
- Vol 40, Issue 2
Rx Evolution: An Ununified Model of MDD and Pharmacological Paradigms
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
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,
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 (
The Birth of Psychopharmacology for Depression
The 1950s was an exciting decade of pharmacological advances in psychiatry for both the treatment of
“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
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
Nonpharmacological FDA-Approved Treatments
Alongside drug development for depression has been a steady advance in neuromodulatory treatments, including
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 is a racemic mixture with 2 active isomers: esketamine and arketamine.
Rapid-Acting Antidepressants
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
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
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.
Esmethadone
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 (
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
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
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;
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 (
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.
References
1. Maletic V, Raison C. The New Mind-Body Science of Depression. W.W. Norton & Company; 2017.
2. Miller JJ.
3. Robitzek EH, Selikoff IJ.
4. Miller JJ.
5. Miller JJ.
6. Rush AJ, Trivedi MH, Wisniewski SR, et al.
7. Nelson JC.
8. Kellner CH.
9. Cohen SL, Bikson M, Badran BW, George MS.
10. Cole EJ, Stimpson KH, Bentzley BS, et al.
11. Berman RM, Cappiello A, Anand A, et al.
12. McIntyre RS, Carvalho IP, Lui LMW, et al.
13. Correia-Melo FS, Leal GC, Vieira F, et al.
14. Miller JJ.
15. Fischer J, Ganellin CR, eds. Analogue-based Drug Discovery. Wiley-VCH; 2006:527.
16. Auvelity. Package insert. Axsome Therapeutics; 2022.
17. Fava M, Stahl S, Pani L, et al.
18. Pinna G.
19. Zorumski CF, Paul SM, Covey DF, Mennerick S.
20. Althaus AL, Ackley MA, Belfort GM, et al.
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.
Articles in this issue
over 2 years ago
Eating Disorders Among Older Adultsover 2 years ago
Addressing Unmet Needs and Clinical Challenges in MDDover 2 years ago
The Status of Neuromodulation Trials in Eating Disordersover 2 years ago
The Fight for Psychiatric Rights and Accountabilityover 2 years ago
Lawmakers Support CMS Rules to Streamline Prior Authorizationsover 2 years ago
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