Lumateperone
Lumateperone is an atypical antipsychotic that has dual action as a serotonin 5-HT2A receptor antagonist and a dopamine modulator. It is approved in the US for the management of both bipolar I and bipolar II depression. In a phase 3 randomized placebo-controlled trial, lumateperone was associated with a significantly greater improvement from baseline in Montgomery-Asberg Depression rating scale (MADRS), compared with placebo, in patients with bipolar I and bipolar II disorders.[250]Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry. 2021 Dec;178(12):1098-106.
https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2021.20091339
http://www.ncbi.nlm.nih.gov/pubmed/34551584?tool=bestpractice.com
Lumateperone is not currently available in Europe.
Olanzapine/samidorphan
Olanzapine/samidorphan is approved in the US for the treatment of bipolar I depression including acute treatment of manic or mixed episodes as monotherapy and as an adjunct to lithium or valproate, or maintenance monotherapy. Olanzapine is an atypical antipsychotic, and samidorphan is an opioid antagonist shown to reduce weight gain associated with olanzapine. Studies show a limited effect on medication-induced weight gain and additional studies are needed to define its role in clinical practice.[251]Monahan C, McCoy L, Powell J, et al. Olanzapine/samidorphan: new drug approved for treating bipolar I disorder and schizophrenia. Ann Pharmacother. 2022 Sep;56(9):1049-57.
http://www.ncbi.nlm.nih.gov/pubmed/35040357?tool=bestpractice.com
Olanzapine/samidorphan is not currently available in Europe.
Iloperidone
Iloperidone is approved in the US for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. Iloperidone is a mixed dopamine D2/serotonin 5-HT2A receptor antagonist and belongs to the class of atypical antipsychotics. The approval was based on results of one phase 3 randomized, double-blind, placebo-controlled trial showing that patients with bipolar mania treated with iloperidone had significant improvement in their Young Mania Rating Scale scores, compared with patients who received placebo, with symptom improvement as early as 14 days after the initial dose.[252]Torres R, Czeisler EL, Chadwick SR, et al. Efficacy and safety of Iloperidone in bipolar mania: a double-blind, placebo-controlled study. J Clin Psychiatry. 2024 Jan 15;85(1):23m14966.
https://www.psychiatrist.com/jcp/efficacy-safety-iloperidone-in-bipolar-mania
http://www.ncbi.nlm.nih.gov/pubmed/38236020?tool=bestpractice.com
Iloperidone is not currently available in Europe (the marketing authorization application was refused).
Dexmedetomidine
Dexmedetomidine is a selective alpha-2-adrenergic agonist sedative that is approved in the US for the management of acute agitation in adults with bipolar I or II. The mechanism of action in the acute management of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors. One randomized controlled trial showed a reduction in agitation scores in adults with bipolar I and bipolar II when treated with dexmedetomidine, compared with placebo.[253]Preskorn SH, Zeller S, Citrome L, et al. Effect of sublingual dexmedetomidine vs placebo on acute agitation associated with bipolar disorder: a randomized clinical trial. JAMA. 2022 Feb 22;327(8):727-36.
https://jamanetwork.com/journals/jama/fullarticle/2789315
http://www.ncbi.nlm.nih.gov/pubmed/35191924?tool=bestpractice.com
Further research is needed to establish its role in clinical practice. Dexmedetomidine is not currently available in Europe for this indication.
Ketamine/esketamine
Ketamine is an NMDA receptor antagonist with actions affecting the glutamatergic system. Esketamine is the active isomer of ketamine. Both are sometimes used as treatments for treatment-resistant (unipolar) major depression, although they are not yet part of standard clinical practice for this indication. Esketamine nasal spray is approved for treatment-resistant depression in adults, with a subsequent expansion of indication to include adults with major depressive disorder with acute suicidal ideation or behavior. Evidence for their efficacy in treatment-resistant bipolar disorder looks promising, but efficacy and safety data for bipolar disorder compared to unipolar major depression is limited and based on small studies; phase 3 studies are currently lacking.[254]Zarate CA, Brutsche NE, Ibrahim L, et al. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012 Jun 1;71(11):939-46.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343177
http://www.ncbi.nlm.nih.gov/pubmed/22297150?tool=bestpractice.com
[255]Martinotti G, Dell'Osso B, Di Lorenzo G, et al. Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment-resistant depression. Bipolar Disord. 2023 May;25(3):233-44.
https://onlinelibrary.wiley.com/doi/10.1111/bdi.13296
http://www.ncbi.nlm.nih.gov/pubmed/36636839?tool=bestpractice.com
[256]McIntyre RS, Lipsitz O, Rodrigues NB, et al. The effectiveness of ketamine on anxiety, irritability, and agitation: Implications for treating mixed features in adults with major depressive or bipolar disorder. Bipolar Disord. 2020 Dec;22(8):831-40.
http://www.ncbi.nlm.nih.gov/pubmed/32406161?tool=bestpractice.com
[257]Kryst J, Kawalec P, Mitoraj AM, et al. Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials. Pharmacol Rep. 2020 Jun;72(3):543-62.
https://link.springer.com/article/10.1007/s43440-020-00097-z
http://www.ncbi.nlm.nih.gov/pubmed/32301056?tool=bestpractice.com
[258]Dean RL, Marquardt T, Hurducas C, et al. Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder. Cochrane Database Syst Rev. 2021 Oct 8;(10):CD011611.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011611.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/34623633?tool=bestpractice.com
Of note, no evidence of an increased risk of mood switching or instability has been identified to date. Potential advantages include rapid symptom reduction, efficacy in severe and treatment-resistant bipolar disorder, and a possible anti-suicidal effect.[259]Rybakowski JK, Permoda-Osip A, Bartkowska-Sniatkowska A. Ketamine augmentation rapidly improves depression scores in inpatients with treatment-resistant bipolar depression. Int J Psychiatry Clin Pract. 2017 Jun;21(2):99-103.
http://www.ncbi.nlm.nih.gov/pubmed/28271731?tool=bestpractice.com
Larger phase 2 trials are currently in progress, after which phase 3 studies will be required before any potential inclusion of ketamine/esketamine within established treatment algorithms for bipolar disorder.
Amilsupride
Amilsupride is a novel atypical antipsychotic that is currently being tested for efficacy in bipolar depression in a large, multicenter phase 3 clinical trial.[260]ClinicalTrials.gov. A clinical study of an investigational drug for the treatment of major depressive episode associated with bipolar I disorder. ClinicalTrials.gov Identifier: NCT05169710. Nov 2023 [internet publication].
https://clinicaltrials.gov/study/NCT05169710
Acetylcysteine
Acetylcysteine is an acetylated form of the amino acid L-cysteine, commonly used as a treatment for acetaminophen overdose and as a mucolytic. Studies into acetylcysteine as an adjunctive treatment for bipolar depression have produced mixed results, and larger trials are warranted.[261]Nery FG, Li W, DelBello MP, et al. N-acetylcysteine as an adjunctive treatment for bipolar depression: a systematic review and meta-analysis of randomized controlled trials. Bipolar Disord. 2021 Nov;23(7):707-14.
http://www.ncbi.nlm.nih.gov/pubmed/33354859?tool=bestpractice.com
[262]Zheng W, Zhang QE, Cai DB, et al. N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials. Acta Psychiatr Scand. 2018 May;137(5):391-400.
http://www.ncbi.nlm.nih.gov/pubmed/29457216?tool=bestpractice.com
Levetiracetam
Levetiracetam, an anticonvulsant with a favorable cognitive profile and low risk for weight gain, has been explored as a potential mood stabilizer for treating both depressive and manic phases of bipolar disorder. The results have been mixed, with some studies showing positive effects and others reporting adverse reactions, including induction of mania.[263]Keshavarzi A, Sharifi A, Jahangard L, et al. Levetiracetam as an adjunctive treatment for mania: a double-blind, randomized, placebo-controlled trial. Neuropsychobiology. 2022;81(3):192-203.
https://karger.com/nps/article/81/3/192/825511/Levetiracetam-as-an-Adjunctive-Treatment-for-Mania
http://www.ncbi.nlm.nih.gov/pubmed/34979513?tool=bestpractice.com
[264]Zarezadeh F, Arbabi M, Shamabadi A, et al. Levetiracetam adjunct to quetiapine for the acute manic phase of bipolar disorder: a randomized, double-blind and placebo-controlled clinical trial of efficacy, safety and tolerability. Int Clin Psychopharmacol. 2022 Mar 1;37(2):46-53.
http://www.ncbi.nlm.nih.gov/pubmed/34864756?tool=bestpractice.com
[265]Park EM, Holmes JA, Reeder-Hayes KE. Acute mania associated with levetiracetam treatment. Psychosomatics. 2014 Jan-Feb;55(1):98-100.
https://www.sciencedirect.com/science/article/pii/S0033318213001084?via%3Dihub
http://www.ncbi.nlm.nih.gov/pubmed/23932538?tool=bestpractice.com
About 16% of patients treated with levetiracetam are at risk for behavioral and psychiatric adverse effects, including aggression, depression, psychosis and mania, with females, those with a history of depression or anxiety, and users of recreational drugs are at higher risk for psychiatric side effects.[266]Josephson CB, Engbers JDT, Jette N, et al. Prediction tools for psychiatric adverse effects after levetiracetam prescription. JAMA Neurol. 2019 Apr 1;76(4):440-6.
https://jamanetwork.com/journals/jamaneurology/fullarticle/2720706
http://www.ncbi.nlm.nih.gov/pubmed/30688969?tool=bestpractice.com
Some studies have found that levetiracetam can improve manic symptoms when used as an adjunctive treatment. A double-blind, randomized, placebo-controlled trial concluded that levetiracetam in combination with lithium improved symptoms of mania, as rated by clinicians, and subjective sleep.[263]Keshavarzi A, Sharifi A, Jahangard L, et al. Levetiracetam as an adjunctive treatment for mania: a double-blind, randomized, placebo-controlled trial. Neuropsychobiology. 2022;81(3):192-203.
https://karger.com/nps/article/81/3/192/825511/Levetiracetam-as-an-Adjunctive-Treatment-for-Mania
http://www.ncbi.nlm.nih.gov/pubmed/34979513?tool=bestpractice.com
Additionally a double-blind, randomized, placebo-controlled study found that levetiracetam in combination with quetiapine resulted in improved acute mania with no differences in tolerability compared to placebo.[264]Zarezadeh F, Arbabi M, Shamabadi A, et al. Levetiracetam adjunct to quetiapine for the acute manic phase of bipolar disorder: a randomized, double-blind and placebo-controlled clinical trial of efficacy, safety and tolerability. Int Clin Psychopharmacol. 2022 Mar 1;37(2):46-53.
http://www.ncbi.nlm.nih.gov/pubmed/34864756?tool=bestpractice.com
Psychostimulants
A systematic review showed that psychostimulants were associated with statistically significant improvement in depressive symptoms in bipolar disorder (odds ratio [OR] 1.42, 95% CI 1.13 to 1.78; P = 0.003). However, response rates differed: dextroamphetamine (OR 7.11, 95% CI 1.09 to 46.44; P = 0.04); methylphenidate (OR 1.49, 95% CI 0.88 to 2.54; P = ns); lisdexamfetamine (OR 1.21, 95% CI 0.94 to 1.56; P = not significant [ns]). Efficacy outcomes were also affected by whether the drugs were used as adjunctive therapy (OR 1.39, 95% CI 1.19 to 1.64) or monotherapy (OR 2.25, 95% CI 0.67 to 7.52).[267]McIntyre RS, Lee Y, Zhou AJ, et al. The efficacy of psychostimulants in major depressive episodes: a systematic review and meta-analysis. J Clin Psychopharmacol. 2017 Aug;37(4):412-8.
http://www.ncbi.nlm.nih.gov/pubmed/28590365?tool=bestpractice.com
More data are needed.
Pramipexole
Pramipexole is a dopamine receptor agonist commonly used in the management of Parkinsonism and restless leg syndrome. It has shown promising results in one small open label trial as an adjunctive treatment for treatment-resistant bipolar depression.[268]Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004 Mar;161(3):564-6.
https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.161.3.564
http://www.ncbi.nlm.nih.gov/pubmed/14992985?tool=bestpractice.com
Transcranial direct current stimulation (tDCS)
A novel treatment using low levels of direct electric current using electrodes on the head to stimulate the brain, tDCS shows promise as a treatment of unipolar major depression. Small studies in bipolar depression have produced mixed results.[269]D'Urso G, Toscano E, Barone A, et al. Transcranial direct current stimulation for bipolar depression: systematic reviews of clinical evidence and biological underpinnings. Prog Neuropsychopharmacol Biol Psychiatry. 2023 Mar 8;121:110672.
http://www.ncbi.nlm.nih.gov/pubmed/36332699?tool=bestpractice.com
[270]Sampaio-Junior B, Tortella G, Borrione L, et al. Efficacy and safety of transcranial direct current stimulation as an add-on treatment for bipolar depression: a randomized clinical trial. JAMA Psychiatry. 2018 Feb 1;75(2):158-66.
http://www.ncbi.nlm.nih.gov/pubmed/29282470?tool=bestpractice.com
Larger multi-site randomized controlled trials are required.