Withdrawal from Antidepressants

Editor’s note: We know that our reviews of the withdrawal literature are incomplete, and we urge readers to help us add to these withdrawal reviews. Please send study citations that are relevant to the withdrawal literature for antidepressants to [email protected].

Introduction

Selective Serotonin Reuptake Inhibitors (SSRIs) have been used in the treatment of depression since the late 1980s. Serotonin–norepinephrine reuptake inhibitors (SNRIs) were introduced in the 1990s. It is proposed that SSRIs work by increasing serotonin activity in the brain, and that SNRIs work by increasing both serotonin and norepinephrine. These are chemicals that have been linked to the regulation of mood.

Although these drugs were initially indicated for depression, they have also been FDA approved for other conditions, including anxiety disorders, posttraumatic stress disorder, premenstrual dysphoric disorder and fibromyalgia. Antidepressant medication (ADM) use has dramatically increased over the last few years in the United States; about 1 in 10 Americans aged 12 and over take an ADM. This document reviews drugs classified as SSRIs or SNRIs, although a bulk of the research focuses on SSRIs.

Mechanism of Action

1) Moncrieff J, Cohen D. Do antidepressants cure or create abnormal brain states? Plos Medicine. 2006;3(7):e240-e. Link

The authors provide evidence against the “disease model” of depression which states that depression is the result of a biochemical abnormality that ADM corrects. They argue for the adoption of a “drug-centred model” which posits that ADM lead to the creation of an abnormal brain that can have an effect on certain symptoms of depression. Treatment decisions should be based on the short-term, known effects of the drug according to this view.

2) Fava GA. Can long-term treatment with antidepressant drugs worsen the course of depression? Journal Of Clinical Psychiatry. 2003;64(2):123-33. Pubmed link

This literature review summarizes research supporting the oppositional tolerance hypothesis, that is continued treatment with ADM may activate processes that go against the initial effects of the drug and lead to a loss of clinical effect. At worse these processes can continue even when the drug is discontinued and increase vulnerability to relapse. The author proposes that withdrawal symptoms that occur after an ADM is discontinued may be clinical evidence of the oppositional tolerance hypothesis.

3) Andrews P, Kornstein S, Halberstadt L, Gardner C, Neale M. Blue Again: Perturbational Effects of Antidepressants Suggest Monoaminergic Homeostasis in Major Depression. Full Text Link

This meta-analysis tests the “oppositional tolerance” hypothesis – that is patients whose symptoms lessen with ADM treatment will have a higher risk of relapse after treatment stops than patients whose symptoms improve without ADM. It further tests the hypothesis that greater oppositional tolerance is linked to the greater disturbance of the monoamine neurotransmitter system in the brain. Both hypotheses were supported – over time ADM use leads to an increased risk of relapse, and this risk is even greater when the drug has more of an impact on the monoamine system. The authors compare these findings to the mechanism of action of of a spring – the further a spring is pulled away from it’s equilibrium or original position, the greater will be the force produced by this spring when it is released.

Animal Studies: Long-term Effects of Exposure to ADMs

4) Kepser L-J, Homberg JR. The neurodevelopmental effects of serotonin: A behavioural perspective. Behavioural Brain Research. 2015 1/15/;277:3-13. Pubmed link

This is a review of animal studies which summarizes the behavioral effects of early exposure to SSRIs. The authors conclude that serotonin disturbances during the prenatal and postnatal phases are linked to an increased risk for mood disorders whereas the risk for autism-like behaviors and sexual abnormalities is linked to increased serotonin levels in the postnatal period. These findings in rats are discussed in relation to similar findings on the role of serotonin exposure in human studies.

5) Maciag D, Simpson KL, Coppinger D, et al. Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology: Official Publication Of The American College Of Neuropsychopharmacology. 2006;31(1):47-57. Pubmed link

This study provides evidence that rats exposed to an SSRI very early in life displayed disruptions in behavior as adult rats, long after the medications had been discontinued. This cluster of behavior changes called the “neonatal antidepressant exposure syndrome” are discussed in light of the implications of exposure to ssris at critical phases of brain development. Similar changes were not seen in rats exposed to ssris as adults.

6) Hilakivi LA, Hilakivi I. Increased adult behavioral ‘despair’ in rats neonatally exposed to desipramine or zimeldine: an animal model of depression? Pharmacology, Biochemistry, And Behavior. 1987;28(3):367-369. Pubmed link

In this study rats were exposed to a tricyclic ADM and an SSRI from 7-18 days after they were born. ADM was stopped after this period. The adult rats were assessed at 2 months and 5 months and it was found that early ADM exposure had negative emotional effects, which was observed in their behavioral responses to a stressful situation. These findings are explained as a cause of a reduction of neurotransmitters like serotonin and dopamine in the forebrain because of early exposure to ADM that cause changes that do not renormalize.

7) de Jong TR, Snaphaan LJAE, Pattij T, et al. Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats. European Neuropsychopharmacology: 2006;16(1):39-48. Pubmed link

Results of this study indicate that there are some effects on adult sexual activity and anxiety behaviors after adolescent SSRI exposure. However, the authors are unclear about whether these findings are limited to adolescent exposure, whether serotonin receptors play a role and did not investigate whether these effects are temporary or permanent.

8) Gouvêa TS, Morimoto HK, de Faria MJSS, Moreira EG, Gerardin DCC. Maternal exposure to the antidepressant fluoxetine impairs sexual motivation in adult male mice. Pharmacology, Biochemistry, And Behavior. 2008;90(3):416-9. Pubmed link

Exposure to SSRIs in utero is associated with impaired sexual motivation in adult male mice.

9) Iñiguez SD, Warren BL, Bolaños-Guzmán CA. Short- and Long-Term Functional Consequences of Fluoxetine Exposure During Adolescence in Male Rats. Biological Psychiatry. 2010;67(11):1057-66. Pubmed Link

The results of this study suggest that adolescent exposure to fluoxetine leads to lower levels of a behavioral response to a stressful situation in adulthood in male rats. This anxiety response reduced when the same rats were given fluoxetine for a few days as adults. The same long-term pattern was not observed in adult rats after their ADM was discontinued. Similarly, fluoxetine exposed adolescent rats showed signs of sexual dysfunction as adults. The authors conclude that exposure to the drug in adolescence can impact behavioral responses in adulthood.

10) Bosker FJ, Tanke MAC, Jongsma ME, et al. Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis. Neurochemistry International. 2010;57(8):948-57. Pubmed link

The results of this study suggest that treatment with citalopram increased the number of serotonin receptors in the brain. The two treatment conditions were divided into a drug washout (abrupt discontinuation) and non-drug washout group (continuation). There were differences observed in these two groups on the turnover and synthesis of serotonin with an increase of both processes in the discontinuation group. There were also behavioral changes observed in the discontinuation but not the continuation or control groups. The authors conclude that chronic SSRI treatment does not impair brain serotonin function, but it may lead to an increased vulnerability fluctuations in its synthesis.

11) Raap DK, Garcia F, Muma NA, Wolf WA, Battaglia G, van de Kar LD. Sustained desensitization of hypothalamic 5-Hydroxytryptamine1A receptors after discontinuation of fluoxetine: inhibited neuroendocrine responses to 8-hydroxy-2-(Dipropylamino)Tetralin in the absence of changes in Gi/o/z proteins. The Journal Of Pharmacology And Experimental Therapeutics. 1999;288(2):561-7. Link

The authors report a continued desensitization of a type of serotonin receptor (the 5-HT1A receptor) 60 days after discontinuation of fluoxetine, an SSRI, indicating that the receptors did not renormalize much after the medication had left the brain tissue. The authors conclude that mechanism of desensitization of receptors when the drugs are being used versus when they are discontinued are likely to be different. The implications of these results for humans are discussed. 

Discontinuation Syndromes

12) Fava, M. . “Prospective Studies of Adverse Events Related to Antidepressant Discontinuation.” Journal of Clinical Psychiatry (2006); 67, suppl. 4, 14-21. Pubmed link

Though varying in frequency and intensity, nearly all classes of antidepressants have been linked with discontinuation reactions and the associated psychological, physical, and somatic discomfort. Spontaneous reports have been typically used to gauge the risks of discontinuation reactions. Judging from a number of prospective studies, spontaneous reports very likely underestimate the occurrence of discontinuation reactions. The author provides a review of studies dealing with discontinuation-related adverse events.

13) Shelton, R. “The Nature of the Discontinuation Syndrome Associated With Antidepressant Drugs. Journal of Clinical Psychiatry (2006); 67, suppl. 4, 3-7.

A common phenomenon accompanying treatment with nearly every major class of antidepressant is the emergence of the discontinuation syndrome. The term withdrawal has been used in the past; however, the distinctions between discontinuation symptoms and drug withdrawal are clear. In addition, awareness of the unique nature of discontinuation effects and a grasp of the typical time frame of their emergence can assist in distinguishing between discontinuation syndrome and relapse. As a result, it is vital that both patients and their relatives be provided with adequate education and a realistic and objective appraisal of expected outcomes upon initiation of antidepressant treatment, which may include experiencing discontinuation adverse events upon cessation of the drug treatment. Pubmed link

14) Smith, P. F. and C. L. Darlington. “A possible explanation for dizziness following SSRI discontinuation.” Acta Oto-Laryngologica 2010; 130(9): 981-983. Pubmed link

The authors provide an explanation for the often experienced symptom of dizziness upon SSRI discontinuation. They link to a reduction in a region of the brain that has an abundance of serotonin receptors. The implications of this finding are discussed.

15) Renoir T. Selective Serotonin Reuptake Inhibitor Antidepressant Treatment Discontinuation Syndrome: A Review of the Clinical Evidence and the Possible Mechanisms Involved. Frontiers in Pharmacology. 2013; April 16, 4:45. Pubmed link

In this review the author examines the evidence for the phenomenon of a discontinuation syndrome and notes that even though it is clear that it exists, there are several limitations of existing studies. These include the absence of studies comparing drugs with similar half-lives but that have different effects upon discontinuation, the short durations of treatment interruptions and the lack of studies designed to take into account the pharmacokinetics of the drug and the role of its metabolite. He also summarizes the preclinical animal studies examining the effects of treatment discontinuation as well the limitations of this body of literature. For instance, they were designed to study the mechanism of action of SSRIs rather than the effects of discontinuation, and they used “normal” animals instead of animal models of depression. Potential directions for future studies that can shed light on our current limited understandings of the mechanism of discontinuation syndrome are discussed.

16) Michelson D, Fava M, Amsterdam J, et al. Interruption of selective serotonin reuptake inhibitor treatment. Double-blind, placebo-controlled trial. Br J Psychiatry. 2000 Apr;176:363-8. Pubmed link

In this controlled study half the patients who had been taking SSRIs were assigned to continue their medication and the other half were given a placebo. The authors found that the effect of stopping the drug was associated with the drug’s half-life – the shorter the half-life, the more severe the adverse effects and functional impairment. The effects were most severe with paroxetine, followed by sertraline whereas no significant effects were observed upon discontinuing fluoxetine. The predominance of physical effects upon discontinuation were hypothesized as representing a drug induced reaction rather than a return of depression.

17) Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44. Pubmed link

This study was conducted to understand the effects of ADM interruption for a brief period in light of “patient noncompliance” or missing doses. After being on a maintenance dose of ADM for anywhere between 4-24 months, 83% (192) patients were given a placebo instead of their ADM for 5-8 days. After this phase ADM was reintroduced. The frequency of psychological and somatic symptoms upon ADM interruption was greatest for paroxetine, followed by sertraline and lastly fluoxetine. Patients treated with sertraline and paroxetine but not fluoxetine also experienced a return of depressive symptoms. When the medication was reintroduced there was a rapid reduction of somatic symptoms and depression scores. Thus the results are hypothesized to reflect a response to the stopping of SSRIs rather than a relapse or return of depression.

18) Judge R, Parry MG, Quail D, et al. Discontinuation symptoms: comparison of brief interruption in fluoxetine and paroxetine treatment. International Clinical Psychopharmacology. 2002;17(5):217-225. Pubmed link

This study was conducted to understand the effects of a shorter treatment interruption of SSRIs (fluoxetine and paroxetine), that is 3-5 days, which has implications for when patients miss taking their medication. Results indicate that there was a significant increase in adverse events (as measured by the Discontinuation Emergent Signs and Symptoms (DESS) scale) reported by the paroxetine but not the fluoxetine group. Stopping ADM also had negative clinical (return of depression) and quality of life implication for the paroxetine but not the fluoxetine group. The depression scores increased as a result of an increase in somatic symptoms upon ADM interruption.

19) Viguera AC, Baldessarini RJ, Friedberg J. Discontinuing antidepressant treatment in major depression. Harvard Review Of Psychiatry. 1998;5(6):293-306. Pubmed link

This literature review summarizes the results of 27 studies on long-term ADM use and effects after discontinuation of the medication. Results indicate that discontinuing treatment leads to higher rates of monthly relapse rates, shorter time to relapse and higher risk of relapse on a yearly basis. Also slower rates of discontinuation did not lead to a lower relapse risk. Lastly being on a maintenance dose for longer after being stabilized with ADM did not protect participants from a lower relapse rate one ADM was discontinued. This goes against the conventional wisdom that patients need to be on a maintenance dose for several months after acute symptoms have remitted.

20) Verbeek-Heida PM, Mathot EF. Better safe than sorry–why patients prefer to stop using selective serotonin reuptake inhibitor (SSRI) antidepressants but are afraid to do so: results of a qualitative study. Chronic Illness. 2006;2(2):133-142. Pubmed link

In this qualitative study the authors interviewed 16 SSRI users (range of use: 6 months to 10 years) to understand their decision making around continuing or stopping their medication. A subset of 9 patients had attempted to discontinue their medication in consultation with their physician, but all had been unsuccessful (the experience upon stopping is not described) and had re-started the drugs. Another relevant theme was that patients received conflicting advice from physicians which made them err toward continuing rather than discontinuing the medication.

21) Bahrick AS. Persistence of sexual dysfunction side effects after discontinuation of antidepressant medications: Emerging evidence. The Open Psychology Journal. 2008;1.

The author summarizes evidence from the literature on the occurrence of sexual side effects that persist long after stopping SSRIs. She notes that a great deal of evidence on this phenomenon emerged outside the professional community, from consumer reports on internet communities. Implications for prescribing and non-prescribing psychologists are discussed.

22) Valuck RJ, Orton HD, Libby AM. Antidepressant discontinuation and risk of suicide attempt: a retrospective, nested case-control study. Journal Of Clinical Psychiatry. 2009;70(8):1069-77. Pubmed link

This study compared a group of individuals who had been diagnosed with depression to a group of individuals who had been diagnosed with depression and attempted suicide. Relevant to discontinuation, the authors found that the first 2 weeks after stopping an ADM is a time for increased risk for suicide as well, whereas using AD was found to be a protective factor. Initiation of AD therapy was associated with the highest rate of suicide attempt, followed by phases where doses were reduced or increased. Also individuals who attempted suicide were more likely to use ADM and have multiple occurrences of depressive episodes.

23) Csoka AB, Shipko S. Persistent sexual side effects after SSRI discontinuation. Psychotherapy And Psychosomatics. 2006;75(3):187-188. Pubmed link

In this paper the authors present 3 cases where patients experienced persistent sexual dysfunction several years after discontinuing their ADM. Some potential hypotheses to explain this phenomenon are discussed.

24) Csoka AB, Bahrick A, Mehtonen O-P. Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors. Journal Of Sexual Medicine. 2008;5(1):227-233. Pubmed link

In this paper the authors present 3 cases where patients experienced persistent sexual dysfunction several years after discontinuing their ADM. These 3 were chosen out of 1300 individuals who self-identified as having sexual problems post SSRI discontinuation. The findings are discussed in light of the changes that SSRIs produce in various systems that do not seem to renormalize upon discontinuing the medication.

25) Green, B. Persistent Adverse Neurological Effects Following SSRI Discontinuation (PANES). Psychiatry on-line. 2000. Available at http://www.priory.com/psych/panes.htm#discussion.

This brief report described four patients on SSRIs who all suffered prolonged neurological symptoms for months after discontinuing their medication. All patients were on drugs that affect the reuptake of serotonin despite being structurally dissimilar and having different mechanisms of action. The authors speculate that this may be responsible for the persistent neurological symptoms observed despite stopping the medication.

26) Bolton JM, Sareen J, Reiss JP. Genital anaesthesia persisting six years after sertraline discontinuation. Journal Of Sex & Marital Therapy. 2006;32(4):327-30 Pubmed link

This paper describes a case study of a 26-year-old man who experienced a sexual side-effect during active use and 6 years after discontinuation of the ADM sertraline, even as his mood remained stable. The authors hypothesize the cause of this persistent dysfunction a) may be related to psychological reasons or b) the sertraline led to long-term functional changes in the brain that did not reverse. The patient believed that his symptoms were an effect of the sertraline.

27) Kauffman, RP Murdock, A. Prolonged post-treatment genital anesthesia and sexual dysfunction following discontinuation of citalopram and the atypical antidepressant nefazodone. The Open Women’s Health Journal. 2007, 1: 1-3.

This paper describes a case of a 32-year-old woman who experienced sexual side effects during 4 weeks of treatment with an SSRI, citalopram which led to switching to nefazodone. Even though her depression symptoms remained in remission, the sexual side effects persisted even after a year of stopping all medication. Possible reasons for this phenomenon are discussed.

28) Sabljić V, Ružić K, Rakun R. Venlafaxine withdrawal syndrome. Psychiatria Danubina. 2011;23(1):117-9. Pubmed link.

Abrupt venlafaxine discontinuation involves a high risk of withdrawal syndrome. Mechanism of its development is similar to that of selective serotonin reuptake inhibitors (SSRIs), but of higher intensity. Venlafaxine withdrawal symptoms may include several somatic symptoms as well as several psychiatric symptoms. In some cases, symptoms may look like a stroke. A treatment option is re-inclusion of venlafaxine or a SSRI antidepressant.

29) Wang J, Greenberg H. Status cataplecticus precipitated by abrupt withdrawal of venlafaxine. Journal Of Clinical Sleep Medicine. 2013;9(7):715-6. Pubmed link

A case study of a narcoleptic patient who developed status cataplecticus after abrupt withdrawal of venlafaxine.

30) Pinzani V, Giniès E, Robert L, Peyrière H, Abbar M, Blayac JP. Venlafaxine withdrawal syndrome: report of six cases and review of the literature. La Revue De Médecine Interne 2000;21(3):282-4. Pubmed link

A case study of six patients who developed withdrawal syndromes after discontinuing venlafaxine.

31) Rosenbaum J,  Zajecka J. Clinical Management of Antidepressant Discontinuation. Journal of Clinical Psychiatry 1997; 58, suppl. 7, 37-40. Pubmed link 

To minimize the symptoms of antidepressant discontinuation, gradual tapering is necessary for all serotonin reuptake inhibitors (SRIs) except fluoxetine, which has an extended half-life.  Discontinuation symptoms, which frequently emerge after abrupt discontinuation or intermittent non-compliance and, less frequently, during dose reduction, are generally mild, short-lived, and self-limiting but can be distressing and may lead to missed work days and decreased productivity. The symptoms may be somatic (e.g., dizziness and light-headedness; nausea and vomiting; fatigue, lethargy, myalgia, chills, and other flu-like symptoms; sensory and sleep disturbances) or psychological (anxiety and/or agitation, crying spells, irritability).

32) El-Mallakh RS, Gao Y, Jeannie Roberts R. Tardive dysphoria: the role of long term antidepressant use in-inducing chronic depression. Medical Hypotheses. 2011;76(6):769-773. Pubmed link

The authors propose a model of tardive dysphoria, which is a potentially chronic depressive state that develops in some individuals who have been using ADM over a longer period of time. Discontinuation of ADM may lead to a gradual improvement in symptoms some people, but in others the chronic state of depression may be permanent and irreversible. A genetic explanation linked to a serotonin transporter gene for this phenomenon is provided. The authors conclude by stating the need for randomized control trials to test the existence of tardive dysphoria. They state that discontinuation may be more likely to be beneficial for those who have had briefer exposure to ADM, have greater brain neuroplasticity and have the long form on the serotonin transporter gene.

33) El-Mallakh RS, Karippot A. Antidepressant-associated chronic irritable dysphoria (ACID) in bipolar disorder: a case series. J Affect Disord 2005;84:267–72. Pubmed link

A case study of six bipolar patients who developed a chronic dysphoric mood, irritability and middle insomnia, which is associated with occupational and social dysfunction, after receiving antidepressants for three years. Discontinuation of antidepressants was associated with a slow and gradual improvement in these symptoms over the ensuing year.

34) Fava GA, Gotti A, Belaise C, Guidi J, Offidani E. Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review. Psychotherapy and Psychosomatics 2015;84 (2):72-81. Full Text.

A systematic review of the research literature for studies that reported on SSRI withdrawal symptoms. These studies showed that discontinuation symptoms typically occur within a few days following discontinuation and last a few weeks. This occurs with gradual tapering too. However, patient experiences are variable, and some may experience late onset of discontinuation symptoms, or disturbances that persist. Such withdrawal symptoms are often misidentified as signs of impending relapse.

Relapse Upon Discontinuation

35) Baldessarini RJ, Tondo L, Ghiani C, et al. Illness Risk Following Rapid Versus Gradual Discontinuation of Antidepressants. American Journal of Psychiatry. 2010;167(8):934-941. Pubmed link

In this naturalistic study patients on ADM were taken off their medication either rapidly (1-7 days) or gradually (over 14 days or more). Results indicate that rapid discontinuation leads not only to early withdrawal or physiological symptoms, but also to a quicker return of a new episode of depression or panic. They also found a link between a drug’s half life and recurrence of illness. They conclude that gradual dose tapering may be especially beneficial when discontinuing older antidepressants and those with shorter half-lives. However, since physiological discontinuation reactions are linked with drugs that act on the serotonin system, they recommend gradual dose tapering for all ADMs.

Tapering Speed

Tapering to be customized for a patient depending on the half life of the ADM being used as well as the dose. The general rule is that drugs with shorter half lives need a longer taper period. Another factor that impacts speed of taper is the dose the patient has been taking. Most guideline documents say “reduce dose gradually” over a certain number of weeks depending on the ADM but do tend not to specify exactly what gradual means.

36) Keks N, Hope J, Keogh S. Switching and stopping antidepressants. Australian Prescriber. 2016;39(3):76-83. Pubmed link

The authors recommend stopping ADMs over 4 weeks at least, but mention other factors that need to be taken into consideration when making this decision. They provide tables listing the approximate half-lives of ADMs, general techniques for switching between ADMs and guidelines for switching between specific ADMs.

37) Khan A, Musgnung J, Ramey T, et al. Abrupt discontinuation compared with a 1-week taper regimen in depressed outpatients treated for 24 weeks with desvenlafaxine 50 mg/d. Journal Of Clinical Psychopharmacology. 2014;34(3):365-368. Pubmed link

This controlled clinical trial was conducted to assess if there were any differences in the emergence of discontinuations symptoms with an abrupt versus a taper protocol. The control group continued taking the medication as usual. The taper protocol switched patients to 25 mg/d for one week after 24 weeks of treatment with 50 mg/d, followed by a placebo for 3 weeks. Symptoms or adverse events after stopping the medication were measured using the Discontinuation Emergent Signs and Symptoms (DESS) scale. The authors conclude that even though there were more absolute adverse events reported by patients in the abrupt taper group compared to the taper group, this difference was not statistically significant.

38) Ogle NR, Akkerman SR. Guidance for the discontinuation or switching of antidepressant therapies in adults. Journal Of Pharmacy Practice. 2013;26(4):389-396. Pubmed link

This is a guidance document based on evaluation of the literature and is intended as a guide for clinicians or other healthcare professionals in their management of patients who want to stop or switch their ADM (see Tables 1 and 2). They note that package inserts for ADMs warn of withdrawal risk but do not provide details about how to taper. They also mention that there is very little evaluation of the data presented and the source documents provide varied information.

39) Phelps J. Tapering antidepressants: is 3 months slow enough? Medical Hypotheses. 2011;77(6):1006-1008. Pubmed link

This study was designed to test a new drug for the treatment of cataplexy (a sleep-related disorder) which has a history of being treated with ADM. This necessitated stopping the ADM patients were taking. Control participants were patients who had never taken ADM. The author concluded based on the higher number of weekly cataplexy attacks for the ADM group that longer taper rates for ADM may be warranted. He proposes discontinuing over 4 months at a rate of 25% reduction per month or 12.5% every 2 weeks. However, he says, this needs further systematic study.

40) Fava M, Rosenbaum JF, Hoog SL, et al. A comparison of symptoms following treatment interruption: Evidence from a randomized, double-blind trial with fluoxetine, sertraline, and paroxetine. European Neuropsychopharmacology 8:S171-S172

This controlled trial followed a protocol where ADM was stopped for 4-6 day periods in a group of patients who had responded to 4-10 weeks of treatment. Adverse events measured using checklists and spontaneous reporting by patients. Results indicate that brief interruption of SSRI treatment results in new or worse adverse events. The frequency of adverse events was greatest for paroxetine, followed by sertraline and lastly fluoxetine.

41) Pringsheim T, Kelly M, Barbui C. Stopping antidepressants following depression. BMJ 2016;352. Pubmed link

This is a 10-minute consultation guide for practitioners. It follows NICE guidelines in recommending ADM to be taperered over 4 weeks if the patient has been well for 6-12 months. If discontinuation symptoms occur they recommend tapering over a longer period, but do not specify how much longer.

42) Tint A, Haddad PM, Anderson IM. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomised study. Journal Of Psychopharmacology (Oxford, England). 2008;22(3):330-332. Pubmed link

This study compared the emergence of SSRI discontinuation on tapering the medication over 3 versus 14 days. Results indicate that there were more adverse events reported upon quicker taper, but these results were not significant. However, the half-life of the drug is an important consideration – drugs with shorter half lives need to be tapered more slowly, especially because of the possibility of increased depressive and suicidal symptoms when SSRIs are discontinued.

43) Kaymaz, N., et al. (2008). Evidence that patients with single versus recurrent depressive episodes are differentially sensitive to treatment discontinuation: a meta-analysis of placebo-controlled randomized trials. The Journal Of Clinical Psychiatry 69(9): 1423-1436. Pubmed link

This review of 30 trials (4890 patients) was conducted to understand what moderates the effect of the finding that ADM prevents the occurrence of relapse after remission from an episode of depression. Relapse rates were found to be greater in patients with recurring episodes of depression. The mode of discontinuation of ADM had an effect on this group, but not single episode patients. The authors found that acute withdrawal was more likely to lead to relapse in recurrent episode patients. Acute withdrawal was not as relevant for single episode patients. The authors conclude that the recommendation that patients should be treated for at least 6 months after achieving remission or that patients with more frequent episodes should receive maintenance treatment is not supported based on these findings. They recommend gradual discontinuation of ADM in general, to manage withdrawal symptoms.

44) Rothschild, Anthony J. Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction: Efficacy of a Drug Holiday. The American Journal of Psychiatry 152.10 (1995): 1514-6. ProQuest. Web. 2 Sep. 2016. Pubmed link

This study was conducted on a group of 30 outpatients who experienced sexual dysfunction upon taking SSRIs to assess whether a “drug holiday” or brief break from medication would lead to improved sexual functioning. ADM was stopped for 4 weekends from Thursday to Sunday. Results indicate that sexual functioning improved in patients taking sertraline and paroxetine, but not fluoxetine. The authors presume this is because of the shorter half lives of sertraline and paroxetine compared to fluoxetine. There were no statistically significant increases in depression scores across all patients.

44) Fava GA, Bernardi M, Tomba E, Rafanelli C. Effects of gradual discontinuation of selective serotonin reuptake inhibitors in panic disorder with agoraphobia. Int J Neuropsychopharmacol 2007;10:835–8.
 Pubmed link

In a study of 20 remitted patients, antidepressants were tapered at the slowest possible pace and with appropriate patient education. Nine of the 20 patients (45%) experienced a discontinuation syndrome, which subsided within a month in all but three patients who had been taking paroxetine for a long time. Discontinuation syndromes appeared to be fairly common even when performed with slow tapering and during clinical remission. In some cases disturbances persisted for months after discontinuation.

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