Selecting Appropriate Treatment for Patients Who Are Nonresponsive to Initial Therapy

J. Sloan Manning, MD

Department of Family Medicine, University of North Carolina, Chapel Hill, and the Moses Cone Family Practice Residency and private practice, Greensboro, North Carolina

Primary care physicians are often surprised to learn that most depressed patients exhibit at least some degree of treatment resistance (ie, failure to remit after 1 adequate antidepressant trial). Many clinicians would be interested in proceeding with more advanced levels of intervention, despite the limitations of antidepressant efficacy, if they had access to sound and clear information on how to identify, assess, and care for the difficult-to-treat patient. This activity summarizes such guidance.

Depression fits best into chronic illness models in terms of clinical approach, level of clinical challenge, and strength of therapeutic alliance and resources required for optimal management. Problems with treatment can result from both patient-related and physician-related factors. These factors include patient health beliefs that negatively influence medication adherence, psychosocial contexts that do not support wellness, and clinical approaches that may not result in a correct diagnosis or methodical, measurement-based, stepwise treatment.

Consequences of and Contributors to Poor Response to Therapy

Robust (ie, complete) and sustained symptom remission is the goal of depression management. Complete remission is associated with a return to premorbid functioning and decreased risk of relapse. The STAR*D trial1 confirmed that patients whose depressive symptoms had remitted by entry to follow-up were less likely to experience relapse than patients whose symptoms had only responded to treatment by entry to follow-up. Additionally, the children of mothers who failed to remit were found to have a greater depressive symptom burden than those whose mothers achieved episode remission.2

The STAR*D trial1 found that a larger number of treatment steps was needed for participants with chronic depressive illness, early onset of depression (at < 18 years of age), concurrent psychiatric disorders (including substance use/abuse), and general medical disorders, all of which are associated with failure to achieve symptom remission. Other factors associated with treatment resistance included difficult psychosocial contexts and comorbid melancholic and anxious features. For further information about consequences of and contributors to treatment resistance, see the activities "Understanding the Burden of Depression" by Larry Culpepper, MD, MPH, and "Implementing Guideline-Based Strategies to Avoid Relapse and Recurrence in Depression" by Roger S. McIntyre, MD, FRCPC.

Strategies to Achieve Remission

The use of well-researched symptom checklists, such as the self-reported QIDS-SR-16 and the PHQ-9, can assist clinicians in identifying treatment-resistant depression. Next, clinicians should ensure that the dose of medication is optimized and the duration of the treatment trial is adequate.

Optimizing the antidepressant dose is essential for success in treating depression. Optimization means using maximally tolerated doses within the usual dosing range. Most antidepressants have starting doses that are lower than the average dose required for full response, so the target dose has to be reached over time until therapeutic efficacy and patient tolerance are balanced. Extending the duration of the acute phase of treatment beyond the 8-week period that is typical for randomized controlled trials is also often necessary in clinical practice. In fact, the STAR*D trial found that a substantial number of patients required 12 to 14 weeks of treatment to reach remission with the initial treatment.3

When a patient’s response to an initial antidepressant agent (usually an SSRI or SNRI) falls short of remission, several options are available.4 Options include switching to a different antidepressant, combining the existing antidepressant with a second antidepressant, or augmenting the antidepressant with a nonantidepressant agent.5,6

Switch or Combine Antidepressants

If remission is not achieved with an adequate trial of initial treatment, switching or combining treatments can be implemented (AV 1AV 1). Switching is often the best strategy for patients who cannot tolerate the initial antidepressant or have had no response to it. Antidepressant switches are often, but not always, accomplished by cross-titration, which is a gradual reduction in dose of the primary agent combined with a gradual introduction of its replacement. Only about one-third of patients reached remission with citalopram monotherapy in level 1 of the STAR*D study.3 In level 2, the switches from citalopram to other antidepressants were equivalently effective (AV 2AV 2).3

Most antidepressant combinations for treatment-resistant depression focus on the therapeutic synergy of synaptic effects. Combinations of antidepressants have also been widely used to treat adverse effects of the primary agent. For example, as shown in Appendix C of the TMAP Procedural Manual,7 pp 53,54 trazodone may be used to manage insomnia, and bupropion may be used for SSRI-related sexual dysfunction. The STAR*D study3 made use of combination strategies in levels 2 and 4 of the trial (see AV 2AV 2). At level 2, bupropion SR was combined with citalopram, and at level 4, venlafaxine XR and mirtazapine were combined.

Augment With a Nonantidepressant

The STAR*D trial3 used a few augmentation strategies to overcome antidepressant treatment resistance. In level 2, citalopram could be augmented with buspirone. In level 3, both liothyronine (T3) and lithium could be used to augment sertraline, bupropion SR, venlafaxine XR, or citalopram. Remission rates varied for these 3 augmentations (see AV 2AV 2).

Psychostimulants have been used as monotherapy or as adjunct therapy for treatment-resistant depression, but a systematic review8 found only modest support for their use. A retrospective pooled analysis9 of modafinil augmentation found overall improvement in CGI-I scores, wakefulness, depressive symptoms, and fatigue.

Two atypical antipsychotics—aripiprazole10 and quetiapine11—have received FDA approval for the adjunctive management of MDD that has inadequately responded to antidepressant monotherapy. In addition, the olanzapine-fluoxetine combination is approved for treatment-resistant depression in adult patients. A post hoc integrated analysis12 of patients with inadequate response to at least 2 antidepressant trials reported a statistically significantly higher remission rate with the olanzapine-fluoxetine combination versus fluoxetine (P < .05) (AV 3AV 3). Augmentation with atypical antipsychotics and other agents is discussed in more detail by Michael E. Thase, MD, in "Using Adjunctive Treatments When First-Line Antidepressants Fail."

Other agents, for example, pindolol, L-methylfolate, and estrogens, have been proposed for antidepressant augmentation or facilitation, ie, enhancing the speed of antidepressant response. Although some of these agents have been evaluated,13 they cannot be recommended for widespread clinical adoption because data for these approaches are from trials that were small, poorly controlled, or negative.


Major depression is often challenging to treat. A majority of patients fail to achieve remission when taking an initial antidepressant at an adequate dose for an adequate duration. Switch and combination strategies with other antidepressant treatments may be effective options for managing initial antidepressant failures. Augmentation strategies with nonantidepressant treatments such as atypical antipsychotics, buspirone, T3, and lithium may also be effective in helping patients achieve remission.

Clinicians who manage depression should be prepared to use long-term strategies in a chronic illness paradigm. This treatment model seeks to enhance therapeutic alliances, uses measurement-based and evidence-based decisions, and involves the patient in disease-state education and familiarization with various treatment approaches.

For Clinical Use

  • When initial antidepressant therapy does not produce remission, first be sure the dose is optimized and the duration of the trial is adequate
  • Next, switch to a different antidepressant, combine 2 antidepressants, or augment with a nonantidepressant agent
  • Keep adjusting the treatment strategy until the patient’s MDD remits

Drug Names

Aripiprazole (Abilify), bupropion (Aplenzin, Wellbutrin, and others), buspirone (BuSpar and others), citalopram (Celexa and others), fluoxetine (Prozac and others), liothyronine (Cytomel and others), lithium (Lithobid and others), mirtazapine (Remeron and others), modafinil (Provigil), nortriptyline (Pamelor, Aventyl, and others), olanzapine (Zyprexa), olanzapine/fluoxetine (Symbyax), quetiapine (Seroquel), sertraline (Zoloft and others), tranylcypromine (Parnate and others), trazodone (Oleptro and others), venlafaxine (Effexor and others).


CGI-I=Clinical Global Impressions–Improvement scale, FDA=US Food and Drug Administration, MDD=major depressive disorder, PHQ-9=9-item Patient Health Questionnaire, QIDS-SR-16=16-Item Quick Inventory of Depressive Symptomatology–Self Report, SNRI=serotonin-norepinephrine reuptake inhibitor, SR=sustained release, SSRI=selective serotonin reuptake inhibitor, STAR*D=Sequenced Treatment Alternatives to Relieve Depression, T3=triiodothyronine (liothyronine), TMAP=Texas Medication Algorithm Project, XR=extended release

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