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Clinical Review  |   March 2020
Antidepressant Discontinuation Syndrome: A Common but Underappreciated Clinical Problem
Author Notes
  • From the Department of Clinical Integration (Dr Rizkalla) at Midwestern University/Chicago College of Osteopathic Medicine (Mr Kowalkowski) and the Department of Pharmacology at the College of Graduate Studies at Midwestern University (Dr Prozialeck) in Downers Grove, Illinois. 
  • Financial Disclosures: None reported. 
  • Support: None reported. 
  •  *Address correspondence to Mireille Rizkalla, PhD, Department of Clinical Integration, Midwestern University Chicago College of Osteopathic Medicine, 555 31st St, Downers Grove, IL 60515-1235. Email: mrizka@midwestern.edu
     
Article Information
Psychiatry
Clinical Review   |   March 2020
Antidepressant Discontinuation Syndrome: A Common but Underappreciated Clinical Problem
The Journal of the American Osteopathic Association, March 2020, Vol. 120, 174-178. doi:https://doi.org/10.7556/jaoa.2020.030
The Journal of the American Osteopathic Association, March 2020, Vol. 120, 174-178. doi:https://doi.org/10.7556/jaoa.2020.030
Antidepressants are a diverse group of medications commonly used as front-line agents for the treatment of various forms of depression. However, many of these medications are also used to manage other conditions, such as obsessive-compulsive disorders, generalized anxiety disorders, eating disorders, neuropathic pain syndromes, and chronic pain syndromes.1 Given the widespread use of antidepressants, physicians may be driven by an overestimated consideration of potential benefits, while appraisal of adverse effects are, by comparison, often overlooked.2 
Antidepressants are typically classified as either first or second generation.1 The first-generation antidepressants include tricyclics, a tetracyclic agent, and the monoamine oxidase inhibitors (MAOIs). Even though they are efficacious in the management of depression and other conditions (eg, anxiety disorders, eating disorders), use of the first-generation agents is often complicated by adverse effects, toxicity in overdose situations, and numerous drug-drug and drug-food interactions.1 Second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and a variety of other agents, such as trazadone, bupropion, and mirtazapine. These agents generally have better side effect profiles and are far less likely to cause death in cases of overdose.1,3,4 
Mechanism of Action of Antidepressants
The mechanisms underlying the therapeutic effects and discontinuation symptoms of antidepressants are not fully understood. Most current theories focus on both the initial primary biochemical effects of the antidepressant, which occur early in therapy, and subsequent adaptive changes in synaptic function and plasticity that occur over time (≥2-6 weeks for most antidepressants).1,5-7 For example, initial biochemical effects involve increased availability of neurotransmitters via inhibition of the synaptic reuptake of neurotransmitter amines, such as serotonin (SSRIs); serotonin and norepinephrine (SNRIs and tricyclics); and norepinephrine and dopamine (buprion).1 Likewise, MAOIs interfere with the metabolic breakdown of neurotransmitters, whereas drugs such mirtazapine and trazadone have direct effects on serotonin receptors.1 Although these biochemical changes are evident within days of therapy, clinical effects such as improvement in mood require several (2-6) weeks of treatment. The time lag between biochemical changes and observed clinical improvement is due to adaptive changes in levels of neurotransmitters, the density of their receptors, alterations in signaling cascades associated with these receptors, and increases in neuroplasticity in limbic regions.1,5,6 
After abrupt antidepressant discontinuation, the sudden deprivation of serotonin coupled with temporary adaptive changes probably triggers the antidepressant discontinuation symptoms (ADSs). Neurologic changes and discontinuation symptoms usually slowly resolve over several weeks; however, this period can be difficult for patients.5 Gradual reductions in dosing rather than abrupt discontinuation allows more synchronous recalibration of adaptive changes and mitigates the severity of discontinuation symptoms.5,6,8,9 Suggested tapering regimens are presented in the Table. 
Table.
Symptoms of Antidepressant Discontinuation Syndrome and Recommendations for Taper Rates8,10
Drug Recommended Taper Rate Discontinuation Symptoms
MAOIs
 Phenelzine Reduction of 15 mg every 2 wk or 10% per wk Headache, insomnia, myoclonic jerks, agitation, catatonia, delirium, delusions, hallucinations
Tricyclics
 ▪Amitriptyline
 ▪Clomipramine
 ▪Desipramine
 ▪Doxepin
 ▪Imipramine
 ▪Nortriptyline
Gradually taper over 3 mo Influenzalike symptoms, headache, lethargy, insomnia, dizziness, nausea, akathisia, parkinsonism, tremor, agitation, anxiety, low mood
SSRIs
 Fluoxetine Gradual taper generally unnecessary due to long half-life and active metabolite Influenzalike symptoms, headache, lethargy, abdominal pain, diarrhea, insomnia, dizziness, nausea, imbalance, electric shock, irritability, anxiety, low mood
 Paroxetine Reduction of 10 mg every 5-7 d with a final dosage of 5-10 mg/d before discontinuation
 Sertraline Reduction of 50 mg every 5-7 d with a final dose of 25-50 mg/d before discontinuation
SNRIs
 Venlafaxine Reduction of 25 mg every 5-7 d with a final dosage of 25-50 mg/d before discontinuation Influenzalike symptoms, headache, lethargy, nausea, insomnia, dizziness, electric shock, anxiety, low mood

Abbreviations: MAOI, monoamine oxidase inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Table.
Symptoms of Antidepressant Discontinuation Syndrome and Recommendations for Taper Rates8,10
Drug Recommended Taper Rate Discontinuation Symptoms
MAOIs
 Phenelzine Reduction of 15 mg every 2 wk or 10% per wk Headache, insomnia, myoclonic jerks, agitation, catatonia, delirium, delusions, hallucinations
Tricyclics
 ▪Amitriptyline
 ▪Clomipramine
 ▪Desipramine
 ▪Doxepin
 ▪Imipramine
 ▪Nortriptyline
Gradually taper over 3 mo Influenzalike symptoms, headache, lethargy, insomnia, dizziness, nausea, akathisia, parkinsonism, tremor, agitation, anxiety, low mood
SSRIs
 Fluoxetine Gradual taper generally unnecessary due to long half-life and active metabolite Influenzalike symptoms, headache, lethargy, abdominal pain, diarrhea, insomnia, dizziness, nausea, imbalance, electric shock, irritability, anxiety, low mood
 Paroxetine Reduction of 10 mg every 5-7 d with a final dosage of 5-10 mg/d before discontinuation
 Sertraline Reduction of 50 mg every 5-7 d with a final dose of 25-50 mg/d before discontinuation
SNRIs
 Venlafaxine Reduction of 25 mg every 5-7 d with a final dosage of 25-50 mg/d before discontinuation Influenzalike symptoms, headache, lethargy, nausea, insomnia, dizziness, electric shock, anxiety, low mood

Abbreviations: MAOI, monoamine oxidase inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

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Antidepressant Discontinuation Syndrome
Withdrawal symptoms following cessation of the prototypical tricyclic antidepressant, imipramine, were first reported in the 1950s.11 Over the years, similar withdrawal symptoms were reported after the use of all major classes of antidepressants, including other tricyclics (eg, amitriptyline, clomipramine, desipramine), MAOIs (eg, tranylcypromine, phenelzine, isocarboxazid), SSRIs (eg, fluoxetine, paroxetine, sertraline), SNRIs (venlafaxine, duloxetine), and other second-generation agents.12 They have clinically been called discontinuation syndromes, with the intention to avoid any association between antidepressants and addictive drugs (with which the term withdrawal may be associated). Antidepressants are not considered to be addictive in the sense that users do not seek them to “get high” but rather to alleviate symptoms of serious medical problems. However, with extended use, they can be notoriously difficult to quit because they can produce a state of physical dependence. Therefore, discontinuation can cause a group of symptoms that are very unpleasant and can lead patients to continue to seek the medications.5,8,10,13-15 The persistent use is not for a high but to alleviate symptoms of disease or to avoid unpleasant ADSs. 
Clinical Manifestations and Diagnostic Considerations
The ADSs typically appear within a few days of stopping an antidepressant and usually last 2 weeks15 or longer.16,17 Even though ADSs are mostly reported after abrupt antidepressant suspension, they can also occur after gradual tapering or after missed doses.7,18 Antidepressant discontinuation symptoms are more likely to occur after longer duration of treatment and with antidepressants that have shorter half-lives for elimination (eg, paroxetine). Symptoms can also vary markedly from one individual to another depending on the drug class. For example, ADSs associated with tricyclic antidepressants closely mimic those of SSRIs but can additionally include profound balance problems and parkinsonian features.8 Certain SNRIs, such as venlafaxine, can cause more severe ADSs than those caused by SSRIs. Antidepressant discontinuation symptoms associated with MAOIs may involve more serious symptoms, such as aggressiveness, catatonia, cognitive impairment, and psychosis and may require more intensive management.19 
In the past 2 decades, efforts have been made to develop clinical indices for diagnosing and detecting ADSs. The FINISH mnemonic (flulike symptoms, insomnia, nausea, imbalance, sensory disturbances [including shocklike “brain zaps”2], hyperarousal) was created to facilitate rapid recognition of symptoms.20 The diagnostic criteria that encompass these symptoms have been proposed by Black et al,9 and the use of the Discontinuation Emergent Signs and Symptoms scale is recommended to quantify symptoms.21 A failure to recognize ADSs may result in misdiagnosis of depressive relapse or treatment tolerance, necessitating a high index of clinical discernment. Unlike the abrupt onset of ADSs, symptoms of depressive relapse typically occur weeks after medication discontinuation and are most often marked by gradual worsening of depression, insomnia, and psychomotor symptoms.22 Moreover, concerns over a possible link between antidepressant use and suicidality, particularly among youth, led the US Food and Drug Administration to issue a series of risk communications, culminating in black-box warnings.23 These warnings, amplified by media coverage, led to research, whose findings suggested that there was an elevated risk of suicidality during both antidepressant use and antidepressant discontinuation, especially those medications with short half-lives.24 Collectively, these findings indicate that patients should be warned about and monitored for the possibility of increased depressive and suicidal symptoms. 
Prevention and Management
Gradual tapering of an SSRI does not completely prevent antidepressant discontinuation syndrome13 but appears to be a reasonable strategy to reduce ADSs.25 When mild symptoms emerge, reassurance is usually sufficient while the syndrome runs its course. In more severe cases, ADSs may last significantly longer.17 Severe cases can be treated symptomatically, or the antidepressant can be reinstated for rapid resolution followed by careful tapering to prevent reemergence.10 In cases where slow tapering is poorly tolerated, a medication with a longer half-life (especially fluoxetine) may be substituted for the shorter-half-life agent. In addition, cognitive behavioral therapy and mindfulness-based therapies may be helpful in some patients.26 Tapering regimens have not been validated in systematic studies; therefore, recommendations are based on anecdotal opinion as an art more than a science.8 Research is needed to provide solid evidence-based recommendations. 
Summary and Perspective
The Figure summarizes considerations for managing discontinuation of antidepressants. Many physicians consider antidepressants the treatment of choice for a variety of conditions. Therapeutic efficacy, simple dosing regimens, and favorable side-effect profiles of second-generation agents have all contributed to their popularity. While antidepressants are important and potentially lifesaving medications, their unrestrained use may be rooted in an underestimation of the potential for antidepressant discontinuation syndrome. A balanced approach to prescribing acknowledges that this syndrome is a clinically relevant phenomenon that consists of a cluster of somatic and psychological symptoms, can be easily misdiagnosed, and can hinder future antidepressant compliance. Physicians should counsel patients about the possibility of ADSs before initiating therapy with antidepressants. 
Figure.
Considerations for antidepressant discontinuation after long-term treatment.
Figure.
Considerations for antidepressant discontinuation after long-term treatment.
References
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Papp A, Onton JA. Brain zaps: an underappreciated symptom of antidepressant discontinuation. Prim Care Companion CNS Disord; 2018;20(6). doi: 10.4088/PCC.18m02311
Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366. doi: 10.1016/S0140-6736(17)32802-7 [CrossRef] [PubMed]
Furukawa TA, Salanti G, Atkinson LZ, et al. Comparative efficacy and acceptability of first-generation and second-generation antidepressants in the acute treatment of major depression: protocol for a network meta-analysis. BMJ Open. 2016;6(7):e010919. doi: 10.1136/bmjopen-2015-010919 [CrossRef] [PubMed]
Renoir T. Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved. Front Pharmacol. 2013;4:45. doi: 10.3389/fphar.2013.00045
Harvey BH, Slabbert FN. New insights on the antidepressant discontinuation syndrome. Hum Psychopharmacol. 2014;29(6):503-516. doi: 10.1002/hup.2429 [CrossRef] [PubMed]
Zabegalov KN, Kolesnikova TO, Khatsko SL, et al. Understanding antidepressant discontinuation syndrome (ADS) through preclinical experimental models. Eur J Pharmacol. 2018;829:129-140. doi: 10.1016/j.ejphar.2018.04.003 [CrossRef] [PubMed]
Warner CH, Bobo W, Warner C, Reid S, Rachal J. Antidepressant discontinuation syndrome. Am Fam Physician. 2006;74(3):449-456. [PubMed]
Black K, Shea C, Dursun S, Kutcher S. Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. J Psychiatry Neurosci. 2000;25(3):255-261. [PubMed]
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Fava GA, Benasi G, Lucente M, Offidani E, Cosci F, Guidi J. Withdrawal symptoms after serotonin-noradrenaline reuptake inhibitor discontinuation: systematic review. Psychother Psychosom. 2018;87(4):195-203. doi: 10.1159/000491524 [CrossRef] [PubMed]
Maund E, Stuart B, Moore M, et al. Managing antidepressant discontinuation: a systematic review. Ann Fam Med. 2019;17(1):52-60. doi: 10.1370/afm.2336 [CrossRef] [PubMed]
Jha MK, Rush AJ, Trivedi MH. When discontinuing SSRI antidepressants is a challenge: management tips. Am J Psychiat. 2018;175(12):1176-1184. doi: 10.1176/appi.ajp.2018.18060692 [CrossRef] [PubMed]
Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: are guidelines evidence-based? Addict Behav. 2019;97:111-121. doi: 10.1016/j.addbeh.2018.08.027 [CrossRef] [PubMed]
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Figure.
Considerations for antidepressant discontinuation after long-term treatment.
Figure.
Considerations for antidepressant discontinuation after long-term treatment.
Table.
Symptoms of Antidepressant Discontinuation Syndrome and Recommendations for Taper Rates8,10
Drug Recommended Taper Rate Discontinuation Symptoms
MAOIs
 Phenelzine Reduction of 15 mg every 2 wk or 10% per wk Headache, insomnia, myoclonic jerks, agitation, catatonia, delirium, delusions, hallucinations
Tricyclics
 ▪Amitriptyline
 ▪Clomipramine
 ▪Desipramine
 ▪Doxepin
 ▪Imipramine
 ▪Nortriptyline
Gradually taper over 3 mo Influenzalike symptoms, headache, lethargy, insomnia, dizziness, nausea, akathisia, parkinsonism, tremor, agitation, anxiety, low mood
SSRIs
 Fluoxetine Gradual taper generally unnecessary due to long half-life and active metabolite Influenzalike symptoms, headache, lethargy, abdominal pain, diarrhea, insomnia, dizziness, nausea, imbalance, electric shock, irritability, anxiety, low mood
 Paroxetine Reduction of 10 mg every 5-7 d with a final dosage of 5-10 mg/d before discontinuation
 Sertraline Reduction of 50 mg every 5-7 d with a final dose of 25-50 mg/d before discontinuation
SNRIs
 Venlafaxine Reduction of 25 mg every 5-7 d with a final dosage of 25-50 mg/d before discontinuation Influenzalike symptoms, headache, lethargy, nausea, insomnia, dizziness, electric shock, anxiety, low mood

Abbreviations: MAOI, monoamine oxidase inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Table.
Symptoms of Antidepressant Discontinuation Syndrome and Recommendations for Taper Rates8,10
Drug Recommended Taper Rate Discontinuation Symptoms
MAOIs
 Phenelzine Reduction of 15 mg every 2 wk or 10% per wk Headache, insomnia, myoclonic jerks, agitation, catatonia, delirium, delusions, hallucinations
Tricyclics
 ▪Amitriptyline
 ▪Clomipramine
 ▪Desipramine
 ▪Doxepin
 ▪Imipramine
 ▪Nortriptyline
Gradually taper over 3 mo Influenzalike symptoms, headache, lethargy, insomnia, dizziness, nausea, akathisia, parkinsonism, tremor, agitation, anxiety, low mood
SSRIs
 Fluoxetine Gradual taper generally unnecessary due to long half-life and active metabolite Influenzalike symptoms, headache, lethargy, abdominal pain, diarrhea, insomnia, dizziness, nausea, imbalance, electric shock, irritability, anxiety, low mood
 Paroxetine Reduction of 10 mg every 5-7 d with a final dosage of 5-10 mg/d before discontinuation
 Sertraline Reduction of 50 mg every 5-7 d with a final dose of 25-50 mg/d before discontinuation
SNRIs
 Venlafaxine Reduction of 25 mg every 5-7 d with a final dosage of 25-50 mg/d before discontinuation Influenzalike symptoms, headache, lethargy, nausea, insomnia, dizziness, electric shock, anxiety, low mood

Abbreviations: MAOI, monoamine oxidase inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

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