Incidence, Impact, and Current Management Strategies for Treatment-Resistant Major Depressive Disorder

Definition of Treatment-resistant depression

Treatment-resistant depression (TRD) typically refers to an inadequate response to at least 1 antidepressant trial of adequate dose and duration among patients suffering from major depressive disorder (MDD).



Incidence, Impact, and Current Management Strategies for Treatment-Resistant Major Depressive Disorder

George I. Papakostas, MDMedscape Psychiatry & Mental Health.  2008; ©2008 Medscape
Posted 05/22/2008

Definition of Treatment-resistant depression

Treatment-resistant depression (TRD) typically refers to an inadequate response to at least 1 antidepressant trial of adequate dose and duration among patients suffering from major depressive disorder (MDD). Adequate duration is often defined as a minimum of 6 weeks of treatment.[1] This definition stems from the observation that fewer than 7% of patients who show little improvement following 6 weeks of treatment with fluoxetine eventually respond (50% decrease in symptom severity) following an additional 2 weeks of treatment,[2] while only 12% of patients who show little or no improvement following 6 weeks of treatment experience at least a partial response following an additional 2 weeks of treatment.[3] Although similar analyses of clinical trials of longer duration (12 weeks) have provided evidence arguing that 6 weeks may be too short a duration to declare an antidepressant trial ineffective,[4] it is also important to keep in mind that spontaneous remission rates can be substantial over time and, therefore, the degree to which delayed onset of clinical improvement (ie, after week 6) is due to a “true” antidepressant effect vs spontaneous remission of symptoms is questionable.[5,6] However, it is also worth pointing out that the original analyses by Nierenberg and colleagues[2] were based on data derived from a fixed-dose trial of fluoxetine 20 mg/day, and that delayed dose escalations are likely to affect how long clinicians need to wait before they assume that the duration of the trial is adequate. The definition of adequate dose varies widely from agent to agent, with values deriving from double-blind, placebo-controlled trials or dose-comparator studies.[1]

Definitions of “adequate response” have varied throughout the course of the past few decades, ranging from the more traditional view in which treatment-resistance is defined as strict nonresponse, to the broadest definition; ie, failure to achieve full symptom remission.[7] Nowadays, most experts agree that inadequate response is the failure to achieve full symptom remission for several reasons.[1] First , as first pointed out by Nierenberg and Amsterdam,[8] patients presenting with moderate-to-severe depression may still be quite symptomatic despite a 25%-50% improvement in depressive symptoms. In addition, residual symptoms have been associated with poorer psychosocial functioning[9], as well as increased relapse rates.[10] Finally, incomplete response (defined as a 25% or greater improvement in depressive symptoms failing to achieve remission) appears to be more than twice as common as strict nonresponse in naturalistic treatment settings (28.7% vs 12.9%, respectively).[11] Therefore, defining TRD as strict nonresponse following adequate treatment rather than failure to achieve remission would actually exclude the majority of patients who have not been successfully treated.

Prevalence of Treatment-Resistant Depression

Prevalence estimates for TRD are available from several sources, including large clinical trials,[12] large meta-analyses,[13] or naturalistic studies.[11,14,15] For example, in the first level of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, only about 30% of patients were in remission following up to 12 weeks of therapy with the selective serotonin receptor inhibitor (SSRI) citalopram.[16] In addition, 15.8% of patients developed an intolerable adverse event, 38.6% moderate-to-severe impairment due to an adverse event, 8.6% discontinued treatment due to adverse events, and 4% developed a serious adverse event, findings that underscore efficacy and tolerability limitations of treatment with a typical first-line antidepressant agent.

Papakostas and Fava[17] reviewed 163 randomized, double-blind, placebo-controlled trials involving the use of antidepressants for MDD. Approximately 53.4% of patients responded following treatment with an antidepressant, compared to 36.6% of patients who responded following the administration of a placebo pill.

Corey-Lisle and colleagues[14] reported that approximately 22% of patients who received treatment for depression by their primary-care physicians remitted following 6 months of treatment, 32% were partial responders, while 45% were nonresponders. Similarly, Rush and colleagues[15] reported an 11% remission rate and 26.3% response rate among depressed outpatients following 12 months of treatment of depression in one of several public-sector community clinics. Petersen and colleagues[11] report a 50.4% remission rate among outpatients with MDD enrolled in 1 of 2 hospital-based, academically affiliated depression specialty clinics (Massachusetts General Hospital, an affiliate of Harvard Medical School and Rhode Island Hospital, an affiliate of Brown University) following an average of 25.8 weeks of treatment. Finally, it is also worth noting that while partial or nonresponse are common, residual symptoms among remitters are also highly prevalent,[18,19] and associated with poorer psychosocial functioning[9] as well as an increased relapse rates.[10]

Management of Treatment-Resistant Depression

The management of TRD can involve the use of pharmacologic as well as nonpharmacologic interventions such as the use of cognitive behavioral psychotherapy,[20] electroconvulsive therapy,[21] vagus nerve stimulation,[22] and transcranial magnetic stimulation.[23,24] Pharmacologic interventions can either involve increasing the dose of an antidepressant,[25] switching to a second antidepressant,[13,26-28] or the use of adjunctive pharmacotherapeutic strategies. When a second antidepressant is added to an existing antidepressant — this is termed combination pharmacotherapy. When a non-antidepressant agent is added, this is termed augmentation treatment. Combination strategies can involve the addition of bupropion,[12] mirtazapine,[28,29] and tricyclic antidepressants[25,30] to an antidepressant treatment regiment. Augmentation strategies can involve the addition of lithium,[25,31,32] triiodothyronine,[32] buspirone,[12] pindolol,[33] omega-3 fatty acids,[34] dopaminergic agents,[35-37] as well as the addition of folates and s-adenosyl methionine (SAMe)[38,39] to an antidepressant treatment regimen. Nevertheless, as described above, despite the broad armamentarium available to clinicians for the management of TRD, many patients remain symptomatic despite several adequate pharmacologic and nonpharmacologic trials. Clearly, there is an urgent need to develop safer, better tolerated, and more effective treatments for MDD.

The Use of Atypical Antipsychotic Agents for Treatment-Resistant Depression

The preclinical rationale for the use of the atypical antipsychotic agents in MDD derives from their complex neuropharmacologic effects at various monoaminergic receptors and transporters.[40] Specifically, all of the atypical antipsychotics are antagonists at the serotonin-2 receptor. Ziprasidone and aripiprazole possess affinity for the serotonin-1A receptor, while ziprasidone and risperidone possess affinity for the serotonin-1D receptor. Ziprasidone has also been shown to inhibit the reuptake of serotonin and norepinephrine, while aripiprazole has been shown to possess mixed agonist and antagonist effects at various dopamine receptors. These effects were thought to be suggestive of potential antidepressant activity.[40]

Early clinical studies focusing on augmentation with atypical antipsychotic agents in depression demonstrated mixed findings. The first clinical report ever to be published focusing on this treatment strategy was a case series describing 8 patients with SSRI-resistant depression who experienced remission of symptoms following the addition of low doses of risperidone (0.5-1 mg).[41] Also notable in the report was the fact that all patients achieved remission of depression symptoms quite rapidly (within 1 week of combined treatment). This preliminary report was soon followed by a double-blind placebo-controlled study that focused on adding olanzapine to fluoxetine among fluoxetine nonresponders.[42] A greater improvement in depressive symptoms was reported among patients treated with the combination of these 2 agents than either agent alone (ie, olanzapine or fluoxetine monotherapy).

However, soon thereafter, doubt was cast on the potential utility of this treatment strategy when 2 subsequent studies combining olanzapine with fluoxetine for either nortriptyline- or venlafaxine-resistant MDD failed to show that combining olanzapine with fluoxetine was more effective than monotherapy with venlafaxine, fluoxetine, or nortriptyline.[43,44]

More recently, however, a number of double-blind, placebo-controlled studies focusing on augmenting antidepressants with risperidone,[45,46] quetiapine,[47-49] or olanzapine[50] for antidepressant-resistant MDD re-kindled clinicians’ interest in this treatment strategy. Specifically, 6 of these 7 trials[45-50] demonstrated greater efficacy in resistant-MDD among patients treated with adjunctive atypical antipsychotic agents than placebo (Thase and colleagues[50] reported 2 separate but identical trials of olanzapine augmentation of fluoxetine, and found olanzapine augmentation to be effective in 1 but not the second study.)

To reconcile the discrepancy in results between “positive” and “negative” studies, we conducted a random-effects model meta-analysis pooling all 10 randomized, double-blind, placebo-controlled clinical trials focusing on augmentation of antidepressants with atypical antipsychotic agents for antidepressant-resistant MDD.[51] The difference in remission rates between the atypical antipsychotic agents and placebo was found to be statistically significant, with a 47% remission rate for augmentation with atypical antipsychotics vs a 22% remission rate for augmentation with placebo. Although the difference in efficacy in favor of this augmentation strategy over placebo was pronounced, tolerability appeared to be a considerable limitation. Specifically, the difference in the rates of discontinuation due to intolerance for patients treated with atypical antipsychotics compared to placebo was also statistically significant (37% for the atypical antipsychotic agents and 12% for placebo, respectively).

More recently, 2 positive, double-blind, placebo-controlled trials investigating the use of adjunctive aripiprazole in MDD were published. In the first such study, Berman and colleagues[52] focused on the use of aripiprazole augmentation for patients resistant to up to 1-3 “retrospective” (historical) antidepressant trials. To “confirm” treatment resistance, those patients underwent an 8-week, open-label trial with either an SSRI (fluoxetine, sertraline, paroxetine, or escitalopram) or a selective norepinephrine receptor inhibitor (SNRI; venlafaxine). The patients who made insufficient symptom improvement had either aripiprazole or placebo added to their SSRI or SNRI regimen, under double-blind conditions and for a total of 6 weeks. A statistically significant difference in remission rates was also observed, with 26% remission for aripiprazole vs 15% remission for placebo (P < .05). This study also reported relatively low rates of discontinuation due to intolerance in the 2 treatment groups (2% for aripiprazole and 1.7% for placebo (P > .05). The results of separate study of identical design recently presented at a major scientific meeting also demonstrated greater remission rates for adjunctive aripiprazole- than placebo-treated patients.[53] The results of these 2 trials lead to the approval, by the US Food and Drug Administration (FDA), of a new treatment indication for aripiprazole as adjunctive treatment to antidepressants for antidepressant-resistant MDD (Figure 1). This was the first-ever approval for an adjunctive treatment in MDD, and the first-ever approval for the use of any medication for TRD by the FDA

Figure 1. 

Adjunctive aripiprazole in antidepressant-resistant MDD: results of 2 identical phase 3 trials.



TRD is a common clinical occurrence, its management posing a formidable clinical challenge for clinicians and patients alike. Despite several pharmacologic and nonpharmacologic treatment options for TRD, many patients continue to remain symptomatic. Thus, there is an urgent need to develop novel treatments for TRD. From the evidence available to date, it appears that augmentation of antidepressants with atypical antipsychotics is effective in some cases of treatment-resistant depression, at least during the acute phase of treatment. However, the long-term efficacy, tolerability, and safety of this treatment are not yet understood. Further research is required exploring how this intervention compares with other augmentation strategies and other strategies for addressing TRD.

This activity is supported by an independent educational grant from Bristol-Myers Squibb.


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George I. Papakostas, MD, Assistant Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts; Director, Treatment-Resistant Depression Studies, Massachusetts General Hospital, Boston, Massachusetts

Disclosure: George I. Papakostas, MD, has disclosed that he has received grants for clinical research from Pfizer, Bristol Myers Squibb, PAMLAB, National Institutes of Mental Health, and Precision Human Bio Laboratories. Dr. Papakostas has also disclosed that he served as a consultant and has received honoraria from Lundbeck, Eli Lilly, GlaxoSmithKline, Wyeth, and Pierre Fabre Medicament.



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