Promising Strategies for Treatment-Resistant Depression

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Psychiatric Times, Vol 39, Issue 5,

In this CME, review novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.


Premiere Date: May 20, 2022

Expiration Date: November 23, 2022

This activity offers CE credits for:

1. Physicians (CME)

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.


Consider novel, promising strategies for treatment-resistant depression in order to help guide discussions with patients about appropriate treatments.


1. Understand novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.

2. Understand currently available and promising neurostimulation treatment options for treatment-resistant depression.


This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.


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The staff members of Physicians’ Education Resource®, LLC, and Psychiatric Times™ have no relevant financial relationships with commercial interests. Dr Zarate is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation; as a coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a coinventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. The peer reviewer has participated in Speaker’s Bureaus for Sunovion, Otsuka/Lundbeck, Allergan, Teva, Neurocrine, Janssen, and Intra-Cellular Therapies.

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Treatment-resistant depression (TRD), which is broadly defined as “the failure to achieve and sustain euthymia with adequate antidepressant treatment,”1 remains a commonly encountered clinical challenge. Treatment response in depression has been characterized by a response curve that demonstrates diminished improvement of symptoms over successive adequate courses of treatment (Figure).2 Data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study confirm what we know from clinical practice—namely that the chances of adequate symptom resolution are very low (single digits) after 2 initial unsuccessful treatment trials. Approximately one-third of patients do not achieve remission after trials with 4 different conventional treatments. In this context, one definition of TRD is nonresponse to 2 or more antidepressant trials, reflecting this sharp drop-off in response after the second treatment.

A number of organizations (eg, the Canadian Network for Mood and Anxiety Treatments, the National Institute of Health and Care Excellence, and the American Psychiatric Association) have put forth clinical algorithms for the treatment of depression. Current standard treatment options across these guidelines include conventional antidepressant medications (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs]), other antidepressant drugs (eg, bupropion, mirtazapine, vilazodone, and vortioxetine), combining antidepressants (eg, bupropion [Wellbutrin, Forfivo] or mirtazapine [Remeron] added to an SSRI or SNRI, augmentation strategies that target associated symptoms such as sleep or anxiety (eg, second-generation antipsychotics, lithium, lamotrigine [Lamictal], buspirone [Buspar], and thyroid hormone), and psychotherapy. Furthermore, new and developing advances in depression therapeutics now offer the prospect of significant improvement when administered in conjunction with, or as alternatives to, standard treatments. These promising therapies include rapid-acting novel antidepressant drugs as well as neurostimulation interventions.


The discovery that ketamine, a glutamatergic modulator, has antidepressant properties has led to a mechanistically new treatment option for individuals with TRD.3 Furthermore, its rapid antidepressant effects manifest within hours compared with weeks for conventional antidepressants. Currently, intravenous (IV) racemic (R,S)-ketamine (hereafter referred to as ketamine, available off-label) and intranasal esketamine (FDA approved with a required risk evaluation and mitigation strategy [REMS] monitoring protocol) are the only routes of administration that have sufficient evidence to support their use. The initial controlled trials of IV ketamine (a single infusion of 0.5 mg/kg over 40 minutes) for TRD found that ketamine exerted rapid (typically within hours) antidepressant effects that peaked at 24 hours, with about 70% of patients demonstrating response.4 Response typically lasted 3 to 7 days postinfusion. Ketamine appears to have broad therapeutic properties, demonstrating particular effectiveness for anxious depression, depression with anhedonic features, and suicidal ideation.5

Preliminary evidence also suggests its usefulness in treating other disorders comorbid with major depressive disorder (MDD), including obsessive-compulsive disorder (OCD), posttraumatic stress disorder, social anxiety disorder, and substance use disorders.6-10 Notably, ketamine has also proven effective for difficult-to-treat atypical features.5 Adverse events associated with subanesthetic-dose ketamine (0.5 mg/kg) are typically transient (eg, somnolence/sedation, hypertension, nausea, dissociation), although risk of abuse and/or dependence have not been sufficiently studied. One key limitation is the short duration of antidepressant effects in response to a single administration, which has prompted use of repeat doses of IV ketamine. Such repeat infusions are typically administered twice per week, and treatments are tapered when maximal response has been reached, which appears to maintain remission.

Esketamine is the S-enantiomer of ketamine and demonstrates greater potency at the glutamate NMDA receptor than the R-enantiomer. In clinical trials, intranasal esketamine (twice weekly, 56 or 84 mg) added to conventional antidepressant therapy significantly improved symptoms compared with placebo.11 Intranasal esketamine (Spravato) received FDA approval for the treatment of adults with TRD in March 2019 and for the treatment of adults with MDD with acute suicidal ideation or behavior in August 2020. Given concerns about adverse events, the FDA approved intranasal esketamine under a REMS, requiring administration and observation in a medically supervised setting. In terms of adverse effects, reports to the FDA through 2020 noted that esketamine was significantly associated with increased risk of dissociation, sedation, and “feeling drunk.”12 Unexpectedly, a small percentage (2.81%) of patients reported onset of suicidal ideation after starting esketamine treatment. Compared with data for venlafaxine, signals remained for suicidal and self-injurious ideation but not for suicide attempt or completed suicide. Despite the difficulty in attributing causality in the population of patients with TRD who receive esketamine, this safety signal warrants further investigation.

A recent systematic review and meta-analysis that conducted a head-to-head comparison of IV ketamine and esketamine found that IV ketamine may hold a slight edge in efficacy in treating both MDD and bipolar depression, despite intranasal esketamine’s FDA approval.13

In terms of risks, a few studies have reported relatively minor adverse events associated with IV ketamine. However, given the lack of a REMS protocol with IV ketamine, and a REMS report following each dose of esketamine, it is likely that the adverse events of esketamine are extensively reported, whereas they are likely underreported for IV ketamine. There is a need for ongoing vigilant adverse events reporting for both treatments.

While consensus on where ketamine should reside in the depression treatment algorithm is still developing, a recent overview suggests that IV ketamine and intranasal esketamine have both demonstrated efficacy for this patient population.14 Both agents may be more efficacious than second-generation antipsychotic drugs, although their relative efficacy compared with electroconvulsive therapy (ECT) has not been established. In selecting next-step and/or adjunctive treatments, important issues to consider include patient preference, adverse event profile, and accessibility (ie, cost, insurance coverage, and availability).14

On the investigational side, interest in the use of arketamine (the R-enantiomer of ketamine) for TRD has also grown. Animal models suggest that arketamine may have more potential antidepressant-like effects than esketamine, and human trials have just begun. The ketamine metabolite (2R,6R)-hydroxynorketamine has also generated significant interest as a treatment for TRD that potentially lacks dissociative adverse events and abuse potential. It is currently being studied in phase 1 human trials.


Another newly developed treatment for depression has a novel mechanism of action. Brexanolone (Zulresso), a neurosteroid and injectable form of allopregnanolone (a GABAA positive allosteric modulator), was developed as a treatment for postpartum depression. Levels of allopregnanolone, which gradually rise throughout pregnancy, fall precipitously post pregnancy. Slowed downregulation of GABAA receptors is thought to contribute to postpartum depression. Significant improvement in depressive symptoms was noted within 24 hours of brexanolone infusion, which is administered as a 60-hour IV infusion during inpatient care; this antidepressant response lasted up to 30 days.15 Brexanolone received FDA approval for postpartum depression in March 2020. An orally administered allopregnanolone analogue, Zuranolone, is currently in phase 3 clinical trials for both MDD and postpartum depression.


The success of ketamine has revived interest in the use of psychedelic agents, particularly psilocybin, for the treatment of depression. Controlled trials of psilocybin offer some evidence of efficacy for MDD patients, although further studies are needed.16 Psychedelic-assisted psychotherapy—that is, the use of psilocybin as an adjunctive treatment to psychotherapy—is in the early stages of investigation. In addition to concerns about prompting illicit use, it should be noted that psilocybin may increase the risk of seizures when coadministered with lithium.17


In addition to new pharmacological treatments for TRD, several viable neurostimulation options currently exist or are emerging. ECT remains the most established treatment for severe TRD, and the FDA reaffirmed ECT’s importance as a treatment option when it reclassified ECT devices in December 2018 as a Class II (moderate risk) device for the indication of major depressive episodes associated with MDD or bipolar depression.18 With response rates greater than 50% by the first week of treatment, ECT should be a serious consideration for patients who have not responded to conventional treatment.19 Patients with psychotic depression and catatonic depression, as well as elderly patients, may particularly benefit from ECT.

However, ECT use remains limited by 2 main issues: the short duration of its effects and the cooccurrence of cognitive adverse events. After a successful course of ECT, relapse rates are quite high without effective relapse prevention strategies. To decrease the chance of relapse after a course of ECT, patients are often given maintenance medication or ECT therapy. The Prolonging Remission in Depressed Elderly study demonstrated that relapse rates can be dramatically reduced by introducing a Symptom-Titrated Algorithm-Based ECT (STABLE) approach that combines pharmacotherapy with continued ECT on a schedule adjusted to individual patient response.20 The STABLE intervention reduced relapse rates more effectively than medications alone and achieved these benefits without substantially worsening cognitive function.21

The most concerning cognitive adverse events of ECT involve short-term and long-term memory. While studies confirm that short-term memory effects usually resolve within weeks of a treatment course, long-term memory deficits may be prolonged. Mitigation strategies used to minimize risk of memory loss include right unilateral electrode placement, ultrabrief pulse width, square wave electrical stimulation, and increasing the length of time between treatments. In addition, new technologies such as magnetic seizure therapy (MST) are under investigation as an alternative method to initiate seizures (which are thought to be the essential aspect of the therapy).22 By shaping the magnetically induced electric field that initiates the seizure to minimize the effect on brain areas related to memory function, MST may ultimately be associated with significantly fewer cognitive adverse events. Published study results suggest that MST leads to fewer cognitive adverse events than ECT while preserving efficacy.23

Repetitive Transcranial Magnetic Stimulation

Another neurostimulation modality for TRD is repetitive transcranial magnetic stimulation (rTMS), which was cleared by the FDA for TRD in 2008. It has an excellent safety profile, with the primary significant adverse event being the rare occurrence of seizures. It was initially unclear whether rTMS demonstrated the speed of response and high degree of effectiveness needed for patients with severe depression or TRD. However, recent work to optimize the dosage of rTMS (including neuronavigated individualized spatial targeting and accelerated delivery of multiple treatment sessions) have improved treatment outcomes. Intermittent theta-burst stimulation (iTBS)—a form of rTMS—was recently cleared by the FDA for use in TRD. iTBS, which cuts treatment session times from 50 minutes to 3 minutes, was cleared based on studies demonstrating comparable results with standard 10 Hz rTMS.24 In addition, further refinements to the treatment (ie, functional-connectivity-guided targeting) may lead to even greater rates of effectiveness.25 Another recently reported approach couples iTBS with individualized circuit-based neuronavigation and an accelerated treatment schedule called the SNT protocol. A randomized controlled trial of SNT found a 52.5% drop in depression scores with active SNT compared with an 11.1% drop with sham.25

Vagus Nerve Stimulation

Vagus nerve stimulation (VNS), which initially received FDA approval for epilepsy, was later discovered to have antidepressant effects; it received FDA approval for TRD in 2005 as an adjunctive treatment for depression that has failed to respond to at least 4 adequately dosed antidepressant treatments. Although the pivotal randomized controlled trial failed to find definitive evidence of efficacy, a 1-year, nonrandomized comparison of open-label VNS versus treatment as usual found a significant advantage in the VNS group.26,27 A new randomized controlled trial is currently underway to provide more definitive evidence (NCT03887715).

Deep Brain Stimulation

A final consideration for severe and refractory TRD patients is deep brain stimulation (DBS). DBS is not FDA approved for depression but is on the US market to treat Parkinson disease, epilepsy, essential tremor, dystonia, and OCD. For TRD, DBS may be accessible in the context of research studies. DBS treatment consists of electrode placement and electrical stimulation of the ventral capsule/ventral striatum or subgenual cingulate cortex. In smaller investigations and case studies, DBS appeared to demonstrate immediate and striking improvements in depression. However, 2 phase 3 trials were terminated early after interim analyses of the results, and further large-scale trials have not yet been undertaken. Research on DBS has continued, but in a different direction (including identification of novel targets, predictors of response, and novel stimulation approaches). One promising strategy has been the development of closed-loop systems, pairing chronic deep-brain sensing to individualize stimulation programs for patients with TRD.28

Concluding Thoughts

In summary, a number of viable new options offer the possibility of optimizing care for patients with TRD. The Table summarizes the currently available, developing, and promising new treatments previously described. Given the field’s relative lack of clinical experience with these treatments, these treatments should be considered cautiously after a comprehensive assessment of benefits and risks. However, given the risks of inadequately treated depression, they deserve consideration. In addition, these mechanistically novel treatments may further our collective understanding of depression and serve to further transform depression therapeutics.

Funding for this work was provided by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002927).

Dr Park is the medical director of the clinical research unit in the experimental therapeutics and pathophysiology branch at the National Institute of Mental Health. Dr Lisanby is director of the NIMH’s Division of Translational Research and director of the Noninvasive Neuromodulation Unit in the NIMH Intramural Research Program; she is also JP Gibbons Professor Emeritus in the Duke University School of Medicine’s Department of Psychiatry and Behavioral Sciences. Dr Zarate is an NIH Distinguished Investigator as well as chief, Section on Neurobiology and Treatment of Mood and Anxiety Disorders, of NIMH’s Experimental Therapeutics and Pathophysiology Branch. He is also clinical professor of psychiatry and behavioral sciences at George Washington University.


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