Jha, 2018 When Discontinuing SSRI Antidepressants Is a Challenge: Management Tips.

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Am J Psychiatry. 2018 Dec 1;175(12):1176-1184. doi: 10.1176/appi.ajp.2018.18060692.

When Discontinuing SSRI Antidepressants Is a Challenge: Management Tips.

Jha MK1, Rush AJ1, Trivedi MH1.

 

No abstract supplied to PubMed, entry at https://www.ncbi.nlm.nih.gov/pubmed/30501420

 

From the paper:

 

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 depres- sion 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 antide- pressant 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 ef- fects, 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 antide- pressant 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, con- sistent 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 symp- tomatic presentations associated with discontinuation of antidepressant medications and some potential mitigation strategies and tactics (gure 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.

We have organized the discussion of discontinuation symp- toms to answer the following clinically relevant questions:

1. What are discontinuation symptoms?
   1. How common are discontinuation symptoms?
   2. How do discontinuation symptoms present?
   3. What is the differential diagnosis for discontinuation symptoms?
   4. 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?

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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, al-though 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).

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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 non- serotonergic antidepressant, such as bupropion; 4) augment- ing 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 trans- cranial magnetic stimulation, vagus nerve stimulation, elec- troconvulsive 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 psy- chiatric 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 modifica- tion 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 pharmacoge- nomic kits that test for genetic variants of several pharma- cokinetic 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 symp- toms 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 dis- continuation 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 se- verity of discontinuation symptoms. A brief trial of fluoxetine can be used if the alternative treatment planned is a non- serotonergic 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 anx- iety or agitation, and antipsychotics for hallucinations, can be used briefly if discontinuation symptoms are severe or resumption of an SSRI is not prudent.

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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 neces- sitates 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 dis- continuation 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, cli- nicians 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.