When Discontinuing SSRI Antidepressants Is a Challenge: Management Tips
Publication: American Journal of Psychiatry
“Ms. A” is a 37-year-old Caucasian woman with major depressive disorder who was admitted to the psychiatry inpatient unit after worsening suicidal ideation. After onset of her first major depressive episode, at age 32, she was started on paroxetine at 20 mg/day by her primary care physician. After 3 months, her dosage was increased to 50 mg/day because of inadequate response to treatment. Her symptoms improved markedly (>75% reduction) at this dosage. This improvement was sustained for more than 6 months, when her physician recommended discontinuation of paroxetine by gradually tapering the dosage by 10 mg/day every week until she was on a dosage of 20 mg/day, and then 20 mg/day every other day for 2 weeks before discontinuing completely.
Two days after discontinuing paroxetine completely, Ms. A started experiencing nausea, light-headedness, tingling in her extremities, “brain zaps,” ringing in her ears, and vivid dreams. Although these symptoms were moderately burdensome, she did not restart medication, and her symptoms resolved spontaneously after a week. During this period, she did not experience any worsening of her mood or changes in anxiety or irritability.
Eight months later, Ms. A sought care from her primary care physician again because of worsening of depressive symptoms. She was restarted on paroxetine, but it was no longer effective, even after treatment at 50 mg/day for 3 months. Her physician therefore reduced the dosage of paroxetine to 20 mg/day and added sustained-release bupropion at 200 mg/day. Six weeks after initiating bupropion, Ms. A experienced marked improvement (>75% reduction) in her symptoms. Her physician recommended that she stay on this regimen indefinitely.
Two years later, at age 36, Ms. A became interested in web sites discussing natural treatments for depression. She decided to wean herself off her antidepressant medications and discontinued bupropion abruptly, without any complaints. To prevent discontinuation symptoms from paroxetine, she crushed and dissolved tablets in 1-liter water bottles and gradually tapered off by sipping progressively smaller amounts of this mixture. After complete discontinuation of antidepressants, she did well, with no symptoms of depression and no adverse discontinuation effects. However, 3 months later, she experienced severe worsening of her depressive symptoms, characterized by pervasive sad mood, little or no interest in her surroundings, social isolation, increased appetite, increased sleep (>10 hours per 24-hour period), poor concentration, low energy, excessive guilt, and an inability to sit still. This was the worst she had ever felt, and she had to go on medical leave because of depression-related absenteeism. She recontacted her primary care physician after she started having thoughts of killing herself. Her physician sent her for urgent psychiatric evaluation, and she was admitted to the inpatient unit.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressant (1) and are recommended as one of the first-line treatments (2–4) for major depressive disorder, an often chronic or recurrent disorder that affects one in six adults during their lifetime (5). Since less than one-third of patients with major depression attain remission with an initial antidepressant trial (6), multiple sequential acute-phase (at least 6–8 weeks) trials are often needed for attainment of symptomatic remission (3, 7). Beyond the acute phase, changes to the patient’s antidepressant medication regimen may be warranted to address residual symptoms, persistent functional impairments, loss of initial therapeutic effect (antidepressant tachyphylaxis), occurrence or prevention of relapse or recurrence, side effects, affordability, or anticipated drug-drug interactions with medications for other medical conditions (8–10). Additionally, patients may discontinue their treatment because of concern about adverse effects (11), which are common with antidepressant medications (12). Clinicians may also recommend discontinuation of treatment for patients with no or few risk factors for relapse or recurrence or upon patient request, consistent with treatment guidelines of 6 to 9 months of continuation-phase treatment after symptomatic remission (2–4).
Treatment guidelines and the U.S. Food and Drug Administration prescribing labels (2–4, 13–17) caution that new-onset symptoms may occur on discontinuation of antidepressant medications and recommend gradual tapering to prevent such symptoms. Here, we discuss the varied symptomatic presentations associated with discontinuation of antidepressant medications and some potential mitigation strategies and tactics (Figure 1). We restricted the scope of this report to the use of SSRIs approved for treatment of major depressive disorder. To provide a fuller picture of the range of discontinuation symptoms, we have also included reports in which SSRIs were prescribed for indications other than major depressive disorder.
FIGURE 1. Consequences of SSRI Discontinuation and Potential Mitigation Strategiesa
a SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin-norepinephrine reuptake inhibitor. Symptoms commonly associated with depression in patients with major depressive disorder include irritability, anxiety, panic, and mania or hypomania.
We have organized the discussion of discontinuation symptoms to answer the following clinically relevant questions:
1.
What are discontinuation symptoms?
A.
How common are discontinuation symptoms?
B.
How do discontinuation symptoms present?
C.
What is the differential diagnosis for discontinuation symptoms?
D.
What is the pathophysiology of discontinuation symptoms?
2.
When do discontinuation symptoms occur and how long do they last?
3.
Who is at risk of discontinuation symptoms?
4.
How are discontinuation symptoms distinct from relapse or recurrence?
5.
What are the best strategies to manage discontinuation symptoms?
What are Discontinuation Symptoms?
Discontinuation symptoms are a constellation of symptoms that start soon after the discontinuation of SSRIs (symptomatic discontinuation), similar to other psychoactive medications and older antidepressants (18–20). In one of the first reports of symptomatic discontinuation involving SSRIs, Stoukides and Stoukides (21) reported development of acute dystonic reaction, hypertension, tachycardia, diaphoresis, and increased muscle tone in the extremities in a man who suddenly discontinued fluoxetine after a 6-month course. More cases of new-onset physical symptoms following SSRI discontinuation were reported in subsequent years, especially after SSRIs with shorter half-lives became available, such as sertraline and paroxetine (22–37). While early reports focused on physical symptoms associated with discontinuation, Bloch et al. (38) reported new-onset hypomanic symptoms following paroxetine discontinuation in two healthy men who were being treated for stuttering and had no history of major psychiatric disorders. Emergence of manic symptoms has also been reported with discontinuation of escitalopram (39). These reports resulted in recommendations that patients be assessed for SSRI discontinuation syndrome, which was defined as emergence of physical and neuropsychiatric symptoms within days to weeks after discontinuation of an SSRI that resulted in significant distress and were not accounted for by other causes (such as a general medical condition or concomitant medications) (40–42). While outside the scope of this review, one in eight cases of discontinuation symptoms with tramadol, a painkiller with serotonergic activity, resemble symptomatic SSRI discontinuation (with symptoms such as psychosis, confusion, anxiety/panic, and numbness and tingling in the extremities) and are distinct from classical opioid withdrawal (43). Similar symptomatic discontinuations occur with serotonin-norepinephrine reuptake inhibitors (SNRIs) (44–47).
How Common are Discontinuation Symptoms?
The true incidence of discontinuation symptoms is difficult to ascertain, because they are not systematically assessed in clinical practice and are typically not assessed in patients who drop out of care. On the basis of spontaneous adverse event reports for SSRIs, Price et al. (48) estimated discontinuation rates ranging from 0.002 (for fluoxetine) to 0.3 (for paroxetine) reports per 1,000 prescriptions. In a recent systematic review of clinical trials, Fava et al. (49) found that up to 40% of patients reported new-onset symptoms after abruptly discontinuing SSRIs. Paroxetine has the highest rates of symptomatic discontinuation (50, 51) as compared with other SSRIs, including sertraline (52, 53), citalopram (54), escitalopram (55), and fluoxetine (52, 53, 56–59). Although abrupt discontinuation of fluoxetine is generally well tolerated, case reports have documented the development of delirium after discontinuation (52, 60–63). Table 1 summarizes the findings of discontinuation symptoms reported for each SSRI that is approved for treatment of major depressive disorder.
| Drug and Type of Report | Study Findings |
|---|---|
| Paroxetine | |
| Clinical trials | Rosenbaum et al. (52): After paroxetine discontinuation for up to 8 days, 66% of patients (N=82) developed significant discontinuation symptoms. The mean severity of discontinuation symptoms was highest for paroxetine, intermediate for sertraline, and lowest for fluoxetine. |
| Baldwin et al. (55): A higher overall severity of discontinuation symptoms was observed with paroxetine compared with escitalopram (study N=323). Over 1 week immediately after discontinuation, specific symptoms were reported more often with paroxetine than with escitalopram: feeling tense (paroxetine=24.5%, escitalopram=12.7%), confusion (paroxetine=22.7%, escitalopram=10.4%), nausea (paroxetine=15.5%, escitalopram=5.2%), forgetfulness (paroxetine=15.5%, escitalopram=4.5%), sweating more than usual (paroxetine=13.6%, escitalopram=3.7%), shaking (paroxetine=11.8%, escitalopram=3.0%), sudden panic (paroxetine=8.2%, escitalopram=1.5%), and diarrhea (paroxetine=9.1%, escitalopram=0.7%). | |
| Michelson et al. (53): Interruption of paroxetine for 5 days was associated with worsening of 13 of 17 items on a solicited adverse event rating scale (N=36), with dizziness being the most common (reported by 57.1%). | |
| Judge et al. (56): Discontinuation of paroxetine for 3–5 days was associated with significantly higher severity of new-onset or worsened symptoms and worsening of depressive symptoms and functional impairments than discontinuation of fluoxetine (study N=150). Dreaming (36%) and dizziness (34%) were the most commonly reported discontinuation symptoms. | |
| Bogetto et al. (57): Discontinuation symptoms were present in 22 of 52 patients (42.3%) who discontinued paroxetine. | |
| Fava et al. (61): Even after gradual discontinuation, five of nine patients on paroxetine developed discontinuation syndrome, which persisted for more than 1 month in three of the patients. | |
| Montgomery et al. (50): Discontinuation of paroxetine was associated with more new symptoms (mean=7.3) in 1 week than continuation of paroxetine (mean=3.5) (study N=192). | |
| Oehrberg et al. (51): After 12 weeks of double-blind paroxetine and placebo treatment, 19 of 55 patients (34.5%) on paroxetine and seven of 52 (13.5%) reported new symptoms during a 2-week blinded discontinuation with placebo. | |
| Case reports | Barr et al. (22): Three of six patients developed discontinuation symptoms 3–7 days after paroxetine discontinuation despite a 1- to 2-week taper. |
| Keuthen et al. (23): Five of 13 patients developed discontinuation symptoms during paroxetine taper or 2–14 days after last dose. These symptoms lasted from 4 days to 2 weeks. In one patient, reinitiation of paroxetine abruptly terminated discontinuation symptoms. | |
| Pyke (27): Discontinuation symptoms developed in a patient 3 days after discontinuation of paroxetine (10–20 mg/day); symptoms resolved in 3 weeks. | |
| Phillips (28): Discontinuation symptoms developed in a patient 3 days after discontinuation of paroxetine (20 mg/day, prescribed for 5 weeks) and resolved on reinitiation of paroxetine but not with initiation of sertraline. | |
| DeBattista et al. (29): In two patients, discontinuation symptoms developed 1–2 days after discontinuation of paroxetine (10 mg/day) and resolved after paroxetine reinitiation. | |
| Frost and Lal (32): Two days after discontinuation of paroxetine (10–20 mg/day), two patients reported electric shock–like sensations, which resolved over 3 weeks. | |
| Dominguez and Goodnick (33): Discontinuation symptoms developed in three patients after discontinuation of paroxetine (40 mg/day). | |
| Bloch et al. (38): Hypomania developed in a patient after abrupt discontinuation of paroxetine (50 mg/day). | |
| Coupland et al. (58): In a retrospective review, 10 of 50 patients who discontinued paroxetine developed discontinuation symptoms. | |
| Peeters et al. (34): Severe discontinuation symptoms, including fever, developed in a patient on gradual reduction and discontinuation of paroxetine, which improved with medication reinitiation. | |
| Bryois et al. 1994: Discontinuation symptoms occurred in a patient after discontinuation of paroxetine. | |
| Fagan (36): Shock-like symptoms occurred in two patients on discontinuation of paroxetine. | |
| Fava and Grandi (24): Discontinuation symptoms started in three patients 7–10 days after discontinuation of paroxetine and persisted for 7–10 days. | |
| Sertraline | |
| Clinical trials | Rosenbaum et al. (52): After sertraline discontinuation for up to 8 days, 60% of patients (N=79) developed significant discontinuation symptoms. |
| Michelson et al. (53): Interruption of sertraline for 5 days was associated with worsening of three of 17 items on a solicited adverse event rating scale (N=34), with dizziness (reported by 42.4%) being the most common. | |
| Case reports | Louie et al. (26): Abrupt discontinuation of sertraline (100 mg/day, prescribed for 5 weeks) led to discontinuation symptoms after 2 days, which resolved with reinitiation of sertraline at 25 mg/day. These symptoms recurred to a milder degree after each dose reduction during a 12-week taper. |
| Coupland et al. (58): In a retrospective review, one of 45 patients who discontinued sertraline developed discontinuation symptoms. | |
| Frost and Lal (32): Sensation of electric shocks was reported by a patient 1 day after discontinuation of sertraline (50 mg/day, which had been gradually tapered down from 150 mg/day over 8 weeks) and persisted with lessening intensity for 13 weeks. | |
| Leiter et al. (37): Discontinuation symptoms started in two patients 1–2 days after discontinuation of sertraline (100–150 mg/day) and lasted up to 1 month. | |
| Fava and Grandi (24): Discontinuation symptoms started in a patient 5 days after discontinuation of sertraline (50 mg/day) and persisted for 1 week. | |
| Citalopram | |
| Clinical trials | Fava et al. (61): One of three patients (33.3%) had four or more discontinuation symptoms after stopping citalopram; symptoms resolved within 1 month. |
| Case reports | Young et al. (54): Two Committee on the Safety of Medicines reports of new-onset or worsened symptoms after discontinuation. |
| Escitalopram | |
| Clinical trials | Baldwin et al. (55): Escitalopram was better tolerated and was associated with fewer study dropouts than paroxetine. Rates of patients reporting individual discontinuation symptoms have been presented earlier with paroxetine. |
| Case reports | De Berardis et al. (39): Manic symptoms emerged after discontinuation of low-dose escitalopram in a patient with major depression; symptoms resolved on reinitiation. |
| Fluoxetine | |
| Clinical trials | Rosenbaum et al. (52): After fluoxetine discontinuation for up to 8 days, 14% of patients (N=81) developed significant withdrawal symptoms. |
| Michelson et al. (53): Interruption of fluoxetine for 5 days was associated with no worsening of any symptoms on a 17-item solicited adverse event rating scale (N=37). | |
| Judge et al. (56): Discontinuation of fluoxetine for 3–5 days was better tolerated than discontinuation of paroxetine. Fatigue (17%) and nervousness (16%) were the most commonly reported new-onset or worsened symptoms. | |
| Bogetto et al. (57): Discontinuation symptoms were present in four of 45 patients (8.9%) who discontinued fluoxetine. | |
| Fava et al. (61): One of three (33.3%) patients had four or more discontinuation symptoms after stopping fluoxetine; symptoms resolved within 1 month. | |
| Zajecka et al. (60): Of 395 fluoxetine responders, 96 were abruptly switched to placebo; those switched to placebo had rates of new or worsened adverse events similar to those who continued on fluoxetine (N=299). Discontinuation of fluoxetine was associated with a slightly higher rate of dizziness at 6 weeks (5% compared with 1%). | |
| Case reports | Stoukides and Stoukides (21): Discontinuation symptoms occurred in a patient 1–2 days after sudden discontinuation of a 6-month course of fluoxetine; symptoms responded to symptomatic management. |
| Einbinder (30): Discontinuation symptoms developed in a patient 3 days after discontinuation of fluoxetine (40 mg/day) on two separate occasions and resolved with reinitiation of fluoxetine each time. Discontinuation symptoms recurred on discontinuation of fluoxetine (5 mg/day) after a taper period. However, using liquid fluoxetine, no discontinuation symptoms occurred on discontinuation of fluoxetine at a dosage of 2.5 mg/day. | |
| Coupland et al. (58): In a retrospective review, none of 20 patients who discontinued fluoxetine developed discontinuation symptoms. | |
| Berlin et al. (31): Discontinuation symptoms occurred in three patients 2–25 days after discontinuation of fluoxetine (20–40 mg/day) and lasted 4–8 weeks. | |
| Blum et al. (62): Delirium developed in a patient after discontinuation of fluoxetine and resolved immediately on reinitiation. | |
| Fan and Liu (63): Delirium developed in a patient 2 days after discontinuation of fluoxetine (20 mg/day) and gradually improved on reinitiation of fluoxetine. |
a
SSRIs=selective serotonin reuptake inhibitors. PubMed and Google Scholar were searched for abstracts for case reports and clinical trials on withdrawal or discontinuation symptoms from SSRIs (fluoxetine, paroxetine, sertraline, citalopram, and escitalopram), and full-text articles were obtained when available; the references of these reports were also reviewed to identify any additional pertinent reports.
How Do Discontinuation Symptoms Present?
Berber (64) proposed the mnemonic “FINISH” for discontinuation symptoms: “flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, and hyperarousal (anxiety/agitation).” For more than 60% of patients, discontinuation of SSRIs will not be associated with any significant symptoms. When present, discontinuation symptoms may be mild, although they can also be moderate to severe in intensity, and in some cases they affect multiple organ systems. To aid clinicians, we have devised a focused review of systems that includes the discontinuation signs and symptoms reported in literature (Table 2).
| System | Signs and Symptoms |
|---|---|
| General | Chills, malaise, flu-like symptoms, fatigue, lethargy, fever, diaphoresis |
| Eyes | Blurred vision, eye movement abnormalities, sore eyes, eye twitch |
| Ears, nose, mouth, and throat | Tinnitus, rhinorrhea, sinus congestion, nasal congestion, increased salivation |
| Respiratory | Shortness of breath |
| Cardiovascular | Palpitation, tachycardia, elevation in systolic and diastolic blood pressure |
| Gastrointestinal | Nausea, vomiting, diarrhea, abdominal pain, stomach cramp, abdominal bloating |
| Genitourinary | Genital hypersensitivity, premature ejaculation |
| Musculoskeletal | Sore muscles, myalgia, arthralgia, muscle cramps |
| Skin and hair | Pruritus |
| Neurological | Disequilibrium (vertigo, dizziness, light-headedness, gait instability, and ataxia), sensory disturbances (unusual sensitivity to sound, electric shock–like sensations, paresthesia, tinnitus, dysgeusia, and brain zaps), neuromuscular symptoms (acute dystonia, myoclonus, tremor, shaking, akathisia), and cognitive symptoms (delirium, amnesia, memory impairments, disorientation, and confusion) |
| Psychiatric | Worsening of mood (dysphoria, hypomania, depression, bouts of crying, tearfulness, impulsiveness, irritability, agitation, anger attacks, mood swings, impaired concentration, muscle tension, suicidal and homicidal ideations), exacerbation of anxiety (tension, panic, and generalized anxiety), sleep disruption (insomnia, hypersomnia, vivid dreams, nightmares, disrupted circadian rhythm), and perceptual impairments (depersonalization, derealization, hypnogogic hallucinations, unusual visual sensations such as geometric shapes and colors, auditory and visual hallucinations) |
What is the Differential Diagnosis for Discontinuation Symptoms?
When considering symptoms due to SSRI discontinuation, it is prudent to rule out other causes for the symptoms. Causal general medical conditions include viral or bacterial infections of the respiratory or gastrointestinal tracts, foodborne illness from contaminated food or drinks, seasonal or other allergies, and stroke or other neurological conditions (65). Additionally, changes in concomitant medications, including discontinuation of other psychoactive drugs, may account for the presence of discontinuation symptoms. In cases of switching or cross-tapering of medications, where one medication is discontinued while another is initiated, discontinuation symptoms may be confused with treatment-emergent symptoms associated with depression, such as irritability, anxiety, panic, and mania or hypomania (66). Typically, a role for SSRI discontinuation is suspected on the basis of the timing (within days to a week after the medication is discontinued) and the types of symptoms (see Table 2).
What is the Pathophysiology of Discontinuation Symptoms?
A greater prevalence of symptoms after discontinuation of SSRIs with shorter half-lives suggests a role for reduced availability of serotonin in the central nervous system with decreasing levels of SSRIs (67). Across multiple SSRIs, Michelson et al. (53) found that greater reduction in serum levels of SSRIs and their active metabolites on discontinuation was associated with higher rates of discontinuation symptoms. Henry et al. (68) found that higher levels of paroxetine in the brain prior to discontinuation (despite the same oral dosage of 20 mg/day; N=4) were associated with higher levels of symptoms after discontinuation; no such association was seen for fluoxetine. In preclinical studies, chronic but not acute use of SSRIs has been associated with down-regulation of autoreceptors and serotonin transporter that may be sustained for weeks after discontinuation (69, 70). The modulation of serotonin receptors and transporters over several weeks of SSRI treatment may account for why symptoms do not emerge after discontinuing SSRIs taken for just 1–2 weeks (71).
Arguably, the strongest evidence for a pharmacological mechanism is inferred by rapid resolution of discontinuation symptoms by reinitiation of SSRI medication or, when symptoms emerge with a decrease in the dosage, by an increase in dosage. This is supported by animal studies in which discontinuation of chronic SSRI treatment has been associated with increased turnover of serotonin and reduced extracellular serotonin levels, along with an increased acoustic startle reflex, suggesting that reduced serotonin levels may account for anxiety-like discontinuation symptoms (72).
The multitude of symptom domains (Table 2) suggests that neurotransmission systems affected by SSRI discontinuation extend beyond serotonin. In fact, discontinuation symptoms have been partly attributed to increased glutamatergic neurotransmission, which is corrected by administration of N-methyl-d-aspartate receptor antagonist (73). Discontinuation of SSRIs has also been postulated to affect dopamine neurotransmission as well as the hypothalamic-pituitary-adrenal axis (67, 73).
When Do Discontinuation Symptoms Occur and How Long Do They Last?
Discontinuation symptoms typically start 1–10 days after abrupt discontinuation or marked dosage reduction of an SSRI (22, 27, 28, 56). With paroxetine, discontinuation symptoms may also occur if doses are skipped for a few days (29, 55). Discontinuation symptoms typically resolve spontaneously over 2–3 weeks (27, 32, 61). Reintroduction of another SSRI or the original SSRI results in improvement of symptoms within 2–3 days (28, 29, 34, 49). However, some reports have documented persistence of symptoms for up to 1 year (61).
Who is At Risk Of Discontinuation Symptoms?
Any patient who either discontinues or markedly reduces the antidepressant medication dosage is at risk of discontinuation symptoms. Antidepressant medications may need to be taken for at least 4–6 weeks before the development of discontinuation symptoms is of concern. In patients with premenstrual dysphoric disorder, discontinuation of SSRIs after up to 2 weeks of daily dosing was not associated with any increased symptoms compared with placebo (71). Patients who are taking the SSRI with the shortest half-life—paroxetine—are at the highest risk of discontinuation symptoms (52, 57). Factors associated with higher likelihood of discontinuation symptoms include earlier age at onset of depression (57), comorbid conditions such as panic disorder (25), and a past history of discontinuation symptoms. Factors not shown to predict development of discontinuation symptoms include duration of SSRI therapy beyond 4–6 weeks prior to discontinuation (52) and length of medication taper (49, 52).
How are Discontinuation Symptoms Distinct From Relapse or Recurrence?
The timing and types of symptoms distinguish discontinuation symptoms from relapse or recurrence. For most patients, the course of major depression is either chronic or recurrent. As expected with other chronic disorders, discontinuation of effective antidepressant treatment is often associated with either a return of the original depressive symptoms or further worsening of symptoms. Return of the original depressive symptoms after SSRI discontinuation can be rapid (hours to days), resembling a rebound phenomenon, which improves rapidly with SSRI reinitiation (74). This symptom trajectory differs from the more insidious return of depressive symptoms over weeks to months following a period of symptomatic remission (relapse) or recovery (recurrence) (75). Relapse or recurrence does occur in patients who had no or minimal discontinuation symptoms immediately after discontinuation of SSRIs. Thus, onset of symptoms affecting multiple organ systems immediately after discontinuation (1–10 days) of an SSRI is suggestive of discontinuation symptoms. Relapse or recurrence can be ascertained by comparing the discontinuation symptoms (affecting multiple systems) with the original depressive symptoms (which may include sad or depressed mood, anhedonia, impaired sleep, changes in weight or appetite, poor concentration or impaired decision making, fatigue or low energy, pessimism or excessive guilt, psychomotor agitation or retardation, and suicidal ideation). Additionally, while discontinuation symptoms typically resolve on reinitiation of SSRIs, attainment of remission after relapse or recurrence may take several weeks or may not occur at all.
What are the Best Strategies to Manage Discontinuation Symptoms?
Discontinuation symptoms can be managed by both prevention and treatment strategies. Preventive strategies include steps to be taken prior to onset of discontinuation symptoms. These include patient education regarding the need to continue antidepressant treatment and maintain adherence. Additionally, patients should be advised that inadvertently missing SSRI doses for a few days, especially with paroxetine, can result in discontinuation symptoms. As changes in ongoing SSRI treatment may be necessitated by partial response, nonresponse, tachyphylaxis, or intolerable side effects, the steps to minimize the risk of discontinuation symptoms include 1) increasing the dosage of the current SSRI to the maximal tolerated dosage; 2) switching to another SSRI or an SNRI; 3) using fluoxetine as a bridge to a nonserotonergic antidepressant, such as bupropion; 4) augmenting the SSRI with an atypical antipsychotic, lithium, buspirone, or liothyronine; 5) adding psychotherapy, light therapy, and/or exercise; and/or 6) consideration of treatments that are specific to treatment-resistant depression—repetitive transcranial magnetic stimulation, vagus nerve stimulation, electroconvulsive therapy, and intravenous ketamine. However, as depression is a chronic disorder, we recommend continued, potentially indefinite, treatment to reduce the risk of relapse or recurrence in patients whose depression is highly recurrent or chronic, is difficult to treat, and is comorbid with other psychiatric and medical conditions (2, 4). Adverse events may also be reduced or mitigated by use of alternative treatments (bupropion for sexual dysfunction, sedatives or cognitive-behavioral therapy for insomnia, exercise and diet modification for weight gain). Use of pretreatment biomarkers such as C-reactive protein may enable personalized selection of an initial antidepressant medication (76, 77). Further studies are needed to demonstrate the utility of biomarkers in reducing the need to switch treatments, which would diminish the risk of discontinuation symptoms. Combinatorial pharmacogenomic kits that test for genetic variants of several pharmacokinetic genes are available and have shown some promise in predicting treatment-emergent side effects (78). However, their utility in predicting risk of discontinuation symptoms remains unclear.
Treatment strategies to manage discontinuation symptoms depend on the consequences of SSRI discontinuation (Figure 1). Active surveillance with a focused review of systems (Table 2) should be undertaken whenever SSRIs are discontinued. Even if discontinuation symptoms develop, the active surveillance can be continued for milder symptoms. Using the measurement-based care paradigm, systematic assessment of frequency, intensity, and burden (79) of discontinuation symptoms can guide next-step treatment strategies. If discontinuation symptoms are burdensome, resumption of the original SSRI medication will typically resolve the symptoms quickly. If the reason for the SSRI discontinuation is to initiate a different treatment, cross-titration with another SSRI or an SNRI can reduce the severity of discontinuation symptoms. A brief trial of fluoxetine can be used if the alternative treatment planned is a nonserotonergic antidepressant. If the goal of SSRI discontinuation is to stop all antidepressant treatment, gradual taper may reduce the severity of discontinuation symptoms as compared with abrupt discontinuation. Smaller doses of medications can be dispensed with the use of liquid formulations. Liquid formulations are available for citalopram (10 mg/5 mL [13]), escitalopram (5 mg/5 mL [14]), paroxetine (10 mg/5 mL [15]), fluoxetine (20 mg/5 mL [16]) and sertraline (100 mg/5 mL [17]). Compounding pharmacies may be used to prepare liquid formulations at very low doses too (80). Symptomatic management, such as use of antihistaminic drugs for acute dystonic reaction, benzodiazepines for anxiety or agitation, and antipsychotics for hallucinations, can be used briefly if discontinuation symptoms are severe or resumption of an SSRI is not prudent.
Recommendations
While the discussion about discontinuation symptoms and the conflation of the presence of discontinuation symptoms with addictive potential of SSRIs is not new, it has gained recent media attention (81). As SSRIs are psychotropic medications, development of new symptoms or worsening of previous symptoms after discontinuation is not surprising. Major depressive disorder is a chronic disorder that necessitates treatment plans that effectively attain optimal symptom control, minimize functional impairments, and reduce the burden associated with treatment modalities. In this context, development of discontinuation symptoms should be considered in the same fashion as treatment-emergent adverse events. Development of rebound or new symptoms and worsening of clinical course on discontinuation is not a trait unique to SSRIs; it is shared by treatments for other chronic conditions, such as beta-blockers for hypertension and hypoglycemic agents for diabetes. Hence, as in these other chronic conditions, clinicians treating patients with major depression need to enhance shared decision-making by providing patient education as well as to proactively consider and discuss the potential risk of discontinuation symptoms when making treatment decisions. Finally, it is essential to ensure that the presenting symptoms are not related to reemergence of the depressive episode, which would require a different management strategy.
Acknowledgments
The authors thank Jeremy Kee, M.A., and Taryn Mayes, M.S., for administrative support.
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Received: 13 June 2018
Revision received: 12 July 2018
Accepted: 16 July 2018
Published online: 1 December 2018
Published in print: December 01, 2018
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Supported through the Center for Depression Research and Clinical Care (principal investigator, Dr. Trivedi) and the Hersh Foundation.Dr. Jha has received contract research funding from Acadia Pharmaceuticals and Janssen Research. Dr. Rush has received consulting fees from Akili, Brain Resource, Compass, Curbstone Consultant, Eli Lilly, the Emmes Corporation, Johnson & Johnson (Janssen), LivaNova, MindLinc, Sunovion, Takeda USA, and Taj Medical; he has received speaking fees from LivaNova and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas (for the Inventory of Depressive Symptoms and its derivatives); and he is named co-inventor on two patents (7,795,033 and 7,906,283, on methods to predict outcome and risk of side effects with antidepressant treatment). Dr. Trivedi has served as a consultant or on advisory boards for Alkermes, Akili Interactive, Allergan Pharmaceuticals, Acadia Pharmaceuticals, Avanir Pharmaceuticals, Brintellix Global, Bristol-Myers Squibb, Caudex, Cerecor, Forest Pharmaceuticals, Global Medical Education, Health Research Associates, Insys, Johnson & Johnson Pharmaceutical Research and Development, Lilly Research Laboratories, Lundbeck Research USA, Medscape, Merck, Mitsubishi Pharma, MSI Methylation Sciences–Pamlab, Navitor, One Carbon Therapeutics, Otsuka America Pharmaceutical, Pfizer, and Takeda Global Research; he has received royalties from Janssen Research and Development; he has author agreements from Janssen Asia Pacific and Oxford University Press; and he has received grants from the Agency for Healthcare Research and Quality, the Cancer Prevention and Research Institute of Texas, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Advancing Translational Sciences, NIMH, NIDA, Johnson & Johnson, and the Patient-Centered Outcomes Research Institute.
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