Strategies for Achieving Full Remission When First-Line Antidepressants Are Not Enough

Andrew A. Nierenberg, MD

Department of Psychiatry and the Depression Clinical and Research Program, Harvard Medical School and Massachusetts General Hospital, Boston

For patients with depression who experience partial to no response with first-line treatment, clinicians must determine other suitable options. The problem is the lack of evidence that clinicians can use to decide next-step treatment because few studies compare second-line options, examine long-term outcomes, describe clinically useful predictors of response, or consider comorbid conditions (AV 1).1,2 In addition, results from randomized controlled trials do not always apply to everyday clinical practice because of the inclusion/exclusion criteria used. Even recommendations for the often-suggested strategies (eg, switching, augmenting) for next-step treatment frequently lack specific tactics.3 Relying on available evidence, clinical judgment, and patient preference, clinicians should assess problems with first-line treatment and consider several options to help partial responders achieve remission.

AV 1. Gaps in Knowledge for the Effective Management of Depression (01:05)

Based on the Agency for Healthcare Research and Quality1

Assessing Problems With First-Line Treatment

Despite the variety of available medications, the efficacy of different first-line antidepressants is quite similar, and the majority of patients do not reach remission with the first treatment trial. An AHRQ meta-analysis4 showed that current evidence does not favor one second-generation antidepressant over another based on efficacy. In fact, only about one-third of patients will reach remission with an initial antidepressant.5 The main difference among agents lies in the side effects and what the patient is willing to tolerate. For example, an 8-week, double-blind study6 found no significant differences in efficacy between escitalopram and venlafaxine XR (remission rates 41% and 37%, respectively). However, escitalopram was better tolerated and associated with less discontinuation due to adverse events (P<.01) than venlafaxine XR.6 Thus, if the first treatment has not had sufficient efficacy, one problem to consider is that the patient may have stopped taking it because of intolerable side effects.

If the patient is adherent but has not fully responded to the first antidepressant, the clinician must then determine if the patient has had sufficient dosage over an adequate amount of time. Patients with MDD may remain on a subtherapeutic dose for too long, which limits or delays response.7 Gradually increasing the antidepressant dose within the recommended range helps to ensure an adequate treatment trial. Most patients who will respond to treatment show improvement between 4 and 12 weeks,3 with the bulk of improvement occurring within the first 4 to 6 weeks.8 Clinicians can also measure patients’ blood levels to ensure that the drug is being absorbed properly.

Another potential problem with initial antidepressant treatment is that the patient could have an untreated co-occurring disorder. Comorbid psychiatric conditions are common in people with lifetime MDD, with almost 60% having an anxiety disorder, almost 25% having a substance use disorder, and 30% having an impulse control disorder.9 Comorbid disorders are associated with poorer outcomes of antidepressant treatment,5 and different first-line treatments may need to be explored when conditions co-occur with MDD.

Addressing Partial Response

If an adequate trial and dosage of antidepressant therapy fails to alleviate patients’ symptoms, several strategies may be considered, including adding psychotherapy, switching to a different antidepressant, augmenting with another medication, or using adjunctive therapy for specific symptoms.

Begin psychotherapy. Psychotherapy has many forms and may focus on correcting dysfunctional thoughts and behaviors (CBT), preventing relapse and maintaining a state of well-being (well-being therapy), instituting thought restructuring through mindful meditation (mindfulness-based cognitive therapy), or guiding interpersonal role transitions, especially through losses (interpersonal therapy). In a 6-year study, Paykel and colleagues10 showed that CBT augmentation of medication reduced residual depressive symptoms and prevented recurrences for up to 3.5 years after the CBT was completed. In another 6-year follow-up study11 of patients who were treated with antidepressants but had residual symptoms, CBT supplemented with well-being therapy and lifestyle modifications produced lower relapse rates (40%) after discontinuing drug therapy compared with usual management (90%; AV 2). Adjunctive mindfulness-based cognitive therapy has reduced recurrence and prevented relapse in depressed patients with 3 or more previous episodes,12 and interpersonal therapy has helped patients with severe depression, depression and comorbid medical illness, peripartum depression, and adolescents and elderly patients with depression.13

AV 2. Relapse Rates for Usual Treatment Vs CBT for Relapse Prevention (00:53)

Data from Fava et al11

Switch antidepressants. The advantages of switching antidepressants over combining or augmenting treatments are reduced cost, fewer drug interactions and side effects, improved adherence, and less patient burden.14 Switching may also allow for a different mechanism of action that may have greater efficacy for the patient than the initial treatment did. Switching tactics have been shown to be successful via clinical experience, case series, effectiveness hybrid studies (such as STAR*D), and randomized controlled trials, although these typically focus on acute phase treatment and lack long-term results.

After an adequate antidepressant trial, clinicians may consider switching either within the same antidepressant class or to a different class, such as from an SSRI to an SNRI, TCA, or MAOI.14 In the STAR*D trial,5 about 25% of patients achieved remission after switching to another antidepressant from their first antidepressant (whether in the same class or not), but subsequent switches yielded remission rates of 10% to 15%. Another study15 found that switching nonresponders to a different class of antidepressants resulted in similar remission rates as switching within the same class (14% and 19%, respectively; AV 3).5,15

AV 3. Remission Rates for Switching Antidepressants Within and Across Classes (0:40)

Data from Rush et al5 and Souery et al15

Augment current antidepressant. Augmenting strategies are meant to enhance the current antidepressant’s effectiveness. The benefits of augmentation include maintaining a partial response, avoiding the ill effects of discontinuation, and accelerating a treatment response. However, clinicians must consider factors such as cost, dose, drug interactions, tolerability, and adherence when deciding to use an augmenting agent.8

Similar to switching tactics, many adjunctive therapies lack empirical evidence and many treatments are off-label. For example, lithium and thyroid hormone augmentation have some efficacy in patients who do not respond to monotherapy.8 In level 3 of the STAR*D trial, patients received either lithium or thyroid hormone (T3) augmentation for up to 14 weeks. Remission rates were 13% with lithium and 25% with T3, and T3 was associated with fewer side effects.5 Bupropion augmentation of citalopram, also in STAR*D, yielded a remission rate of 39%, while buspirone augmentation had a 33% remission rate but more adverse events.5


Several atypical antipsychotics have been studied as augmentation to antidepressants, but only aripiprazole has received FDA-approval for this use.16 A meta-analysis17 yielded a higher pooled remission rate for adjunctive atypical antipsychotics (47%) than placebo (22%), but these results do not reflect long-term treatment. The disadvantages of atypical antipsychotics include a significant side effect burden (eg, metabolic syndrome, weight gain, EPS) and increased medication cost.17 Therefore, adjunctive therapy with atypical antipsychotics may be considered after at least 1 second-line treatment strategy is tried.18

Adjunctive therapy can also be used to target specific symptoms that do not resolve with antidepressant treatment. These symptoms may be persistent symptoms of depression, a side effect of treatment, or the result of a comorbid condition. Most patients who meet remission criteria after acute treatment still have residual symptoms.19 Common residual symptoms, such as fatigue or insomnia, may require targeted treatment. For example, patients with residual fatigue or sleepiness while taking SSRI medication experienced symptom improvement with adjunctive modafinil, a wake-promoting agent.20 Similarly, sleep aids may be used to treat insomnia. For example, patients with MDD and insomnia responded better and faster to fluoxetine plus eszopiclone than to fluoxetine alone.21 If the symptoms are caused by the current treatment, clinicians may need to consider dosing changes or switching options.


Among patients with MDD, the majority will not achieve remission after their first adequate antidepressant trial of sufficient dose and duration, and those who do often have residual symptoms. Clinicians should assess any problems with first-line treatment and make adjustments based on patient preference, clinical judgment regarding efficacy and tolerability, and the presence of any comorbid conditions. Some patients with inadequate response to first-line treatment may benefit from psychotherapy. Clinicians may also try switching to another antidepressant or augmenting the current treatment with other antidepressants or agents to target particular residual symptoms. Both strategies have advantages and disadvantages related to cost, tolerability, adherence, and available evidence. Patients with partial response pose unique challenges for clinicians, but strategies are available to help them achieve full remission.

Clinical Points

  • If patients have no response to first-line treatment, consider switching to another antidepressant either in the same class or another class
  • To improve partial response, try augmenting the current antidepressant with psychotherapy, another antidepressant, lithium, thyroid hormone, or atypical antipsychotics
  • Treat residual symptoms with targeted adjunctive therapy

Drug Names

aripiprazole (Abilify), bupropion (Wellbutrin, Aplenzin, and others), citalopram (Celexa and others), escitalopram (Lexapro and others), eszopiclone (Lunesta), fluoxetine (Prozac and others), lithium (Lithobid and others), modafinil (Provigil and others), venlafaxine (Effexor and others)


AHRQ = Agency for Healthcare Research and Quality, CBT = cognitive-behavioral therapy, EPS = extrapyramidal symptoms, MAOI = monoamine oxidase inhibitor, MDD = major depressive disorder, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, T3 = triiodothyronine, TCA = tricyclic antidepressant, XR = extended release

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