Translating Clinical Science Into Effective Therapies

Michael E. Thase, MD

Department of Psychiatry, Perelman School of Medicine, University of Pennsy​lvania, Philadelphia

Case Presentation

CS is a 42-year-old man who was diagnosed by his primary care physician with MDD approximately 8 months ago. He has completed adequate trials of 2 different SSRIs (sertraline 100 mg/qd and citalopram 40 mg/qd) and is currently still taking citalopram 40 mg. He has tolerated the citalopram well and says he feels a little better but still is not functioning well, cannot concentrate, remains irritable, and thinks his family would be better off without him.

Should this patient be referred to a specialist for further assessment? How do you evaluate treatment-resistant depression (TRD)? For this patient, would you recommend either augmenting current treatment or switching to a different antidepressant? The goal of this article is to assist clinicians in identifying patients with TRD and making treatment choices based on pharmacologic principles and the neurobiology of depression.

Introduction and Overview of TRD

MDD is generally considered treatment-resistant when at least 2 appropriate antidepressant trials (usually from 2 different pharmacologic classes) fail to produce significant improvement.1 Results from the STAR*D trial2 of 3,671 prospectively treated outpatients with nonpsychotic MDD indicate that remission rates for patients following the first through fourth medication trials were 37%, 31%, 14%, and 13%, respectively. Relapse rates increased with each new treatment trial, as did drug side effect intolerance, leading to treatment attrition.2

Patients with residual symptoms of depression at the end of acute treatment are at a higher risk of recurrence, relapse, and TRD. Patients with TRD are twice as likely to be hospitalized for general medical- and depression-related reasons, have more outpatient visits, and use more psychotropic medications (including antidepressants) than patients with depression with an acceptable treatment response.3 Up to 40% of MDD-associated costs in the US are attributable to treatment resistance.1 The total annual MDD cost burden in the US is estimated to be $80 to $130 billion.1

AV 1. The Assessment and Treatment of Patients With Difficult-to-Treat or Treatment-Resistant Depression (03:00)


According to the American Psychiatric Association (APA) practice guidelines, lack of response can be due to an inaccurate diagnosis or concurrent medical and/or psychiatric disorders, inadequate medication dosage or psychotherapy frequency, poorly managed side effects, nonadherence to treatment, and several other factors (AV 1).4

Risk Factors for TRD

A number of clinical variables differentiate patients with TRD from patients with depression who exhibit a good treatment response. These variables include anxiety comorbidity (eg, panic disorder, social phobia), personality disorder, suicidality, melancholia, higher numbers of hospitalizations and recurrent episodes, early age at symptom onset, and nonresponse to the first antidepressant ever tried.1 A range of concurrent medical conditions, including thyroid dysfunction, may also contribute to TRD.5

A number of common patient- and physician-related risk factors for treatment resistance may complicate TRD diagnostic attempts.5,6 Common risk factors include a lack of compliance with initial or subsequent antidepressant courses, adverse events (intolerability), and failure to follow evidence-based guidelines for MDD diagnosis and treatment (eg, misdiagnosis [“pseudoresistance”], use of ineffective doses of antidepressant, and failure to incorporate psychotherapy).5,6

Excessive stress, another common TRD risk factor, may result in neuronal structural alterations that contribute to the reduced prefrontal cortex and hippocampus volumes seen in patients with depression.6,7 Neurobiologic TRD risk factors include polymorphisms in receptor genes and metabolic enzymes that can influence antidepressant responses.6,8 So far, the most promising TRD-associated genes code for the serotonin transporter SLC6A4, presynaptic serotonin autoreceptor 5-HTR1A, catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and the transcription factor CREB1.8 Other neurobiologic risk factors include sleep abnormalities and synapse loss in the prefrontal cortex.6,7 Synapse loss in the prefrontal cortex alters the density and function of 5-HT receptors and transporters and may cause reduced cognitive abilities and emotional dysfunction.6,7

Treatment resistance may also be influenced by individual differences in neurotransmitter availability.6 For example, serotonin availability is dependent on plasma levels of the amino acid tryptophan.6 Tryptophan-depletion in SSRI-treated patients causes depressive symptoms to return. Similarly, depleting norepinephrine in patients treated with noradrenergic reuptake inhibitors also leads to a depressive relapse. Interestingly, depleting serotonin in patients responding to norepinephrine reuptake inhibitors and depleting norepinephrine in patients responding to SSRIs does not result in depression relapses.6 This phenomenon is characterized as "the neurotransmitter that gets you well, keeps you well."6

Assessment and Recognition of Patients with TRD

When evaluating whether a patient has TRD, the first step is to perform a comprehensive assessment to ensure that evidence-based treatment trials have been undertaken and determine the impact of treatment on patient outcomes, including symptoms, functioning, quality-of-life, and social relationships.1 The potential benefit that could be derived from psychotherapies such as cognitive-behavioral therapy and interpersonal psychotherapy should also be considered.1,9

APA guidelines4 recommend regularly and systematically assessing patient outcomes to aid treatment planning and decision-making. It is widely believed that diagnoses for mental disorders should be based solely on ICD or DSM criteria; consequently, clinicians rely heavily on standardized cases and instruments/interviews.10 A meta-analysis11 of more than 50,000 patients in 41 studies, however, found that using standardized instruments or interviews to diagnose depression results in poor sensitivity and significant misclassification. Physicians correctly identified and recorded depression in only 33.6% of patients.11 Standardized diagnostic interviews should be used to catch unspecific syndromes but not to make specific differential diagnoses.10 Although using validated instruments is an important part of MDD diagnosis and ongoing management, clinicians need to appreciate these tools’ limitations and the importance of including clinical judgment and assessing functioning when determining symptom remission.10 Overestimating MDD remission potentially leads to undertreating residual symptoms.

Clinicians should supplement their clinical judgment regarding choice of therapy by implementing measurement-based care using standard tools such as the 9-item Patient Health Questionnaire (PHQ-9) and the Quick Inventory of Depressive Symptomatology (QIDS) to assess depressive symptoms throughout the course of treatment.4,12,13 Other psychometric tools that measure depressive symptoms, such as the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Åsberg Depression Rating Scale (MADRS), are commonly used in antidepressant research trials but are too cumbersome for use in busy day-to-day practices.12 A simple clinical risk-stratification tool for predicting treatment resistance in MDD has been recently developed using data drawn from the STAR*D study.14 This decision-making tool may eventually enable clinicians to identify individuals at high risk for TRD who could potentially benefit from the early addition of cognitive-behavioral therapy or from the early use of combination pharmacotherapy or novel antidepressant interventions.14

Current Treatment Strategies

One strategy commonly employed in treating depression that has not responded to first-line antidepressants is to increase the dose.15 However, several randomized high-dose versus low-dose double-blind studies15–17 have failed to show an advantage to this approach. Increasing the dose may actually delay recognition of early-state resistant depression and may increase the incidence of discontinuation symptoms if the failed medication is stopped.15 Another common strategy used to treat depression that has not responded to first-line antidepressants is to switch to a different antidepressant class.15 Results of a meta-analysis18 comparing 2 switch strategies for patients with depression failing to respond to an SSRI, a second SSRI or a different class of antidepressant suggest a marginal benefit of switching from one class to another on remission rates only. However, several other meta-analyses15 and a recent study19 reported that this approach confers no advantage.

Adjunctive strategies preserve the benefits of the initial antidepressant for partial responders and have the potential to enhance the antidepressant’s effect through complementary mechanisms of action.20 Adjunctive strategies typically target the patient’s specific residual symptoms, such as insomnia or anxiety. Although shown to be effective when added to TCAs, lithium augmentation is infrequently used today.21 Additional studies are needed to demonstrate the effectiveness of lithium augmentation with SSRIs and SNRIs, especially considering the disadvantages of lithium use (eg, an up-titration period of up to 6 weeks that is needed for response, and the need for blood drug level monitoring). Thyroid hormone augmentation is easier to implement and has a smaller side effect burden than lithium augmentation.22 A meta-analysis of studies of thyroid hormone augmentation of TCAs in TRD found evidence of increased response and decreased symptom severity compared with control subjects.23 While the effectiveness in depressed patients with normal TSH levels and normal thyroid function is currently inconclusive, thyroid hormone augmentation should be considered for patients with TRD and low thyroid function (including those with an elevated TSH level but without clinical hypothyroidism).4

Psychostimulants may be used as adjunct TRD therapy, but a systematic review revealed only modest support for their use.24 Modafinil, a wake-promoting psychostimulant, has been shown to improve the residual symptoms of fatigue and sleepiness in patients taking SSRI medication.25 Anxiolytic agents including benzodiazepines can augment antidepressants in treating anxious depression.4 Patients in the STAR*D study who received the SSRI citalopram plus buspirone, a non–habit-forming anxiolytic, had about the same probability of responding or remitting as patients receiving combined antidepressant therapy with citalopram and bupropion.26 Patients suffering from severe depression with psychomotor slowing have reduced dopamine turnover.27 While evidence for the adjunctive efficacy of the dopamine receptor agonist pramipexole was suggested in a naturalistic prospective study,28 more controlled clinical trials are needed to clarify the role of dopamine receptor agonists in augmenting antidepressants.

Antidepressant augmentation with atypical antipsychotics is supported by a large evidence database.29 A meta-analysis29 of randomized, double-blind, placebo-controlled studies involving 3,480 patients found that augmentation with atypical antipsychotics improved response and remission rates versus placebo (these results were statistically significant; P<.00001 for both). The atypical antipsychotic olanzapine in combination with fluoxetine is approved by the FDA for use in patients with TRD.30 A statistically significantly higher remission rate was observed after 8 weeks with the olanzapine/fluoxetine combination versus fluoxetine (P<.05) in a post-hoc integrated analysis of patients with inadequate response to at least 2 antidepressant trials.31 Patients receiving olanzapine/fluoxetine should be monitored for weight gain and metabolic side effects that are often associated with olanzapine treatment.30

AV 2. Primary Endpoint Efficacy Results for Adjunctive Aripiprazole for Treatment-Resistance Depression (03:15)


Quetiapine XR and aripiprazole are FDA-approved adjunctive treatments to antidepressants in patients who have inadequately responded to antidepressant monotherapy.30 A recent pooled analysis32 of 2 placebo-controlled trials showed that 150 mg/d and 300 mg/d of quetiapine XR significantly increased remission rates over adjunctive placebo by week 6 (P<.01 for both doses vs placebo). Adjunctive aripiprazole was associated with significantly greater remission and response rates than placebo in 3 randomized, double-blind, placebo-controlled studies (AV 2).33–35

Neuromodulation strategies such as ECT, rTMS, and DBS have demonstrated efficacy in patients with TRD.1 ECT, which has been in use since the 1930s, is relatively effective in TRD and may have a rapid onset of action.1 Unfortunately, relapse rates after ECT are high, and common side effects include memory loss and headaches. Some studies have reported the effectiveness of rTMS while others have not.1 Currently, rTMS does not have FDA approval for treating TRD. The procedure appears to be safe but can result in mild side effects such as tinnitus, headaches, and facial twitches. DBS is considered experimental and, due to its invasiveness, tends to be used as a last resort for patients at high risk from untreatable depression.1


Beyond Serotonin and Norepinephrine: Expanding Views on Depression (AV 3)

AV 3. New Developments in the Therapeutics of Treatment-Resistant Depression, Part 1 (4:30)


The suboptimal efficacy associated with first-line antidepressants may be partly explained by their inability to address specific symptom patterns.36 When making treatment decisions, clinicians should consider how the mechanisms of action of established and novel therapeutic options address specific MDD symptoms (including residual symptoms). For example, while serotonergic antidepressants may reduce symptoms associated with increased negative affect, including guilt, irritability, anxiety, and fear, they appear to inadequately address symptoms associated with decreased positive affect, such as loss of pleasure, loss of interest, fatigue, and loss of energy.36 In contrast, while antidepressants that enhance noradrenergic and dopaminergic activity may reduce symptoms associated with positive affect, they appear to inadequately address symptoms associated with negative affect.36 It is, therefore, conceivable that symptoms in patients exhibiting treatment resistance may be reduced by using combination/augmentation strategies (ie, using 2 or more agents with different mechanisms of action) or by using novel monotherapies with multiple mechanisms of action.

The serotonin transporter is the common therapeutic target for monoamine-based therapies. Serotonin neurotransmission is also modulated by 5-HT receptor subtypes, some of which appear to be independent therapeutic targets.37 For example, the anxiolytic buspirone is a partial agonist at the postsynaptic 5-HT1A receptor.20

As mentioned, dopamine neurotransmitters are linked to depression. Antidepressants such as venlafaxine and bupropion inhibit presynaptic dopamine uptake,20 and therapeutic effects have been achieved by increasing dopamine levels using the melatonergic agonist agomelatine.38 Furthermore, as discussed earlier, atypical antipsychotics augment the effectiveness of antidepressants.29 All atypical antipsychotics exhibit dopamine D2 receptor affinity and antagonize the 5-HT2 receptor, with varying degrees of relative potency.30 Atypical antipsychotics also have varying degrees of α1-adrenergic (associated with orthostatic hypotension), antihistaminergic (associated with weight gain and sedation), and antimuscarinergic (associated with cognitive dysfunction, dry mouth, and constipation) activities.30

AV 4. Effect of the NMDA Antagonist Ketamine in Treatment-Resistant Depression (3:15)


The glutamate system, a major excitatory neurotransmitter system in the brain essential for cognitive processing, is also implicated in MDD etiology.37 Increasing synaptic glutamate neurotransmission is a common goal for cognition-enhancing drugs.37 However, improving mood and cognition by directly modulating glutamatergic neurotransmission can result in excessive glutamatergic activation, leading to excitotoxic effects and cognitive impairment.37 Ketamine, a noncompetitive NMDA receptor antagonist, is an example of an agent that appears to directly increase glutamatergic neurotransmission.37 Clinical studies37,39,40 indicate that ketamine is associated with fast and relatively long-lasting antidepressant effects in patients with TRD (AV 4).

The fast action of ketamine is accompanied by rapid neuronal and synaptic adaptation.37 Neuroadaptive changes represent a key event during antidepressant treatment and may play a role in the delayed onset of efficacy of monoamine-based antidepressants.37

Advances in TRD Neurobiology: Implications for Therapy (AV 5)

Novel “multimodal” pharmacotherapies (ie, drugs with diverse potentially beneficial mechanisms of action) that exert varying degrees of activity across multiple monoamine systems, including those regulated by serotonin, dopamine, and glutamate, are in development. Interestingly, multiple serotonin receptor subtypes, including 5-HT3, 5-HT1A, 5-HT7, and 5-HT1B receptors, appear to indirectly modulate glutamate neurotransmission in select brain regions.37 In fact, preclinical evidence suggests that ketamine’s rapid antidepressant activity can be abolished by serotonin depletion.41 The opportunity therefore exists to integrate monoamine and glutamate strategies to treat both lowered mood and impaired cognition.

AV 5. New Developments in the Therapeutics of Treatment-Resistant Depression, Part 2 (2:34)


Vilazodone and vortioxetine are examples of multimodal serotonergic antidepressants, which are capable of directly modulating serotonin neurotransmission and indirectly modulating glutamate transmission by targeting specific 5-HT receptor subtypes.37 Brexpiprazole/OPC-34712, a novel multimodal adjunctive therapy in development for patients with inadequate responses to antidepressant therapy,42 exhibits broad activity across multiple monoamine systems, including partial agonist activity at dopamine D2 receptors and enhanced affinity for specific 5-HT receptors (eg, 5-HT1A, 5-HT2A and 5-HT7).

In 2003, the President’s New Freedom Commission on Mental Health issued a report entitled “Achieving the Promise: Transforming Mental Health Care in America.”43 In this report, the Commission states “in a transformed mental health system, consistent use of evidence-based, state-of-the art medications and psychotherapies will be standard practice throughout the mental health system.” This stated goal underscores the importance of translating the latest scientific developments and knowledge into patient care as rapidly as possible. The approval and acceptance of novel clinical antidepressant strategies that have multifunctional pharmacologic mechanisms will hopefully continue to improve the therapeutic outcomes of patients with TRD.

Clinical Points


  • Follow evidence-based practice guidelines for depression diagnosis and treatment
  • Supplement clinical judgment regarding choice of therapy by implementing measurement-based care using standard tools such as the PHQ-9 and the QIDS to assess depressive symptoms throughout the course of treatment
  • Assess possible reasons for partial response
  • Acknowledge that suboptimal efficacy associated with first-line antidepressants may be partly explained by their inability to address specific symptom patterns
  • Appreciate how mechanisms of action of established and novel therapeutic antidepressant approaches may be integrated to address TRD symptoms


Drug List

aripiprazole (Abilify), bupropion (Wellbutrin and others), citalopram (Celexa and others), ketamine (Ketalar and others), lithium (Lithobid and others), modafinil (Provigil and others), olanzapine/fluoxetine combination (Symbyax), pramipexole (Mirapex and others), quetiapine XR (Seroquel XR), sertraline (Zoloft and others), venlafaxine (Effexor and others), vilazodone (Viibryd), vortioxetine (Brintellix)


AD=antidepressant, APA=American Psychiatric Association, DBS=deep brain stimulation, DSM=Diagnostic and Statistical Manual of Mental Disorders, ECT=electroconvulsive therapy, FDA=US Food and Drug Administration, HDRS=Hamilton Depression Rating Scale, ICD=International Classification of Diseases, LOCF=last observation carried forward, MADRS=Montgomery-Asberg Depression Rating Scale, MDD=major depressive disorder, NMDA=N-methyl-D-aspartate, PHQ-9=9-item Patient Health Questionnaire, QIDS=Quick Inventory of Depressive Symptomatology, rTMS=repetitive transcranial magnetic stimulation, SNRI=serotonin-norepinephrine reuptake inhibitor, SSRI=selective serotonin reuptake inhibitor, STAR*D=Sequenced Treatment Alternatives to Relieve Depression, TCA=tricyclic antidepressant, TRD=treatment-resistant depression, XR=extended release

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