When antidepressants don't work: New targets for TRD

By Naveed Saleh, MD, MS
Published February 28, 2022

Key Takeaways

  • Treatment-resistant depression (TRD) is a difficult disease to treat, much less to define.

  • New research focuses on 5-HT4 receptors, which are a specific type of serotonin receptor, and ketamine.

  • Psychotherapy is an important part of managing TRD, but many HCPs gloss over this modality in favor of medications.

The phenomenon of treatment-resistant depression (TRD) has evolved since its recognition 40 years ago. Currently, the CDC defines it as depression that persists after two failed courses of antidepressant therapy.

While antidepressants can be an important therapy for some, not everyone finds these psychotropic medications effective.

Recent research has focused on the mechanisms and novel drug targets in treatment-resistant depression, as well as on newer treatments.

Varying definitions

TRD definitions vary in the literature. The definitions differ in how they define trial adequacy, retrospective vs prospective response, medication classes, and number of trials. Interestingly, prospectively defined nonresponse is considered a more robust measurement when identifying TRD.

Other definitions reflect the failure of not only pharmacotherapy, but also of neuromodulation (eg, electroconvulsive therapy). STAR*D—one of the largest TRD studies—was one of the few studies that included psychotherapy (alone or with medication) among its prospective trials.

An emerging target

Mood-related disorders, including anxiety and major depressive disorder, involve the serotonergic neurotransmitter system.

Most antidepressants are selective serotonin reuptake inhibitors (SSRIs). However, there are 14 different types of serotonin receptors, and it is unclear which of these mediate depression.

Traditional antidepressants require weeks to take effect. In recent preclinical studies, the 5-HT4 receptor has emerged as a target based on rodent studies that demonstrate 5-HT4 receptor agonists trigger rapid antidepressant-like responses.[]

The 5-HT4 receptor is mediated by CK2 at transcriptional and post-transcriptional levels.

Related: Why patients lie about their mental health


The FDA approved esketamine for TRD in March 2019. This agent is delivered intranasally in an outpatient or inpatient setting, and it acts within 2 hours to decrease depression symptoms in about half of TRD patients.

The story of esketamine is rooted in a slowdown in the pace of the development of psychotropics in the 1990s.[2] At the time, improvements in monoamine agents, such as serotonin, norepinephrine, and dopamine virtually ceased.

Yale researchers turned their attention to glutamate. They noted that the NMDA receptor, which is a type of glutamate receptor, was important in the moderation of monoamines. Pilot studies showed that low doses of ketamine could reduce depressive symptoms. Ketamine also began to work within just a few hours, whereas monoaminergic antidepressants took weeks to show results.

Over 20 years, various NIHM-sponsored trials demonstrated that ketamine decreased symptoms of depression when administered intravenously. In 2006, transformative research demonstrated that ketamine resulted in rapid, sustained, and powerful antidepressant effects in patients with treatment-resistant depression who had failed more than six previous antidepressant therapies.

Later research has demonstrated that ketamine also worked in those with bipolar depression and suicidal ideation.

Other studies demonstrated that the benefits of ketamine were experienced in half of those taking it, and effects could last from several days to weeks, with multiple doses providing added relief.

The intravenous route involved in administering ketamine, however, was expensive and inconvenient. Researchers later isolated the S-ketamine isomer, which was amenable to nasal delivery. The new drug was called esketamine.

According to the director of the NIMH, Joshua A. Gordon, MD, PhD, who provided a detailed history of the use of ketamine and esketamine in the treatment of TRD, more research needs to be done.[]

"Ketamine and esketamine work, but both have significant drawbacks."

Joshua A. Gordon, MD, PhD

“Many patients experience uncomfortable dissociative symptoms, hypertension, or other side effects for a few hours after administration," Gordon continued. "Because of these symptoms, as well as the potential for abuse, both need to be administered in a doctor’s office. These aren’t medications you can pick up at the pharmacy and take on your own.”

Dr. Gordon pointed to the need to better elucidate the mechanisms of ketamine to develop safer alternatives.

Other concerns include whether ketamine and esketamine can be used long-term or can decrease immediate risk of suicidal thoughts. The role of these agents in comprehensive regimens for severe depression and suicidal thoughts also needs to sussed out.

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Even though pharmacotherapy is preferred as a primary prevention in the treatment of depression, 75% of patients prefer psychotherapy.

Unfortunately, prescribers often gloss over these preferences.

Pharmacotherapy provides quicker relief vs psychotherapy, but medications do not allow for patients to manage their illness on their own and structure their lives more effectively, like behavioral therapy does.

Cognitive therapy can also help patients with TRD to tackle painful and distorted thinking, as well as with using emotions to find answers to interpersonal difficulties and secure social support.

“Psychotherapy may emotionally alter patients’ self-regard, distinguishing self from illness: recognizing they are not ‘defective,’ as they often believe, but ill,” wrote the authors of an article published in the American Journal of Psychiatry.[] “This distinction is salient when beleaguered by TRD."

"Patients improving in psychotherapy credit themselves more than do those swallowing pills."

Markowitz, et al.

What this means for you

TRD is a challenging diagnosis to treat, much less define. Although SSRI use is still prevalent in those with TRD, newer psychotropics such as esketamine may help. Although psychotherapy has been shown to be preferable by patients with TRD, the therapy option is often glossed over by clinicians. Clinicians should understand that TRD treatment is likely to consist of a mix of pharmacotherapy and psychotherapy for proper management of the disease.

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