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REVIEW

Treatment-Resistant Bipolar Depression: Therapeutic Trends, Challenges and Future Directions

, , & ORCID Icon
Pages 2927-2943 | Received 16 Sep 2022, Accepted 08 Dec 2022, Published online: 16 Dec 2022

References

  • Clemente AS, Diniz BS, Nicolato R, et al. Bipolar disorder prevalence: a systematic review and meta-analysis of the literature. Braz J Psychiatry. 2015;37(2):155–161. doi:10.1590/1516-4446-2012-1693
  • Burdick KE, Millett CE, Yocum AK, et al. Predictors of functional impairment in bipolar disorder: results from 13 cohorts from seven countries by the global bipolar cohort collaborative. Bipolar Disord. 2022;24(7):709–719. doi:10.1111/bdi.13208
  • Gardner HH, Kleinman NL, Brook RA, Rajagopalan K, Brizee TJ, Smeeding JE. The economic impact of bipolar disorder in an employed population from an employer perspective. J Clin Psychiatry. 2006;67(8):1209–1218. doi:10.4088/JCP.v67n0806
  • Altshuler LL, Post RM, Black DO, et al. Subsyndromal depressive symptoms are associated with functional impairment in patients with bipolar disorder: results of a large, multisite study. J Clin Psychiatry. 2006;67(10):1551–1560. doi:10.4088/JCP.v67n1009
  • Kupka RW, Altshuler LL, Nolen WA, et al. Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disord. 2007;9(5):531–535. doi:10.1111/j.1399-5618.2007.00467.x
  • Mendlewicz J, Massat I, Linotte S, et al. Identification of clinical factors associated with resistance to antidepressants in bipolar depression: results from an European Multicentre Study. Int Clin Psychopharmacol. 2010;25(5):297–301. doi:10.1097/YIC.0b013e32833c4ceb
  • Yatham LN, Kennedy SH, Parikh SV, et al. Canadian network for mood and anxiety treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97–170. doi:10.1111/bdi.12609
  • Park JH, Nunez NA, Gardea-Resendez M, et al. Short term second-generation antidepressant monotherapy in acute depressive episodes of bipolar II disorder: a systematic review and meta-analysis. Psychopharmacol Bull. 2022;52(2):45–72.
  • Sachs GS. Treatment-resistant bipolar depression. Psychiatr Clin North Am. 1996;19(2):215–236. doi:10.1016/S0193-953X(05)70285-9
  • Yatham LN, Calabrese JR, Kusumakar V. Bipolar depression: criteria for treatment selection, definition of refractoriness, and treatment options. Bipolar Disord. 2003;5(2):85–97. doi:10.1034/j.1399-5618.2003.00019.x
  • Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163(2):210–216. doi:10.1176/appi.ajp.163.2.210
  • Gitlin M. Treatment-resistant bipolar disorder. Mol Psychiatry. 2006;11(3):227–240. doi:10.1038/sj.mp.4001793
  • Gajwani P. Treatment-refractory bipolar disorder: classification to aid in clinical management. Expert Opin Pharmacother. 2009;10(12):1907–1915. doi:10.1517/14656560903064170
  • Pacchiarotti I, Mazzarini L, Colom F, et al. Treatment-resistant bipolar depression: towards a new definition. Acta Psychiatr Scand. 2009;120(6):429–440. doi:10.1111/j.1600-0447.2009.01471.x
  • Lipsman N, McIntyre RS, Giacobbe P, Torres C, Kennedy SH, Lozano AM. Neurosurgical treatment of bipolar depression: defining treatment resistance and identifying surgical targets. Bipolar Disord. 2010;12(7):691–701. doi:10.1111/j.1399-5618.2010.00868.x
  • Malhi GS, Bargh DM, Cashman E, Frye MA, Gitlin M. The clinical management of bipolar disorder complexity using a stratified model. Bipolar Disord. 2012;14(Suppl 2):66–89. doi:10.1111/j.1399-5618.2012.00993.x
  • Poon SH, Sim K, Sum MY, Kuswanto, CN, Baldessarini, RJ. Evidence-based options for treatment-resistant adult bipolar disorder patients. Bipolar Disord. 2012;14(6):573–584. doi:10.1111/j.1399-5618.2012.01042.x.
  • Hidalgo-Mazzei D, Berk M, Cipriani A, et al. Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition. Br J Psychiatry. 2019;214(1):27–35. doi:10.1192/bjp.2018.257
  • Fountoulakis KN, Yatham LN, Grunze H, et al. The CINP guidelines on the definition and evidence-based interventions for treatment-resistant bipolar disorder. Int J Neuropsychopharmacol. 2020;23(4):230–256. doi:10.1093/ijnp/pyz064
  • American Psychiatric Association. Practice Guideline for the Treatment of Patients with Bipolar Disorder (Revision). American Psychiatric Pub; 2002.
  • Grunze H, Vieta E, Goodwin GM, et al. The world federation of societies of biological psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2010 on the treatment of acute bipolar depression. World J Biol Psychiatry. 2010;11(2):81–109. doi:10.3109/15622970903555881
  • National Institute for Health and Care Excellence (NICE). National institute for health and care excellence: guidelines. In: Bipolar Disorder: Assessment and Management. London: National Institute for Health and Care Excellence (NICE) Copyright © NICE 2019; 2018.
  • Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495–553. doi:10.1177/0269881116636545
  • Malhi GS, Bell E, Bassett D, et al. The 2020 royal Australian and New Zealand college of psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2021;55(1):7–117. doi:10.1177/0004867420979353
  • van der Loos ML, Mulder PG, Hartong EG, et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(2):223–231. doi:10.4088/JCP.08m04152
  • Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20(6):607–614. doi:10.1097/00004714-200012000-00004
  • van der Loos ML, Mulder P, Hartong EG, et al. Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine. Acta Psychiatr Scand. 2010;122(3):246–254. doi:10.1111/j.1600-0447.2009.01537.x
  • Bocchetta A, Bernardi F, Burrai C, Pedditzi M, Del Zompo M. A double-blind study of L-sulpiride versus amitriptyline in lithium-maintained bipolar depressives. Acta Psychiatr Scand. 1993;88(6):434–439. doi:10.1111/j.1600-0447.1993.tb03487.x
  • Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160–168. doi:10.1176/appi.ajp.2013.13070984
  • Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158(6):906–912. doi:10.1176/appi.ajp.158.6.906
  • Sachs GS, Ice K, Chappell P. Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder. J Clin Psychiatry. 2011;72(10):1413–1422. doi:10.4088/JCP.09m05934
  • 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;161(3):564–566. doi:10.1176/appi.ajp.161.3.564
  • Murphy BL, Ravichandran C, Babb SM, Cohen BM. Naltrexone in bipolar disorder with depression: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2014;34(6):749–751. doi:10.1097/JCP.0000000000000222
  • Nunez NA, Singh B, Romo-Nava F, et al. Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: a meta-analysis of randomized controlled trials. Bipolar Disord. 2020;22(2):109–120. doi:10.1111/bdi.12859
  • Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242–1249. doi:10.1176/appi.ajp.2007.06060981
  • Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA. Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2010;71(10):1363–1370. doi:10.4088/JCP.09m05900gry
  • Calabrese JR, Frye MA, Yang R, Ketter TA. Efficacy and safety of adjunctive armodafinil in adults with major depressive episodes associated with bipolar I disorder: a randomized, double-blind, placebo-controlled, multicenter trial. J Clin Psychiatry. 2014;75(10):1054–1061. doi:10.4088/JCP.13m08951
  • Ketter TA, Yang R, Frye MA. Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder. J Affect Disord. 2015;181:87–91. doi:10.1016/j.jad.2015.04.012
  • Halaris A, Cantos A, Johnson K, Hakimi M, Sinacore J. Modulation of the inflammatory response benefits treatment-resistant bipolar depression: a randomized clinical trial. J Affect Disord. 2020;261:145–152. doi:10.1016/j.jad.2019.10.021
  • Calkin CV, Chengappa KNR, Cairns K, et al. Treating insulin resistance with metformin as a strategy to improve clinical outcomes in treatment-resistant bipolar depression (the TRIO-BD Study): a randomized, quadruple-masked, placebo-controlled clinical trial. J Clin Psychiatry. 2022;83:2. doi:10.4088/JCP.21m14022
  • Zeinoddini A, Sorayani M, Hassanzadeh E, et al. Pioglitazone adjunctive therapy for depressive episode of bipolar disorder: a randomized, double-blind, placebo-controlled trial. Depress Anxiety. 2015;32(3):167–173. doi:10.1002/da.22340
  • Aftab A, Kemp DE, Ganocy SJ, et al. Double-blind, placebo-controlled trial of pioglitazone for bipolar depression. J Affect Disord. 2019;245:957–964. doi:10.1016/j.jad.2018.11.090
  • Fries GR, Walss-Bass C, Bauer ME, Teixeira AL. Revisiting inflammation in bipolar disorder. Pharmacol Biochem Behav. 2019;177:12–19. doi:10.1016/j.pbb.2018.12.006
  • Kohler-Forsberg O, Hjorthoj C, Nordentoft M, Mors O, Benros ME. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019;139(5):404–419. doi:10.1111/acps.13016
  • Castillo MFR, Cohen A, Edberg D, et al. Vascular endothelial growth factor in bipolar depression: a potential biomarker for diagnosis and treatment outcome prediction. Psychiatry Res. 2020;284:112781. doi:10.1016/j.psychres.2020.112781
  • Edberg D, Hoppensteadt D, Walborn A, Fareed J, Sinacore J, Halaris A. Plasma C-reactive protein levels in bipolar depression during cyclooxygenase-2 inhibitor combination treatment. J Psychiatr Res. 2018;102:1–7. doi:10.1016/j.jpsychires.2018.02.004
  • Edberg D, Hoppensteadt D, Walborn A, Fareed J, Sinacore J, Halaris A. Plasma MCP-1 levels in bipolar depression during cyclooxygenase-2 inhibitor combination treatment. J Psychiatr Res. 2020;129:189–197. doi:10.1016/j.jpsychires.2020.06.010
  • Calkin CV, Ruzickova M, Uher R, et al. Insulin resistance and outcome in bipolar disorder. Br J Psychiatry. 2015;206(1):52–57. doi:10.1192/bjp.bp.114.152850
  • Singh B, Sundaresh V. Thyroid hormone use in mood disorders: revisiting the evidence. J Clin Psychiatry. 2022;83:5. doi:10.4088/JCP.22ac14590
  • Kelly T, Lieberman DZ. The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS. J Affect Disord. 2009;116(3):222–226. doi:10.1016/j.jad.2008.12.010
  • Law AJ, Deakin JF. Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. Neuroreport. 2001;12(13):2971–2974. doi:10.1097/00001756-200109170-00043
  • McCullumsmith RE, Kristiansen LV, Beneyto M, Scarr E, Dean B, Meador-Woodruff JH. Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. Brain Res. 2007;1127(1):108–118. doi:10.1016/j.brainres.2006.09.011
  • Woo TU, Walsh JP, Benes FM. Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch Gen Psychiatry. 2004;61(7):649–657. doi:10.1001/archpsyc.61.7.649
  • Brennan BP, Hudson JI, Jensen JE, et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology. 2010;35(3):834–846. doi:10.1038/npp.2009.191
  • Zarate CA, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57(4):430–432. doi:10.1016/j.biopsych.2004.11.023
  • Sanacora G, Frye MA, McDonald, W. American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399–405. doi:10.1001/jamapsychiatry.2017.0080
  • Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. Acta Pharmacol Sin. 2016;37(7):865–872. doi:10.1038/aps.2016.5
  • Joseph B, Parsaik AK, Ahmed AT, Erwin PJ, Singh B. Systematic review on the efficacy of intravenous racemic ketamine for bipolar depression. J Clin Psychopharmacol. 2021. 41. 1:71–75. doi:10.1097/JCP.0000000000001317
  • Singh B, Vande Voort JL, Frye MA, Kung S. Can ketamine be a safe option for treatment-resistant bipolar depression? Expert Opin Drug Saf. 2022;21(6):717–720. doi:10.1080/14740338.2022.2045272
  • Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620–630. doi:10.1176/appi.ajp.2018.17060720
  • Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–354. doi:10.1016/S0006-3223(99)00230-9
  • Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793–802. doi:10.1001/archgenpsychiatry.2010.90
  • 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;71(11):939–946. doi:10.1016/j.biopsych.2011.12.010
  • Xu AJ, Niciu MJ, Lundin NB, et al. Lithium and valproate levels do not correlate with ketamine’s antidepressant efficacy in treatment-resistant bipolar depression. Neural Plast. 2015;2015:858251. doi:10.1155/2015/858251
  • Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry. 2014;4:e469. doi:10.1038/tp.2014.105
  • Saligan LN, Luckenbaugh DA, Slonena EE, Machado-Vieira R, Zarate CA. An assessment of the anti-fatigue effects of ketamine from a double-blind, placebo-controlled, crossover study in bipolar disorder. J Affect Disord. 2016;194:115–119. doi:10.1016/j.jad.2016.01.009
  • Villasenor A, Ramamoorthy A, Silva Dos Santos M, et al. A pilot study of plasma metabolomic patterns from patients treated with ketamine for bipolar depression: evidence for a response-related difference in mitochondrial networks. Br J Pharmacol. 2014;171(8):2230–2242. doi:10.1111/bph.12494
  • Zheng W, Zhou YL, Wang CY, et al. Neurocognitive effects of six ketamine infusions and the association with antidepressant effects in treatment-resistant bipolar depression: a preliminary study. PeerJ. 2020;8:e10208. doi:10.7717/peerj.10208
  • Singh B, Vande Voort JL, Kung S. Ketamine for treatment-resistant bipolar depression-need for more data! Bipolar Disord. 2021;23(7):728–729. doi:10.1111/bdi.13129
  • Murata S, Murphy M, Hoppensteadt D, Fareed J, Welborn A, Halaris A. Effects of adjunctive inflammatory modulation on IL-1beta in treatment resistant bipolar depression. Brain Behav Immun. 2020;87:369–376. doi:10.1016/j.bbi.2020.01.004
  • Wilkowska A, Wlodarczyk A, Galuszko-Wegielnik M, Wiglusz MS, Cubala WJ. Intravenous ketamine infusions in treatment-resistant bipolar depression: an open-label naturalistic observational study. Neuropsychiatr Dis Treat. 2021;17:2637–2646. doi:10.2147/NDT.S325000
  • Schoeyen HK, Kessler U, Andreassen OA, et al. Treatment-resistant bipolar depression: a randomized controlled trial of electroconvulsive therapy versus algorithm-based pharmacological treatment. Am J Psychiatry. 2015;172(1):41–51. doi:10.1176/appi.ajp.2014.13111517
  • Kessler U, Schoeyen HK, Andreassen OA, et al. The effect of electroconvulsive therapy on neurocognitive function in treatment-resistant bipolar disorder depression. J Clin Psychiatry. 2014;75(11):e1306–e1313. doi:10.4088/JCP.13m08960
  • Bjoerke-Bertheussen J, Schoeyen H, Andreassen OA, et al. Right unilateral electroconvulsive therapy does not cause more cognitive impairment than pharmacologic treatment in treatment-resistant bipolar depression: a 6-month randomized controlled trial follow-up study. Bipolar Disord. 2018;20(6):531–538. doi:10.1111/bdi.12594
  • Sienaert P, Vansteelandt K, Demyttenaere K, Peuskens J. Ultra-brief pulse ECT in bipolar and unipolar depressive disorder: differences in speed of response. Bipolar Disord. 2009;11(4):418–424. doi:10.1111/j.1399-5618.2009.00702.x
  • Bailine S, Fink M, Knapp R, et al. Electroconvulsive therapy is equally effective in unipolar and bipolar depression. Acta Psychiatr Scand. 2010;121(6):431–436. doi:10.1111/j.1600-0447.2009.01493.x
  • Fitzgerald PB, Hoy KE, Elliot D, McQueen S, Wambeek LE, Daskalakis ZJ. A negative double-blind controlled trial of sequential bilateral rTMS in the treatment of bipolar depression. J Affect Disord. 2016;198:158–162. doi:10.1016/j.jad.2016.03.052
  • Tavares DF, Myczkowski ML, Alberto RL, et al. Treatment of bipolar depression with deep TMS: results from a double-blind, randomized, parallel group, sham-controlled clinical trial. Neuropsychopharmacology. 2017;42(13):2593–2601. doi:10.1038/npp.2017.26
  • Kito S, Miyazi M, Nakatani H, et al. Effectiveness of high-frequency left prefrontal repetitive transcranial magnetic stimulation in patients with treatment-resistant depression: a randomized clinical trial of 37.5-minute vs 18.75-minute protocol. Neuropsychopharmacol Rep. 2019;39(3):203–208. doi:10.1002/npr2.12066
  • Chen L, Thomas EHX, Kaewpijit P, et al. Accelerated theta burst stimulation for the treatment of depression: a randomised controlled trial. Brain Stimul. 2021;14(5):1095–1105. doi:10.1016/j.brs.2021.07.018
  • Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005;58(5):347–354. doi:10.1016/j.biopsych.2005.05.025
  • Nierenberg AA, Alpert JE, Gardner-Schuster EE, Seay S, Mischoulon D. Vagus nerve stimulation: 2-year outcomes for bipolar versus unipolar treatment-resistant depression. Biol Psychiatry. 2008;64(6):455–460. doi:10.1016/j.biopsych.2008.04.036
  • McAllister-Williams RH, Sousa S, Kumar A, et al. The effects of vagus nerve stimulation on the course and outcomes of patients with bipolar disorder in a treatment-resistant depressive episode: a 5-year prospective registry. Int J Bipolar Disord. 2020;8(1):13. doi:10.1186/s40345-020-0178-4
  • Holtzheimer PE, Kelley ME, Gross RE, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry. 2012;69(2):150–158. doi:10.1001/archgenpsychiatry.2011.1456
  • Intra-Cellular Therapies I. Clinical trial evaluating lumateperone monotherapy in the treatment of bipolar depression or major depressive disorder; 2020. Available from: https://ClinicalTrials.gov/show/NCT04285515. Accessed December 8, 2022.
  • University FAHoZ, University Z. Vortioxetine adjunctive treatment in bipolar depression; 2022. Available from: https://ClinicalTrials.gov/show/NCT05481957. Accessed December 8, 2022.
  • Clinic M, Hope L. 8 week multi-site study of MYDAYIS® for bipolar depression; 2020. Available from: https://ClinicalTrials.gov/show/NCT04235686. Accessed December 8, 2022.
  • Institute DMHU, University M, Hospital JG. Brexpiprazole treatment for bipolar I depression; 2021. Available from: https://ClinicalTrials.gov/show/NCT04569448. Accessed December 8, 2022.
  • University Health Network T. Maintenance ketamine infusions for treatment-resistant bipolar depression; 2022. Available from: https://ClinicalTrials.gov/show/NCT05339074. Accessed December 8, 2022.
  • Center SMH. Efficacy and safety of peropirone hydrochloride tablets in the treatment of adolescent bipolar disorder depression; 2020. Available from: https://ClinicalTrials.gov/show/NCT04826510. Accessed December 8, 2022.
  • Clinic M. Ketamine associated ACC GABA and glutamate change and depression remission; 2019. Available from: https://ClinicalTrials.gov/show/NCT03573349. Accessed December 8, 2022.
  • Consorcio Centro de Investigación Biomédica en Red MP, Institute SMR. Trehalose as add-on therapy in bipolar depression; 2016. Available from: https://ClinicalTrials.gov/show/NCT02800161. Accessed December 8, 2022.
  • Fe IdISL, Medicines SAo, Products H, Fe HUL. Efficacy of TBS in treatment resistant depression; 2021. Available from: https://ClinicalTrials.gov/show/NCT04998773. Accessed December 8, 2022.
  • Fitzgerald PB, Chen L, Richardson K, Daskalakis ZJ, Hoy KE. A pilot investigation of an intensive theta burst stimulation protocol for patients with treatment resistant depression. Brain Stimul. 2020;13(1):137–144.
  • Hallahan DB, Institute SMR, National University of Ireland G, Ireland, HRB Clinical Research Facility Galway I, Galway UCH. Scopolamine in bipolar depression; 2021. Available form: https://ClinicalTrials.gov/show/NCT04211961. Accessed December 8, 2022.
  • Health NIoM, Center NIoHC. Transcranial Electric Stimulation Therapy (TEST) for Treatment Resistant Depression (TRD; 2022. Available from: https://ClinicalTrials.gov/show/NCT05172271. Accessed December 8, 2022.
  • Hospital MG. Xenon inhalation therapy for major depressive disorder and bipolar disorder; 2019. Available from: https://ClinicalTrials.gov/show/NCT03748446. Accessed December 8, 2022.
  • Hospital MG, Brain, Foundation BR, Willard J, Foundation ASM. BezafibrateTreatment for Bipolar Depression: a Proof of Concept Study; 2015. Available from: https://ClinicalTrials.gov/show/NCT02481245. Accessed December 8, 2022.
  • Janssen Pharmaceutica N.V. B. A Study of JNJ-55308942 in the treatment of bipolar depression; 2022. Available from: https://ClinicalTrials.gov/show/NCT05328297. Accessed December 8, 2022.
  • Kong CUoH. Adjunctive bright light therapy in patients with bipolar depression and eveningness; 2022. Available from: https://ClinicalTrials.gov/show/NCT05357313. Accessed December 8, 2022.
  • Korea Otsuka Pharmaceutical Co. A study of abilify® tablet (aripiprazole) as an adjunctive treatment in the bipolar depression; 2018. Available from: https://ClinicalTrials.gov/show/NCT03423680. Accessed December 8, 2022.
  • NeuroRx I, Prevail Infoworks I. NRX101 for bipolar depression and sub-acute suicidal ideation and behavior; 2022. Available from: https://ClinicalTrials.gov/show/NCT03395392. Accessed December 8, 2022.
  • Paris AP-Hd, Pharma I. Low dose IL-2 therapy in patients with a depressive episode in the course of a bipolar disorder; 2020. Available from: https://ClinicalTrials.gov/show/NCT04133233. Accessed December 8, 2022.
  • Paulo UoS. Creatine monohydrate as adjuvant therapy for bipolar depression; 2012. Available from: https://ClinicalTrials.gov/show/NCT01655030. Accessed December 8, 2022.
  • Paulo UoS, Paulo FdAàPdEdS. Electro-magnetic convulsive therapies for depression: a non-inferiority study; 2021. Available from: https://ClinicalTrials.gov/show/NCT05054699. Accessed December 8, 2022.
  • Pennsylvania Uo. Intensive TMS for bipolar depression; 2022. Available from: https://ClinicalTrials.gov/show/NCT05228457. Accessed December 8, 2022.
  • Sunovion. A clinical study of an investigational drug for the treatment of major depressive episode associated with bipolar I disorder; 2021. Available from: https://ClinicalTrials.gov/show/NCT05169710. Accessed December 8, 2022.
  • Taylor V, University Health Network T, Hospital WsC. Safety and efficacy of fecal microbiota transplantation in a population with bipolar disorder; 2018. Available from: https://ClinicalTrials.gov/show/NCT03279224. Accessed December 8, 2022.
  • The University of Texas Health Science Center H. Adjunctive allogeneic mesenchymal stem cells for treatment-resistant bipolar depression; 2021. Available from: https://ClinicalTrials.gov/show/NCT03522545. Accessed December 8, 2022.
  • University G, AB ACR. OSU6162 in bipolar depression (OBID); 2021. Available from: https://ClinicalTrials.gov/show/NCT05296356. Accessed December 8, 2022.
  • University JH, Fund BBR, Medical M, Austin UoTa. iTBS in bipolar I depression; 2022. Available from: https://ClinicalTrials.gov/show/NCT05375214. Accessed December 8, 2022.
  • University of California SF. Psilocybin therapy for depression in bipolar II disorder; 2022. Available from: https://ClinicalTrials.gov/show/NCT05065294. Accessed December 8, 2022.
  • University Qs, Clinic OP. Delivering electronic cognitive behavioural therapy to patients with bipolar disorder and residual depressive symptoms; 2020. Available from: https://ClinicalTrials.gov/show/NCT04664257. Accessed December 8, 2022.
  • Brown ES, Khaleghi N, Van Enkevort E, et al. A pilot study of brexpiprazole for bipolar depression. J Affect Disord. 2019;249:315–318. doi:10.1016/j.jad.2019.02.056
  • 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;178(12):1098–1106. doi:10.1176/appi.ajp.2021.20091339
  • Frampton JE. Vortioxetine: a review in cognitive dysfunction in depression. Drugs. 2016;76(17):1675–1682. doi:10.1007/s40265-016-0655-3
  • Gdansk MUo. A naturalistic study of ketamine for treatment resistant mood disorders; 2019. Available from: https://ClinicalTrials.gov/show/NCT04226963. Accessed December 8, 2022.
  • System SPH, Pathways C. The safety and efficacy of psilocybin in participants with type 2 bipolar disorder (BP-II) depression; 2021. Available from: https://ClinicalTrials.gov/show/NCT04433845. Accessed December 8, 2022.
  • Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3(7):619–627. doi:10.1016/S2215-0366(16)30065-7
  • Kisely S, Connor M, Somogyi AA, Siskind D. A systematic literature review and meta-analysis of the effect of psilocybin and methylenedioxymethamphetamine on mental, behavioural or developmental disorders. Aust N Z J Psychiatry. 2022;48674221083868. doi:10.1177/00048674221083868
  • Hendin HM, Penn AD. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: a case report. Bipolar Disord. 2021;23(7):733–735. doi:10.1111/bdi.13095
  • McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383–399. doi:10.1176/appi.ajp.2020.20081251
  • The University of Texas Health Science Center H. Magnetic seizure therapy in bipolar depression (MST-BpD); 2022. Available from: https://ClinicalTrials.gov/show/NCT04080778. Accessed December 8, 2022.
  • Bosch OG, Halm S, Seifritz E. Psychedelics in the treatment of unipolar and bipolar depression. Int J Bipolar Disord. 2022;10(1):18. doi:10.1186/s40345-022-00265-5
  • Seshadri A, Sundaresh V, Prokop LJ, Singh B. Thyroid hormone augmentation for bipolar disorder: a systematic review. Brain Sci. 2022;12(11):1540. doi:10.3390/brainsci12111540