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Interim results from an open-label study of evenamide as an add-on in patients with chronic treatment-resistant schizophrenia (TRS) showed an improvement in symptoms of psychosis in the first 100 participants.

The first-of-its-kind study is an international, 6-week, open-label, randomized, rater-blinded, multi-center study examining the effects of adding evenamide—a new chemical entity (NCE) antipsychotic—to treatment for 180 participants with TRS who are moderately to severely ill (CGI-S of 4 to 6), with a baseline PANSS score between 70 and 90, predominant positive symptoms, and functional deficits, who had not been responding to prior treatment with antipsychotic medications. Researchers are evaluating the tolerability and safety of adding evenamide orally at 3 fixed doses—7.5, 15, and 30 mg bid—compared with a stable therapeutic dose of a single antipsychotic (other than clozapine) as well as conducting safety and efficacy assessments in 1- to 2-week intervals. The study is being conducted by Newron Pharmaceuticals.

Interim results for the first 100 participants showed a 12% reduction in the participants’ PANSS scores, CGI-S improvement of 0.7, and CGI-C ratings demonstrating that 77% of participants responded to the treatment.

“We are excited to present the interim results of this study, which demonstrate the potential of evenamide as an add-on therapy to antipsychotics in patients with treatment-resistant schizophrenia,” said Ravi Anand, MD, Newron Pharmaceuticals chief medical officer, in a press release. “The data presented today confirm evenamide’s potential to improve symptoms of psychosis in patients who, despite treatment with various antipsychotics, continue to experience severe symptoms of psychosis and functional disabilities. These patients represent about one third of the overall schizophrenia population and thus a significant unmet medical need.”

As part of its ongoing Phase II/III development plan for evenamide, Newron announced it will initiate a multinational, randomized, placebo-controlled study in patients with TRS during the first quarter of 2023.

 “Evenamide acts through selective attenuation of an abnormal release of glutamate and synergizing with the background antipsychotic activity,” Anand said in a press release. “The outcome of this study may change the treatment of future TRS patients when confirmed in a larger, placebo-controlled study.”

1. Newron presents encouraging interim results for evenamide in patients with treatment-resistant schizophrenia (TRS) at the 33rd CINP Hybrid World Congress of Neuropsychopharmacology. News release. Newron Pharmaceuticals. June 7, 2022. Accessed June 17, 2022. 

https://www.newron.com/news-and-media/regulatory-news/newron-presents-encouraging-interim-results-evenamide-patients

Interim study results show 77% treatment response rate among participants.

New Chemical Entity Improves Symptoms in Individuals With Treatment-Resistant Schizophrenia

A study found a temporal relationship between methylphenidate (MPH) exposure and risk of depression in children and teenagers with attention-deficit/hyperactivity disorder (ADHD).

The study aimed to test the clinical concern that MPH exposure may increase risk of depression, especially in children. To explore this, the investigators pulled claims data from the Health Insurance Review and Assessment Service database, looking at ADHD medication prescription, depression diagnosis, and antidepressant medication prescription between January 2007 and December 2016. They identified 43,259 individuals between the ages of 6 and 19 who had been diagnosed with ADHD between July and December 2007. Of these, 2330 individuals were deemed eligible for participation in the study. The investigators then conducted a self-controlled case series study examining the occurrence of depression in the participants when they were exposed to MPH compared to when they we were not exposed to MPH.

They found an elevated risk of major depressive disorder (MDD) in participants during the 90 days prior to MPH exposure, with an incidence rate ratio of 12.12 (95% confidence interval; 10.06 to 14.61, 

 < 0.0001). The incidence rate ratio during MPH treatment was 18.06 with a 95% confidence interval of 16.67 to 19.56 (

 < 0.0001), although the rate returned to baseline level after 31 days following the discontinuation of MPH treatment. For participants between ages 6 and 9 years, the incidence rate ratio was 13.11 (95% confidence interval of 9.58 to 17.95) during the 90 days before exposure to MPH and 17.7 (95% confidence interval of 15.6 to 20.08) during MPH treatment; this also returned to baseline level after MPH treatment was discontinued.

The investigators concluded that, although the absolute risk of depression is low, it is a risk that clinicians should consider, particularly during the period immediately after MPH treatment begins.

 “Our findings suggest that use of methylphenidate medication in young people with ADHD is temporally associated with the emergence of depression,” they wrote. “With the increased global use of ADHD drugs, the benefits of methylphenidate should be carefully evaluated against the potential risk of depression in children and adolescents.”

Association between attention deficit hyperactivity disorder medication and depression: a 10-year follow-up self-controlled case study

Investigators observed higher levels of depression in children and adolescents with ADHD during MPH treatment.

Study Examines Relationship Between Methylphenidate and Risk of Depression

The first patient has been dosed in the TRANQUILITY II study of an acute treatment for agitation in patients with Alzheimer disease.

The TRANQUILITY II study, led by BioXcel Therapeutics, focuses on BXCL501, an orally dissolving thin film formulation of dexmedetomidine. In research incorporating multiple measurement scales, BXCL501 has demonstrated statistically significant reductions in agitation with no severe adverse events at doses of both 30 mcg and 60 mcg.

 The US Food and Drug Administration (FDA) granted BXCL501 breakthrough therapy designation for the acute treatment of agitation in connection with dementia in March 2021.

“We believe the recent FDA approval of BXCL501 for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults has laid a strong foundation for pursuing this Alzheimer’s-related agitation program to potentially address this debilitating symptom for patients,” Robert Risinger, MD, chief medical officer of BioXcel Therapeutics, said in a press release. “Importantly, we are also expanding TRANQUILITY II to more than 10 clinical trial sites in the US, and with no current FDA-approved treatments for agitation associated with this disease, we are making strong and swift efforts to potentially bring BXCL501 and its proven ability to address agitation to this large market.”

TRANQUILITY II is 1 of 2 studies—along with TRANQUILITY III—in BioXcel Therapeutics’ Phase 3 TRANQUILITY program, in which both studies measure the efficacy of BXCL501 in adults aged 65 years and older currently in assisted living facilities or nursing homes. BioXcel has reported that top-line data for TRANQUILITY II is expected in late 2022 or early 2023, and patient enrollment in TRANQUILITY III will begin later in 2022.

BioXcel Therapeutics announces first patient dosed in TRANQUILITY II phase 3 trial for acute treatment of agitation in patients with Alzheimer’s disease

. News release. GlobeNewswire. May 3, 2022. Accessed May 3, 2022.

BioXcel Therapeutics receives FDA Breakthrough Therapy Designation for BXCL501 for the acute treatment of agitation associated with dementia

. News release. BioSpace. March 15, 2021. Accessed May 3, 2022.

Top-line data for study is expected in late 2022, early 2023.

Phase 3 Study on Treatment of Agitation in Alzheimer Disease Doses First Patient

The US Food and Drug Administration (FDA) has approved Qelbree (viloxazine extended-release capsules) for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults.

This approval marks an expanded indication for Qelbree, a novel nonstimulant developed by Supernus Pharmaceuticals,

 as the FDA approved the drug for the treatment of ADHD in children and adolescents aged 6 to 17 in April 2021.

 Approval for its treatment of ADHD in adults aged 18 and older is based on positive results obtained by a randomized, double-blind, placebo-controlled Phase III study in adults with ADHD.

Qelbree is reported to have a proven tolerability and safety profile and no evidence of abuse potential, and it has shown symptom improvement and efficiency early in treatment. Its approval is the first FDA approval of a novel nonstimulant treatment specifically for adults with ADHD in 20 years.

“Today’s approval marks a major advancement in the treatment of ADHD and is an important milestone just 1 year after the approval of Qelbree to treat pediatric patients,” said Jack Khattar, president and CEO of Supernus Pharmaceuticals, in a press release. “We are proud to bring a new novel nonstimulant option for adults into the market after 2 decades.”

Supernus announces FDA approval of Qelbree for the treatment of ADHD in adults

. News release. Supernus Pharmaceuticals. May 2, 2022. Accessed May 3, 2022.

Approval comes 1 year after the drug was approved for the treatment of ADHD in children and adolescents.

FDA Approves Novel Nonstimulant for Treatment of ADHD in Adults

The US Food & Drug Administration (FDA) issued warning letters to 2 websites that have been illegally selling Schedule II stimulants marketed as Adderall.

The warning letters were sent to Kubapharm.com and Premiumlightssupplier.com, claiming that the drugs being sold on these websites are misbranded and in violation of the Federal Food, Drug, and Cosmetic (FD&C) Act. The FDA also stated that the websites are in violation of the Ryan Haight Online Pharmacy Act (RHA), as they had not registered their online pharmacies with the US Drug Enforcement Administration (DEA). Both websites have been given 15 business days to respond to the agencies with the steps they plan to take to address these violations.

Because Adderall has a high potential for addiction and abuse, selling it without a prescription, and without the supervision of a licensed health care provider, places consumers at risk for abuse and addiction, as well as other potential harmful effects associated with the drug quality. Similarly, if the drug is being sold illegally, there is no guarantee that the drug is not inauthentic, contaminated, expired, or otherwise harmful.

“This action underscores the FDA’s commitment to use all available regulatory and compliance tools to stop online businesses illegally selling potentially harmful drug products to consumers,” said FDA Commissioner Robert M. Califf, MD, in a press release. “The illegal sale of prescription drug stimulants online puts Americans at risk and contributes to potential abuse, misuse, and overdose. These particular types of online pharmacies also undermine our efforts to help consumers safely purchase legitimate prescription medicines over the internet. FDA will continue partnering with DEA in an effort to safeguard public health and protect consumers who need access to these important medicines.”

FDA and FEA warn online pharmacies illegally selling Adderall to consumers

. News release. United States Food & Drug Administration. April 12, 2022. Accessed April 13, 2022.

The warnings cite consumer risks, as well as FD&C, RHA violations.

FDA Sends Warning to Websites Over Illegal Sale of Adderall

Patients need to be educated frequently about what can increase or decrease their lithium levels, leading to either toxicity or loss of effectiveness. Prescribers need to be reminded as well.

The following are some common circumstances that can increase lithium levels (instruct patients to inform you of any symptoms and get extra levels in these situations):

Dehydration (eg, from vomiting or diarrhea, as may occur in acute gastroenteritis)

Reduced renal filtration rate (eg, in glomerulonephritis and diabetic nephropathy; also age related)

Thiazide diuretics (eg, hydrochlorothiazide) can produce increases from 25% to 400% (very unpredictable).

Nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen, naproxen, meloxicam) and probably COX-2 inhibitors (eg, celecoxib, diclofenac) can increase levels 10% to 400% over the course of days to months.

Angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril, enalapril) can induce up to a 400% increase over several weeks.

Angiotensin II inhibitors (eg, losartan, valsartan) probably prompt similar effects to ACE inhibitors.

The following can decrease lithium levels:

Mania may cause levels to go down 50% despite confirmed adherence.

 The mechanism is unclear, but it might be that lithium goes into the intracellular compartment during mania. If you increase dose to improve the plasma level, toxicity symptoms can appear—or they may appear after the mania remits and the lithium returns to the extracellular space.

Caffeine may promote renal excretion of lithium.

The following have little effect on lithium levels

Amiloride is a potassium-sparing diuretic and sometimes does raise levels (need to monitor).

Sulindac is an NSAID that may or may not raise levels (need to monitor).

 we discussed the importance of keeping maintenance lithium levels in the range of 0.6 to 0.8 mEq/L as well as avoiding even brief occurrences of levels more than 1.0 to minimize the risk of long-term kidney impairment.

During meetings with patients, it is important to give frequent reminders of the aforementioned factors that affect levels so that patients will be more likely to call and inform prescribers and to have lithium levels drawn when necessary. Temporary adjustment of doses while waiting for levels (or if it is impossible to get levels) may be advised in some cases.

is associate professor of psychiatry at Harvard Medical School and codirector, US Department of Veterans Affairs, National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. He is also an Editorial Board member for 

. The author reports no conflicts of interest concerning the subject matter of this article.

The Maudsley Prescribing Guidelines in Psychiatry, 14th Edition

Mood-dependent changes of serum lithium concentration in a rapid cycling patient maintained on stable doses of lithium carbonate

3. Mester R, Toren P, Mizrachi I, et al. 

Caffeine withdrawal increases lithium blood levels

4. Ciraulo DA, Shader RI, Greenblatt DJ, Creelman W. 

. Lippincott Williams & Wilkins; 2006:272-275.

Tips for lithium dosing for optimal renal safety

Here are a few reminders to help avoid both toxicity and loss of effectiveness.

Lithium Levels—What Increases and Decreases Them?

As part of a psychedelic revolution, careful research is underway to see how these compounds may benefit patients with psychiatric disorders. In this episode, Amir Inamdar MBBS, DNB (Psych), MFPM, shares insights and thoughts about the work being done and its potential to make a difference in patient care. 

Research is underway to make psychedelics agents a treatment option for psychiatric disorders.   

Here's to a Psychedelic Revolution

A recent study found that exposure to lithium among older adults was linked to a decreased risk of developing dementia and its subtypes, Alzheimer disease (AD) and vascular dementia (VD).

The retrospective cohort study, conducted by researchers from the University of Cambridge and the Cambridgeshire and Peterborough NHS Foundation Trust, aimed to identify preventive interventions that could help delay the onset of dementia, as dementia is the leading cause of disability and death among older adults in Western populations. Lithium has been suggested as a treatment option, but little research has investigated this possibility at the population level. To assess the role of lithium, the investigators collected data from the electronic clinical records of 548 patients who had been exposed to lithium and 29,070 patients who had not been exposed to lithium between January 1, 2005, and December 31, 2019. Among the participants, 40.2% were male, and the mean age was 73.9 years, with all patients being at least 50 years old at baseline. In the lithium-exposed group, 9.7% of patients received a diagnosis of dementia, including 6.8% with AD and 2.6% with VD. In the group that had not been exposed to lithium, 11.2%, or 3244, received a diagnosis of dementia, including 2276 with AD and 698 with VD. The investigators used Cox proportional hazard models to analyze the data, finding that lithium exposure was associated with a decreased incidence of dementia, AD, and VD, and in both short-term (≤1-year) and long-term (>5-year) exposure durations. Although no significant changes were identified in immediate durations, the longer the duration of lithium exposure, the lower the risk of developing dementia.

The study’s main limitation, according to the investigators, was that 73% of patients in the lithium-exposed group had been diagnosed with mania/bipolar affective disorder (BPAD), which itself is a considerable risk factor for dementia. Although this might be expected to cause an increase in dementia in the lithium-exposed group, the investigators found the opposite. They suggested that, given the specific nature of the lithium-exposed group in this study, researchers should be cautious in extending the findings of this study to the general population.

“Our findings support the possibility that lithium treatment could decrease the risk of developing dementia and supports the need for further randomized controlled trials (RCTs) to test the efficacy of lithium as a disease-modifying drug in dementia,” the investigators concluded.

1. Chen S, Underwood BR, Jones PB, et al. 

Association between lithium use and the incidence of dementia and its subtypes: a retrospective cohort study

Research also finds surprising results in patients with bipolar affective disorder.

Study Links Lithium With Lower Risk of Dementia

Researchers shared results of a study on the impact of educating patients about the heightened risks of concurrent benzodiazepine and opioid use in a poster presentation at the American Pharmacists Association (APhA) Annual Meeting & Exposition.

Because more than 30% of overdoses involve a combination of benzodiazepines and opioids, and more than 115 Americans die from opioid overdose every day, the investigators conducted this study to assess how much patients know about the increased risk of adverse events, overdose, and death associated with taking benzodiazepines and opioids concurrently. They also focused on the role of education, surveying study participants both before and after educational intervention. The study included 9 participants (33% male; 66% female; median age 59) who had been prescribed a benzodiazepine (Xanax [alprazolam], 77%; Klonopin [alonazepam], 22%; or Ativan [lorazepam], 11%) and an opioid (Norco [hydrocodone/acetaminophen], 55%; Percocet [oxycodone/acetaminophen], 22%; Roxicodone [oxycodone], 11%; or Roxanol [morphine sulfate], 11%). Participants were surveyed both before and after receiving information detailing the increased risks associated with concurrent benzodiazepine and opioid use. Each survey asked them to rank their knowledge of the medications, the potential side effects and overdose risk of the medications, and the risks of alcohol consumption on a scale from “unaware” to “minimal” to “good” to “excellent.”

In the pre-survey, each category was divided among “excellent,” “good,” and “unaware” rankings, with “minimal” only appearing in the knowledge of overdose category at a little over 20%. Most participants ranked their knowledge as “excellent” in only the knowledge of medications category (a little more than 40%), with “good” rankings taking the lead in the potential side effects and alcohol consumption categories at nearly 60% and a little more than 40%, respectively. Around 20% of participants ranked their knowledge as “unaware” across all 4 knowledge categories. In the post-survey, no participants ranked their knowledge as “unaware” or “minimal” in any category. In both the knowledge of medications and the potential side effects categories, patients ranked their knowledge as “good” or “excellent” at around 80% and around 20%, respectively. In knowledge of alcohol consumption risks, the majority of participants (around 90%) ranked their knowledge as “excellent,” with the remaining 10% ranking it as “good,” and 100% of participants ranked their knowledge of overdose—the most divisive category in the pre-survey—as “excellent.”

Although patient education resulted in clear improvement of self-reported knowledge and understanding, only 1 participant changed their medication regimen to lower the risks of adverse events. According to the investigators, this means that patients are reluctant to change their prescribed medications even with greater awareness of the risks.

“Overall, patients can have a good baseline knowledge, but the results of this study demonstrate how pharmacists can further improve patient understanding… and knowledge of the medications [patients] are currently prescribed,” the investigators concluded.

1. Anderson M, Garofoli GK. Evaluation of patient perceptions on coadministration of benzodiazepines and opioids. Poster presentation. Presented at 

American Pharmacists Association Annual Meeting & Exposition

. March 18-21, 2022. Accessed March 18, 2022.

Results highlight the impact of education on patient understanding of potential adverse events.

Study Shows Risk Awareness of Concurrent Benzodiazepine, Opioid Use Among Patients

A study comparing the acute effects of lysergic acid diethylamide (LSD) and psilocybin in healthy participants found that the primary differences between the 2 are dose-, rather than substance-dependent.

In the study—a double-blind, randomized, placebo-controlled, crossover design—investigators evaluated 28 healthy individuals during 5 sessions, each 10 days apart and lasting 25 hours. In each session, participants were given LSD (100 and 200 µg), psilocybin (15 and 30 mg), or placebo, with outcome measures including self-rating scales for subjective and autonomic effects, adverse effects, and effect durations, plus plasma levels of brain-derived neurotrophic factor (BDNF), oxytocin, cortisol, prolactin, and pharmacokinetics.

Results showed that the 200 μg LSD dose received higher anxiety and ego-dissolution ratings, as well as control and cognition impairments, compared with the 100 μg LSD dose. The 200 μg LSD dose also significantly increased ratings of ineffability compared with the 30 mg dose of psilocybin. The investigators noted that both LSD doses demonstrated longer effect durations than the psilocybin doses, although both the LSD doses and the high psilocybin dose produced similar quantitative and qualitative subjective effects in the participants. Overall, investigators reported that these findings suggest that 20 mg psilocybin is equivalent to 100 μg LSD, and 30 mg psilocybin is equivalent to 150 μg LSD.

“The results in this publication continue to expand our knowledge of the differences between LSD and psilocybin with regard to their acute effects, similarities, and dose equivalence,” said Matthias Liechti, MD, professor of clinical pharmacology and internal medicine at University Hospital Basel, and principal investigator on the study, in a press release. “Although both substances are used as pharmacological tools, there are no modern studies investigating and directly comparing the acute effects of these substances within the same clinical study, using well-defined doses and validated psychometric tools.”

As there is a lack of contemporary clinical studies comparing the acute effects of LSD and psilocybin, the findings of this study can potentially help clinicians with dosing for psychiatric and neurologic disorders, designing trials, and evaluating these psychedelics for therapeutic utility in future research.

“LSD and psilocybin have recently become promising candidates for the treatment of various psychiatric and neurologic disorders, and thus a deeper understanding of their differential subjective effects in humans is needed,” said Miri Halperin Wernli, PhD, MindMed executive president, in a press release. “This study brings us one step closer to maximizing the therapeutic potential of these molecules, by providing valuable dose-finding context and enabling more direct comparisons when interpreting clinical results.”

MindMed announces publication of study comparing the acute effects of lysergic acid diethylamide and psilocybin in healthy subjects

. Cision PR Newswire. News release. March 2, 2022. Accessed March 3, 2022.

Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects

Drug comparison has significant implications for dose- and substance-dependence.

Psychopharmacology