drug Analysis Print, Medicines Control Agency/Committee on Safety of Medicines, 15 October 1998

J.S. Price, P.C.Waller, S.M. Wood (MCA), A.V.P. Mackay (CSM), A comparison of the post-marketing safety of four selective serotonin reuptake inhibitors including the investigation of symptoms occurring on withdrawal, Br. J. Clin. Pharmacol., 1996, 42, 757-763.

J F Rosenbaum, M Fava, S L Hoog, R C Ascroft, W B Krebs: Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome: A Randomised Clinical Trial, Biol Psychiatry, 1998, 44, 77-87

Royal College of Psychiatry, Royal College of General Practice, Defeat Depression Campaign, (1992-1997)

A.H. Young, A Currie, Physicians' knowledge of antidepressant withdrawal effects: a survey, J Clin Psychiatry, 1997, 58 (suppl 7), 28-30.

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