Summary of Newly Approved Antipsychotics

By Flavio Guzman, MD

Two new second-generation antipsychotics were approved in 2015: brexpiprazole (Rexulti) and cariprazine (Vraylar). Like aripiprazole (Abilify), they are both D2 partial agonists and are associated with risk of akathisia.

Aripiprazole, brexpiprazole and cariprazine are FDA-approved for the treatment of schizophrenia.

Aripiprazole and cariprazine are approved for the treatment of manic episodes in bipolar disorder, while aripiprazole and brexpiprazole are approved as adjunct treatment to antidepressants for major depressive disorder.

Indication Aripiprazole
Brexpiprazole Cariprazine
Schizophrenia X X X
Bipolar disorder: mania and mixed episodes X X
Major depressive disorder: adjunct treatment X X

Brexpiprazole (Rexulti)

Approval date: July 13, 2015

Otsuka Pharmaceutical Company Ltd / Lundbeck A/S.




  • Antagonist at 5-HT receptors:
    • 5HT2A
    • 5HT2B
    • 5HT7


  • Antagonist at alpha receptors:
    • Alpha-1A
    • Alpha-1B
    • Alpha-1D
    • Alpha-2C

FDA-approved indications

  • Adjunctive therapy for the treatment of major depressive disorder
    • Recommended dose: 2 mg/day
    • Maximum dose: 3 mg/day
  • Treatment of schizophrenia
    • Recommended dose: 2-4 mg/day
    • Maximum dose: 4 mg/day

Dosage forms and strengths

  • Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg

Drug interactions

Patients Taking CYP2D6 Inhibitors and/or CYP3A4 Inhibitors

  • Strong CYP2D6 or CYP3A4 inhibitors
    • Administer half of usual dose
  • Strong/moderate CYP2D6 with Strong/ moderate CYP3A4 inhibitors
    • Administer a quarter of usual dose
  • Known CYP2D6 Poor Metabolizers taking strong/moderate CYP3A4 inhibitors
    • Administer a quarter of usual dose

Patients Taking CYP3A4 Inducers

  • Strong CYP3A4 inducers
    • Double the usual dose and further adjust based on clinical response

Brexpiprazole may be administered without dosage adjustment in patients with MDD when administered with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine)

Adverse reactions

Adverse effects occurring in ≥5% of patients taking brexpiprazole and more frequently than in those taking placebo in at least 1 clinical trial included: akathisia, weight gain, headache, and somnolence. Mean weight gain over 6 weeks was 1.0-1.3 kg greater with brexpiprazole 2 mg/day than with placebo.


Brexpiprazole has a clinical and pharmacological profile very similar to aripiprazole. Future evidence derived from head-to-head clinical trials will allow us to compare brexpiprazole to more established second-generation antipsychotics.


Cariprazine (Vraylar)

Approval date: September 17, 2015

Actavis Pharmaceuticals


  • Partial agonist at:
    • D2 receptors
    • D3 receptors
    • 5-HT1A receptors


  • Antagonist at:
    • 5-HT2B receptors
    • 5-HT2A receptors


  • Antagonist at (moderate to low affinity):
    • H1 receptors
    • 5-HT2C receptors


FDA-approved indications

  • Treatment of schizophrenia
    • Starting dose: 1.5 mg/day
    • Recommended dose: 1.5 mg to 6 mg/day
  • Acute treatment of manic or mixed episodes associated with bipolar disorder
    • Starting dose: 1.5 mg/day
    • Recommended dose: 3 mg – 6 mg/day

Dosage forms and strengths

  • Capsules: 1.5 mg, 3 mg, 4.5 mg and 6 mg

Drug interactions

  • Metabolized by CYP3A4
    • Strong CYP3A4 inhibitors: reduce dosage by half
    • CYP3A4 inducers: do not recommend use with cariprazine

Adverse reactions

  • Schizophrenia trials: extrapyramidal symptoms and akathisia
  • Bipolar mania trials: extrapyramidal symptoms, akathisia, dyspepsia, somnolence, restlesness


It has been suggested that 5-HT1A and 5-HT2B receptor affinity could improve negative symptoms via activation of dopaminergic neurotransmission in frontocortical regions. So far, there is no conclusive data from randomized controlled trials supporting this effect for cariprazine.

Like aripiprazole, cariprazine is a D2 and D3 partial agonist. The difference is that it has 10 times greater affinity for D3 receptors than for D2 receptors. Cariprazine side effect profile is notable for extrapyramidal symptoms and akathisia.

Future evidence derived from head-to-head clinical trials will allow us to compare cariprazine to more established second-generation antipsychotics.


  1. Rexulti (Brexpiprazole) [Prescribing Information] Marlborough, MA: Sunovion Pharmaceuticals Inc.
  2. Vraylar (Cariprazine) [Prescribing Information] Parsippany, NJ: Actavis Pharma, Inc
  3. Abilify (Aripiprazole) [Prescribing Information] Rockville, MD: Otsuka Pharmaceutical Co.,

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