Rx Evolution: An Ununified Model of MDD and Pharmacological Paradigms

Psychiatric TimesVol 40, Issue 2



Despite persistent attempts to create a unified pathophysiological model of a unipolar major depressive episode, most experienced and sophisticated clinicians and researchers have concluded that depression is not a single entity.

Rather, depression is an emotional state with extensive heterogeneous factors that can either contribute to or protect against a depressive episode when a person is confronted with significant life stressors or biological perturbations. The coauthors Maletic and Raison provide an outstanding review of the wide-ranging factors that have been implicated in depression.1 Adapted from the information in their textbook, Table 1 lists a subset of the extensive and diverse evidence to date that adds to the ever-growing mosaic of possible contributors to a depressive episode.1

TABLE 1. Example Biological Factors and Their Role in Depressive Episodes

Table 1. Example Biological Factors and Their Role in Depressive Episodes1

Before delving into the evolving pharmacological treatments for depression, I would be remiss to bypass the numerous evidence-based nonpharmacological treatments that currently exist and should always be considered as a primary or combination treatment (Table 2).2 Additionally, prior to concluding that an indvidual’s diagnosis is a major depressive episode, other possible diagnoses should be ruled out, including medical etiology, medication-induced etiology, substance-related etiology, bereavement, and other primary psychiatric diagnoses.

TABLE 2. Nonpharmacological Treatment Modalities for Depression

Table 2. Nonpharmacological Treatment Modalities for Depression2

The Birth of Psychopharmacology for Depression

The 1950s was an exciting decade of pharmacological advances in psychiatry for both the treatment of psychosis and depression. The introduction of chlorpromazine into the US in the early 1950s launched our first pharmacological treatment for psychosis, which led to a major deinstitutionalization of previously “untreatable” individuals with various psychotic disorders. Also in the early 1950s, isoniazid and iproniazid—2 newly discovered drugs that successfully treated tuberculosis—were serendipitously discovered to improve depression. Further research demonstrated that both drugs functioned as cytoplasmic monoamine oxidase inhibitors and had the effect of increasing neuronal levels of serotonin, norepinephrine, and dopamine in the human brain. In the 1952 publication written by tuberculosis researchers Robitzek and Selikoff, they observed the following in patients with tuberculosis that they were treating3:

“So accentuated has been the feeling of the sense of well-being, that disciplinary measures have been necessary; the feeling of well-being may be due to a ‘resurgent animal [vigor].’ Patients usually feel better before any objective measurements of improvement can be made.”

In 1957, imipramine—derived chemically from chlorpromazine—was shown to have significant antidepressant properties and subsequent studies demonstrated it inhibited the neuronal reuptake of serotonin and norepinephrine. It was the FDA approval of iproniazid in 1958 and imipramine in 1959 that unfortunately edified the monoamine hypothesis of depression into the mainstream of pharmacological research for depression for the next 60 years. All 29 FDA-approved monotherapies for the treatment of a unipolar major depressive episode had their primary mechanism of action (MOA) directly related to the monoamines serotonin, norepinephrine, and/or dopamine until August 2022.

The field of neuropsychopharmacology has learned a great deal during these past 60 years. For the interested reader, these lessons are expanded upon in previous issues of Psychiatric Times™.2,4,5

One of the most frustrating clinical challenges of our monoamine antidepressant armamentarium is the delayed onset of action ranging from 4 to 8 weeks. Even when we start to see efficacy, only 50% of patients will experience a response and roughly only 37% remission with their first antidepressant, based on findings from the highly referenced STAR*D study funded by the National Institute of Mental Health.6,7

Over the decades, many augmentation strategies have been—and continue to be—utilized to further improve depressive symptoms. In 2007, the first augmenting agent, aripiprazole (Abilify), was FDA approved, followed by the 2009 FDA approvals of quetiapine XR (Seroquel XR) and of the olanzapine/fluoxetine combination (Symbyax), the 2015 FDA approval of brexpiprazole (Rexulti), and the 2022 approval of cariprazine (Vraylar). All 5 FDA-approved antidepressant augmenting agents are atypical antipsychotics, which continue to modulate receptors in the monoamine system. Non–FDA-approved augmenting agents have included lithium (LithoBID), thyroid hormone, buspirone (BuSpar), adding 2 antidepressants, modafinil (Provigil), armodafinil (Nuvigil), methylphenidate (Ritalin), dextroamphetamine (Dexedrine), mixed amphetamine salts, pramipexole (Mirapex), and ropinirole (Requip), to list a few.

Nonpharmacological FDA-Approved Treatments

Alongside drug development for depression has been a steady advance in neuromodulatory treatments, including electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and vagus nerve stimulation. Ugo Cerletti, an Italian psychiatrist, first performed ECT in 1938, and the treatment rapidly grew in popularity. Because of US psychiatrists’ extensive clinical experience with ECT, in 1976, the FDA grandfathered the approval of ECT technology as class III devices. To eliminate the need for additional clinical trials to demonstrate efficacy and safety, the FDA reclassified ECT in 2018 as a class II device but limited its official approval to the treatment of unipolar depression, bipolar depression, and catatonia. ECT remains a safe and effective treatment in use throughout the US.8

rTMS is a noninvasive treatment for depression that most commonly delivers a magnetic field to stimulate the left dorsolateral prefrontal cortex. Initially, a course of treatment involved 30 minutes of stimulation 5 days per week for 4 to 6 weeks. In 2008, the FDA approved rTMS for the treatment of major depressive disorder (MDD) in adults who had not responded to prior antidepressant medication trials. Since that time, major advances have been made in this neuromodulatory technology, and in 2018, the FDA approved intermittent theta-burst stimulation (iTBS).9

Most recently, an accelerated course of treatment developed at Stanford University delivers 10 iTBS treatments per day over 5 consecutive days—a protocol named SAINT (Stanford Accelerated Intelligent Neuromodulation Therapy). The protocol was studied in an open-label trial of 21 patients with treatment-resistant depression. Nineteen of the 21 participants achieved remission (Montgomery Äsberg Depression Rating Scale [MADRS] score < 11). Neuropsychological testing performed before and after treatment found no negative cognitive adverse effects. The SAINT protocol was FDA approved on September 6, 2022.10

Beyond Monoamines: The Ketamine Story

Ketamine, a dissociative anesthetic, was FDA approved in 1970 and remains FDA approved for general anesthesia and the treatment of moderate to severe pain. During the 1990s, researchers at Yale University observed a rapid antidepressant effect following the intravenous (IV) administration of ketamine to patients who had not responded to traditional antidepressants. This research ultimately led to a publication in 2000 reporting on 7 patients with MDD who had a significant antidepressant effect within 72 hours of receiving IV ketamine.11 The benefit was transitory but began a plethora of research into ketamine as a treatment for depression, as well as an attempt to understand its possible MOA in treating depression. Currently, ketamine’s MOA is believed to be a result of its noncompetitive N-methyl D-aspartate (NMDA) receptor antagonism and likely resulting downstream effects that ultimately improve synaptogenesis, strengthening connections between neurons, especially in the prefrontal cortex.

Ketamine is a racemic mixture with 2 active isomers: esketamine and arketamine. Esketamine has a stronger binding affinity to the NMDA-glutamate receptor than arketamine. Both isomers have clinically relevant activity, but the similarities and differences remain to be elucidated. Janssen Pharmaceuticals, Inc developed an intranasal delivery system for esketamine, which was extensively studied in clinical trials in which it was used in conjunction with an oral antidepressant. In March 2019, intranasal esketamine (Spravato) in combination with an oral antidepressant received FDA approval for MDD treatment-resistant depression and subsequently received FDA approval for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior. No head-to-head studies have compared IV ketamine with intranasal esketamine, and published literature supports similar efficacy for both formulations.12,13

Rapid-Acting Antidepressants

FIGURE. Putative Mechanism of NMDA-Glutamate Receptor Antagonism Rapidly Increasing Synaptogenesis for Some RAADs

Figure. Putative Mechanism of NMDA-Glutamate Receptor Antagonism Rapidly Increasing Synaptogenesis for Some RAADs14

Recognizing the likely role that NMDA-glutamate antagonism plays in the rapid antidepressant effects of both ketamine and esketamine—with clinical improvement observed in as little as 4 hours and lasting up to 72 hours—a tremendous amount of preclinical and clinical research has attempted to piece together how this clinical observation of rapid symptom improvement, albeit short-lived, occurs. The Figure depicts a putative model of how NMDA-glutamate antagonism may initiate a cascade of molecular events that travels through a neuronal circuit, which concludes with the activation of mTOR.14

Activated mTOR orchestrates the production of scaffolding proteins and directs the strengthening of synaptic connections. This increased plasticity may allow the brain to better utilize additional resources (psychotherapy, nutrition, social connectedness, quality sleep, stress reduction, anti-inflammation, and physical activity) to increase the likelihood of emotional wellness and improved function. Antidepressants with other MOAs may provide additional benefits at other circuits that may synergize with the mTOR activation, resulting in additional improvement. This model provides a template that is consistent with depression as a heterogeneous condition.

NMDA-Glutamate Antagonism/Sigma-1 Agonism

In August 2022, the FDA approved the combination drug dextromethorphan/bupropion (Auvelity) as the first oral NMDA-glutamate receptor antagonist to treat MDD. At first glance, it may seem that the antidepressant effect must come from bupropion. However, this drug combination provides a good example of pharmacodynamics and pharmacokinetics in action.

In 1949, dextromethorphan (DM) was patented after its development by researchers funded by the US Navy and Central Intelligence Agency who were seeking a nonaddictive codeine analog cough suppressant. DM was FDA approved in 1953 as a prescription antitussive medication and was approved as an OTC medication 5 years later.15 DM has a short half-life of approximately 7 hours and is rapidly metabolized by CYP2D6 to the active metabolite dextrorphan. DM is known to have NMDA-glutamate receptor uncompetitive antagonism, sigma-1 receptor agonism, and a tincture of serotonin reuptake inhibition. Its rapid metabolism as a monotherapy would require high doses at frequent intervals throughout the day.

Bupropion was specifically added due to its potent inhibition of CYP2D6, which prolongs the DM half-life to approximately 22 hours and allows for BID dosing to achieve steady-state kinetics. Bupropion also inhibits the reuptake pumps of both norepinephrine and dopamine. As with all antidepressants, the MOA of this combination drug is unknown but appears to be in some way due to the NMDA-glutamate and sigma-1 activity.

The phase 2 study of the combination drug randomly assigned patients with MDD to receive either the DM/bupropion extended-release (45 mg/105 mg) combination or the equivalent dosage of bupropion sustained release (105 mg) orally BID for 6 weeks. The primary outcome was change in MADRS scores over 6 weeks. The combination drug was found to be superior to bupropion monotherapy, demonstrating that DM contributed to the antidepressant effect.

The phase 3 study compared the change in MADRS score in patients with MDD on DM/bupropion extended-release (45 mg/105 mg) combination versus placebo orally BID for a duration of 6 weeks. The combination drug demonstrated a statistically significant improvement versus the placebo group at week 1 and week 2, and this improvement continued to the primary outcome measure at week 6, when it improved the MADRS score 3.9 points more than placebo.16

There are a lot of moving parts with this drug combination. DM demonstrated in the phase 2 study that it plays a significant role in the antidepressant effect, which emerged as early as week 1. Like ketamine/esketamine, DM binds to the NMDA-glutamate receptor as an antagonist, albeit uncompetitive rather than noncompetitive. Additionally, the FDA-approved product insert calls out the sigma-1 agonism as a possible contributor to its MOA. There is no clear understanding of the function of the sigma-1 receptor; however, it is known to reside in the endoplasmic reticulum, and it is speculated to have a role in monoamine and glutamate modulation. Finally, the serotonin (DM) and norepinephrine/dopamine (bupropion) reuptake inhibition may also contribute to the antidepressant effect.


Like many biologically active drugs, methadone is a racemic mixture containing equal concentrations of dextromethadone (esmethadone) and levomethadone. Esmethadone has considerably less affinity at the μ-opioid receptor than levomethadone. Rather, esmethadone is a noncompetitive NMDA-glutamate receptor antagonist and is believed to activate the glutamate system in a similar manner as ketamine, esketamine, and DM. Preclinical animal studies demonstrated no opioid effect but did demonstrate an antidepressant response associated with increased synaptic proteins in the medial prefrontal cortex of mice, along with increased levels of BDNF and mTOR.17

Once this was established, a phase 2A 7-day, double-blind, placebo-controlled, randomized study enrolled psychiatric inpatients with MDD who had inadequate response to 1 to 3 courses of antidepressants during the current major depressive episode, which had been present for 8 weeks to 36 months. All patients were continued on their baseline selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or bupropion. Daily doses of esmethadone (25 mg or 50 mg) or placebo were administered for 7 days. Depression scores were assessed using the MADRS on days 2, 4, 7, and 14. Both esmethadone doses significantly outperformed placebo on day 7, and this benefit persisted to day 14. Further studies are underway.17

GABA-A–Positive Allosteric Modulators

Pharmacologically, γ-aminobutyric acid type A (GABA-A)–receptor-positive allosteric modulators are commonly prescribed or used recreationally (benzodiazepines, barbiturates, and alcohol). These molecules bind to their own receptors, and when a GABA molecule agonizes a GABA-A receptor, the opening of the GABA-A ion channel is enhanced by these other drug-receptor complexes, resulting in an increased inhibitory effect. Because of heterogeneity of the GABA-A receptors (due to a diversity of subunits) and different binding sites of these 3 positive allosteric modulators, they each have a range of effects on 4 primary GABA-A–mediated processes: antianxiety, sedation, muscle relaxation, and antiseizure.

A fourth class of GABA-A–positive allosteric modulators, neurosteroids, have taught us about yet another effect: successfully treating postpartum depression and appearing to provide a rapid antidepressant effect that endures beyond 14 days of treatment either as a monotherapy or as an adjunct to a traditional antidepressant. This story begins with the endogenous neuroactive steroid allopregnanolone, a progesterone metabolite, which is a GABA-A–receptor-positive allosteric modulator. As pregnancy progresses, serum levels of allopregnanolone increase and peak in the third trimester. Following delivery, allopregnanolone levels drop, and this drop is more precipitous in women who develop postpartum depression. Brexanolone (Zulresso), a formulation of allopregnanolone that is administered intravenously, was FDA approved in 2019 as the first specific pharmacological treatment of postpartum depression. It is administered as a continuous IV infusion over 60 hours under the supervision of a health care provider who must be available on site. Improvement occurred in 2 to 3 days of treatment, and the improvement persisted at least 30 days.

It was discovered that pregnancy reduces GABA-A γ- and δ-containing subunits and that allopregnanolone enhances tonic inhibition in GABA-A receptors containing δ subunits. These and other findings prompted clinical trials that demonstrated the efficacy of IV allopregnanolone in postpartum depression with a rapid-acting effect.18

GABA-A receptors are a complex family of pentameric chloride ion channels that are opened by GABA, resulting in an influx of negatively charged chloride that hyperpolarizes the cell. Currently, 19 different subunits have been characterized, with most GABA-A receptors containing 2 α, 2 β, and a third subunit. At synapses, γ is the most common third subunit, and in extrasynaptic locations, δ is more commonly found. Consequently, significant heterogeneity exists among the structures of GABA-A receptors, which would explain how different drugs that share the property of positive allosteric modulation can have different clinical responses. For example, benzodiazepines, barbiturates, and alcohol do not treat depression. Allopregnanolone acts as a positive allosteric modulator of GABA-A receptors located both synaptically and extrasynaptically, which may explain its antidepressant activity.19,20

Zuranolone is an oral formulation of allopregnanolone that is administered once daily for 14 days and has been studied extensively either as a monotherapy or adjunctive to a traditional antidepressant in doses of either 30 or 50 mg. Sage Therapeutics designed 2 separate clinical development programs, NEST (2 studies assessing efficacy in postpartum depression) and LANDSCAPE (5 studies assessing efficacy in MDD in men and women). In an analysis of the 4 completed placebo-controlled studies (ROBIN, MDD-201B, MOUNTAIN, and WATERFALL), improvement of depression was seen by day 15 and was sustained at time points ranging from 42 to 70 days, depending on the study. Most common adverse effects of brexanolone and zuranolone are sedation and dizziness.21

5-HT2A Agonists

Psilocybin is a naturally occurring molecule that exists in more than 200 species of Basidiomycota mushrooms found throughout the world. Over the past 10 years, there has been an explosion of research into the antidepressant effects of psilocybin, which, like lysergic acid diethylamide and mescaline, is an agonist at the 5-HT2A receptor. These 3 hallucinogens are classified by the US Drug Enforcement Administration as Schedule I drugs, but this status may change if they receive FDA approval; psilocybin and LSD are currently being studied in numerous investigational clinical trials registered with the FDA for a wide range of psychiatric and nonpsychiatric diagnoses.

Most of the phase 2 and phase 3 clinical trials involve an integrated treatment protocol with either 1 or 2 doses of psilocybin—administered by therapists specifically trained for this treatment—nested in a comprehensive psychotherapy model. The initial results are positive.22 Psychiatric Times™ reported on psilocybin extensively in 2022, and the interested reader is encouraged to explore these articles on the website.

Concluding Thoughts

A simple review of the many depressive disorders with unrelated or barely overlapping etiologies is evidence enough that depression is a syndrome of significant heterogeneity. It is refreshing to see the explosion of basic science, clinical observations, and studies that are forcing the field of psychiatry to move beyond our affinity to limit frontline pharmacotherapy to drugs that interface with only the serotonin, norepinephrine, and dopamine neurotransmitter systems.

Specific to pharmacological treatments for depression, drugs that modulate the glutamate system are now part of our FDA-approved armamentarium for both monotherapy and adjunctive treatment of MDD. GABAergic-modulating drugs appear to be close behind.

Targeting glutamate and GABA receptors to change the neurophysiology of the depressed brain should not be a surprise. Glutamate is the primary excitatory neurotransmitter, and GABA is the primary inhibitory neurotransmitter in the human brain; they are responsible either directly or through interneurons for bringing balance to systems that are dysregulated.

Untraditional treatments such as psilocybin combined with comprehensive psychotherapy protocols are challenging our models of delayed response of serotonergic treatments. The dizzying number of factors associated with MDD (Table 1) shines light on 2 interrelated concepts: (1) Many novel treatments remain to be identified and developed to improve our success in treating MDD to remission, and (2) MDD is a heterogeneous disorder that deserves a radical revision in how we characterize, diagnose, treat, define, educate about, and understand it.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times™; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre Massachusetts.


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16. Auvelity. Package insert. Axsome Therapeutics; 2022.

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20. Althaus AL, Ackley MA, Belfort GM, et al. Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator. Neuropharmacology. 2020;181:108333.

21. Clayton AH, Deligiannidis KM, Kanes SJ, Doherty J. Sustained improvement in depressive symptoms: results from zuranolone clinical development program (major depressive disorder/postpartum depression). Presented at: American Psychiatric Association Annual Meeting; May 21-25, 2022; New Orleans, LA.

22. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637-1648.

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