Medication Pipeline: Antidepressants and ADHD Rx

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In this second part of a 2-part series reviewing novel agents in the psychiatric pipeline, the focus is on treatments for unipolar major depressive disorder (MDD) and attention-deficit/hyperactivity disorder (ADHD). In last month’s part 1, we reviewed the pipeline for novel agents that have the potential to broaden our armamentarium for the treatment of all 3 symptom domains in schizophrenia—the positive, negative, and cognitive symptom clusters—as well as the long-awaited submission for US Food and Drug Administration (FDA) approval of 3,4-methylenedioxymethamphetamine (MDMA)–assisted therapy for posttraumatic stress disorder (PTSD).

Three brain receptors associated with depression may soon see novel agents to expand our current large armamentarium of treatments for MDD: the N-methyl-D-aspartate (NMDA) glutamate receptor, opioid κ receptor (κ-receptor), and serotonin 5-HT_2A receptor. MDD continues to challenge even the most skilled clinicians. Much has been written about the high prevalence of partial response or frank treatment resistance for patients experiencing moderate to severe depressive episodes. The first step in the treatment of patients with depression and with partial or no response to current treatments is a comprehensive, open-minded reassessment to consider other diagnoses as the primary or major contributary etiology (Table 1).

Table 1. The Differential Diagnosis of Depression (Partial List)

In many of these other diagnoses, the criteria for a major depressive episode may, in fact, still be met, but unless the treatment plan is modified to address the additional factors and etiologies, response and/or remission may not be attained.

Unipolar major depression creates significant suffering and disability in the United States as well as globally. Many nonpharmacological treatments exist and should be considered and discussed with any patient with depression as part of our informed consent process of treatment options. When the decision is made to treat with an antidepressant medication, there is no paucity of options. In patients with partial or no response to 1 or several monotherapies, numerous FDA-approved augmentation agents exist, both pharmacological as well as neuromodulatory.

Additionally, psychotherapies should be utilized ranging from the general psychodynamic styles to the more depression-focused psychotherapies including cognitive behavioral therapy, interpersonal therapy, mindfulness-based cognitive therapy, acceptance and commitment therapy, and group therapies.

Despite these wide-ranging treatments currently available, approximately one-third of patients with depression remain significantly symptomatic. A robust pipeline of novel drugs will always be welcome.

The past 2 years have proven quite challenging regarding access to the 2 primary classes of drugs most effective in the treatment of ADHD: methylphenidate and amphetamine. The reasons for this are multifactorial and were exacerbated by the COVID-19 pandemic’s virtual ADHD clinics, which proliferated once the US Drug Enforcement Administration (DEA) temporarily appended its regulations to allow for virtual assessment and treatment of patients to be prescribed scheduled medications that previously had to be prescribed in person.

One consequence of this stimulant shortage was an increase in the prescribing of unscheduled medications for ADHD, especially drugs whose primary mechanism is inhibition of the norepinephrine transport pump, which results in increased synaptic norepinephrine and dopamine in the prefrontal cortex.¹ A new agent may be joining this subset of ADHD medications.

Novel Agents for the Treatment of MDD

Esmethadone

NMDA receptor antagonism is the putative mechanism of action of 2 of the most recent FDA- approved drugs for the treatment of unipolar major depression: intranasal esketamine (Spravato) as an augmentation agent and the combination of dextromethorphan and bupropion (Auvelity) as a first-line monotherapy. However, not all NMDA receptor antagonists demonstrate antidepressant activity. Two notable examples are memantine and amantadine.

From a basic science perspective, this is not surprising, given the complexity of the NMDA receptors, which are heterotetrameric ion channels with a large number of polymorphic variations of 3 subunits: GluN1, GluN2, and GluN3. This provides a plethora of binding sites that can result in a wide range of unique clinical outcomes.² Esmethadone is an uncompetitive NMDA receptor antagonist and is believed to modulate the glutamate system to produce an antidepressant effect.

Methadone is a racemic mixture containing equal concentrations of dextromethadone (esmethadone) and levomethadone. Esmethadone has considerably less affinity at the opioid μ receptor (μ-receptor) than levomethadone. Preclinical animal studies demonstrated no opioid effect of esmethadone but did demonstrate an antidepressant response associated with increased synaptic proteins in the medial prefrontal cortex of mice, along with increased levels of brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin, common downstream effects following antagonism of the NMDA receptor.

Healthy volunteers participated in a single-site, randomized, double-blind, placebo-controlled, phase 1 clinical trial and were admitted to a clinical research unit for 14 days. Esmethadone 25 mg or placebo was administered orally for 10 days, and BDNF plasma levels were measured predose on day 1 and subsequently on days 2, 6, and 10. Plasma BDNF levels in the participants receiving 25 mg of esmethadone increased on day 10 from 2 to 17 times the pretreatment levels. In the placebo group, BDNF plasma levels were unchanged throughout the 10 days. Additionally, plasma levels of BDNF significantly correlated with plasma levels of esmethadone.³

This was followed by a phase 2a 7-day, double-blind, placebo-controlled, randomized study that 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 Montgomery-Åsberg Depression Rating Scale on days 2, 4, 7, and 14. Both esmethadone doses significantly outperformed placebo on day 7, and this benefit persisted to day 14. Phase 3 studies are underway.⁴

Clinical Significance

If esmethadone continues to demonstrate utility as an augmenting agent in MDD in patients having an inadequate response to their primary antidepressant, it could become the third antidepressant whose mechanism is based on antagonism of the NMDA receptor. In its phase 2a study, esmethadone was adjunctively administered along with the established antidepressant for 7 days and sustained its 7-day improvement at day 14. Consistent with the complexity of the NMDA receptor, different binding sites by different antidepressants appear to require different dosing and treatment protocols.

Navacaprant

In 2019, the FDA declined approval of combination drug buprenorphine/samidorphan as an adjunctive treatment for patients who did not respond to monotherapy antidepressant medication for treatment of a unipolar major depressive episode. The hypothesis was that dysregulation of the endogenous opioid system was contributing to major depressive episodes. Buprenorphine, an antagonist/partial agonist at the μ-receptor and a functional antagonist at the κ-receptor, was used for its property as a κ-receptor antagonist. Samidorphan, a potent μ-receptor antagonist, was used in combination to prevent any partial agonism of the μ-receptor by buprenorphine, hence eliminating any abuse potential.⁵

Dynorphins are endogenous opioid peptides that agonize the κ-receptor and cause dysphoria and are believed to contribute to a depressed mood. The hypothesis was that this drug combination would improve depression by buprenorphine’s κ-receptor antagonism displacing dynorphins, while the samidorphan would antagonize the μ-receptor, preventing buprenorphine’s activity there.

Navacaprant, a κ-receptor antagonist in development by Neumora Therapeutics, recently demonstrated a significant improvement in depressive symptoms in 100 patients with moderate to severe MDD during an 8-week phase 2 study, as well as improving symptoms of anhedonia. Navacaprant is a novel, highly selective κ-receptor antagonist that is dosed orally at 80 mg as a monotherapy. Neumora has begun its KOASTAL Program, which includes 3 phase 3 studies.⁶

Clinical Significance

Agonism of the opioid κ system with endogenous dynorphins has long been associated with depression and anhedonia. The highly selective antagonism of this system by navacaprant, which lacks affinity to the μ-receptor and opioid δ receptor, may target symptoms of major depression and anhedonia directly and as a monotherapy. This novel drug mechanism would provide welcome additional circuitry to treat depression, possibly improving symptoms in patients with depression who currently respond poorly or do not respond to current antidepressants. We will eagerly await results from the 3 phase 3 studies.

Psilocybin

Psilocybin has become a household word throughout the United States, with many popular misconceptions that it has already been deemed safe and effective for the treatment of depression. In truth, although being aggressively studied in double-blind, placebo-controlled trials registered with the FDA, psilocybin is still in the investigational phase of drug development.

Psilocybin is a naturally occurring molecule that exists in more than 200 species of Basidiomycota mushrooms found throughout the world. Clinical trials use either psilocybin extracted from these mushrooms or a synthetic form. It is classified as a hallucinogen, and, similar to lysergic acid diethylamide (LSD) and mescaline, its mechanism of action appears to be due to its agonism at the serotonin 5-HT_2A receptor, although other receptors may also be involved in contributing to the mechanism of all 3 of these drugs.

This 5-HT_2A receptor agonism is highly significant in psychopharmacology, as many drugs currently used in the United States to treat depression and psychotic disorders antagonize this receptor. These include the antidepressants mirtazapine and trazodone, as well as most atypical antipsychotics.

These 3 hallucinogens are currently classified by the DEA as Schedule I drugs, but this status will likely change if FDA approval is achieved. 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.

In the January 2021 issue of Psychiatric Times, I authored an article reviewing the psychiatric pipeline at that time, including psilocybin. According to the US National Library of Medicine database ClinicalTrials.gov, as of November 29, 2020, there were 56 psilocybin clinical trials registered in various stages. When I accessed this same database on December 30, 2023, there were 147 registered clinical trials using psilocybin as the search drug.⁷

Putative neurophysiological mechanisms that may result from psilocybin’s agonism of the 5-HT_2A receptor include disruption of dysregulated brain circuits associated with depression; disruption of the default mode network; decreasing activity in the subgenual cingulate cortex; increasing synaptic neuroplasticity; and modifying connections between the frontal cortex and subcortical areas, such as the amygdala.⁸

Table 2. Disorders Currently in Clinical Trials Assessing the Benefits of Psilocybin⁷

Although clinical trials exploring the benefits of psilocybin in the treatment of MDD are the most commonly discussed trials in both psychiatric and public forums, the large number of diverse diagnoses under study as listed in Table 2⁷ supports the likelihood that there is a more generalizable effect of psilocybin impacting human consciousness that we do not yet understand. Functional magnetic resonance imaging (fMRI) in 2 different clinical trials of depression demonstrated a rapid antidepressant response to psilocybin, which correlated with a global increase in brain network integration, suggesting neuroplasticity as a putative mechanism of effect.⁹

In the treatment of MDD, 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 of phase 2 studies have been mostly positive.¹⁰

A phase 2 double-blind, randomized, controlled trial compared psilocybin with escitalopram in 59 patients with moderate to severe MDD over 6 weeks. Patients were randomly assigned 1:1 to receive either 2 doses of 25 mg of psilocybin 3 weeks apart along with 6 weeks of daily placebo or 2 doses of 1 mg of psilocybin 3 weeks apart along with 6 weeks of escitalopram. All participants also received psychological support. The primary outcome measure was improvement at week 6 on the 16-Item Quick Inventory of Depressive Symptomatology self-report. The 6-week between-group difference favored psilocybin by 2 points, but this difference was not statistically significant (P = .17).¹¹

Phase 3 studies are currently underway that, once completed, should provide the necessary information to determine the efficacy and safety of psilocybin for the treatment of MDD as a monotherapy and for treatment-resistant depression (TRD).¹²

Clinical Significance

From 1938 until 1966, hallucinogenic drugs, including LSD and psilocybin, were extensively studied in psychiatry. A Google Scholar search on December 30, 2023, for the keyword LSD in publications between the years 1950 and 1970 resulted in 20,200 results. An identical search of the PubMed database produced 1999 results. Much of present-day psychiatry has forgotten or is unaware of the rich research by psychiatrists combining LSD with psychotherapies that is well published.

During the early 1960s, cultural, political, and legal forces led to laws in 1966 that prohibited the synthesis, sale, or ingestion of hallucinogens. Finally, in 1970, the Controlled Substance Act was passed, which categorized LSD, psilocybin, and other hallucinogens as Schedule I drugs. During the past decade, reports of dramatic symptom improvements in patients who had been diagnosed with TRD turned our attention once again to the potential clinical role of hallucinogens, especially psilocybin.

Analogous to the research with MDMA for the treatment of PTSD, the clinical trials using psilocybin for the treatment of significant depression couple limited doses of this hallucinogen with a highly structured protocol of psychotherapy, which is essential to the treatment. Additionally, as has been shown with the intravenous administration of ketamine, fMRI studies demonstrate an increase in global brain connectivity.^13,14

There appears to be significant momentum behind the eventual FDA approval of psilocybin for the treatment of depression, with many other possible clinical applications being intensively studied. If approved by the FDA, there will likely be specific treatment guidelines, and we must educate our patients and the public about the clinical guardrails for the use of psilocybin that we all must respect.

Treatment of ADHD

Centanafadine

The 2 medications that have proven most effective for the treatment of ADHD are methylphenidate (used since the 1960s) and amphetamine (used since the 1970s), collectively called stimulants. These 2 drugs are so effective that there are at least 35 FDA-approved medications for ADHD containing them in different formulations, structural modifications, or delivery systems currently available in the United States.¹⁵ The FDA approval of serdexmethylphenidate and dexmethylphenidate (Azstarys) in 2021 added yet a new formulation combining the prodrug serdexmethylphenidate with dexmethylphenidate.¹⁶

When these 2 stimulants classes do not work or are contraindicated for various reasons, 2 other classes of medications exist: presynaptic α₂-adrenergic receptor agonists (clonidine extended release [Kapvay] and guanfacine extended release [Intuniv]) and primary norepinephrine reuptake inhibitors (NRIs) (atomoxetine [Strattera] and viloxazine extended release [Qelbree]). Centanafadine, a novel NRI described as a triple monoamine reuptake inhibitor, is in the final stages of development with completed phase 3 studies that may soon be joining the ADHD medication armamentarium. The most common adverse events reported in these phase 3 studies were headache and decreased appetite.¹⁷

Although described mechanistically as a reuptake inhibitor of the transporters for norepinephrine (NET), dopamine (DAT), and serotonin (SERT), an adaptive-design PET phase 1 study in healthy adult males evaluated the occupancy time course of NET, DAT, and SERT, as well as the relationship to centanafadine plasma concentrations. The estimated in vivo affinities demonstrated that centanafadine bound 11.9 times stronger to the NET than the DAT, 13.3 times stronger at the NET than the SERT, and 1.1 times stronger at the DAT than the SERT at the 400-mg total daily dose.¹⁸

These in vivo numbers are reasonably similar to in vitro measurements of half-maximal inhibitory concentrations (IC₅₀) of centanafadine at the 3 monoamine reuptake transporters previously established.¹⁹ In that study, the IC₅₀ values for NET, DAT, and SERT were 6 nm, 38 nm, and 83 nm, respectively. Hence, similar to atomoxetine and viloxazine extended release, the primary mechanism of centanafadine in the treatment of ADHD symptoms appears to be inhibition of the NET, with all 3 drugs demonstrating different secondary binding properties and kinetics.

Clinical Significance

It is well established that despite the 2 stimulant classes having similar mechanisms of action, some patients with ADHD respond well to and tolerate one while having an adverse experience with the other. Other patients do not tolerate either of the stimulants, and the NRIs have proven to be effective for many of them. Additionally, some patients or their families prefer the NRIs to the stimulants, as the NRIs are not a controlled substance, which eliminates the additional strict requirements of being prescribed a Schedule II drug.

Finally, all patients respond differently to different medications, and having a third NRI as a treatment option for ADHD may benefit a subpopulation of patients who are not optimally treated with the medications currently available.

The 3 NRIs share the same primary mechanism of action but have very different secondary mechanisms of action and pharmacokinetics and ultimately are distinct molecules. Centanafadine may soon join the ADHD armamentarium of medications, and if it does, our patients will teach us its benefits and limitations.^20,21

Concluding Thoughts

This 2-part overview of the pharmacological pipeline as we enter 2024 provides just a sampling of a broad range of innovative medications in development with the goal of providing us psychiatric clinicians with novel treatments in our quest to decrease patient suffering and improve function and quality of life.

Each of the medications reviewed has a unique biography dating back decades to millennia. As research and understanding of the human brain incrementally evolves, drug targets will continue to appear for the basic scientists to vet and develop, hoping to ultimately enhance our clinical drug armamentarium.

The convergence and integration of all the knowledge that becomes available to neuroscience literally on a daily basis will only continue to fill us with awe and inspire us to return to the clinical trenches every day to share our small contribution to the healing of humanity.

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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