What are the newer antipsychotics, including those in phase 2 and 3 trials, for treating conditions like schizophrenia, bipolar disorder, and major depressive disorder?

Medical Advisory BoardAll articles are reviewed for accuracy by our Medical Advisory Board
Educational purpose only • Exercise caution as content is pending human review
Article Review Status
Submitted
Under Review
Approved

Last updated: November 6, 2025 • View editorial policy

Personalize

Help us tailor your experience

Which best describes you? Your choice helps us use language that's most understandable for you.

Newer Antipsychotics: Current FDA-Approved Agents and Pipeline Medications

The newest generation of antipsychotics includes third-generation agents (aripiprazole, cariprazine, brexpiprazole, and lumateperone) that are FDA-approved, along with several second-generation agents approved in 2009-2010 (iloperidone, asenapine, and lurasidone), while investigational agents with antipsychotic action currently in trials include roluperidone, bitopertin, fananserine, avisetron, and centbutindol. 1

FDA-Approved Newer Antipsychotics

Third-Generation Antipsychotics (Most Recent)

  • Lumateperone: The newest FDA-approved third-generation antipsychotic 1
  • Brexpiprazole: Third-generation agent with efficacy in schizophrenia and as adjunctive treatment in major depressive disorder 1, 2
  • Cariprazine: Third-generation antipsychotic effective for both positive and negative symptoms of schizophrenia, as well as bipolar mania and depression 1, 2
  • Aripiprazole: Established third-generation agent with partial dopamine agonist properties 1, 2

Second-Generation Antipsychotics (2009-2010 Approvals)

  • Lurasidone: FDA-approved in 2010 for acute schizophrenia in adults; dosed once daily with food; associated with dose-related akathisia but relatively benign metabolic profile 3, 4, 2
  • Asenapine: FDA-approved in 2009 for acute schizophrenia, maintenance treatment of schizophrenia, and bipolar manic or mixed episodes (as monotherapy or adjunct to lithium/valproate); unique sublingual administration; dosed twice daily; can be initiated at potentially therapeutic dose; associated with dose-related akathisia and sedation/somnolence 3, 4, 2
  • Iloperidone: FDA-approved in 2009 for acute schizophrenia in adults; requires 4 days of titration to minimize orthostatic hypotension; dosed twice daily; essentially free of extrapyramidal adverse effects or akathisia throughout recommended dose range; relatively benign metabolic profile 3, 4

Other Established Second-Generation Agents

  • Blonanserin: Listed as a second-generation antipsychotic in recent systematic reviews 1
  • Levosulpiride: Included among second-generation antipsychotics 1

Investigational Antipsychotics in Phase 2/3 Trials

Agents with Antipsychotic Action Currently in Clinical Trials

  • Roluperidone: Selective neurokinin-3 receptor antagonist with antipsychotic action under investigation 1
  • Bitopertin: Glycine reuptake inhibitor being studied for schizophrenia treatment 1
  • Fananserine: Novel agent with antipsychotic action in clinical trials 1
  • Avisetron: Investigational agent with antipsychotic properties 1
  • Centbutindol: Novel compound with antipsychotic action under study 1

Other Investigational Approaches

  • Selective glycine transporter GlyT-1 inhibitors: Multiple agents in this class are being evaluated for schizophrenia 1
  • Pimavanserin: Atypical antipsychotic with unique mechanism being studied for various psychotic conditions 2

Key Clinical Distinctions Among Newer Agents

Metabolic Profile Advantages

The expectation for these newer agents (iloperidone, asenapine, lurasidone, and third-generation antipsychotics) is that they will be less problematic regarding treatment-emergent weight gain and metabolic disturbances compared to several other second-generation antipsychotics. 3, 4, 2

Extrapyramidal Symptom Profiles

  • Lowest EPS risk: Iloperidone is essentially free of extrapyramidal adverse effects throughout its recommended dose range 3, 4
  • Dose-related akathisia: Both asenapine and lurasidone are associated with dose-related treatment-emergent akathisia 3, 4
  • Third-generation agents: Generally have favorable extrapyramidal symptom profiles due to partial dopamine agonist properties 2

Efficacy Spectrum

New atypical antipsychotics (aripiprazole, cariprazine, lurasidone, asenapine, brexpiprazole, lumateperone, pimavanserin) demonstrate effectiveness against negative and cognitive symptoms of schizophrenia, as well as affective symptoms observed in depression. 2

Important Clinical Caveats

  • No clear dose-response relationship: Short-term clinical trials have not demonstrated clearly evident therapeutic dose responses for iloperidone, asenapine, or lurasidone 3
  • Limited long-term data: Longer-term and naturalistic studies are needed to fully evaluate these agents and their role in psychiatric treatment 3, 4
  • Titration requirements: Iloperidone requires 4 days of titration to reach recommended target dose range, while asenapine and lurasidone can be initiated at potentially therapeutic doses 3, 4
  • Administration considerations: Asenapine requires sublingual administration (first antipsychotic with this route), while lurasidone must be taken with food 3, 4

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Research

New Atypical Antipsychotics in the Treatment of Schizophrenia and Depression.

International journal of molecular sciences, 2022

Related Questions

What antipsychotic (atypical or typical) is best for a 20-year-old man with acute bipolar depression who wants to minimize weight gain risk?
What antipsychotic with low akathisia and sedation risk and long-acting injectable formulation is suitable for a truck driver with type I bipolar disorder?
What treatment options are available for a patient with intermittent explosive disorder who cannot take antipsychotics?
What is the best antipsychotic medication for a patient with a history of bipolar disorder who is feigning seizures?
What is the optimal management for a 38-year-old male patient experiencing manic episodes, who has been given intravenous (IV) diazepam and an antipsychotic, but continues to exhibit aggression and agitation, until psychiatric evaluation is available?
What is the management plan for a patient with severe coronary artery disease, extensive atherosclerotic disease, and high Agatston Calcium Score?
What is the recommended dosing of Levoflox (levofloxacin) for tracheal colonization?
What is the appropriate workup and differential diagnosis for a patient presenting with unilateral hip pain?
Is endovenous ablation therapy (CPT code 36475) medically necessary for a 60-year-old male with chronic venous insufficiency of the left leg, who has not had prior ablation and has reflux in the Great Saphenous Vein (GSV), but no documented reflux at the Saphenofemoral Junction (SFJ) or Saphenopopliteal Junction (SPJ)?
What causes brown fingernails and how are they treated?
What is the differential diagnosis and management for a patient with enthesophyte (bone spur) calcification of the Achilles tendon and tibiotalar ossification?

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

Have a follow-up question?

Our Medical A.I. is used by practicing medical doctors at top research institutions around the world. Ask any follow up question and get world-class guideline-backed answers instantly.

Ask Question