Leah Kuntz

The National Commission on Correctional Health Care (NCCHC) and 166 national organizations recently signed a letter to Senate leadership advocating for increased access to buprenorphine, an FDA-approved medication for opioid use disorder (OUD). They urged US Senate to pass the bipartisan 

Mainstreaming Addiction Treatment (MAT) Act

“In the midst of a deadly and accelerating overdose crisis, the MAT Act is a common-sense solution that will prevent overdoses, increase access to treatment, and reduce stigma,” the letter reads.

Buprenorphine, along with methadone and extended-release naltrexone, is 1 of 3 medications currently approved by the FDA to treat OUD and is considered the “gold standard” treatment. It also keeps individuals with OUD from returning to illicit drug use—and to jail.

However, the X-waiver severely hinders access to buprenorphine by preventing health care providers from prescribing it. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), only about 1 in 10 people with OUD receive medications for the condition because of the X-waiver. Furthermore, the Department of Health and Human Services claims that fully 40% of US counties do not have any health care providers who can prescribe buprenorphine.

If passed, the MAT Act will eliminate the X-waiver and make buprenorphine more available and accessible for Americans with OUD.

The letter was sent to Majority Leader Chuck Schumer, Minority Leader Mitch McConnell, Chair Patty Murray, and Ranking Member Richard Burr on August 31, Overdose Awareness Day. The letter can be found 

This article originally appeared on Psychiatric Times.

1. NCCHC Supports Access to MOUD. National Commission on Correctional Health Care. September 9, 2022. Accessed September 21, 2022. 

https://www.ncchc.org/ncchc-supports-access-to-moud/

2. The Mainstreaming Addiction Treatment Act (“MAT Act”, S. 445 / H.R. 1384). August 31, 2022. Accessed September 21, 2022. 

https://static1.squarespace.com/static/5eb15fa07d53aa0e85b448d7/t/6317704dfeb1183bfc5ada54/1662480461791/MAT+Act+(S+445)+-+167+Organizations+Submit+Letter+to+Senate+Leadership+Urging+Passage+with+Sept.+CR+(Aug22).pdf

Articles

The National Commission on Correctional Health Care and 166 other national organizations recently signed a letter to Senate leadership advocating for increased access to buprenorphine.

Advocating for Increased Access to Medication for Treating Opioid Use Disorder

In his presentation, “Psychiatric Complications of COVID-19” at the 

2022 Annual Psychiatric Times™ World CME Conference

 in San Diego, John J. Miller, MD, explored the broad range of psychiatric and neuropsychiatric effects of COVID-19.

“We’ve all seen it and we’re still dealing with them,” said Miller. “The mental health crisis is not only for people with the infection itself, but care for their parents, their families, and us as clinicians.”

According to research, the most common psychiatric symptoms include depression, anxiety, insomnia, posttraumatic stress disorder (PTSD), fear, grief, phobias, social avoidance/isolation, increased substance abuse, suicidal ideation, psychosis, and obsessive-compulsive behaviors.1 One systematic review and meta-analysis of long term physical and mental sequelae found at least 1 sequelae symptom occurred in 50.1% of COVID-19 survivors for up to 12 months after infection. Some of the symptoms included cognitive deficits (19.7%), depression (18.3%), and PTSD (17.9%).2

“We know that any type of stress will only bring out underlying genetic and biological and epigenetic vulnerabilities,” Miller said.

As to neuropsychiatric symptoms, some of the most common are delirium (50% of COVID-19 ICU patients), confusion, fatigue, memory impairment, encephalopathy, seizures, cerebral vascular accidents, and more.3

“The bottom line is every person is going to have a different trajectory in terms of how their immune system, how their body, the probabilities of their genetics, other psychosocial circumstances, how their comorbidities will impact their journey through the virus.”

SARS-CoV-2 may traverse the olfactory mucosa—causing loss of smell, especially in the original variants—to gain access to infect the brain, potentially through the olfactory tract, vagal nerve, or trigeminal nerve. Damage to endothelial cells can lead to inflammation and thrombi, which can cause direct damage to the brain, Miller shared. He noted that astrocytes appear to be the primary brain cell type infected and can contribute to fatigue and “brain fog.”4,5

“It will probably take us another 5 or 10 years to figure out the real story. At the end of the day, we must say vaccinate, vaccinate, vaccinate, and remember our role as educators and health promoters is to be compassionate and provide accurate education to our patients and communities,” Miller concluded. “No one is safe until everyone is safe.”

A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action.

3. Manolis TA, Apostolopoulos EJ, Manolis AA, et al. 

COVID-19 infection: a neuropsychiatric perspective.

COVID and the brain: researchers zero in on how damage occurs.

What are the long term psychiatric and neuropsychiatric complications of COVID-19?

COVID-19: An Attack on the Brain

The US Food and Drug Administration (FDA) sent a Complete Response Letter (CRL) regarding the supplemental new drug application (sNDA) for pimavanserin (Nuplazid) for the treatment of hallucinations and delusions associated with Alzheimer disease psychosis (ADP), according to Acadia Pharmaceuticals.

The CRL indicated that the FDA has completed review of the application and could not approve the sNDA in its present form. The FDA recommended that Acadia conduct an additional trial in ADP.

“We are disappointed with this outcome. The treatment of Alzheimer disease psychosis continues to be an area of high unmet need, for which there is no approved therapy,” said Steve Davis, chief executive officer. “We want to express our gratitude to all of the patients, their families and investigators who have participated in our clinical trials.”

In Study 019, the FDA agreed the results demonstrated a statistically significant treatment effect on its primary endpoint, but the agency concluded there are limitations in the interpretability of said results. The FDA also stated that the positive treatment effect of pimavanserin on dementia-related psychosis in Study 045 (HARMONY) appeared to be driven by the robustly positive results in the Parkinson disease dementia subgroup, a condition they stated is subsumed within the currently approved Nuplazid Parkinson disease psychosis (PDP) indication.

This recent sNDA was Acadia's second attempt to secure approval for expanded use of the drug. In early 2021, the FDA rejected Acadia’s clinical trial data, which they stated were not sufficient to support approval of pimavanserin in patients with dementia-related psychosis.

1. Acadia Pharmaceuticals receives complete response letter from U.S. FDA for supplemental new drug application for pimavanserin for the treatment of hallucinations and delusions associated with Alzheimer’s disease psychosis. Business Wire. August 4, 2022. Accessed August 8, 2022. 

https://www.businesswire.com/news/home/20220804006095/en/Acadia-Pharmaceuticals-Receives-Complete-Response-Letter-from-U.S.-FDA-for-Supplemental-New-Drug-Application-for-Pimavanserin-for-the-Treatment-of-Hallucinations-and-Delusions-Associated-with-Alzheimer’s-Disease-Psychosis

2. U.S. FDA declines to approve expanded use of Acadia's antipsychotic drug. Reuters. August 5, 2022. Accessed August 8, 2022. 

https://www.reuters.com/business/future-of-health/us-fda-declines-approve-expanded-use-acadias-antipsychotic-drug-2022-08-05/

Alzheimer disease psychosis treatment pimavanserin receives Complete Response Letter from the FDA.

FDA Asks for More Info on Expanded Use of Pimavanserin

Successful results were announced from the ONWARD trial, a phase 3 clinical study evaluating the efficacy, safety, and tolerability of AD04 in patients with alcohol use disorder (AUD) and selected polymorphisms in the serotonin transporter and receptor genes. AD04 achieved statistically significant mean reduction in heavy drinking days among the prespecified group of “heavy drinkers,” and showed a better safety and tolerability profile compared with placebo. Adial Pharmaceuticals conducted the study.

Professor Hannu E.R. Alho, Emeritus Professor of Addiction Medicine at the University of Helsinki and Principal Investigator for the ONWARD trial, said, “These study results may provide hope to millions of people worldwide suffering from AUD, as well to the families of those impacted by this devastating disease. Among heavy drinkers, which make up the majority of my practice, we saw a clear and statistically significant reduction in heavy drinking days for those patients receiving AD04 versus placebo. These results demonstrate the effectiveness of AD04 for heavy drinker AUD patients.”

Participants who received AD04 achieved a statistically significant reduction from baseline at month 6 in heavy drinking days for the prespecified patient group of heavy drinkers who averaged less than 10 drinks per drinking day at baseline; 

=0.03. A similar trend was seen in the combined month 5 and 6 analysis in the reduction from baseline (

 =0.07). In the last month of the trial, patients who were heavy drinkers and received AD04 had a mean reduction of approximately 79% in heavy drinking compared with baseline.

In addition, AD04 resulted in a reduction from baseline at month 6 compared with placebo in heavy drinking days for the combined trial population of heavy and very heavy drinkers (

=NS). At conclusion of the trial, compared with placebo, AD04 in the heavy drinking group resulted in an overall significant difference in the severity of the AUD diagnosis (

. For the group of those who no longer met AUD criteria (less than 2 symptoms), the comparisons were 27.4% versus 14.9% (ie, an 84% decrease), of AD04 and placebo, respectively. These data underscore the clinical relevance of the findings that patients who are heavy drinkers who receive AD04 appear more likely to recover from the disease by the end of the treatment regimen.

“It has been my life mission to develop new therapies that provide patients with a means to either curb the impulse to drink, or abstain from alcohol entirely,” said Bankole Johnson, MD, Chief Medical Officer of Adial. “AUD accounts for more than 5% of deaths worldwide and is the number one indicator of death for men and women ages 15 to 49, the prime of their lives. The ONWARD study reinforces that AUD is a multi-factorial disease with a diverse set of neurobiological components. The ONWARD data appears to support our earlier findings that AD04 is a genetically targeted medical treatment addressing the biology of AUD. We believe our finding that AD04 appears as safe as placebo should increase its acceptability in general practice and eventually lead to widespread adoption of AD04 for treatment of AUD.”

The safety and tolerability profile was similar to placebo and consistent with the phase 2b trial. Adverse effects reported with a frequency of 5% or more of patients in either group were headache (11% on placebo, 12% on AD04), insomnia (3% on placebo, 7% on AD04), blood magnesium decreased (5% on placebo, 6% on AD04), and fatigue (3% on placebo, 6% on AD04). All were reported as mild to moderate.

William Stilley, Chief Executive Officer of Adial, commenting on the trial results, said, “Alcohol use disorder is an unmet medical need that affects tens of millions of people each year, and, based on the strength of these ONWARD results in heavy drinking patients that have the target genetics, and the fact that AD04 demonstrated an exceptional safety profile, and was well-tolerated during the trial, we intend to advance AD04. We will work with regulatory authorities in Europe and the US to achieve this goal.”

1. Adial Pharmaceuticals announces topline results for Onward™ phase 3 trial for AD04 in patients with alcohol use disorder. Adial. Published July 20, 2022. Accessed July 20, 2022. 

https://www.adial.com/adial-pharmaceuticals-announces-topline-results-for-onward-phase-3-trial-for-ad04-in-patients-with-alcohol-use-disorder/

Positive results from the phase 3 trial of AD04 show a 79% reduction in heavy drinking.

Medication Treating Alcohol Use Disorder Shows Promise in Trial

Axsome Therapeutics announced the publication of the results from the pivotal ASCEND phase 2 clinical trial of dextromethorphan-bupropion (AXS-05) in major depressive disorder (MDD).

 Dextromethorphan-bupropion is an oral, investigational N-methyl-D-aspartate (NMDA) receptor antagonist with multimodal activity.

“Major depressive disorder is highly prevalent, debilitating and potentially life-threatening. There is an urgent need for mechanistically new treatments that are effective and well tolerated,” said Dan Iosifescu, MD, professor of psychiatry at the New York University School of Medicine, Director of the Clinical Research Division at the Nathan Kline Institute for Psychiatric Research, and coauthor of the publication. “Due to its novel mechanism of action targeting glutamate and sigma-1 receptors, and to its robust antidepressant efficacy demonstrated in this study, AXS-05 has the potential to become an important and very useful new treatment for patients with major depressive disorder.”

The trial assessed the efficacy and safety of dextromethorphan-bupropion versus bupropion in 80 participants with moderate to severe MDD. Participants were randomized to receive dextromethorphan-bupropion (45 mg dextromethorphan/105 mg bupropion tablet) (n=43), or bupropion (105 mg tablet) (n=37), once daily for the first 3 days and then twice daily for the following 6 weeks. The primary endpoint was overall treatment effect on the Montgomery-Åsberg Depression Rating Scale (MADRS) score.

Dextromethorphan-bupropion demonstrated rapid, statistically significant improvement in depressive symptoms and remission compared with bupropion. The mean change from baseline in MADRS score over weeks 1 to 6 was significantly better with dextromethorphan-bupropion than with bupropion (-13.7 points vs. -8.8 points; least-squares mean difference=-4.9; 

<0.001). Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and every time point thereafter (week 6: 46.5% vs 16.2%; least-squares mean difference=30.3%; 

“We are very pleased with the publication of the ASCEND trial results in 

, the most widely read psychiatric journal in the world,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. “ASCEND is one of the pivotal efficacy trials that forms the basis of our NDA for AXS-05 in depression, which is currently under review by the FDA. Axsome is positioned to move expeditiously to make this product available to patients as quickly as possible, should it be approved.”

AXS-05 was generally well tolerated in the trial. Common adverse effects included dizziness, nausea, dry mouth, decreased appetite, and anxiety. AXS-05 was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.

The article, “Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized, Double-Blind, Controlled Trial,” can be found in 

This article was originally posted by Psychiatric Times.

1. Tabuteau H, Jones A, Anderson A, et al. 

Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial.

. 2022;appiajp21080800. Online ahead of print.

2. Axsome Therapeutics announces publication of pivotal ascend phase 2 trial of AXS-05 in major depressive disorder in the American Journal of Psychiatry. 

 News release. May 18, 2022. Accessed May 19, 2022. 

https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-publication-pivotal-ascend-phase-2

Axsome Therapeutics announced the robust antidepressant efficacy demonstrated in this latest study.

ASCEND Phase 2 Clinical Trial for Dextromethorphan-Bupropion Produces Positive Results

According to the results of a new study, individuals seeking treatment for depression with lower incomes, lower education levels, and those who identify as minorities tend to have worse outcomes even when receiving equal access to treatment.

 Jeffrey Mills, PhD, and Jeffrey Strawn, MD, led the University of Cincinnati cross-college collaborative research.

Investigators analyzed data from a large clinical trial, the Combining Medications to Enhance Depression Outcomes study, that enrolled 665 participants seeking treatment for depression. All participants had the same access to treatment without differences due to health insurance or income. The study also controlled for sex, age, and treatment type. Following 12 weeks of antidepressant medication treatment, participants who were nonwhite improved 11.3% less compared to white patients. Participants who were unemployed saw 6.6% less improvement compared to employed patients. Participants the 25th percentile of income distribution had 4.8% reduced improvement when compared to participants in the 75th percentile. Patients who were nonwhite, unemployed, without degree, and in the 25th income percentile had 26% less improvement compared to patients who were white, employed, with a college degree, and in the 75th income percentile.

“We think about these things in terms of access, we think about them in terms of income inequality, and I realize that education does track with those, but just having a college degree while controlling for all of these other factors still had a significant impact,” said Strawn, professor in the Department of Psychiatry and Behavioral Neuroscience in UC’s College of Medicine and a UC Health adolescent psychiatrist.

Strawn also noted that while the findings are still preliminary, results suggest that participants without a college degree had 9.6% less improvement compared to college graduates. Furthermore, previous research indicates that individuals seeking treatment for depression with lower income and less education have worse outcomes because of a lack of access to quality health care, but socioeconomic factors are hard to isolate.

Mills, professor of economics in UC’s Carl H. Lindner College of Business, said that the findings do not negate the fact that a lack of access makes an impact on treatment outcomes, but it does show the importance of including a patients’ home environment when analyzing the effectiveness of treatment.

“If you’re going home to a wealthy neighborhood with highly educated parents or spouse, then you’re arguably in a much better environment for the treatment to be effective than if you’re going to a poor neighborhood with other problems,” said Mills.

Strawn believes future studies should consider socioeconomic variables that may have been previously overlooked.

“When we don’t control for these variables, which we often do not in our clinical trials because of differences in populations, we may miss detecting an effective treatment because its effect is obscured,” Strawn said. “It can potentially jeopardize our treatment development by not accounting for these factors.”

Moving forward, the investigators want to combine data from other depression trials to produce more powerful results with a larger dataset.

This article originally appeared on Psychiatric Times. 

1. Mills JA, Suresh V, Chang L, et al. Socioeconomic predictors of treatment outcomes among adults with major depressive disorder. 

2. Socioeconomic factors affect response to depression treatment. News release. April 15, 2022. Accessed May 6, 2022. 

https://www.newswise.com/articles/socioeconomic-factors-affect-response-to-depression-treatment

Home environments have a clear impact on depression treatment outcomes. 