There is much to look forward to in the realm of improved treatments for patients with psychiatric illness.
Despite a diverse and ever-expanding menu of psychotropic medications, most clinicians still look expectantly down the psychiatric drug pipeline, hoping for novel agents to improve their treatment outcomes for everything from psychosis to depression. The history of psychotropic medication may be full of serendipity and setbacks (Sidebar), but it has included undeniable successes, serving as a powerful ally in our mission to decrease emotional pain and suffering by offering actionable modification of the brain’s architecture.
Fortunately, there are a number of agents in the current psychiatric pharmacological pipeline (Table). Not only do they offer promise of new treatments to help patients, but they also further our understanding of brain function and dysfunction. The following is a sampling, in no particular order, of drugs in various stages of clinical development.
Kar-XT: Combination of Xanomeline and Trospium
The muscarinic cholinergic system has been of interest in psychiatry since the US Food and Drug Administration (FDA) approval of chlorpromazine, which has significant anticholinergic adverse effects. Additionally, 3 FDA-approved medications for the treatment of Alzheimer disease are centrally active acetylcholinesterase inhibitors that increase acetylcholine levels in the brain. There are 5 muscarinic cholinergic subreceptors (M1 through M5), and all are metabotropic. They are in sharp contrast to those in the nicotinic cholinergic receptor family, which are all ion channels.
Xanomeline is a muscarinic M1/M4 receptor-preferring agonist that has demonstrated improvement of both positive and negative schizophrenia symptoms in clinical trials. Theoretically, M1 agonism in the prefrontal cortex improves cognition and negative symptoms, whereas M4 agonism in subcortical areas maintains dopamine homeostasis, which is believed to decrease positive symptoms. In patients who received monotherapy with xanomeline, the drug was poorly tolerated due to the cholinergic adverse effects, including vomiting, nausea, diarrhea, excessive sweating, and salivation.
Trospium is a peripheral muscarinic antagonist that does not cross the blood-brain barrier, and it was added to xanomeline in the combination drug Kar-XT. Recently, the agent demonstrated positive results in a phase 2 trial in schizophrenia, with a reduction in positive and negative symptoms as well as good tolerability.1
SEP-856: TAAR-1 and 5HT1A Agonist
SEP-856 (also known as SEP-363856) is an intriguing molecule. It has demonstrated efficacy, according to the results of a published phase 2 study of the treatment of an acute exacerbation of schizophrenia. The approximate pretreatment mean baseline Positive and Negative Syndrome Scale (PANSS) score of participants was 100. At week 4, investigators found a 17.2-point decrease in the PANSS for SEP-856 in the active treatment group, versus a 9.7-point decrease in the placebo group. The rates of extrapyramidal symptoms (EPS), change in lipids and hemoglobin A1C, and prolactin levels in the treatment group were similar to those in the placebo group.2 A phase 3 study is currently under way.
A significant pharmacodynamic property of SEP-856 is that it demonstrates no activity at any of the 5 dopamine receptors.
SEP-856’s mechanism of action can be best understood by reviewing how caffeine indirectly increases dopamine levels in the brain through a receptor complex of 2 different types of receptors known as heterodimers. In the absence of caffeine during the course of the day, the neurotransmitter adenosine increases in concentration and agonizes adenosine receptors, increasing drowsiness. This results directly from the heterodimer complex of adenosine receptors and dopamine2 receptors (D2Rs). As adenosine increases in the brain, it decreases dopamine activation.
Caffeine is structurally similar to adenosine. It functions as a noncompetitive antagonist at the adenosine site of the adenosine-dopamine receptor heterodimer complex. As brain caffeine levels increase, adenosine is displaced from this heterodimer resulting in increased dopamine activity.3
Similarly, in the human brain, trace amine-associated receptor 1 (TAAR-1) forms a heterodimer receptor complex with the D2R. TAAR-1 is a G-protein coupled receptor that functions like a rheostat on the D2R; it is located in brain regions related to the limbic system, reward circuits, cognitive processes, and mood.
Trace amines are endogenous monoamines that are related to dopamine, norepinephrine, and serotonin. The 2 most common trace amines are p-tyramine and 2-phenylethylamine, both of which naturally occur in concentrations 2 orders of magnitude lower than dopamine/norepinephrine/serotonin. Agonism of TAAR-1 by these trace amines decreases dopamine activity, including a decrease in mesolimbic dopamine neuronal firing.
It is hypothesized that SEP-856’s efficacy in improving the PANSS score in individuals with schizophrenia is related to its agonism of the TAAR-1 receptor, which would indirectly decrease dopamine activity. Additionally, SEP-856 agonizes the serotonin 5HT1A receptor, and further research is under way to determine how this mechanism may contribute to improvement in schizophrenia symptoms.4
In 2019, the FDA approved brexanolone (intravenous [IV] allopregnanolone) as a first-in-class medication for the treatment of postpartum depression. Allopregnanolone is an endogenous neuroactive steroid that functions as a γ-aminobutyric acid (GABA) type A receptor positive allosteric modulator.5 Although its mechanism of action is unknown, allopregnanolone is believed to improve symptoms of depression and anxiety by amplifying GABAergic signaling throughout the brain. GABA is the primary inhibitory neurotransmitter in the brain. When it binds to the GABA-A receptor, there is a resulting influx of chloride ions (negatively charged) into the neuron; this results in a hyperpolarization of that neuron, hence the inhibitory effect.
GABAA receptors have multiple subunits, α 1 through α 6, and various GABAA receptor active drugs bind only to certain subsets of these polymorphic receptors. Examples of other drugs that allosterically activate the GABAA receptors include alcohol, benzodiazepines, and barbiturates. Adverse effects of these drugs include sedation, somnolence, and loss of consciousness. SAGE-217 (zuranolone) is an oral formulation of allopregnanolone currently in clinical trials for postpartum depression, and the treatment of major depressive disorder (MDD) in men and women.6
AXS-05: Combination of Dextromethorphan and Bupropion
During the 1940s, the US Navy and Central Intelligence Agency funded research to develop a nonaddictive synthetic analogue of codeine that could be used as a cough suppressant. Dextromethorphan, the result of this research, was patented in 1949; approved by the FDA in 1954; and approved as an over-the-counter drug in 1958. Dextromethorphan has a complex pharmacology that includes activity as an uncompetitive NMDA-glutamate antagonist; sigma-1 agonism; and nonselective serotonin reuptake inhibition.
In 1985, the FDA approved bupropion as the first selective norepinephrine/dopamine reuptake inhibitor. It is currently approved for MDD, seasonal affective disorder, and nicotine dependence. Later it was discovered that bupropion is a potent inhibitor of the cytochrome P450 2D6 (CYP2D6) enzyme, which is the pathway that metabolizes dextromethorphan to dextrorphan.
The fixed combination of these 2 old drugs (oral dextromethorphan 45 mg/bupropion 105 mg po twice a day) is AXS-05. Dextromethorphan shares some of the same pharmacological properties as ketamine and its isomers. Prolonging dextromethorphan’s serum level by the potent CYP2D6 inhibition of bupropion, and adding in the norepinephrine/dopamine reuptake inhibition of bupropion, is the putative mechanism of AXS-05’s antidepressant effect.
GEMINI, a phase 3 randomized double-blind, placebo-controlled study in patients with MDD, found AXS-05 improved the Montgomery Asberg Depression Rating Scale (MADRS) score by 4.7 points compared with placebo (P = .002) at 6 weeks (the primary end point). Additionally, at the week 1 key secondary end point, AXS-05 improved the MADRS score by 2.4 points compared with placebo (P = .007).7
TAK-831: D-Amino Acid Oxidase Inhibitor
Life began on Earth approximately 3.5 billion years ago. Amino acids are the building blocks of all proteins in living organisms, and 20 amino acids are used in protein construction in humans. With the exception of glycine (which is achiral) amino acids have a chiral carbon, meaning they are all stereoisomers, often explained as having 2 structurally unique forms that are mirror images of each other. One way to determine the stereoisomer of a particular amino acid is to shine polarized light through it, which will result in the light turning clockwise (dextrorotation, dextro or D) or counterclockwise (levorotation, levo or L). When life evolved on Earth, for reasons we do not understand, all structural amino acids in all living systems were the levo isomers.
Anevolutionary advantage of this phenomena was the availability of all the D-amino acid isomers for other biological functions. Such is the case in humans, where there are only 2 D-amino acids with a biological function: D-aspartate and D-serine. L-serine exists ubiquitously in humans as a building block in most proteins. The enzyme serine racemase converts L-serine to D-serine in neurons and plays an important role in the agonism of the NMDA glutamate receptor (NMDAR). In order for the ion channel NMDAR to open, 2 glutamate molecules need to be bound to it, as well as either 2 glycine molecules or 2 D-serine molecules. Significantly, D-serine binds more tightly to the glycine binding site on the NMDAR than glycine itself. The enzyme D-amino acid oxidase metabolizes D-serine to inactive products.
TAK-831 is a selective and potent D-amino acid oxidase inhibitor, hence it prolongs the activity of D-serine as an agonist at the NMDAR. In the presence of enough glutamate, the end result is increased activity of the NMDAR, which theoretically can improve negative symptoms in schizophrenia as well as treat Friedreich ataxia.8
NV-5138: Sestrin Modulator
The protein kinase mammalian target of rapamycin (mTOR) forms part of a protein complex that is responsible for many functions, including cell growth and synaptogenesis. Researchers have hypothesized that several antidepressants, including esketamine/ketamine, increase neuronal levels of mTOR as one of the final actions in a molecular cascade to treat depression. The amino acid leucine activates mTOR Complex 1 (mTORC1) by binding to the upstream regulator sestrin. NV-5138 is a selective small molecule modulator of sestrin, which readily crosses the blood-brain barrier and putatively facilitates sestrin’s activation of the mTORC1, ultimately providing a rapid antidepressant effect through synaptogenesis in the medial prefrontal cortex (mPFC).
In theory, NV-5138 would bypass much of the molecular cascade that is currently necessary to increase brain derived neurotropic factor (BDNF) and ultimately activate mTORC1, hence providing a more direct path to synaptogenesis. This might result in a targeted response with less adverse effects. A single dose of NV-5138, in the required presence of BDNF, resulted in a rapid and long-lasting antidepressant effect in rats by putatively increasing synaptogenesis in the mPFC.9
The FDA approval of intranasal esketamine in March 2019 introduced the first nonmonoamine drug into our pharmacopeia for the treatment of MDD, and it is approved for both treatment-resistant depression in adults and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Similarly, IV ketamine has been used off-label for severe depression since the late 1990s. The chemist Calvin L. Stevens, PhD, discovered ketamine in 1962, and the FDA approved the agent in 1970 as a dissociative anesthetic; it is still in common use as such.
Esketamine/ketamine demonstrate antidepressant effects in less than 24 hours. Although their mechanisms of action remain to be elucidated, both likely involve increasing levels of BDNF and ultimately increasing activity of mTOR. mTOR increases protein synthesis at synapses; this in turn increases synaptogenesis, especially in the prefrontal cortex.10 Ketamine is a 50:50 mixture of its 2 enantiomers esketamine and arketamine, both of which are metabolized to hydroxynorketamine. Hydroxynorketamine does not bind to the NMDA glutamate receptor, but rather activates the AMPA glutamate ion channel with downstream effects increasing BDNF and mTOR. Hydroxynorketamine has demonstrated rapid antidepressant activity in animal models. Since the drug has no abuse potential and no dissociative effects, investigators are studying hydroxynorketamine as a possible ketamine/esketamine alternative.11
Currently, there are 56 psilocybin clinical trials in various stages registered with the FDA.12 These trials are addressing a range of diagnoses, including treatment resistant depression, MDD, obsessive compulsive disorder, anorexia nervosa, migraine headaches, alcohol use disorder, and advanced stage cancer, as well as for pharmacokinetics and functional brain mapping.
Psilocybin is in the class of drugs called hallucinogens, which have been used in religious and spiritual ceremonies throughout the world for thousands of years. In 1938, chemist Albert Hofmann, PhD, working at the Swiss pharmaceutical company Sandoz created lysergic acid diethylamide (LSD). From 1938 until 1966, hallucinogenic drugs, including LSD and psilocybin, were extensively studied in psychiatry.
Regrettably, during the early 1960s, Harvard University’s Timothy Leary, PhD, and Richard Alpert, PhD, applied misguided research protocols to study both LSD and psilocybin, and they were ultimately fired from Harvard. Simultaneously, the use of hallucinogens by anti-Vietnam War activists and the highly visible counterculture sullied the reputation of hallucinogens in the United States. Finally, in 1966, laws prohibiting the synthesis, sale, or ingestion of hallucinogens were passed, and in 1970 they became a Schedule 1 drug. Over the past 50 years, the steady undercurrent of hallucinogenic use with numerous individual reports of significant transcendental psychological experiences has resulted in a revival of clinical interest. The political winds may be shifting, too, as voters in the state of Oregon recently approved the use of psilocybin for mental health purposes.13
Clinical trials are still in the early stages, but researchers at prominent universities in the United States and England and around the rest of the world have been captivated by the benefits of psilocybin when used in 1 or 2 sessions in a safe and controlled environment. Robin Carhart-Harris, PhD, head of the Centre for Psychedelic Research, Division of Brain Sciences at Imperial College, London, England, is a leading pioneer in this research, and results of exploratory open-label studies without placebo control groups have demonstrated impressive improvements in patients with treatment-resistant depression.14,15
MIN-101: Roluperidone—a 5-HT2A and Sigma-2 Receptor Antagonist
A huge unmet need is novel agents to treat the negative and cognitive symptoms of schizophrenia. All current antipsychotic medications antagonize (through antagonism or antagonism/partial agonism) the D2R. This antagonism of the D2R in the mesolimbic tract seems essential for treating positive symptoms, namely hallucinations and delusions, with this class of drugs. However, this same D2R antagonism in the mesocortical tract likely worsens the negative and cognitive symptoms that are more pervasive in schizophrenia, and these are the symptoms that ultimately contribute more to functional disability than the positive symptoms.
MIN-101 has no affinity to any of the dopamine receptors. It is a novel agent that binds equipotently to the 5-HT2A and sigma-2 receptors (inhibition constants 7.53 nM and 8.19 nM for 5-HT2A and sigma-2 receptors, respectively). A phase 2b clinical trial enrolled 244 patients with schizophrenia whose positive symptoms were considered symptomatically stable by their treating psychiatrist. To be part of the study, patients needed to demonstrate at least moderately severe negative symptoms for 3 or more months. All patients were hospitalized, during which time all psychiatric drugs were discontinued. After at least 5 days, patients were randomized in a double-blind, placebo-controlled design to receive oral MIN-101 32 mg/day, MIN-101 64 mg/day, or placebo in a 1:1:1 ratio for 12 weeks. The primary outcome was improvement at the end of week 12 in the negative factor score from the PANSS (items N1-N4, G5-G8, G13, and G14).
Both doses of MIN-101 demonstrated a statistically significant improvement in the PANSS negative factor score as compared with placebo (32 mg/day with P ≤ .024 and 64 mg/day with P ≤ .004). There was no significant improvement in positive symptoms compared with placebo in either dose.16
Much is known in psychiatry about the 5-HT2A receptor, and its antagonism of this receptor is an integral property of many of the atypical antipsychotics. In contrast, we know little about the sigma-2 receptor. We await phase 3 clinical trial results to see whether MIN-101 continues to demonstrate improvement in negative and cognitive symptoms in patients with schizophrenia.
ALKS 3831: Combination of Olanzapine and Samidorphan
Olanzapine needs little introduction. The FDA approved it in 1966 as the third atypical antipsychotic, following clozapine and risperidone. Olanzapine has garnered many FDA-approved indications for various psychiatric disorders over the past 24 years, and it has become available as a generic medication. Olanzapine has established efficacy, but confers many possible adverse effects, including significant weight gain, hyperglycemia, hyperlipidemia, and sedation (in addition to the other common possible adverse effects of antipsychotic medications). Samidorphan is a potent mu-opioid receptor antagonist, similar in pharmacodynamics to naltrexone and naloxone.
ALKS 3831 is a combination of olanzapine and samidorphan developed to reduce the propensity for weight gain from olanzapine monotherapy. The phase 1 proof of concept study was a randomized, double-blind, placebo-controlled trial in healthy male volunteers with a stable body weight (body mass index, 18 kg/m2 to 25 kg/m2), which compared the change in weight over a 3-week period of time in 4 cohorts: olanzapine 10 mg/samidorphan 5 mg; olanzapine 10 mg; samidorphan 5 mg; and placebo. The primary end point was change in weight at 3 weeks, which was +2.2 kg, +3.1 kg, +0.1, kg, and +0.8 kg, respectively.17
Phase 3 studies of ALKS 3831 have been completed. In addition, a New Drug Application has been submitted to the FDA for adults with schizophrenia and adults with bipolar I disorder; approval is pending.
This overview of 10 agents in our psychiatric pharmacological pipeline demonstrates the wide range of mechanisms of action currently under investigation. Each of them could add an important novel medication to our clinical psychopharmacological toolbox. These agents draw upon established mechanisms of action, as well as putative mechanisms that remain to be proven as therapeutic advances. Although our current armamentarium of medications is helpful to a subset of patients, it remains suboptimal, leaving many patients in partial remission of their symptoms, or with no improvement at all.
We have come a long way since the serendipity of drug discovery in the 1950s. Sometime in the future we will look back at our current treatments as outdated, and some of them will have been discarded. Not because they never worked, but because the new options are more effective.
Dr Miller is medical director, Brain Health, Exeter, NH; editor in chief, Psychiatric TimesTM; staff psychiatrist, Seacoast Mental Health Center, Exeter, New Hampshire; consulting psychiatrist, Exeter Hospital, Exeter; consulting psychiatrist, Insight Meditation Society, Barre, Massachusetts.
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