What are the new medications for bipolar disorder?

Five New Bipolar Medications

The five newest medications for bipolar disorder are: (1) cariprazine (Vraylar) - approved 2022 for adjunctive treatment of depression, (2) lumateperone (Caplyta) - expected approval late 2024 for adjunctive depression treatment, (3) zuranolone (Zurzuvae) - approved 2023 for postpartum depression with potential bipolar applications, (4) xanomeline/trospium (KarXT) - expected approval September 2024 as the first muscarinic agonist for psychosis, and (5) Auvelity (dextromethorphan/bupropion) - approved 2023 for depression with rapid onset. 1

Recently Approved Medications (2022-2024)

Cariprazine (Vraylar) - 2022

• Cariprazine became the latest second-generation antipsychotic approved in 2022 for adjunctive treatment of resistant major depression in bipolar disorder. 1
• The optimal dose is 1.5 mg daily, which was significantly more effective than placebo when added to antidepressants after 6 weeks of inadequate response. 1
• The 3 mg dose was less consistently effective, making dosing straightforward with the starting dose being therapeutic for most patients. 1
• Major advantages include minimal weight gain in short-term trials and simple once-daily dosing. 1
• Most common side effects are akathisia/restlessness, fatigue, and nausea. 1

Zuranolone (Zurzuvae) - 2023

• Zuranolone is an oral analog of IV brexanalone, approved in 2023 for postpartum depression with a unique 14-day treatment course. 1
• It acts as an allosteric modulator of GABA-A receptors, producing clinically meaningful improvement by day 15 that continued to day 45 (one month post-treatment). 1
• Unlike most antidepressants, zuranolone requires only 14 days of treatment rather than continuous dosing. 1
• The most common side effect is somnolence (36% vs 6% placebo), along with dizziness, diarrhea, and fatigue. 1
• While FDA declined approval for non-postpartum major depression, positive studies exist with smaller effect sizes, and ongoing research continues for depression with anxious distress. 1
• Zuranolone is a Schedule IV controlled substance. 1

Auvelity (Dextromethorphan/Bupropion) - 2023

• Auvelity combines dextromethorphan 45 mg with bupropion SR 105 mg twice daily, approved in 2023 for major depression. 1
• The combination exploits pharmacokinetic synergism: bupropion inhibits CYP2D6, preventing rapid metabolism of dextromethorphan and maintaining therapeutic levels. 1
• Dextromethorphan acts on NMDA receptors and Sigma-1 receptors, complementing bupropion's norepinephrine effects. 1
• This combination appears more effective than equivalent-dose bupropion alone for both speed of response and achieving remission. 1
• Most common side effects are dizziness, headache, and dry mouth, with good overall tolerability. 1

Medications Expected for Approval (Late 2024)

Lumateperone (Caplyta)

• Lumateperone has positive Phase III data for adjunctive treatment of major depression and is expected to file for approval in late 2024. 1
• This would expand its current indication beyond schizophrenia to include bipolar depression treatment. 1

Xanomeline/Trospium (KarXT)

• Xanomeline/trospium represents the first truly novel mechanism since clozapine - a muscarinic M1/M4 agonist expected for FDA decision in September 2024. 1
• Trospium is added as a peripheral muscarinic antagonist to block cholinergic side effects. 1
• In Phase III trials with 407 schizophrenia patients, doses of 125 mg xanomeline/30 mg trospium twice daily were significantly more effective than placebo for both positive and negative symptoms over 5 weeks. 1
• The side effect profile differs completely from all current antipsychotics: no risk of extrapyramidal symptoms (not a dopamine antagonist) and no significant metabolic effects. 1
• Side effects are cholinergic in nature: constipation, dry mouth, and nausea. 1

Clinical Context and Positioning

How These Fit Into Current Treatment Guidelines

• The American Academy of Child and Adolescent Psychiatry continues to recommend lithium, valproate, or atypical antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone) as first-line treatments for acute mania. 2
• These newer medications primarily serve as adjunctive options for treatment-resistant cases or when metabolic concerns limit use of older agents. 2, 1
• Cariprazine and lumateperone specifically address the unmet need for effective adjunctive treatments in bipolar depression with lower metabolic burden than quetiapine or olanzapine. 2, 1

Important Caveats

• None of these newer agents have demonstrated superior efficacy to lithium, which remains the most effective drug overall for bipolar disorder despite being introduced decades ago. 3
• The treatment landscape has advanced more in tolerability and safety than in efficacy over the past 10-15 years. 4
• Lithium continues to show superior evidence for long-term efficacy in preventing both manic and depressive episodes. 2
• Full remission with any single agent occurs only in a subset of patients, and many require combination therapy. 3

Common Pitfalls to Avoid

• Do not use these newer antidepressant-focused agents (Auvelity, zuranolone) as monotherapy in bipolar disorder without mood stabilizer coverage, as this risks triggering manic episodes or rapid cycling. 2
• Cariprazine's optimal dose is 1.5 mg daily - higher doses (3 mg) were less effective, so avoid automatic dose escalation. 1
• Zuranolone's 14-day course may seem inadequate, but extending treatment beyond this has not been studied and the drug is Schedule IV. 1
• These agents do not replace established mood stabilizers but serve as adjunctive treatments for specific symptom domains. 2, 1