Evidence-Based Strategies for Achieving Remission and Treating Residual Symptoms in MDD

MODULE 2: Evidence-Based Strategies for Achieving Remission and Treating Residual Symptoms in MDD Introduction Major depressive disorder (MDD) is a complex disease that is challenging to treat. While the ultimate goal of treatment in MDD is remission, which is linked to a greater likelihood of return to normal psychosocial functioning and reduced risk for relapse, many patients only partially respond or do not respond to initial antidepressant treatment.1,2 In fact, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial indicated that approximately 50% of patients with MDD do not achieve response to initial antidepressant treatment, and that two-thirds will ultimately achieve remission with use of up to four treatment strategies, illustrating that optimal MDD treatment may require frequent treatment adjustments as necessary.3,4 This module describes pharmacologic strategies to help manage inadequate response and prevent residual symptoms. Initial Management Strategy When selecting an initial treatment for MDD (Table 1), studies show that antidepressants and psychotherapy are equally effective.5-7 For patients in rural settings, access to psychiatrists and psychologists may be difficult, and thus rural primary care practitioners need greater emphasis on pharmacologic strategies. Table 1. Select FDA-Approved Agents for the Treatment of MDD5 Class Agents First-generation antidepressants Tricyclic/tetracyclic antidepressants Amitriptyline, desipramine, doxepin, imipramine, maprotiline, (TCAs/TeCAs) nortriptyline, protriptyline, trimipramine Monoamine oxidase inhibitors Isocarboxazid, phenelzine, selegiline transdermal system, (MAOIs) tranylcypromine Second-generation antidepressants Selective serotonin reuptake Citalopram, escitalopram, fluoxetine, paroxetine, sertraline inhibitors (SSRIs) Serotonin-norepinephrine reuptake Desvenlafaxine, duloxetine, levomilnacipran, venlafaxine inhibitors (SNRIs) Other Noradrenergic and specific serotonergic antidepressant Mirtazapine (NaSSA) Norepinephrine-dopamine Bupropion reuptake inhibitor (NDRI) Serotonin receptor antagonist and Trazodone reuptake inhibitor (SARI) SRI, 5HT1A receptor partial agonist Vilazodone SRI, 5HT1A receptor agonist, 5-HT3 Vortioxetine receptor antagonist FDA, US Food and Drug Administration Second-generation antidepressants have similar efficacy and effectiveness.8 Thus, the choice of initial pharmacotherapy is typically guided by side effect profile, tolerability, potential for drug-drug interactions, patient preference, cost, and response to previous MDD treatment. Comparative or drug- specific adverse events of second-generation antidepressants are shown in Table 2.7,9 Table 2. Specific Adverse Effects of Select Second-Generation Antidepressants7,9 Agenta Comparative or Drug-Specific Adverse Effects Lower incidence of sexual dysfunction than escitalopram, Bupropion/Bupropion SR fluoxetine, paroxetine, and sertraline Possible increased risk for QT interval prolongation and Citalopram torsade de pointes (dosages >40 mg/day) Fluoxetine Lowest rates of discontinuation syndrome vs other SSRIs Greater weight gain than with fluoxetine, paroxetine, Mirtazapine trazodone, venlafaxine Highest rates of sexual dysfunction and discontinuation Paroxetine syndrome than other SSRIs; weight gain Sertraline Higher incidence of diarrhea Higher rates of somnolence than with bupropion, fluoxetine, Trazodone mirtazapine, paroxetine, and venlafaxine Higher rates of nausea and vomiting than SSRIs as a class; Venlafaxine/ higher rates of discontinuations due to adverse events than Venlafaxine XR SSRIs as a class; highest rates of discontinuation syndrome aThis table is not all inclusive. See prescribing information for full details. It is important to consider side effects when counseling patients on treatment decisions. For example, SSRIs and SNRIs may not be appropriate for patients with sexual dysfunction.8 In addition, for patients who are obese or overweight, agents associated with weight gain (eg, mirtazapine or paroxetine) should be avoided if possible. In addition, all second-generation antidepressants contain a black box warning regarding an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should be monitored for worsening and emergence of suicidal thoughts and behaviors. Response to treatment as well as emergence of side effects or adherence issues should be assessed using measurement-based tools early after treatment initiation and regularly thereafter, particularly at critical decision points to manage MDD aggressively and treat to remission (Table 3).8,10,11 Table 3. Assessment Tools for MDD10,11 Measurement Assessment Tools • Beck Depression Inventory-II (BDI-II) • Patient Health Questionnaire-9 (PHQ-9) Depressive symptoms • Quick Inventory of Depressive Symptomatology (QIDS), clinician- rated or self-report Side effects • Frequency, Intensity, and Burden of Side Effects-Rating (FIBSER) • Brief Medication Questionnaire (BMQ) Medication adherence • Medication Adherence Rating Scale (MARS) • Medication Adherence Questionnaire (MAQ) Remission is defined as absence of sad mood and reduced interest for ≥3 weeks, and ≤3 residual symptoms.8 This outcome is often measured using the following rating scale scores 12,13: • PHQ-9 score ≤4. • QIDS score ≤5. Management of Nonresponse or Partial Response In patients who show only a partial response in the initial weeks of treatment, the dose should be maximized as tolerated, and treatment continued for at least 4 to 8 weeks before switching to a different antidepressant.8 Patients with no symptomatic improvement in the initial weeks of treatment may require an earlier switch to a different antidepressant.8 In addition to switching antidepressants, other strategies for patients with nonresponse or partial response at 4 to 8 weeks include changing to or augmenting with psychotherapy.8 Augmentation therapy or electroconvulsive therapy may be considered.8 It is important to rule out potential contributing factors to poor response including the following8,14,15: • Inaccurate diagnosis. • Inadequate treatment or nonadherence. • Failure to address comorbid psychiatric disorders. • Pharmacogenetics variations in drug response. • Different primary disorder (eg, bipolar disorder, psychotic depression). • History of physical, sexual, or emotional abuse. • Comorbid medical illness. The decision of whether to switch or augment therapy may be guided by the factors in Table 4.16 Table 4. To Switch or To Augment?16 Consider Switching Consider Augmenting • 1st antidepressant trial • ≥2 antidepressant trials • Intolerable side effects • Current treatment is tolerable • <25% treatment response to 1st • >25% treatment response treatment • Severe symptoms = less time to wait for • Less severe symptoms = more time to response wait for response • Patient preference • Patient preference • Specific residual symptoms can be targeted with adjunctive agents Switching Strategies Rates of remission and response are similar among patients who are switched to an antidepressant in the same antidepressant class or to a different class.3,4 It is essential that the patient is given an adequate trial of dose and duration following treatment switch, usually ≥6 weeks of at least a moderate dose.16 Augmentation Strategies First-line options for antidepressant augmentation include atypical antipsychotics, lithium, and thyroid hormone (T3).1-3 Addition of a second antidepressant is common in clinical settings, but has limited evidence to support its use.2 The evidence base supporting medication augmentation with atypical antipsychotics is most substantial, and addition of these agents to treatment is linked to an approximately two-fold increased likelihood of remission versus placebo.17,18 Atypical antipsychotics that are approved by the FDA as adjunctive treatments for MDD include1,4: • Aripiprazole. • Brexpiprazole. • Olanzapine-fluoxetine combination. • Quetiapine ER. A meta-analysis of 18 randomized controlled trials (>4000 patients) found that the efficacy of adjunctive atypical antipsychotic therapy for treatment-resistant depression was similar among all reviewed agents when given at standard doses.19 The study included varying doses of aripiprazole, olanzapine/fluoxetine, quetiapine, and risperidone (not FDA approved for the treatment of MDD). Notably, this study was published before brexpiprazole was approved, and thus data on this agent were not included in the analysis. All of the agents included in the analysis were associated with adverse events, including akathisia (aripiprazole), sedation (quetiapine, olanzapine/fluoxetine, aripiprazole), and weight gain (all agents included in this analysis, especially olanzapine/fluoxetine). With all standard-dose atypical antipsychotic agents except for risperidone, discontinuations because of side effects were significantly higher than with placebo.19 Thus, the benefits of using atypical antipsychotics need to be weighed against the risk of potential adverse effects.2 The most common adverse events associated with atypical antipsychotics approved as adjunctive strategies, as listed in the agents’ prescribing information, are shown in Table 5. Table 5. Adverse Effects of Atypical Antipsychotics Approved as Adjunctive Treatments for MDD17,20-22 Agent Most Common Adverse Eventsa,b Aripiprazole Akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision Brexpiprazole Weight increased and akathisia Olanzapine and Sedation,

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