Redirecting the revolution: New developments in drug development for psychiatry

1. Introduction

Psychiatric disorders are the leading causes of disability worldwide, and there is an urgent need for new treatments [1]. The exodus of many pharmaceutical companies from psychiatric drug development and the lack of translation from advances in molecular mechanisms of disease and human genetics has hampered progress over the past few decades, creating a “Revolution Stalled”, per one astute observer [2]. Recent scientific and regulatory developments suggest that this trend may be reversing, raising hope for the community of individuals affected by mental illnesses.

2. What has changed

2.1. The scientific landscape

Advances in genomic approaches to mental illnesses, coupled with novel consortia, provide the backdrop for new opportunities in drug development in psychiatry. Many of these developments are spearheaded by the National Institute of Mental Health (NIMH), working with other Institutes and Centers of the National Institutes of Health (NIH).

Progress in genomics depends on collaborative efforts to acquire and study the large samples required for discovery in complex mental illnesses like schizophrenia and major depressive disorder (MDD). The Psychiatric Genomics Consortium [3], a global consortium dedicated to open science and data sharing, has spearheaded identification of hundreds of loci in the genome linked to psychiatric disorders using DNA from large cohorts (10,000-100,000) [4]. A related but independent effort, the PsychENCODE Consortium [5], has generated and shared an integrative atlas of gene expression in the human brain using samples from >2,000 individuals with and without mental illnesses. These datasets reveal relationships of neuropsychiatric risk genes to biology [6], and are being mined for putative therapeutic targets.

Earlier hopes that gene discoveries would rapidly yield targets for drugs with novel mechanisms of action were largely unfulfilled [2], but the approach still has value. Targets emerging from genomic approaches can follow a linear path from identification to validation and testing with new tools available to both academia and industry. These include methods to quantify target engagement in living subjects such as positron emission tomography tracers to assess molecular interactions, as well as high-density electroencephalography and functional magnetic resonance imaging (fMRI) to measure effects of drugs on brain circuits. We can now assess whether manipulating previously untestable targets alters domains of brain function relevant to psychiatric disorders and, when coupled with clinical trials, correlate to measures of safety and efficacy.

2.2. The regulatory landscape

These scientific opportunities coincide with the recognition by Federal regulators that drug development for high medical need areas like serious mental illness requires additional support.

In 2012, the US Food and Drug Administration (FDA) Safety and Innovation Act created the Breakthrough Therapy designation to expedite development of promising drugs intended to treat serious or life-threatening conditions. This provides for more intensive feedback and expedited review than the earlier Fast Track designation [7]. The FDA has also issued guidances that reflect their current thinking on drug development tools [8], biomarker qualification for specific Contexts of Use [9], and in psychiatry, trial designs for antidepressant drugs [10].

There is a parallel rejuvenation of interest in psychiatric therapeutics by the pharmaceutical industry. In March of 2019, the FDA approved two new antidepressant medications: esketamine nasal spray for treatment-resistant depression and intravenous brexanolone for postpartum depression. Both are mechanistically novel and act rapidly, driving clinical improvement in hours to days instead of 3-4 weeks for traditional antidepressants. Both received Breakthrough Therapy designations before approval. More generally, for all FDA new drug approvals in 2018, 24% had Breakthrough Therapy designations [11].

The future for psychiatric medications is beginning to look up. Table 1 presents an overview of the psychiatric drug pipeline from 2013 to present. Including brexanolone and esketamine, nine promising drug candidates have been granted 11 Breakthrough Therapy designations. These include three additional rapidly acting antidepressants, as well as mechanistically new compounds for schizophrenia, autism, and post-traumatic stress disorder. Six received Fast Track designations for depression and schizophrenia. Many novel mechanisms are represented among the drugs in early phase testing, suggesting opportunities for truly transformative treatments.

Table 1.

Psychiatric Drug Pipeline (2013-2019)¹

FDA Breakthrough Therapy Designations	Mechanism of action	Indication	Company	Date of Designation
esketamine	noncompetitive NMDA receptor antagonist	treatment-resistant depression (RAAD)	Janssen Pharmaceutical Companies*	Nov. 2013
pimavanserin	5-HT2A receptor inverse agonist, less so at 5-HT2C receptor	hallucinations and delusions in Parkinson’s disease psychosis	Acadia Pharmaceuticals Inc.	Sept. 2014
NaBen (SND-13)	DAAO inhibitor	schizophrenia, adjunctive treatment	SyneuRx International	Dec. 2014
rapastinel (GLYX-13, BV-102)	NMDA receptor partial agonist	major depressive disorder, adjunctive treatment (RAAD)	Allergan Inc.2,*	Jan. 2016
esketamine	noncompetitive NMDA receptor antagonist	major depressive disorder with imminent risk of suicide (RAAD)	Janssen Pharmaceutical Companies*	Aug. 2016
brexanalone (SAGE-547)	GABA-A receptor positive allosteric modulator	post-partum depression (RAAD)	Sage Therapeutics, Inc.3	Sept. 2016
MDMA-assisted psychotherapy for post-traumatic stress disorder	indirect serotonin agonist	post-traumatic stress disorder	COMPASS Pathways Ltd.	Aug. 2017
pimavanserin (Nuplaxid™)	5-HT2A receptor inverse agonist, less so at 5-HT2C receptor	dementia-related psychosis	Acadia Pharmaceuticals Inc.	Oct. 2017
balovaptan (RG7314, RO5285119)	V1A receptor antagonist	autism spectrum disorder, social communication	Hoffman-LaRoche Inc.*	Feb. 2018
SAGE-217	GABA-A receptor positive allosteric modulator	major depressive disorder (RAAD)	Sage Therapeutics, Inc.	Feb. 2018
NRX-101 fixed dose combination of D-cycloserine and lurasidone	NMDA receptor antagonist and 5-HT2A receptor antagonist	severe bipolar depression with acute suicidal ideation and behavior (RAAD)	NeuroRx, Inc.4	Nov. 2018
AXS-05 fixed dose combination of dextromethorphan and bupropion	NMDA receptor antagonist/σ-1 receptor agonist and NDRI	treatment-resistant depression	Axsome Therapeutics Inc.	Mar. 2019
SEP-363856	5-HT1A receptor agonist and TAAR1 receptor agonist	schizophrenia	Sunovion Pharmaceuticals Inc.	May 2019
FDA Fast Track Designations				Date of Designation
rapastinel	NMDA receptor partial agonist (glycine site partial agonist)	major depressive disorder, adjunctive treatment (RAAD)	Naurex, Inc.	Mar. 2014
AVP-786 fixed dose combination of deudextromethorphan (d-DM) and quinidine	σ-1 receptor agonist/uncompetitive NMDA receptor antagonist/SNRI and cytochrome P450 2D6 inhibitor	agitation in Alzheimer’s disease	Avanir Pharmaceuticals	Nov. 2015
AXS-05 fixed dose combination of dextromethorphan and bupropion	NMDA receptor antagonist/σ-1 receptor agonist and NDRI	treatment-resistant depression	Axsome Therapeutics Inc.	Feb. 2017
NRX-101 fixed dose combination of D-cycloserine and lurasidone	NMDA antagonist and 5-HT2A receptor antagonist	severe bipolar depression with acute suicidal ideation and behavior (RAAD)	NeuroRx, Inc.5	Aug. 2017
lumateperone (ITI-007)	5-HT2A receptor antagonist, DPPM	schizophrenia	Intra-Cellular Therapeutics Inc.	Nov. 2017
AV-101	NMDA receptor glycine B site antagonist	major depressive disorder, adjunctive treatment (RAAD)	VistaGen Therapeutics, Inc.	Jan. 2018
AGN-241751	NMDA receptor modulator	major depressive disorder (RAAD)	Allergan Inc.*	July 2018
FDA New Drug Approvals				Date of Approval
esketamine, intranasal (Spravato™)	noncompetitive NMDA receptor antagonist	treatment-resistant depression, adjunctive treatment (RAAD)	Janssen Pharmaceutical Companies*	Mar. 2019
brexanalone, intravenous (Zulresso™)	GABA-A receptor positive allosteric modulator	post-partum depression (RAAD)	Sage Therapeutics, Inc.6	Mar. 2019
deutrabenazine (Austedo™)	VMAT2 inhibitor	tardive dyskinesia in adults	Teva Pharmaceutical Industries Ltd.	Aug. 2017
valbenazine (Ingrezza™)	VMAT2 inhibitor	tardive dyskinesia in adults	Neurocrine Biosciences, Inc.	Apr. 2017
pimavanserin (Nuplaxid™)	5-HT2A receptor inverse agonist, less so at 5-HT2C receptor	hallucinations and delusions in Parkinson’s disease psychosis	Acadia Pharmaceuticals Inc.	Apr. 2016
aripiprazole lauroxil extended release (Aristada™)	D2 receptor and 5-HT1A receptor partial agonist, 5-HT2A receptor antagonist	schizophrenia	Alkermes plc*	Oct. 2015
cariprazine (Vraylar™)	D2 receptor and 5-HT1A receptor partial agonist, 5-HT2A receptor antagonist	schizophrenia; manic or mixed episodes associated with bipolar disorder	Allergan Inc.*	Sept. 2015
brexpiprazol (Rexulti™)	5-HT1A receptor and D2 receptor partial agonist, 5-HT2A receptor antagonist	major depressive disorder adjunctive treatment; schizophrenia	Otsuka Pharmaceutical Company Ltd.*	July 2015
vortioxetine (Brintellix™)	SSRI, 5-HT3 receptor antagonist, 5-HT1A receptor agonist	major depressive disorder	Takeda Pharmaceutical Company Ltd.*	Oct. 2013
levomilnacipran (Fetzima™)	SNRI	major depressive disorder	Forest Laboratories	July 2013
New Drug Application Submissions				Date of Submission
ALKS 54617 fixed dose combination of samidorphan and buprenorphine	μ opioid receptor antagonist/partial agonist at μ and κ opioid receptors, antagonist at δ opioid receptor	major depressive disorder adjunctive treatment	Alkermes plc*	Apr. 2018
lumateperone (ITI-007)	5-HT2A receptor antagonist, DPPM	schizophrenia	Intra-Cellular Therapeutics Inc.	Dec. 2018
rykindo (LY03004)	risperidone extended-release microsphere	schizophrenia	Luye Pharma Group Ltd.	Mar. 2019
Drugs in Early Phase Industry-Sponsored Clinical Trials (currently recruiting)
HTL0014242 Early Phase 1	mGluR5 negative allosteric modulator	neurology indications	Heptares Therapeutics Ltd. (Sosei Heptares)
HTL0016878 Early Phase 1	M4 receptor agonist	neurobehavioral symptoms associated with Alzheimer’s disease	Heptares Therapeutics Ltd. (Sosei Heptares)
AUT00206 Early Phase 1	Kv3.1/3.2 potassium channel modulator	schizophrenia, Fragile X syndrome8	Autifony Therapeutics Limited
Sage-718 Early Phase 1	NMDA receptor positive allosteric modulator	Huntington’s disease	Sage Therapeutics, Inc.
CORT118335 Early Phase 1	GR modulator, MR antagonist	schizophrenia, adjunctive therapy for treating obesity	Corcept Therapeutics
NV-5138 Phase 1	sestrin2 modulator/mTORC1 activator	treatment-resistant depression, major depressive disorder (RAAD)	Navitor Pharmaceuticals, Inc.
CVN058 Phase 1	5-HT3 receptor antagonist	cognitive improvement associated with schizophrenia, mismatch negativity biomarker study	Cerevance Alpha, Inc.
LY03005 (ansofaxine) Phase 1	SNDRI, prodrug of desvenlafaxine	major depressive disorder	Luye Pharma Group Ltd.
LY03010 Phase 1	paliperidone, intramuscular injection	schizophrenia	Luye Pharma Group Ltd.
TAK-041 Phase 1	GPR139 agonist	schizophrenia	Takeda Pharmaceutical Company, Ltd.*
KAR-004 fixed dose combination of xanomeline and trospium (KarXT) Phase 2	M1/M4 receptor agonist and peripherally-selective pan muscarinic receptor antagonist	schizophrenia	Karuna Therapeutics
Lu AF11167 Phase 2	PDE10 inhibitor	schizophrenia, negative symptoms	H. Lundbeck A/S*
BI 425809 plus behavioral training Phase 2	glyT1 inhibitor	schizophrenia	Boehringer-Ingelheim Pharmaceuticals, Inc.*
TAK-831 Phase 2	DAAO inhibitor	schizophrenia	Takeda Pharmaceutical Company, Ltd.*
BI 425809 Phase 2	glyT1 inhibitor	schizophrenia, add-on treatment for cognitive impairment	Boehringer-Ingelheim Pharmaceuticals, Inc.*
BI 409306 Phase 2	PDE9 inhibitor	schizophrenia	Boehringer-Ingelheim Pharmaceuticals, Inc.*
ASP4345 Phase 2	D1 receptor modulator	schizophrenia add-on treatment for cognitive impairment	Astellas Pharma Inc.
basmisanil Phase 2	GABA-A α5 negative allosteric modulator	cognitive improvement associated with schizophrenia	Hoffman-LaRoche Inc.*
BIIB104 (PF-04958242) Phase 2	AMPA receptor positive allosteric modulator	cognitive improvement associated with schizophrenia	Biogen Inc.*
TAK-041 Phase 2	GPR139 agonist	schizophrenia, motivational anhedonia (BOLD/monetary incentive delay task), add-on to anti-psychotic drugs	Takeda Pharmaceutical Company, Ltd.*
RO6889450 Phase 2	undisclosed mechanism, effects on DA synthesis capacity	schizophrenia	Hoffman-LaRoche Inc.*
lumateperone, (ITI-007) Phase 2	5-HT2A receptor antagonist, DPPM	schizophrenia	Intra-Cellular Therapeutics Inc.
esketamine Phase 2	NMDA receptor antagonist glycine site partial agonist	treatment-resistant depression, treatment-resistant bipolar disorder	Janssen Pharmaceutical Companies*
SEP-4199 Phase 2	undisclosed mechanism	major depressive disorder episodes in bipolar 1 depression	Sunovion Pharmaceuticals Inc.
MIJ821 Phase 2	NMDA receptor 2B-selective negative allosteric modulator	treatment-resistant depression	Novartis Pharmaceuticals
pimavanserin (Nuplaxid™) Phase 2	5-HT2A receptor inverse agonist and antagonist, less so at 5-HT2C receptor	depression in Parkinson’s disease	Acadia Pharmaceuticals Inc.
SEP-363856 Phase 2	5-HT1A receptor agonist and TAAR1 receptor agonist	Parkinson’s disease psychosis	Sunovion Pharmaceuticals Inc.
vortioxetine Phase 2	SSRI, 5-HT3 receptor antagonist, 5-HT1A receptor agonist	major depressive disorder	Takeda Pharmaceutical Company Ltd.*
rapastinel (GLYX-13, BV-102) Phase 2	NMDA receptor partial agonist	rapid treatment of suicidality in major depressive disorder (RAAD)	Allergan Inc.
AV-101 Phase 2	NMDA receptor glycine B site antagonist	major depressive disorder adjunctive treatment	VistaGen Therapeutics, Inc.
NRX-101 fixed dose combination of D-cycloserine and lurasidone Phase 2	NMDA receptor antagonist and 5-HT2A receptor antagonist	bipolar depression, Glx (glutamate plus glutamine) biomarker study (RAAD)	NeuroRx, Inc.
JNJ-18038683 Phase 2	5-HT7 receptor antagonist	BPD, cognition and depression	Janssen Pharmaceutical Companies*
JNJ-42165279 Phase 2	FAAH inhibitor	autism spectrum disorder, Autism Behavior Inventory core domain	Janssen Pharmaceutical Companies*
balovaptan (RO5285119) Phase 2	V1A receptor antagonist	autism spectrum disorder	Hoffman-LaRoche Inc.*
SRX246 Phase 2	V1A receptor antagonist	post-traumatic stress disorder	Azevan Pharmaceuticals
Cannabis Phase 2		post-traumatic stress disorder	Tilray Pharmaceutical Company
troriluzole (BHV-4157) Phase 2	glutamate modulator (prodrug of riluzole)	obsessive-compulsive disorder	Biohaven Pharmaceuticals, Inc.
SXC-2023 Phase 2	cystine-glutamate antiporter activator	obsessive-compulsive disorder adjunctive treatment	Promentis Pharmaceuticals, Inc.
NaBen (SND-13) Phase 2/3	DAAO inhibitor	schizophrenia, add-on treatment	SyneuRx International
NRX-101 fixed dose combination of D-cycloserine and lurasidone Phase 2/3	NMDA receptor antagonist and 5-HT2A receptor antagonist	schizophrenia, Glx (glutamate plus glutamine) biomarker validation study (RAAD)	NeuroRx, Inc.
AVP-786 Phase 2/3 fixed dose combination of deudextromethorphan (d-DM) and quinidine	σ-1 receptor agonist/uncompetitive NMDA receptor antagonist/SNRI and cytochrome P450 2D6 inhibitor	schizophrenia	Avanir Pharmaceuticals

Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DA, dopamine; D2, dopamine 2 receptor subtype; DAAO, D-amino acid oxidase; DPPM, dopamine receptor phosphoprotein modulator; FAAH, fatty acid amide hydrolase; GABA-A, gamma-aminobutyric acid A; GPR, G-protein coupled receptor; GR, glucocorticoid receptor; glyT1, glycine transporter 1; 5-HT, 5-hydroxytryptamine (serotonin); M1/M4, muscarinic cholinergic receptor subtypes; mGluR5, metabotropic glutamate receptor 5; MR, mineralocorticoid receptor; mTORC1, mammalian target of rapamycin complex 1; NDRI, norepinephrine and dopamine uptake inhibitor; NE, norepinephrine; NMDA, N-methyl-D-aspartate; PDE, phosphodiesterase; RAAD, rapid-acting antidepressant; SNDRI, serotonin, norepinephrine, and dopamine reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TAAR1, trace amine-associated receptor 1; V1A, vasopressin V1A; VMAT2, vesicular monoamine transporter 2;

^*is used to designate large pharmaceutical company based on revenue

¹The data in Table 1 were assembled from a search of ClinicalTrials.gov, FDA, and company websites.

²Failed to meet primary end point (Mar 2019); a phase 3 monotherapy program is underway; a phase 2 proof of concept study is underway in major depressive disorder subjects at imminent risk of suicide

³Also received PRIME designation from the European Medicines Agency

⁴Received FDA Special Protocol Agreement for the phase2b/3 trial and an FDA Biomarker Qualification Letter of Support for increased Glx (glutamate plus glutamine) levels associated with D-cycloserine in May 2018.

⁵Received FDA Special Protocol Agreement for the phase2b/3 trial and a FDA Biomarker Qualification Letter of Support in May 2018

⁶The NDA was granted FDA Priority Review Status in May 2018; this is Sage Therapeutics’ first commercial product

⁷FDA has asked for additional clinical data (Feb. 2019); a phase 3 trial in treatment-resistant depression is underway

⁸Orphan Drug Designation, July 2017

2.3. Collaborative approaches that support tools for drug development

Consortia support both drug discovery and tools for drug development. One consortium that has delivered such tools is the Alzheimer’s Disease Neuroimaging Initiative [12], a public-private partnership coordinated by NIH and the Foundation for the NIH (FNIH). Cerebrospinal fluid and PET imaging biomarkers are used in clinical trials to enroll patients with pathologic brain changes that could formerly only be detected after death. Biomarker data are also being used to interpret clinical trial data [13].

More recently, the FNIH has turned its attention to opportunities in psychiatry, helping coordinate the Autism Biomarkers Consortium [14] project in conjunction with the NIMH and other partners. This project focuses on validating biomarkers to inform treatment development through stratification of individuals in this very heterogenous group.

Meanwhile, the NIMH has been fostering smaller scale efforts such as the FAST-Fail initiative, which is aimed at testing mechanistic hypotheses underlying potential treatments [15]. One FAST-Fail project assessed whether κ-opioid receptor antagonism enhances activation of reward circuitry in human brain measured by fMRI response to a monetary incentive delay task [16]. Whether the ability to alter reward responsivity in this manner has therapeutic benefit remains to be determined, but the biomarkers in this study allowed association of target engagement, brain effect, and a clinical scale of anhedonia, a core symptom of depression.

The North American Prodromal Longitudinal Study [17], funded by NIMH, is another consortium defining disease trajectory, points of intervention, and outcomes of individuals at high risk for psychosis. NAPLS works together with the Philadelphia Neurodevelopmental Cohort [18], PRONIA [19], and PSYSCAN [20] in an international consortia called HARMONY (for Harmonization of At Risk Multisite Observational Networks for Youth) to develop and cross-validate cognitive and imaging biomarkers and clinical-behavioral risk predictors of disease trajectory in Clinical High Risk individuals. Predictive algorithms emerging from the projects are poised to inform studies of early interventions for psychotic syndromes [21,22].

Most recently, a consortia has been initiated to develop an FNIH Accelerating Medicine Partnership [23] on schizophrenia, catalyzed by a National Alliance on Mental Illness/Broad Advancing Discovery Summit [24] series. This initiative is based on the understanding that the Clinical High Risk syndromal diagnosis includes one or more developmental pathophysiologies that may be amenable to early interventions.

3. Expert Opinion: a path forward

Despite the progress noted here there is much that remains to be done to further facilitate drug development. For example, novel approaches to decipher the biological relevance of psychiatric risk genes are needed in order to translate these findings into actionable neuroscience. There are a range of such approaches, from combinatorial manipulation of human stem cell-derived neurons and organoids to bioinformatic pathway analysis of transcriptomics, epigenetics, and proteomics, systems biology, and more. Whether they will prove feasible remains to be determined. One thing is clear, however: a disciplined translational approach is necessary to efficiently explore these and other opportunities.

NIMH-supported academic research cannot be the only path forward. Drivers of progress include consortia to validate biomarkers, FDA initiatives to encourage mechanistically novel submissions, and the engagement of pharmaceutical companies to assess targets through development to approval. Venture capital has played a critical part of the equation for small companies to advance molecules, especially for more limited indications, such as brexanalone. Its pathway to success, from a basic neuroscience finding to a conceptually simple clinical application, was aided by focusing on a more narrowly defined disorder rather than broadly defined depression. Leveraging FDA Breakthrough Therapy and Fast Track drug designations while focusing on such narrower indications provides a promising path for novel drug applications in areas of unmet medical need. Additionally, harnessing existing biomarkers, standardized and optimized for application to drug development, can accelerate the pace at which novel mechanistic targets are tested for therapeutic potential. Biomarker data ensure that doses tested for efficacy are actually having the targeted brain effect and can help select subjects for whom the drug will likely be effective.

The message should be clear: multilateral collaborations between academia, the non-profit sector, and pharmaceutical industry are the most certain near-term path to progress, harnessing existing capabilities under a pre-competitive model. Instead of competing academic or businesses “secretly” using individual study designs and paradigms, consortia share risks and rewards by working together to select the best targets, biomarkers, and mechanisms, limiting redundancy and waste. Additionally, engaging with advocacy groups will be critical to guide the scope of pre-competitive efforts to rapidly bring new safe and effective treatments to patients.

We are optimistic that many of the molecular targets that have emerged from the field of neuroscience will be evaluated over the next few years, yielding better treatments for patients. As predicted in a 2014 commentary, new technologies are defining disease phenotypes [25]. And if multi-modality biomarker efforts are realized, it will be possible in the not-to-distant future to alter the trajectory of individuals at risk for psychiatric disorders. Instead of a “Revolution Stalled”, we argue that we can implement a “Revolution Redirected” if stakeholders can be aligned around the principles and opportunities described above.