Psychiatry Month in Review: October 2024

Recent developments in psychiatry highlight critical FDA actions and emerging research that may reshape mental health treatment. In the latter half of the month, the US Food and Drug Administration (FDA) once again issued a complete response letter (CRL) for ketamine to treat pain, mental health, anesthesia, sedation, and neurological indications. The month also brought unpromising phase 2 data, where a drug for major depressive disorder (MDD) failed to meet its primary endpoint.

This Month in Review captures not only the negative data rolling out in the psychiatry field but several trials on schizophrenia, such as what antipsychotics to avoid, how air pollution can impact episodes, and older age being a predictor of longevity in patients with schizophrenia in long-term care.

FDA Updates in the Psychiatry Sphere

FDA Issues CRL for Ketamine to Treat Pain, Mental Health, and More

The FDA issued a complete response letter (CRL) on October 22, 2024, to PharmaTher's ketamine (KETARX) application, citing minor deficiencies related to drug substance, product, manufacturing, and microbiology. This marks the second CRL PharmaTher received this year, following a similar letter in April. The delay impacts the wider availability of ketamine in the U.S., where a supply shortage has persisted since 2018. PharmaTher noted the FDA did not request new trials and expressed no concern over the stability of existing batches, and they plan to address the identified issues promptly.

Unsuccessful Phase 2 Data

Alto Neuroscience’s ALTO-100 Fails to Beat Placebo in Improving Depressive Symptoms

Alto Neuroscience reported that its phase 2b trial for ALTO-100, a treatment for major depressive disorder (MDD), failed to outperform placebo, leading to a 60% drop in share prices. The trial did not replicate phase 2a results or meet the primary endpoint of symptom improvement on the Montgomery-Åsberg Depression Rating Scale, nor did it show efficacy in secondary analyses. Despite the setback, the drug maintained a favorable safety profile, with adverse events comparable to placebo. Alto plans to analyze the full dataset and continues to develop ALTO-203 and ALTO-300, with trials anticipated in 2025.

New Data on Schizophrenia

Cognitive Deficits in Schizophrenia: Which Antipsychotics Should Be Avoided?

A recent study suggests patients with schizophrenia experiencing cognitive deficits should avoid dopamine-blocking antipsychotics, especially haloperidol, fluphenazine, and clozapine, which ranked lowest in cognitive outcomes due to their receptor-binding profiles. Although molindone and thioridazine showed potential cognitive benefits, the small sample sizes and narrow focus on processing speed limit their support.

Newer cognitive-focused drugs, such as iclepertin, may offer a more promising approach. Although some drugs, such as paliperidone and brexpiprazole, showed slight cognitive benefits in certain domains, no antipsychotic was recommended for cognitive improvement.

Age at Onset Predicts Longevity in Long-Term Care of Schizophrenia

A new study identified key predictors of longevity in patients with schizophrenia residing in long-term care, finding that older age at onset, longer length of stay, and lower activities of daily living (ADL) scores were significant indicators. The retrospective study reviewed records of 138 patients with schizophrenia who died in care facilities between 2015 and 2017. Longevity was defined as living to the 90th survival percentile for schizophrenia patients. Those in the longevity group, averaging an age of 80.5 years at death, had an older age at onset, lower antipsychotic dosages, and a higher proportion of males.

Short-Term Surge in Air Pollution May Trigger Schizophrenia Episodes

A new study has linked short-term increases in air pollution levels to an increased risk of hospitalizations for schizophrenia, regardless of absolute pollution levels. Analyzing over 800,000 hospital records from 259 cities between 2013 and 2017, investigators found sustained daily rises in air pollutants, such as PM2.5, PM10, nitrogen dioxide, sulfur dioxide, and carbon monoxide, over a 5-to-6-day period were most strongly associated with schizophrenia hospitalizations. These effects were statistically significant even after accounting for the overall pollution levels, suggesting that continuous air pollution spikes may trigger acute schizophrenia episodes due to cumulative stress.

Is Black-Box Warning on Antidepressants Doing More Harm Than Good?

Youth Reluctant to Seek Mental Health Care Post-Black-Box Warning on Antidepressants

A recent study found FDA’s black-box warnings on antidepressants for youth have backfired, leading to decreased medication use and increased suicide attempts and deaths. Analyzing 1841 research reports from 2003 to 2022, the review revealed < 5% of pediatric patients were monitored for suicidality, unchanged from before the warnings. Additionally, antidepressant use dropped by 20% to 50%, with rising psychotropic drug poisonings. Investigators recommend the FDA reconsider or remove these warnings, as they have not improved youth mental health outcomes.