First Aid for Mental Health: Investigational Drugs to the Rescue
Need a New Drug?
A quick glance at recent FDA drug approvals may lead you to believe that new therapies for mental illnesses - such as depression, anxiety, or ADHD - have all but dried up. But that could not be further from the truth. In fact, according to a 2016 report by PhRMA, there are over 100 medicines under development in this area, ranging from Phase I through FDA new drug application (NDA) review.
However, development of new drugs in mental health is a painstaking process. Pinpointing mechanisms, sites of actions and finding new therapeutic targets can be common setbacks for researchers.
The Burden of a Mental Health Illness
The numbers can be quite staggering when you look at statistics in the U.S.
In 2015 there were an estimated 43.4 million U.S. adults aged 18 or older (17.9%) with any mental illness within the past year.
Major depressive disorder is widespread; in 2015, an estimated 16.1 million U.S. adults aged 18 or older (6.7%) had at least one major depressive episode in the past year.
Schizophrenia - a disabling psychotic condition often associated with substance abuse - affects roughly 1.1% of the U.S. population.
Overall, costs of substance abuse and addiction - including drug abuse, alcohol, and tobacco - are more than $740 billion annually related to crime, lost work productivity and health care
Here's 10 drugs under research to help alleviate these costly and devastating burdens.
Aloradine (PH94B), Social Anxiety Disorder
Social anxiety disorder, or social phobia, affects about 15 million adults. Patients with social phobia experience a persistent fear of most social, performance or speaking situations. Developed by Pherin Pharmaceuticals, aloradine (PH94B) has had success in Phase 3 trials of social phobia in men and women.
Aloradine is in a new drug class called "pherines" known as sensory receptor cell modulators and is given as a spray in the nose. It targets brain receptors via nasal chemosensory neurons with a 15 minute onset.
As reported by the manufacturer, patients in Phase 3 feasibility studies were randomized to 2 weeks of treatment with aloradine nasal spary or a placebo nasal spray, used on an as-needed basis up to 4 times daily. Patients self-administered the product 15-minutes before entering a feared situation. Patients carried a diary to rate the severity of their anxiety in a scale from 0 to 100.
Aloradine nasal spray improved social anxiety symptoms on the primary endpoint significantly better than placebo (p = 0.006), and the drug superiority over placebo was similar for men and women. Side effects so far appear to be minimal.
Aloridine is also being looked at in depression and cognitive impairment.
Dextromethorphan/Quinidine (AVP-923), Agitation in Alzheimer's Disease
Agitation in Alzheimer's disease can lead to a dangerous use of antipsychotic drugs to calm dementia patients; a use that is contraindicated by the FDA with a black-box warning and is associated with a higher risk of death. Dementia-related agitation is also a common cause of institutionalization in the U.S.
Avanir is developing AVP-786, a combo drug with deuterium-modified dextromethorphan and an ultra-low dose of quinidine, a heart drug used to treat irregular heartbeat. AVP-786 is under study for the treatment of agitation in patients with Alzheimer’s disease. Adding deuterium to the dextromethorphan molecules reduces first-pass liver metabolism. Dextromethorphan is an NMDA receptor antagonist, sigma-1 receptor agonist and inhibitor of serotonin and norepinephrine transporters and quinidine is a cytochrome P450 2D6 (CYP2D6) inhibitor that increases the bioavailability of dextromethorphan in this combination.
In November 2015, Avanir initiated Phase III studies (TRIAD-1 and TRIAD-2) with AVP-786, also given fast-track designation by the FDA. The studies are multicenter, randomized, double-blind, placebo-controlled trials that will evaluate two doses of AVP-786 versus placebo over a period of 12-weeks for Alzheimer's associated agitation. Roughly 700 patients will be enrolled.
Another combination of these drugs known as Nuedexta is already approved to treat pseudobulbar affect, a condition of sudden, frequent outbursts of crying or laughing that may occur in conditions such as multiple sclerosis and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease).
Dasotraline for ADHD and Binge Eating Disorder
Attention deficit/hyperactivity disorder (ADHD) results in a lack of focus, overactivity, uncontrolled behavior, or some combination of these behaviors. Dasotraline, developed by Sunovion, is in Phase III studies for ADHD.
Dasotraline is a dopamine and norepinephrine reuptake inhibitor (DNRI) being evaluated in attention deficit hyperactivity disorder (ADHD). It's being developed as a once-daily treatment due to it's long half-life. Dasotraline is also being evaluated for its use in binge eating disorder, where a person loses control over eating, but does not purge, therefore putting the person at risk for obesity.
Pivotal phase III study results for ADHD were reported in April 2017. In a laboratory classroom setting in children between six and 12 years, dasotraline 4 mg/day showed significant improvement in ADHD symptoms compared to placebo throughout the day (12 to 24 hours post-dose), demonstrating a duration of effect of up to 24 hours, and was generally well tolerated. The most common side effects included insomnia, decreased appetite, affect lability (rapid change in emotion), headache and irritability.
Sunovion plans to submit the New Drug Application (NDA) to the FDA by March 2018 for the treatment of ADHD.
Fluoxetine Rapid Dissolve (AT001), Autistic Repetitive Behaviors
Fluoxetine is a well-known SSRI antidepressant that inhibits serotonin reuptake in the central nervous system. AT001, developed by Autism Therapeutics, is in Phase III trials for the treatment of autistic repetitive behaviors in children and adolescents and has completed phase II studies for adults.
If FDA approved, this formulation would be the first treatment for autistic patients suffering with repetitive behaviors. AT001 is being developed in a "Zydis" rapid orally disintegrating tablet (ODT) in several strengths which will be taste-masked. The use of AT001 in autism has received orphan drug designation and Fast Track status from the FDA.
Eleven clinical trials on the effect of fluoxetine in autism spectrum disorders in children and adolescents, adults, or mixed populations, have been conducted.
Cariprazine (Vraylar), Schizophrenia and Bipolar Disorder
Cariprazine (Vraylar) was FDA-approved on September 17, 2015. Cariprazine, an oral atypical antipsychotic developed by Gedeon Richter/Allergan, is a potent dopamine D3/D2 receptor partial agonist. It is used for the treatment of patients with schizophrenia and for patients with manic or mixed episodes associated with bipolar I disorder.
Vraylar is also being studied for bipolar depression and as an adjunct for major depressive disorder. Common side effects reported with Vraylar include muscle movements, upset stomach and vomiting, drowsiness or feeling restless. The NDA was resubmitted after an FDA rejection in December 2014.
Rapastinel (GLYX-13), Depression
A new investigational class, the N-methyl-d-aspartate (NMDA) receptor modulators, has shown a rapid and long-lasting effect in majoe depressive disorder. Rapastinel (GLYX-13), under research by Allergan, is in Phase III studies. The proposed use is intravenous (IV) add-on therapy for patients who don't have an adequate response to their current antidepressant. Rapastinel received Breakthrough Therapy designation from the FDA for adjunctive treatment of Major Depressive Disorder (MDD). This follows the Fast Track Designation for rapastinel granted by the FDA in 2014.
In Phase II clinical trials, effects occurred as quickly as 2 hours and lasted for 7 days after a single dose. Repeat dosing led to clinical effects lasting at least 10 weeks after the drug was stopped. Psychotic-like side effects, common with NMDA drugs, were not seen.
Randomized, placebo-controlled, Phase III studies are ongoing for adjunctive therapy in major depressive disorder and recruiting participants as of September 2017. This study will evaluate the efficacy, safety, and tolerability of two doses of rapastinel, 225 milligrams (mg) and 450 mg, compared to placebo adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who have a partial response to ADT.
Apimostinel (NRX-1074) for Major Depressive Disorder
Allergan is also developing apimostinel (NRX-1074), an intravenous (IV) and orally administered NMDA agonist which acts as a selective partial agonist of an allosteric site of the glycine site of the NMDA receptor complex. Currently, NRX-1074 is in Phase II trials for the treatment of depression. It is fast-acting and does not appear to elicit psychotic side effects as with some drugs that affect the NMDA receptor. It's mechanism and effects are similar to rapastinel (GLYX-13), under development as an adjunctive therapy for treatment-resistant depression. However, apimostinel can be given orally and and 100-fold more potent than rapastinel.
Positive effects in depression have been noted as quickly as 24 hours after administration, instead of the 3 to 4 weeks for an SSRI antidepressant effect. It is reported as well tolerated and lacks the NMDA psychotomimetic such as with ketamine. Severe forms of depression or even suicidal risk may be important uses for NRX-1074.
A Phase II clinical trial evaluating the efficacy and safety of NRX-1074 following a single IV dose in subjects with major depressive disorder are posted as completed. In this study, IV doses of 1, 5, and 10 mg were evaluated. Oral dose ranging studies have looked at 375, 500, and 750 mg strengths.
NMDA modulators are in active research by several pharma companies.
Abilify Digital for Schizophrenia, Bipolar Disorder
Taking a medicine as prescribed can be hardship, especially with a mental health disorder. For example, patients with schizophrenia are often on long-term treatment and are at high risk for skipping or even stopping treatment.
In Sept. 2015, Proteus Digital Health and Otsuka Pharmaceuticals submitted a drug-device combination for approval to the FDA. Abilify (aripiprazole), a blockbuster atypical antipsychotic, has been combined with an ingestible sensor embedded in the tablet to measure medication-taking patterns. The information is communicated by Bluetooth to the patient and physician/caregiver (with patient consent) via a wearable patch sensor.
However, in April 2016 a Complete Response Letter from the FDA was sent to the sponsors. The FDA completed its review and has requested additional information, including data regarding the performance of the product under the conditions in which it is likely to be used, and further human factors investigations. Approval status is pending.
The Value of Mental Health Research
The burden of a mental health disorder can be eased with medications that vastly boost one's quality of life. For example, the antidepressant class known as selective-serotonin re-uptake inhibitors (SSRIs) has changed the face of depression. Advances in delayed-release properties have eased dosing for school children with ADHD. Long-acting injected agents can boost compliance and outcomes in difficult-to-treat schizophrenia patients.
Yet many people still have treatment failures - whether it be due to lack of effectiveness or side effects - and need other treatment options. As research continues to identify biological mechanisms responsible for mental health disorders, novel therapies can be developed based on the latest scientific discovery.
Finished: First Aid for Mental Health: Investigational Drugs to the Rescue
- Avanir Pharmaceuticals Announces Initiation of Phase III Trial of AVP-786 for Agitation in Patients with Alzheimer’s Disease. Avanir Pharmaceuticals. Press Release. Accessed 9/5/2017 at https://www.avanir.com/press/avanir-pharmaceuticals-announces-initiation-phase-iii-trial-avp-786-agitation-patients
- National Institute of Mental Health (NIMH). Any Mental Illness (AMI) Among U.S. Adults. Accessed 9/5/2017 at https://www.nimh.nih.gov/health/statistics/prevalence/any-mental-illness-ami-among-us-adults.shtml
- Social Anxiety Disorder (Social Phobia). Pherin Clinical Development Programs. Pherin Pharmaceuticals. Accessed 9/5/2017 at http://www.pherin.com/programs.html#Social
- PhRMA. Medicines in Development for Mental Health. 2016 Report. Accessed 9/5/2017 at http://phrma.org/sites/default/files/pdf/medicines-in-development-drug-list-mental-illnesses.pdf.
- Liebowitz M. Salman E. Nicolini H., et al. Effect of an Acute Intranasal Aerosol Dose of PH94B on Social and Performance Anxiety in Women With Social Anxiety Disorder. American Jounral of Psychiatry. June 2014;171:675-82. http://dx.doi.org/10.1176/appi.ajp.2014.12101342. Accessed 9/5/2017 at http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.2014.12101342
- University of Cambridge. The next decade of mental health drugs. Published online March 15, 2012 http://www.cam.ac.uk/research/news/the-next-decade-of-mental-health-drugs. Accessed 9/5/2017.
- Koblan KS, Hopkins SC, Sarma K, et al. Dasotraline for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial in Adults. Neuropsychopharmacology. May 2015. doi: 10.1038/npp.2015.124. Accessed 9/5/2017 at http://www.ncbi.nlm.nih.gov/pubmed/25948101.
- Jagalekar A. Why the new NIH guidelines for psychiatric drug testing worry me. Scientific American. Published online March 21, 2014. Accessed 9/5/2017 at http://blogs.scientificamerican.com/the-curious-wavefunction/why-the-new-nih-guidelines-for-psychiatric-drug-testing-worry-me/
- Comstock J. Proteus, Otsuka submit first commercial drug with built-in sensor to FDA. Published online Sept. 10, 2015. Accessed 9/5/2017 at http://mobihealthnews.com/46680/proteus-otsuka-submit-first-commercial-drug-with-built-in-sensor-to-fda/