Newly Approved Medications

psychopharmref.com · 2026-07-23

The FDA approved an expanded indication for Auvelity (dextromethorphan hydrobromide and bupropion hydrochloride, manufactured by Axsome Therapeutics) in April 2026, authorizing its use for agitation associated with dementia due to Alzheimer's disease in adults. This marks the first time a non-antipsychotic agent has received regulatory approval for this specific neuropsychiatric indication (FDA, 2026). Auvelity was initially approved in 2022 for major depressive disorder; the current labeling expansion represents a distinct regulatory action supported by new trial data.

The mechanism relevant to this indication combines NMDA receptor antagonism — attributable to dextromethorphan — with sigma-1 receptor agonism, the latter thought to modulate neuronal excitability and stress signaling (NEI Global, 2026). Bupropion functions in this combination primarily as a pharmacokinetic enhancer, inhibiting CYP2D6-mediated metabolism of dextromethorphan and thereby raising its plasma concentration to therapeutically relevant levels. This fixed-dose oral combination is the same formulation approved for MDD.

Approval was supported by the Phase 3 ADVANCE-1 and ACCORD-2 trials (NEI Global, 2026). Both studies enrolled adults with Alzheimer's disease and clinically significant agitation. Primary efficacy endpoints demonstrated statistically significant improvement in agitation symptoms relative to placebo, and trial data additionally showed a longer time to relapse of agitation in the active treatment arm compared with placebo (Neurology Advisor, 2026). Specific effect sizes and full sample sizes from these trials were not detailed in the retrieved sources. The agent received both Breakthrough Therapy and Priority Review designations from the FDA during its development for this indication, reflecting the absence of approved non-antipsychotic alternatives.

Also notable from earlier in the current approval cycle: milsaperidone (Bysanti), an atypical antipsychotic approved in February 2026 for schizophrenia and acute bipolar I mania and mixed episodes, received clearance on the basis of bioequivalence data referencing iloperidone — an established second-generation antipsychotic — rather than independent Phase 3 trials (Psychiatric Times, 2026). That approval pathway is less common and merits attention when evaluating the evidence base supporting the new brand.

For a deeper look at antipsychotic-associated movement disorders relevant to the agents discussed here, see the PsychoPharmRef post linked below.

Further reading on PsychoPharmRef: Antipsychotic Movement Disorders: Akathisia and Tardive Dyskinesia, Antipsychotic Medications: A Comprehensive Clinical Review

Psychopharmref.com updates

First, I want to say I appreciate all the traffic this site has been getting; it is starting to feel like a success. Second, I wanted to thank everyone who has taken the time to submit feedback.

Thanks again, everyone, Jerad R. Shoemaker MD

psychopharmref.com · 2026-07-23

The Mixed State Severity Index (MSSI) is a clinician-rated scale developed to quantify symptom severity in mixed-state presentations of bipolar disorder — episodes in which depressive and manic or hypomanic features co-occur simultaneously. Mixed states have long posed a measurement problem: the two dominant legacy instruments, the Young Mania Rating Scale (the Y-MRS, developed by Young and colleagues in 1978 as an 11-item clinician-rated scale for manic episode severity) and the Montgomery–Åsberg Depression Rating Scale (the MADRS, a 10-item clinician-administered tool published in 1979, designed to be sensitive to antidepressant-related change), were each built for unipolar mood pole assessment and were not designed to capture the phenomenological overlap that defines mixed states. The MSSI attempts to address this gap by integrating items spanning both poles within a single instrument.

A 2026 validation study published in Psychiatry Investigation examined the MSSI's psychometric properties in a bipolar disorder sample, reporting acceptable internal consistency and inter-rater reliability, with findings supporting its use as a dimensional measure of mixed-state severity (Psychiatry Investigation, 2026). The scale is clinician-administered and draws on structured interviewing, requiring familiarity with DSM-5 mixed-features specifier criteria and with rating conventions from established mania and depression scales. Estimated administration time is not standardized across sites, and the absence of a single widely adopted training protocol remains a practical limitation — a concern that echoes the broader problem of inconsistent rater training noted in psychiatric trial methodology literature (BMJ Evidence-Based Medicine, 2025).

Scoring thresholds for clinical severity categories have not yet achieved the cross-study consensus that surrounds the Y-MRS cutoffs (a score above 20 conventionally indicating moderate-to-severe mania) or the MADRS cutoffs (a score above 30 indicating severe depression). Clinicians adopting the MSSI should treat published thresholds as provisional pending larger multi-site normative data. The scale is most useful as a research or specialist-clinic tool for longitudinal tracking in patients with confirmed mixed-state episodes; it is not positioned as a first-line screen.

For routine outpatient monitoring of bipolar depression or mania as separate poles, the MADRS and Y-MRS remain better-validated and more widely operationalized choices with robust normative datasets. When the clinical question specifically involves mixed-features detection rather than severity rating, the Koukopoulos Mixed State Rating Scale offers an alternative framework that emphasizes dysphoric mania, though its validation base is similarly limited compared to pole-specific instruments. Clinicians using either tool in integrated care settings should note that CMS guidance for Collaborative Care Models (CoCM) (a structured primary-care-based model that uses a care manager and consulting psychiatrist to deliver measurement-based behavioral health treatment; it receives dedicated CMS billing codes) specifies validated rating scales for registry tracking, but does not currently designate a standard mixed-state instrument, leaving scale selection at the clinician's discretion (CMS, 2026).

For a deeper look at capacity evaluation and other bedside psychiatric assessments, see the PsychoPharmRef post linked below.

Further reading on PsychoPharmRef: Psychiatric Changes in Severe Organ Dysfunction, Decision-Making Capacity: Assessment and Clinical Application

psychopharmref.com · 2026-07-23

The confinement of persons with mental illness long predated any formal ethical constraint on the physicians who ordered it. For most of the asylum era, involuntary institutionalization operated under parens patriae doctrine — the state's authority to act as guardian for those deemed unable to care for themselves — with minimal procedural protection and no profession-specific ethical code to check its use. The World Medical Association has noted that historically many societies regarded patients with mental illness primarily as threats rather than as persons requiring support, a framing that licensed indefinite confinement with little clinical justification (WMA Statement on Ethical Issues Concerning Patients with Mental Illness, date unavailable). The profession itself did not begin to generate its own ethical guardrails until surprisingly late: the American Psychiatric Association published its first annotated code only in 1973, and the World Psychiatric Association followed in 1977 with the Declaration of Hawaii (Ethical challenges in contemporary psychiatry, 2024). The Declaration was prompted in part by documented political abuse of psychiatric commitment in the Soviet Union, where dissidents were diagnosed with "sluggish schizophrenia" and confined to special psychiatric hospitals — an episode that demonstrated how easily a commitment framework without transparent standards could be repurposed for social control.

In the United States, the legal architecture of civil commitment was reshaped during the 1970s. O'Connor v. Donaldson (1975) established that a state cannot constitutionally confine a non-dangerous individual who is capable of surviving in the community, effectively requiring that commitment serve a purpose beyond custodial warehousing. Addington v. Texas (1979) then set the evidentiary floor at "clear and convincing evidence," a standard higher than the preponderance used in ordinary civil proceedings but lower than the criminal standard of beyond a reasonable doubt. Together these decisions shifted commitment from a broadly paternalistic act to one requiring a specific showing of danger to self or others, or — in some jurisdictions — grave disability.

The psychiatrist's role in this system is evaluative and time-limited: certifying that statutory criteria are met, testifying when required, and recommending a treatment plan. The final commitment decision rests with a judge or hearing officer, not with the clinician. Structural incentives can, however, distort the process. Hospitals operating under capacity pressure may encourage shorter certification periods regardless of clinical need; conversely, facilities reimbursed on a per-diem basis may have a financial incentive to extend involuntary stays. Law enforcement agencies that lack crisis-diversion resources may rely on emergency psychiatric holds as a de facto booking alternative, inflating the volume of commitments that are administrative rather than clinical in origin. The APA's own Ethics Committee opinions, dating to 1973, have repeatedly addressed the tension between the psychiatrist's therapeutic obligation and the coercive authority the state delegates through the commitment process (Opinions of the Ethics Committee on The Principles of Medical Ethics, date unavailable).

Clinicians seeking a comprehensive forensic reference on commitment standards across jurisdictions may consult the AAPL Practice Guidelines or Rosner's Principles and Practice of Forensic Psychiatry. For a deeper look at a related topic, see the PsychoPharmRef post linked below.

Further reading on PsychoPharmRef: Psychiatric Changes in Severe Organ Dysfunction, Medical Note Writing and the Mental Status Exam: A Clinical Guide

Found this useful? Reply to this email with your thoughts, or become a paid supporter to keep this going.