The recent furore caused by publication of evidence about the serious nature of antidepressant withdrawal made me reflect on the lasting damage that can sometime be done by prescription drugs, and how it has often taken concerted efforts by users of these drugs to bring these effects to public attention.
Historically, the medical community has been slow to appreciate the extent to which drugs can interfere with and alter normal brain and body functions in both predictable and unpredictable ways. It took psychiatrists a long time to acknowledge that tardive dyskinesia was caused by neuroleptics, and they tried hard to pin it on something else (schizophrenia) (1). It has taken three decades for the withdrawal effects of antidepressants to be taken seriously. The prescription opioid epidemic in the United States continues despite mounting evidence that the drugs can exacerbate chronic pain rather than relieve it (2).
Withdrawal effects are, in themselves, an indication that the body has been altered by the ingestion of a drug. We associate withdrawal effects with long-term use, but in fact, the body can change, temporarily, even after a single dose of a drug. Animal studies show that one acute treatment with an opiate provokes a period of heightened to pain (known as hyperalgesia), which follows after the direct analgesic effect of the drug and lasts for a few days (3). Similarly, taking sleeping pills for just one or two days improves sleep initially, at least slightly, but when the pill is stopped, people find it even more difficult to sleep than they did before they took it (4). This sometimes referred to as ‘rebound’ insomnia, and ‘rebound’ is the general term used to describe these compensatory-type effects that occur after the acute effects of a drug have worn off.
When drugs have been taken for long periods, withdrawal symptoms can be more severe and longer-lasting. They usually last for weeks, even if the drugs are reduced gradually. After discontinuation of some drugs, however, the effects can sometimes go on for months and even years. In these instances, the body is taking a long time to return to its pre-drug state, and it seems that in some cases it never quite does, and the drug-induced alterations are permanent.
Protracted withdrawal following benzodiazepine cessation was recognised back in 1991 by Heather Ashton (5). She documented withdrawal symptoms such as anxiety, tinnitus, paraesthesia (burning pain, tingling and numbness), that lasted for many months and sometimes years. In most, though not all, instances there was a gradual improvement over time. Drugs like alcohol and opiates seem less likely to cause protracted withdrawal, but the hypersensitivity to pain that is a recognised feature of opiate withdrawal took up to five months to normalise in an experiment with recently detoxified opiate addicts (6).
Evidence on antidepressant withdrawal suggests a picture similar to the benzodiazepines. There is a range of intensity and duration of withdrawal, with not everyone experiencing debilitating or even noticeable symptoms, but there are numerous reports of withdrawal symptoms being severe and protracted. An analysis of respondents on an antidepressant withdrawal web forum that I conducted with some colleagues revealed that withdrawal symptoms following reduction or cessation of Selective Serotonin Reuptake Inhibitors (SSRIs) were reported as lasting an average of almost 2 years (91 weeks) and those associated with Serotonin and Noradrenalin Reuptake Inhibitors (SNRIs) lasted just under a year on average (51 weeks) (7). Although people resorting to an online forum are likely to be those experiencing most difficulty with withdrawal, this nevertheless shows that long-lasting effects are a significant problem for some people. As Davies & Read concluded in their recent review, it is difficult to estimate an overall average duration of symptoms from current research, especially as most studies were not set up to assess this directly, but reports of symptoms lasting several months are common across many recent studies (8).
Most reports suggest that symptoms of benzodiazepine and antidepressant withdrawal usually improve gradually even years after the drugs are stopped. Worryingly, however, Ashton’s initial description of protracted benzodiazepine withdrawal includes one or two cases where symptoms were still problematic several years after withdrawal, in some cases even when people had resumed benzodiazepines. This suggests that occasionally drugs can induce permanent changes in brain functioning.
Some accounts indicate that protracted withdrawal followed from abrupt discontinuation of the medication in question (9). Within addiction services in the United Kingdom there seems to be increasing appreciation that rapid withdrawal of benzodiazepines is undesirable, although I can find no discussion of a possible link between rapid detoxification and protracted withdrawal effects in any official literature or guidance. However, Ashton’s description of persistent withdrawal states mostly involved people who were undergoing, or had completed, a slow reduction, so it may be that although abrupt discontinuation is likely to be more risky, gradual reduction may not always protect against experiencing a complicated and prolonged withdrawal.
We have known for decades that some psychiatric drugs can produce permanent and detrimental changes to brain function. Tardive dyskinesia, the syndrome of abnormal movements that is associated with a degree of cognitive impairment, was recognised back in the 1960s to be a consequence of neuroleptic administration (1). It was noted that it persisted after neuroleptics were stopped, sometimes for months and even years, depending on how long people were followed up for.
It has been proposed, although never demonstrated, that tardive dyskinesia is caused by ‘supersensitivity’ of dopamine receptors. The abnormal movements are similar to those of Huntingdon’s Chorea which are associated with excessive dopamine activity (10). The fact that tardive dyskinesia often occurs while people are still taking neuroleptics, suggests that the brain overcompensates for the effects of dopamine-blocking drugs. In attempting to balance out their effects, the body overshoots, and disrupts normal mechanisms for movement control along with more general functions that impact on cognition.
The recently characterised condition termed opioid-induced hyperalgesia may represent a similar situation, with the body over-adjusting to the presence of pain suppressing drugs resulting in increased levels of pain (2). Although opioid-induced hyperalgesia typically occurs during opioid therapy, there is little research on whether or not it persists after the drugs are withdrawn.
Post SSRI sexual dysfunction
Further evidence of long-lasting changes associated with antidepressants, in this case, comes from the emerging literature on post-SSRI-sexual dysfunction. It is well established that SSRIs commonly impair sexual function while they are being taken, but there are mounting reports of persistence of some difficulties following cessation of the drugs for months and sometimes years (11). Persistent sexual impairment is also demonstrated in male rats treated with SSRIs during adolescence (12, 13). It is difficult to estimate the prevalence of persistent sexual dysfunction given the currently limited data, but one survey identified that 34% of respondents showed evidence of possibly having the condition, and 4.3% showed a high probability of having it (14). I have heard some psychiatrists protest that post SSRI sexual dysfunction is ‘psychological’ and simply a re-emergent symptom of an underlying depression, but the fact that it is consistent with known acute effects of SSRIs and with animal research into lasting effects makes it difficult to uphold this position. It seems more likely that it is another example of a long-lasting, and possibly occasionally permanent, change to normal bodily functions induced by some prescribed psychiatric drugs.
Increased risk of mania and psychosis
Research that suggests the discontinuation of some drugs can increase the risk of having an episode of an underlying psychiatric disorder, such as mania or psychosis, also indicates how long-term use of some prescribed drugs can cause significant changes to brain processes. The evidence is most clear for lithium, where studies show that in people with a diagnosis of manic depression (bipolar 1), the risk of having an episode, especially of mania, is higher after stopping lithium than it was before lithium was started (15-17). This is true despite the fact that lithium is not commonly reported to provoke a severe, acute withdrawal reaction. Despite this, it seems the removal of the neurological suppression produced by the sedating effects of lithium can trigger the state of hyperarousal known as mania, possibly through a delayed rebound type of effect. Some research suggests a similar picture in people diagnosed with psychosis or schizophrenia who have been treated with long-term antipsychotics. Evidence shows that the risk of relapse is heightened in the first few months following discontinuation, and declines thereafter, suggesting that discontinuation is not just revealing an underlying tendency, but is provoking an episode that might not otherwise have occurred, at least at that point (18). Thus it seems that the alterations produced by long-term treatment with certain sedative drugs increase a person’s vulnerability to having an acute episode of mania or psychosis. Some argue that this effect also occurs with antidepressants (19), although the evidence for this is less clear.
Lack of research
It is astonishing that iatrogenic problems such as persistent diseases and dysfunctions induced by prescribed drugs have received so little attention from the research community. We remain uncertain about the proportion of people who can expect to experience an adverse withdrawal-related reaction following different lengths of treatment with different drugs. We know very little about how long such withdrawal reactions are likely to last, and indeed whether they may sometimes be permanent. We do not know for certain whether rapid reduction increases the risk of protracted withdrawal, nor whether very gradual reduction can prevent its occurrence. The occurrence of post SSRI sexual dysfunction is probably unknown to most prescribers, and there is little research on its prevalence or duration.
The mechanisms of these effects also remain obscure. There is research on the mechanisms of acute withdrawal from opiates and benzodiazepines, there is little research into what produces states of prolonged withdrawal. There is no research on the mechanisms underlying antidepressant withdrawal or post SSRI sexual dysfunction.
Yet is has been estimated that around 16% of the population of the United Kingdom are taking antidepressants currently (20) and the latest data from the United States, from 2011-2014, put the figure at 12% (21). If even a small proportion of these people experience protracted withdrawal or post SSRI sexual dysfunction, it is a sizeable problem! Furthermore, recent figures from the England show that prescriptions have doubled in the last decade, now topping 70 million for a population of 56 million. It is unbelievable that the leaders of the medical profession are so unconcerned about this situation that the president of the Royal College of General Practitioners cautioning against viewing the increase in prescriptions ‘as a bad thing’ (22).
There is a large-scale failure to appreciate the risks involved in taking drugs that alter brain function on a long-term basis. Some of these risks are foreseeable, some less so. We should have been able to anticipate that SSRIs and other new drugs for depression and anxiety would produce withdrawal syndromes, although once again we were taken unawares, and there seems to have been no research into this possibility before the drugs were launched. A syndrome like tardive dyskinesia, or opioid-induced hyperalgesia should remind us, however, that the effects of drugs cannot always be predicted, and that we must always be vigilant for complex and unusual reactions.
The fact that it has taken single-minded and dedicated campaigners, many of them users of the drugs concerned, to bring these effects to the attention of the scientific and professional community is shameful, and highlights the naivety of the medical profession.
To anticipate some of the criticism I will receive from people who feel that medication has helped, I am not saying that these drugs should never be considered. I have certainly seen situations in which someone has managed to stop drinking harmful amounts of alcohol through using small doses of a benzodiazepine, for example, and benzodiazepines are definitely the least dangerous option in this situation. I also believe that neuroleptics, despite their many noxious effects, are sometimes preferable to a severe and intractable psychosis. People must have all the facts though. Doctors must understand and explain that drugs change the brain, and other parts of the body, in ways that we do not fully understand, that are almost always harmful to some degree, and that may, even, be irreversible.
- Moncrieff J. The Bitterest Pills: the troubling story of antipsychotic drugs. London: Palgrave Macmillan; 2013.
- Velayudhan AB, G.; Morely-Forster, P. Opioid-induced hyperalgesia. Continuing Education in Anaesthesia, Critical Care and Pain. 2014;14(3):125-9.
- Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology. 2000;92(2):465-72.
- Soldatos CR, Dikeos DG, Whitehead A. Tolerance and rebound insomnia with rapidly eliminated hypnotics: a meta-analysis of sleep laboratory studies. Int Clin Psychopharmacol. 1999;14(5):287-303.
- Ashton H. Protracted withdrawal syndromes from benzodiazepines. JSubstAbuse Treat. 1991;8(1-2):19-28.
- Treister R, Eisenberg E, Lawental E, Pud D. Is opioid-induced hyperalgesia reversible? A study on active and former opioid addicts and drug naive controls. J Opioid Manag. 2012;8(6):343-9.
- Stockmann T, Odegbaro D, Timimi S, Moncrieff J. SSRI and SNRI withdrawal symptoms reported on an internet forum. Int J Risk Saf Med. 2018;29(3-4):175-80.
- Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based? Addict Behav. 2018.
- Anonymous. Rapd withdrawal and misprescribing of a benzodiazepine leads to £1.35m settlement for Luke Montagu, CEP co-founder. 2015 [Available from: http://cepuk.org/2015/07/18/rapid-withdrawal-misprescribing-benzodiazepine-leads-1-35m-settlement-luke-montagu-cep-co-founder/.
- Cepeda C, Murphy KP, Parent M, Levine MS. The role of dopamine in Huntington’s disease. Prog Brain Res. 2014;211:235-54.
- Bala A, Nguyen HMT, Hellstrom WJG. Post-SSRI Sexual Dysfunction: A Literature Review. Sex Med Rev. 2018;6(1):29-34.
- de Jong TR, Snaphaan LJ, Pattij T, Veening JG, Waldinger MD, Cools AR, et al. Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats. Eur Neuropsychopharmacol. 2006;16(1):39-48.
- Simonsen AL, Danborg PB, Gotzsche PC. Persistent sexual dysfunction after early exposure to SSRIs: Systematic review of animal studies. Int J Risk Saf Med. 2016;28(1):1-12.
- Ben-Sheetrit J, Aizenberg D, Csoka AB, Weizman A, Hermesh H. Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship. J Clin Psychopharmacol. 2015;35(3):273-8.
- Cundall RL, Brooks PW, Murray LG. A controlled evaluation of lithium prophylaxis in affective disorders. PsycholMed. 1972;2(3):308-11.
- Baldessarini RJ, Tondo L, Viguera AC. Discontinuing lithium maintenance treatment in bipolar disorders: risks and implications. BipolarDisord. 1999;1(1):17-24.
- Suppes T, Baldessarini RJ, Faedda GL, Tohen M. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. ArchGenPsychiatry. 1991;48(12):1082-8.
- Viguera AC, Baldessarini RJ, Hegarty JD, van Kammen DP, Tohen M. Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. ArchGenPsychiatry. 1997;54(1):49-55.
- Fava GA. Can long-term treatment with antidepressant drugs worsen the course of depression? JClinPsychiatry. 2003;64(2):123-33.
- (DHSC) DoHaSC. Hansard- prescription drugs: written question 128871 London2018 [Available from: https://www.parliament.uk/business/publications/written-questions-answers-statements/written-question/Commons/2018-02-21/128871/.
- Pratt LA, Brody DJ, Gu Q. Antidepressant Use Among Persons Aged 12 and Over:United States,2011-2014. NCHS Data Brief. 2017(283):1-8.
- Guardian T. Antidepressant prescriptions in England double in a decade. London: The Guardian; 2019 [updated 29th March 2019. Available from: https://www.theguardian.com/society/2019/mar/29/antidepressant-prescriptions-in-england-double-in-a-decade.