Your 16-year-old with schizophrenia has failed several good antipsychotic trials. He’s now gained significant weight on risperidone and still struggles with hallucinations, and an extensive medical workup is negative. The family wonders whether “newer antipsychotics” are safer or more effective. Should you consider one of these agents?

Second-generation antipsychotics (SGAs) are mainstays for psychosis and bipolar disorder, but their side effects—weight gain, metabolic changes, neurotoxicity (cortical thinning, several kinds of extrapyramidal symptoms [EPS])—demand great caution. Newer agents are emerging with novel mechanisms of action. In this update, we review what’s FDA approved for youth, highlight promising new options, and consider how neuroscience-based nomenclature (NbN) may change how we think about these drugs.

FDA-approved SGAs in youth
Many SGAs are FDA approved in children and adolescents (see table below for a full list). Aripiprazole and risperidone are the most used, with additional approvals for olanzapine, quetiapine, and others. All carry risks of weight gain, metabolic disturbance, and sedation, though the degree varies.

• Aripiprazole: Often chosen first for schizophrenia and bipolar disorder in teens; somewhat less weight gain than risperidone or olanzapine but can cause akathisia and insomnia.
• Asenapine: Alternative administration routes by sublingual tablets and transdermal patches; high rates of sedation and metabolic risk.
• Brexpiprazole: Approval for schizophrenia was inferred from adult studies, but a pediatric trial has shown reduction in schizophrenia symptoms compared to placebo; however, this may not result in significant clinical differences (Ward C et al, Lancet Psychiatry 2025;12(5):345–354).
• Lurasidone: Used for schizophrenia and bipolar I depression. Must be taken with at least 350 calories of food for absorption.
• Olanzapine: Powerful for acute psychosis and mania but typically avoided in youth because of extreme metabolic risk.
• Paliperidone: Has the youngest age range approval for schizophrenia (12 years); however, it carries increased risk of increasing prolactin, like risperidone.
• Quetiapine: Useful in acute mania and when sedation is desired (eg, comorbid insomnia) but has limited evidence for schizophrenia in adolescents compared with risperidone or aripiprazole.
• Risperidone: Like aripiprazole, has a broad range of approvals, including for autism-related irritability; highly effective but carries significant risk of weight gain, prolactin elevation, and metabolic issues.

NbN drug classification
Traditionally, we’ve described medications by indication. NbN classifies drugs by mechanism of action, highlighting how receptors map onto symptoms and side effects. This can help clinicians think beyond “first-line SGA” toward mechanism-based choices. Below, we review biochemical pathways relevant to antipsychotics.

• Dopamine: Excess mesolimbic dopamine produces hallucinations and delusions; reduced prefrontal dopamine contributes to apathy and impaired executive function (Orzelska-Górka J et al, Int J Mol Sci 2022;23(18):10624).
• Glutamate: Dysregulation worsens both positive symptoms and cognition (Orzelska-Górka et al, 2022).
• Serotonin (5-HT): Modulates dopamine activity and affects both positive and negative symptoms.
• Muscarinic (M1/M4): Links to attention, memory, and motivation (Syed YY, Drugs 2025;85:103–109).
• Trace amine associated receptor 1 (TAAR1) agonists: Regulates dopaminergic and serotonergic activity, with antipsychotic-like and pro-cognitive effects (Achytes ED et al, Eur Arch Psychiatry Clin Neurosci 2023;273(7):1543–1556).

New meds through the NbN lens
Instead of lumping new drugs together as “antipsychotics,” NbN can distinguish a multi-receptor modulator from a muscarinic agonist. A patient with weight gain on risperidone may benefit from a dopamine-sparing mechanism, while someone with apathy might try muscarinic or glutamatergic pathways. Here are some new agents with different mechanisms.

Lumateperone (Caplyta)

• Mechanism: Multi-receptor modulator (D2 full antagonist postsynaptic, partial agonist presynaptic; 5-HT2A antagonist; glutamatergic activity).
• Benefits: Reduces psychosis with less metabolic burden than risperidone or olanzapine; potential effects on cognition.
• Adverse effects: Somnolence, sedation, fatigue, constipation.
• Status: FDA approved for adult schizophrenia (Correll CU et al, JAMA Psychiatry 2020;77(4):349–358). Pediatric studies are lacking.
• Clinical pearl: Consider off-label only when metabolic concerns dominate and established SGAs are poorly tolerated.

Xanomeline/trospium (Cobenfy)

• Mechanism: M1/M4 receptor agonist with no D2 activity. Trospium reduces peripheral cholinergic side effects.
• Benefits: Improves positive, negative, and cognitive symptoms without weight gain or EPS.
• Adverse effects: Constipation, dyspepsia, nausea, vomiting.
• Status: FDA approved for adult schizophrenia in 2024 (Syed, 2025). No pediatric data.
• Clinical pearl: Promising for patients who are limited by EPS or metabolic burden, but the GI side effects can be significant.

TAAR1 agonists (Ulotaront, Ralmitaront)

• Mechanism: TAAR1 agonists reduce presynaptic dopamine synthesis; Ulotaront also has 5-HT1A activity.
• Benefits: Early studies suggest small effect sizes (0.2–0.3) in psychosis but minimal metabolic, neurologic, or endocrine side effects.
• Adverse effects: Somnolence, agitation, nausea, diarrhea.
• Status: Investigational. Ulotaront is in a six-week placebo-controlled trial including adolescents (Achytes et al, 2023; Kane JM, J Clin Psychopharmacol 2022;42(5):S1–S13).
• Clinical pearl: Not ready for practice, but may one day offer a non-dopamine alternative for psychosis.

Established therapies
Most pediatric antipsychotic use remains off-label, guided by adult trials and clinical judgment, and comparative data between newer agents and standard SGAs in youth are limited. SGAs should be used only when truly indicated—high-dose use carries an 80% increased mortality risk in adolescents and young adults, though lower doses have not been associated with significant risk. Risperidone and aripiprazole remain the most evidence-based choices, particularly as a last resort for autism-related irritability.

Practical considerations for use in youth
Several issues limit the role of these new agents:

• Lack of pediatric data. Lumateperone and xanomeline/trospium are approved in adults. Trials in youth are limited or ongoing. Until we have pediatric safety and efficacy data, use should be cautious and highly selective.
• Formulations. Long-acting injectables are not yet available for these newer medications.
• Side effects. Metabolic and neurologic risks may be lower, but different mechanisms bring challenges, particularly GI effects with muscarinic agents.
• Access and cost. High price and limited insurance coverage when compared with generics like risperidone.
• Monitoring. Standard monitoring applies (weight, BMI, metabolic labs, Abnormal Involuntary Movement Scale [AIMS]), as does remaining alert for new side effects.

After discussing risks and the lack of pediatric approval, you and the family try lumateperone off-label, given the boy’s severe condition. You document your rationale and monitor for sedation, constipation, and symptom response.

CARLAT VERDICT
Newer antipsychotics (lumateperone, xanomeline/trospium, TAAR1 agonists) may offer benefits for carefully selected patients who can’t tolerate or don’t respond to standard SGAs, though these newer drugs lack pediatric data and are expensive. We recommend caution with all antipsychotics due to metabolic and neurotoxic side effects. Use them if you must, but try other means and (gently) reduce and discontinue antipsychotics when possible.

From the Clinical Update
“New Antipsychotic Formulations for Children and Adolescents: Caution Prevails”
by Rebecca F. Young, MD and Max Rosen, MD
The Carlat Child Psychiatry Report, Volume 17, Issue 3 & 4
April/May/June 2026
www.thecarlatreport.com