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Medications for Bipolar Disorder

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Tasman’s Psychiatry
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Abstract

This chapter reviews current evidence for medications in the treatment of patients with bipolar disorder. It will overview the historic “mood stabilizers” such as lithium, valproate, and carbamazepine, and also lamotrigine and the medications for psychosis (antipsychotics). This pragmatic approach is cognizant of the major shift in prescribing patterns for bipolar disorder which has occurred internationally over the last two decades, with a dramatic increase in the use of medications for psychosis for this condition. A wide range of treatments have now been shown to be effective for the acute treatment of mania, with it now evident that medications for psychosis are to be preferred in the short-term control of this urgent presentation. Bipolar depression remains a therapeutic challenge and remains an area in urgent need of new and more effective treatments. Maintenance therapy is critical in view of the high rates of relapse and disability with this condition. While lithium remains the gold standard treatment option for prevention of mania, lamotrigine has been shown to be effective in preventing depressive recurrences. Further, many of the dopamine serotonin blockers (atypical antipsychotics) have also been found to be useful, particularly for manic relapse, with long-acting injectables having a demonstrable advantage. Finally, growing evidence is confirming that optimal treatment comprises effective mood-stabilizing pharmacotherapy concurrent with evidence-based psychological therapies.

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References

  • Ali, Z., & El-Mallakh, R. S. (2021). Lithium nephropathy and renal microcysts. Current Psychiatry, 20(6), 34–38, 50.

    Google Scholar 

  • Ali, Z., Tegin, C., & El-Mallakh, R. S. (2020). Evaluating lurasidone as a treatment option for bipolar disorder. Expert Opinion in Pharmacotherapy, 21(3), 253–260. https://doi.org/10.1080/14656566.2019.1695777

    Article  Google Scholar 

  • Amare, A. T., Schubert, K. O., Hou, L., et al. (2018). Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study. JAMA Psychiatry, 75, 65–74.

    PubMed  Google Scholar 

  • Amare, A. T., Schubert, K. O., Hou, L., et al. (2020). Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. Molecular Psychiatry. Online ahead of print.

    Google Scholar 

  • Bahji, A., Hawken, E. R., Sepehry, A. A., et al. (2019). ECT beyond unipolar major depression: Systematic review and meta-analysis of electroconvulsive therapy in bipolar depression. Acta Psychiatrica Scandinavica, 139, 214–226.

    CAS  PubMed  Google Scholar 

  • Bahji, A., Ermacora, D., Stephenson, C., et al. (2020). Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: A systematic review and network meta-analysis. Journal of Affective Disorders, 269, 154–184.

    Article  CAS  PubMed  Google Scholar 

  • Bauer, M., Andreassen, O. A., Geddes, J. R., et al. (2018). Areas of uncertainties and unmet needs in bipolar disorders: Clinical and research perspectives. Lancet Psychiatry, 5, 930–939.

    Article  PubMed  Google Scholar 

  • Bellivier, F., & Marie-Claire, C. (2018). Molecular signatures of lithium treatment: Current knowledge. Pharmacopsychiatry, 51, 212–219.

    Article  CAS  PubMed  Google Scholar 

  • Berwaerts, J., Lane, R., Nuamah, I. F., et al. (2011). Paliperidone extended-release as adjunctive therapy to lithium or valproate in the treatment of acute mania: A randomized, placebo-controlled study. Journal of Affective Disorders, 129, 252–260.

    Article  CAS  PubMed  Google Scholar 

  • Berwaerts, J., Xu, H., Nuamah, I., et al. (2012a). Evaluation of the efficacy and safety of paliperidone extended-release in the treatment of acute mania: A randomized, double-blind, dose-response study. Journal of Affective Disorders, 136, e51–e60.

    Article  CAS  PubMed  Google Scholar 

  • Berwaerts, J., Melkote, R., Nuamah, I., et al. (2012b). A randomized, placebo-and active-controlled study of paliperidone extended-release as maintenance treatment in patients with bipolar I disorder after an acute manic or mixed episode. Journal of Affective Disorders, 138, 247–258.

    Article  CAS  Google Scholar 

  • Bond, D. J., Lam, R. W., & Yatham, L. N. (2010). Divalproex sodium versus placebo in the treatment of acute bipolar depression: A systematic review and meta-analysis. Journal of Affective Disorders, 124, 228–234.

    Article  CAS  PubMed  Google Scholar 

  • Bowden, C. L., Brugger, A. M., Swann, A. C., et al. (1994). Efficacy of divalproex vs. lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA, 271, 918–924.

    Article  CAS  Google Scholar 

  • Bowden, C. L., Calabrese, J. R., McElroy, S. L., et al. (2000). A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Archives of General Psychiatry, 57, 481–489.

    Article  CAS  Google Scholar 

  • Bowden, C. L., Calabrese, J. R., Sachs, G., et al. (2003). A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Archives of General Psychiatry, 60, 392–400.

    Article  CAS  PubMed  Google Scholar 

  • Bowden, C. L., Grunze, H., Mullen, J., et al. (2005). A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. Journal of Clinical Psychiatry, 66, 111–121.

    Article  CAS  PubMed  Google Scholar 

  • Bowden, C. L., Swann, A. C., Calabrese, J. R., et al. (2006). A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania. Journal of Clinical Psychiatry, 67, 1501–1510.

    Article  CAS  PubMed  Google Scholar 

  • Bowden, C. L., Vieta, E., Ice, K. S., et al. (2010). Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: A 6-month, randomized, placebo-controlled, double-blind trial. Journal of Clinical Psychiatry, 71, 130–137.

    Article  CAS  PubMed  Google Scholar 

  • Brown, E. B., McElroy, S. L., Keck, P. E., Jr., et al. (2006). A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. Journal of Clinical Psychiatry, 67, 1025–1033.

    Article  CAS  PubMed  Google Scholar 

  • Cade, J. F. (1949). Lithium salts in the treatment of psychotic excitement. Medical Journal of Australia, 2, 349–352.

    Article  CAS  PubMed  Google Scholar 

  • Calabrese, J. R., Bowden, C. L., Sachs, G. S., et al. (1999). A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. Journal of Clinical Psychiatry, 60, 79–88.

    Article  CAS  PubMed  Google Scholar 

  • Calabrese, J. R., Sullivan, J. R., Bowden, C. L., et al. (2002). Rash in multicenter trials of lamotrigine in mood disorders: Clinical relevance and management. Journal of Clinical Psychiatry, 63, 1012–1019.

    Article  PubMed  Google Scholar 

  • Calabrese, J. R., Bowden, C. L., Sachs, G., et al. (2003). A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Journal of Clinical Psychiatry, 64, 1013–1024.

    Article  CAS  PubMed  Google Scholar 

  • Calabrese, J. R., Keck, P. E., Jr., MacFadden, W., et al. (2005). A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. American Journal of Psychiatry, 162, 1351–1360.

    Article  PubMed  Google Scholar 

  • Calabrese, J. R., Huffman, R. F., White, R. L., et al. (2008). Lamotrigine in the acute treatment of bipolar depression: Results of five double-blind, placebo-controlled clinical trials. Bipolar Disorders, 10, 323–333.

    Article  CAS  Google Scholar 

  • Calabrese, J. R., Pikalov, A., Streicher, C., et al. (2017a). Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. European Neuropsychopharmacology, 27, 865–876.

    Article  CAS  PubMed  Google Scholar 

  • Calabrese, J. R., Sanchezm, R., Jin, N., et al. (2017b). Efficacy and safety of aripiprazole once-monthly in the maintenance treatment of bipolar I disorder: A double-blind, placebo-controlled, 52-week randomized withdrawal study. Journal of Clinical Psychiatry, 78(3), 324–331. https://doi.org/10.4088/JCP.16m11201

    Article  PubMed  Google Scholar 

  • Calabrese, J. R., Durgam, S., Satlin, A., et al. (2021). Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: A phase 3 randomized placebo-controlled trial. The American Journal of Psychiatry, 178(12), 1098–1106. https://doi.org/10.1176/appi.ajp.2021.20091339

    Article  PubMed  Google Scholar 

  • Chakrabarty, T., Keramatian, K., & Yatham, L. N. (2020). Treatment of mixed features in bipolar disorder: An updated view. Current Psychiatry Reports, 22, 15.

    Article  PubMed  Google Scholar 

  • Chen, T. Y., Kamali, M., Chu, C. S., et al. (2019). Divalproex and its effect on suicide risk in bipolar disorder: A systematic review and meta-analysis of multinational observational studies. Journal of Affective Disorders, 245, 812–818.

    Article  CAS  PubMed  Google Scholar 

  • Chwieduk, C. M., & Scott, L. J. (2011). Asenapine: A review of its use in the management of mania in adults with bipolar I disorder. CNS Drugs, 25, 251–267.

    Article  CAS  PubMed  Google Scholar 

  • Cipriani, A., Barbui, C., Salanti, G., et al. (2011). Comparative efficacy and acceptability of antimanic drugs in acute mania: A multiple-treatments meta-analysis. The Lancet, 378, 1306–1315.

    Article  CAS  Google Scholar 

  • Cohen, J. M., Huybrechts, K. F., Patorno, E., et al. (2019). Anticonvulsant mood stabilizer and lithium use and risk of adverse pregnancy outcomes. Journal of Clinical Psychiatry, 80, 18m12572.

    PubMed  Google Scholar 

  • Curtin, F., & Schulz, P. (2004). Clonazepam and lorazepam in acute mania: A Bayesian meta-analysis. Journal of Affective Disorders, 78(3), 201–208. https://doi.org/10.1016/S0165-0327(02)00317-8

    Article  CAS  PubMed  Google Scholar 

  • Davis, J. M., Janicak, P. G., & Hogan, D. M. (1999). Mood stabilizers in the prevention of recurrent affective disorders: A meta-analysis. Acta Psychiatrica Scandinavica, 100, 406–417.

    Article  CAS  PubMed  Google Scholar 

  • Davis, L. L., Bartolucci, A., & Petty, F. (2005). Divalproex in the treatment of bipolar depression: A placebo-controlled study. Journal of Affective Disorders, 85, 259–266.

    Article  CAS  PubMed  Google Scholar 

  • de Miranda, A. S., de Miranda, A. S., & Teixeira, A. L. (2019). Lamotrigine as a mood stabilizer: Insights from the pre-clinical evidence. Expert Opinion on Drug Discovery, 14, 179–190.

    Article  PubMed  Google Scholar 

  • Del Matto, L., Muscas, M., Murru, A., et al. (2020). Lithium and suicide prevention in mood disorders and in the general population: A systematic review. Neuroscience and Biobehavioral Reviews, 116, 142–153.

    Article  PubMed  Google Scholar 

  • Diav-Citrin, O., Shechtman, S., Zvi, N., et al. (2017). Is it safe to use lamotrigine during pregnancy? A prospective comparative observational study. Birth Defects Research, 109, 1196–1203.

    Article  CAS  PubMed  Google Scholar 

  • Durgam, S., Earley, W., Lipschitz, A., et al. (2016). An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. American Journal of Psychiatry, 173, 271–281.

    Article  PubMed  Google Scholar 

  • Earley, W., Burgess, M. V., Rekeda, L., et al. (2019). Cariprazine treatment of bipolar depression: A randomized double-blind placebo-controlled phase 3 study. American Journal of Psychiatry, 176, 439–448.

    Article  PubMed  Google Scholar 

  • Earley, W. R., Burgess, M. V., Khan, B., et al. (2020). Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study. Bipolar Disorders, 22, 372–384.

    Article  CAS  PubMed  Google Scholar 

  • El-Mallakh, R. S., & Huff, M. O. (2001). Mood stabilizers and ion regulation. Harvard Review of Psychiatry, 9(1), 23–32. https://doi.org/10.1080/10673220127873

    Article  CAS  PubMed  Google Scholar 

  • El-Mallakh, R. S., & Watkins, J. (2009). Prolactin elevations and the permeability glycoprotein. Primary Care Companion CNS Disorders, 21(3) pii: 18nr02412.

    Google Scholar 

  • Ferrari, A. J., Stockings, E., Khoo, J. P., et al. (2016). The prevalence and burden of bipolar disorder: Findings from the Global Burden of Disease Study 2013. Bipolar Disorders, 18, 440–450.

    Article  PubMed  Google Scholar 

  • Frankland, A., Roberts, G., Holmes-Preston, E., et al. (2018). Clinical predictors of conversion to bipolar disorder in a prospective longitudinal familial high-risk sample: Focus on depressive features. Psychological Medicine, 48, 1713–1721.

    Article  PubMed  Google Scholar 

  • Fu, D. J., Turkoz, I., Simonson, R. B., et al. (2015). Paliperidone palmitate once-monthly reduces risk of relapse of psychotic, depressive, and manic symptoms and maintains functioning in a double-blind, randomized study of schizoaffective disorder. Journal of Clinical Psychiatry, 76(3), 253–262. https://doi.org/10.4088/JCP.14m09416

    Article  PubMed  Google Scholar 

  • Fung, V. C., Overhage, L. N., Sylvia, L. G., et al. (2019). Complex polypharmacy in bipolar disorder: Side effect burden, adherence, and response predictors. Journal of Affective Disorders, 257, 7–22.

    Article  Google Scholar 

  • Gao, K., Kemp, D. E., Fein, E., et al. (2011). Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics. Journal of Clinical Psychiatry, 72, 1063–1071.

    Article  PubMed  Google Scholar 

  • Gao, K., Pappadopulos, K., Karayal, O. N., et al. (2013). Risk for adverse events and discontinuation due to adverse events of ziprasidone monotherapy relative to placebo in the acute treatment of bipolar depression, mania, and schizophrenia. Journal of Clinical Psychopharmacology, 33, 425–431.

    Article  CAS  PubMed  Google Scholar 

  • Geddes, J. R., Calabrese, J. R., & Goodwin, G. M. (2009). Lamotrigine for treatment of bipolar depression: Independent meta-analysis and meta-regression of individual patient data from five randomized trials. British Journal of Psychiatry, 94, 4–9.

    Article  Google Scholar 

  • Geddes, J. R., Goodwin, G. M., Rendell, J., et al. (2010). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomized open-label trial. BALANCE Investigators and Collaborators. The Lancet, 375, 385–395.

    Article  Google Scholar 

  • Gerner, R. H., Post, R. M., & Bunney, W. E., Jr. (1976). A dopaminergic mechanism in mania. American Journal of Psychiatry, 133, 1177–1180.

    Article  CAS  PubMed  Google Scholar 

  • Gijsman, H. J., Geddes, J. R., Rendell, J. M., et al. (2004). Antidepressants for bipolar depression: A systematic review of randomized, controlled trials. American Journal of Psychiatry, 161, 1537–1547.

    Article  PubMed  Google Scholar 

  • Goodwin, G. M., Bowden, C. L., Calabrese, J. R., et al. (2004). A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. Journal of Clinical Psychiatry, 65, 432–441.

    Article  CAS  PubMed  Google Scholar 

  • Hayes, J. F., Marston, L., Walters, K., et al. (2016a). Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: A population-based UK cohort study using electronic health records. World Psychiatry, 15, 53–58.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hayes, J. F., Pitman, A., Marston, L., et al. (2016b). Self-harm, unintentional injury, and suicide in bipolar disorder during maintenance mood stabilizer treatment: A UK population-based electronic health records study. JAMA Psychiatry, 73, 630–637.

    Article  Google Scholar 

  • Hayes, J. F., Marston, L., Walters, K., et al. (2016c). Adverse renal, endocrine, hepatic, and metabolic events during maintenance mood stabilizer treatment for bipolar disorder: A population-based cohort study. PLoS Medicine, 13, e1002058.

    Article  PubMed Central  Google Scholar 

  • Hirschfeld, R. M., Baker, J. D., Wozniak, P., et al. (2003). The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. Journal of Clinical Psychiatry, 64, 841–846.

    Article  CAS  Google Scholar 

  • Hirschfeld, R. M., Keck, P. E., Jr., Kramer, M., et al. (2004). Rapid antimanic effect of risperidone monotherapy: A 3-week multicenter, double-blind, placebo-controlled trial. American Journal of Psychiatry, 161, 1057–1065.

    Article  PubMed  Google Scholar 

  • Hlaing, P. M., Isoardi, K. Z., Page, C. B., et al. (2020). Neurotoxicity in chronic lithium poisoning. Internal Medicine Journal, 50, 427–432.

    Article  CAS  Google Scholar 

  • Hou, L., Heilbronner, U., Degenhardt, F., et al. (2016). Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study. The Lancet, 387, 1085–1093.

    Article  CAS  Google Scholar 

  • Hussein, Z., & Posner, J. (1997). Population pharmacokinetics of lamotrigine monotherapy in patients with epilepsy: Retrospective analysis of routine monitoring data. British Journal of Clinical Pharmacology, 43(5), 457–465. https://doi.org/10.1046/j.1365-2125.1997.00594.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jann, M. W., & Penzak, S. R. (2018). Long-acting injectable second-generation antipsychotics: An update and comparison between agents. CNS Drugs, 32, 241–257.

    Article  CAS  PubMed  Google Scholar 

  • Kato, T., Ishigooka, J., Miyajima, M., et al. (2020). Double-blind, placebo-controlled study of lurasidone monotherapy for the treatment of bipolar I depression. Psychiatry and Clinical Neurosciences, 74(12), 635–644. https://doi.org/10.1111/pcn.13137

    Article  CAS  PubMed Central  Google Scholar 

  • Keck, P. E., Jr., Versiani, M., Potkin, S., et al. (2003a). Ziprasidone in the treatment of acute bipolar mania: A three-week, placebo-controlled, double-blind, randomized trial. American Journal of Psychiatry, 160, 741–748.

    Article  PubMed  Google Scholar 

  • Keck, P. E., Jr., Marcus, R., Tourkodimitris, S., et al. (2003b). A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. American Journal of Psychiatry, 160, 1651–1658.

    Article  PubMed  Google Scholar 

  • Keck, P. E., Jr., Calabrese, J. R., McQuade, R. D., et al. (2006). A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. Journal of Clinical Psychiatry, 67, 626–637.

    Article  CAS  PubMed  Google Scholar 

  • Keller, M. B., Lavori, P. W., Kane, J. M., et al. (1992). Subsyndromal symptoms in bipolar disorder. A comparison of standard and low serum levels of lithium. Archives of General Psychiatry, 49, 371–376.

    Article  CAS  Google Scholar 

  • Keramatian, K., Chakrabarty, T., & Yatham, L. N. (2019). Long-acting injectable second-generation/atypical antipsychotics for the management of bipolar disorder: A systematic review. CNS Drugs, 33, 431–456.

    Article  CAS  Google Scholar 

  • Kessing, L. V., Bauer, M., Nolen, W. A., et al. (2018). Effectiveness of maintenance therapy of lithium vs other mood stabilizers in monotherapy and in combinations: A systematic review of evidence from observational studies. Bipolar Disorders, 20, 419. https://doi.org/10.1111/bdi.12623. Online ahead of print.

    Article  Google Scholar 

  • Khanna, S., Vieta, E., Lyons, B., et al. (2005). Risperidone in the treatment of acute mania: Double-blind, placebo-controlled study. British Journal of Psychiatry, 187, 229–234.

    Article  Google Scholar 

  • Kishi, T., Ikuta, T., Matsuda, Y., et al. (2020a). Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: A systematic review and network meta-analysis of randomized controlled trials. Molecular Psychiatry. https://doi.org/10.1038/s41380-020-00946-6. Online ahead of print.

  • Kishi, T., Matsuda, Y., Sakuma, K., et al. (2020b). Recurrence rates in stable bipolar disorder patients after drug discontinuation v. drug maintenance: A systematic review and meta-analysis. Psychological Medicine, 13, 1–9. https://doi.org/10.1017/S0033291720003505. Online ahead of print.

    Article  Google Scholar 

  • Kripalani, M., Shawcross, J., Reilly, J., et al. (2009). Lithium and chronic kidney disease. British Medical Journal, 339, b2452.

    Article  Google Scholar 

  • Lähteenvuo, M., Tanskanen, A., Taipale, H., et al. (2018). Real-world effectiveness of pharmacologic treatments for the prevention of rehospitalization in a Finnish nationwide cohort of patients with bipolar disorder. JAMA Psychiatry, 75, 347–355.

    Article  PubMed Central  Google Scholar 

  • Loebel, A., Cucchiaro, J., Silva, R., et al. (2014a). Lurasidone monotherapy in the treatment of bipolar I depression: A randomized, double-blind, placebo-controlled study. American Journal of Psychiatry, 171(2), 160–168.

    Article  PubMed  Google Scholar 

  • Loebel, A., Cucchiaro, J., Silva, R., et al. (2014b). Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: A randomized, double-blind, placebo-controlled study. American Journal of Psychiatry, 171(2), 169–177.

    Article  Google Scholar 

  • Lombardo, I., Sachs, G., Kolluri, S., et al. (2012). Two 6-week, randomized, double-blind, placebo-controlled studies of ziprasidone in outpatients with bipolar I depression: Did baseline characteristics impact trial outcome? Journal of Clinical Psychopharmacology, 32, 470–478.

    Article  CAS  Google Scholar 

  • López-Muñoz, F., Shen, W. W., D’Ocon, P., et al. (2018). A history of the pharmacological treatment of bipolar disorder. International Journal of Molecular Sciences, 19, 2143.

    Article  PubMed  PubMed Central  Google Scholar 

  • Macfadden, W., Alphs, L., Haskins, J. T., et al. (2009). A randomized, doubleblind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disorders, 11, 827–839.

    Article  CAS  PubMed  Google Scholar 

  • McElroy, S. L., Weisler, R. H., Chang, W., et al. (2010). A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). Journal of Clinical Psychiatry, 71, 163–174.

    Article  CAS  PubMed  Google Scholar 

  • McIntyre, R. S., Brecher, M., Paulsson, B., et al. (2005). Quetiapine or haloperidol as monotherapy for bipolar mania – A 12-week, double-blind, randomized, parallel-group, placebo-controlled trial. European Neuropsychopharmacology, 15, 573–585.

    Article  CAS  PubMed  Google Scholar 

  • McIntyre, R. S., Cohen, M., Zhao, J., et al. (2009). A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disorders, 11, 673–686.

    Article  CAS  PubMed  Google Scholar 

  • McIntyre, R. S., Cohen, M., Zhao, J., et al. (2010). Asenapine in the treatment of acute mania in bipolar I disorder: A randomized, double-blind, placebo-controlled trial. Journal of Affective Disorders, 122, 27–38.

    Article  CAS  PubMed  Google Scholar 

  • McIntyre, R. S., Berk, M., Brietzke, E., et al. (2020). Bipolar disorders. Lancet, 396, 1841–1856.

    Article  CAS  PubMed  Google Scholar 

  • McKnight, R. F., Adida, M., Budge, K., et al. (2012). Lithium toxicity profile: A systematic review and meta-analysis. Lancet, 379, 721–728.

    Article  CAS  PubMed  Google Scholar 

  • Merikangas, K. R., Jin, R., He, J. P., et al. (2011). Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Archives of General Psychiatry, 68, 241–251.

    Article  PubMed  PubMed Central  Google Scholar 

  • Miklowitz, D. J., Efthimiou, O., Furukawa, T. A., et al. (2021). Adjunctive psychotherapy for bipolar disorder: A systematic review and component network meta-analysis. JAMA Psychiatry, 78, 141–150.

    Article  PubMed  Google Scholar 

  • Miller, J. N., & Black, D. W. (2020). Bipolar disorder and suicide: A review. Current Psychiatry Reports, 22, 6.

    Article  Google Scholar 

  • Mitchell, P. B. (1999). On the 50th anniversary of John Cade’s discovery of the anti-manic effect of lithium. Australian and New Zealand Journal of Psychiatry, 33, 623–628.

    CAS  PubMed  Google Scholar 

  • Mitchell, P. B., & Hadzi-Pavlovic, D. (1999). John Cade and the discovery of lithium treatment for manic depressive illness. Medical Journal of Australia, 171, 262–264.

    Article  CAS  PubMed  Google Scholar 

  • Mitchell, P. B., Goodwin, G. M., Johnson, G. F., et al. (2008). Diagnostic guidelines for bipolar depression: A probabilistic approach. Bipolar Disorders, 10, 144–152.

    Article  Google Scholar 

  • Mitchell, P. B., Johnston, A. K., Frankland, A., et al. (2013). Bipolar disorder in a national survey using the World Mental Health Version of the Composite International Diagnostic Interview: The impact of differing diagnostic algorithms. Acta Psychiatrica Scandanivica, 127, 381–393.

    Article  CAS  Google Scholar 

  • Muzina, D. J., El-Sayegh, S., & Calabrese, J. R. (2002). Antiepileptic drugs in psychiatry–focus on randomized controlled trials. Epilepsy Research, 50, 195–202.

    Article  CAS  PubMed  Google Scholar 

  • Muzina, D. J., Elhaj, O., Gajwani, P., et al. (2005). Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder. Acta Psychiatrica Scandinavica. Supplementum, 111(426), 21–28.

    Google Scholar 

  • Muzina, D. J., Gao, K., Kemp, D. E., et al. (2011). Acute efficacy of divalproex sodium versus placebo in mood stabilizer-naive bipolar I or II depression: A double-blind, randomized, placebo-controlled trial. Journal of Clinical Psychiatry, 72, 813–819.

    Article  CAS  PubMed  Google Scholar 

  • Nemeroff, C. B., Evans, D. L., Gyulai, L., et al. (2001). Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. American Journal of Psychiatry, 158, 906–912.

    Article  CAS  PubMed  Google Scholar 

  • Nierenberg, A. A., McIntyre, R. S., & Sachs, G. S. (2015). Improving outcomes in patients with bipolar depression: A comprehensive review. Journal of Clinical Psychiatry, 76, e10.

    Article  PubMed  Google Scholar 

  • Nierenberg, A. A., McElroy, S. L., Friedman, E. S., Ketter, T. A., Shelton, R. C., Deckersbach, T., et al. (2016). Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness): a pragmatic 6-month trial of lithium versus quetiapine for bipolar disorder. Journal of Clinical Psychiatry, 77(1), 90–99. https://doi.org/10.4088/JCP.14m09349

    Article  Google Scholar 

  • Pacchiarotti, I., Bond, D. J., Baldessarini, R. J., et al. (2013). The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. American Journal of Psychiatry, 170, 1249–1262.

    Article  PubMed  Google Scholar 

  • Pakpour, A. H., Modabbernia, A., Lin, C.-Y., et al. (2017). Promoting medication adherence among patients with bipolar disorder: A multicenter randomized controlled trial of a multifaceted intervention. Psychological Medicine, 47, 2528–2539.

    Article  CAS  PubMed  Google Scholar 

  • Patorno, E., Huybrechts, K. F., Bateman, B. T., et al. (2017). Lithium use in pregnancy and the risk of cardiac malformations. New England Journal of Medicine, 376, 2245–2254.

    Article  CAS  PubMed  Google Scholar 

  • Plenge, P., Stensgaard, A., Jensen, H. V., et al. (1994). 24-hour lithium concentration in human brain studied by Li-7 magnetic resonance spectroscopy. Biological Psychiatry, 36, 511–516.

    Article  CAS  PubMed  Google Scholar 

  • Rhee, T. G., Olfson, M., Nierenberg, A. A., et al. (2020). 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. American Journal of Psychiatry, 177, 706–715.

    Article  PubMed  Google Scholar 

  • Sachs, G. S., Grossman, F., Ghaemi, S. N., et al. (2002). Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: A double-blind, placebo-controlled comparison of efficacy and safety. American Journal of Psychiatry, 159, 1146–1154.

    Article  PubMed  Google Scholar 

  • Sachs, G., Chengappa, K. N., Suppes, T., et al. (2004). Quetiapine with lithium or divalproex for the treatment of bipolar mania: A randomized, doubleblind, placebo-controlled study. Bipolar Disorders, 6, 213–223.

    Article  CAS  PubMed  Google Scholar 

  • Sachs, G., Sanchez, R., Marcus, R., et al. (2006). Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: A 3-week placebo-controlled study. Journal of Psychopharmacology, 20, 536–546.

    Article  CAS  PubMed  Google Scholar 

  • Sachs, G. S., Nierenberg, A. A., Calabrese, J. R., et al. (2007). Effectiveness of adjunctive antidepressant treatment for bipolar depression. New England Journal of Medicine, 356, 1–12.

    Article  Google Scholar 

  • Sachs, G. S., Ice, K. S., Chappell, P. B., et al. (2011). Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder: A randomized, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry, 72, 1413–1422.

    Article  CAS  Google Scholar 

  • Sajatovic, M., Tatsuoka, C., Cassidy, K. A., et al. (2018). A 6-month, prospective, randomized controlled trial of customized adherence enhancement versus bipolar-specific educational control in poorly adherent individuals with bipolar disorder. Journal of Clinical Psychiatry, 79, 17m12036.

    Google Scholar 

  • Salcedo, S., McMaster, K. J., & Johnson, S. L. (2017). Disparities in treatment and service utilization among Hispanics and non-Hispanic whites with bipolar disorder. Journal of Racial and Ethnic Health Disparities, 4, 354–363.

    Article  PubMed  Google Scholar 

  • Sanghani, H. R., Jagannath, A., Humberstone, T., et al. (2020). Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder. Molecular Psychiatry, 26, 5252. https://doi.org/10.1038/s41380-020-0769-6. Online ahead of print.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saraf, G., Pinto, J. V., & Yatham, L. N. (2019). Efficacy and safety of cariprazine in the treatment of bipolar disorder. Expert Opinion in Pharmacotherapy, 20, 2063–2072.

    Article  CAS  Google Scholar 

  • Sawai, Y., Okamoto, T., Muranaka, Y., et al. (2019). In vivo evaluation of the effect of lithium on peripheral circadian clocks by real-time monitoring of clock gene expression in near-freely moving mice. Scientific Reports, 9, 10909.

    Article  PubMed  PubMed Central  Google Scholar 

  • Schoot, T. S., Molmans, T. H. J., Grootens, T. P., et al. (2020). Systematic review and practical guideline for the prevention and management of the renal side effects of lithium therapy. European Neuropsychopharmacology, 31, 16–32.

    Article  CAS  PubMed  Google Scholar 

  • Schou, M., Juel-Nielsen, N., Stromgren, E., et al. (1954). The treatment of manic psychoses by the administration of lithium salts. Journal of Neurology, Neurosurgery and Psychiatry, 17, 250–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Segal, J., Berk, M., & Brook, S. (1998). Risperidone compared with both lithium and haloperidol in mania: A double-blind randomized controlled trial. Clinical Neuropharmacology, 21, 176–180.

    CAS  PubMed  Google Scholar 

  • Shelton, R. C., & Stahl, S. M. (2004). Risperidone and paroxetine given singly and in combination for bipolar depression. Journal of Clinical Psychiatry, 65, 1715–1719.

    Article  CAS  Google Scholar 

  • Smith, L. A., Cornelius, V., Warnock, A., et al. (2007). Acute bipolar mania: A systematic review and meta-analysis of co-therapy vs. monotherapy. Acta Psychiatrica Scandinavica, 115, 12–20.

    Article  CAS  PubMed  Google Scholar 

  • Stout, J., Hozer, F., Coste, A., et al. (2020). Accumulation of lithium in the hippocampus of patients with bipolar disorder: A lithium-7 magnetic resonance imaging study at 7 Tesla. Biological Psychiatry, 88, 426–433.

    Article  CAS  PubMed  Google Scholar 

  • Suppes, T., Marangell, L. B., Bernstein, I. H., et al. (2008). A single blind comparison of lithium and lamotrigine for the treatment of bipolar II depression. Journal of Affective Disorders, 111, 334–443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suppes, T., Vieta, E., Liu, S., et al. (2009). Maintenance treatment for patients with bipolar I disorder: Results from a North American study of quetiapine in combination with lithium or divalproex (trial 127). American Journal of Psychiatry, 166, 476–488.

    Article  PubMed  Google Scholar 

  • Suppes, T., Datto, C., Minkwitz, M., et al. (2010). Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. Journal of Affective Disorders, 121, 106–115.

    Article  CAS  PubMed  Google Scholar 

  • Thase, M. E., Macfadden, W., Weisler, R. H., et al. (2006). Efficacy of quetiapine monotherapy in bipolar I and II depression: A double-blind, placebo-controlled study (the BOLDER II study). Journal of Clinical Psychopharmacology, 26, 600–609.

    Article  CAS  PubMed  Google Scholar 

  • Thase, M. E., Jonas, A., Khan, A., et al. (2008). Aripiprazole monotherapy in nonpsychotic bipolar I depression: Results of 2 randomized, placebo-controlled studies. Journal of Clinical Psychopharmacology, 28, 13–20.

    Article  CAS  PubMed  Google Scholar 

  • Tohen, M., Sanger, T. M., McElroy, S. L., et al. (1999). Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. American Journal of Psychiatry, 156, 702–709.

    Article  CAS  PubMed  Google Scholar 

  • Tohen, M., Jacobs, T. G., Grundy, S. L., et al. (2000). Efficacy of olanzapine in acute bipolar mania: A double-blind, placebo-controlled study. The Olanzapine HGGW Study Group. Archives of General Psychiatry, 57, 841–849.

    Article  CAS  PubMed  Google Scholar 

  • Tohen, M., Chengappa, K. N., Suppes, T., et al. (2002). Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Archives of General Psychiatry, 59, 62–69.

    Article  CAS  PubMed  Google Scholar 

  • Tohen, M., Ketter, T. A., Zarate, C. A., et al. (2003a). Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: A 47-week study. American Journal of Psychiatry, 160, 1263–1271.

    Article  PubMed  Google Scholar 

  • Tohen, M., Vieta, E., Calabrese, J., et al. (2003b). Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Archives of General Psychiatry, 60, 1079–1088.

    Article  CAS  PubMed  Google Scholar 

  • Tohen, M., Chengappa, K. N., Suppes, T., et al. (2004). Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabilizer v. mood stabilizer alone. British Journal of Psychiatry, 184, 337–345.

    Article  Google Scholar 

  • Tohen, M., Greil, W., Calabrese, J. R., et al. (2005). Olanzapine versus lithium in the maintenance treatment of bipolar disorder: A 12-month, randomized, double-blind, controlled clinical trial. American Journal of Psychiatry, 162, 1281–1290.

    Article  Google Scholar 

  • Tohen, M., Calabrese, J. R., Sachs, G. S., et al. (2006). Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. American Journal of Psychiatry, 163, 247–256.

    Article  PubMed  Google Scholar 

  • van der Loos, M. L., Mulder, P. G., Hartong, E. G., et al. (2009). Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: A multicenter, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry, 70, 223–231.

    Article  Google Scholar 

  • Vieta, E., Suppes, T., Eggens, I., et al. (2008). Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). Journal of Affective Disorders, 109, 251–263.

    Article  CAS  Google Scholar 

  • Vieta, E., Nuamah, I. F., Lim, P., et al. (2010). A randomized, placebo-and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disorders, 12, 230–243.

    Article  CAS  PubMed  Google Scholar 

  • Viktorin, A., Lichtenstein, P., Thase, M. E., et al. (2014). The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. American Journal of Psychiatry, 171, 1067–1073.

    Article  PubMed  Google Scholar 

  • Weisler, R. H., Kaiali, A. H., & Ketter, T. A. (2004). A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. Journal of Clinical Psychiatry, 65, 478–484.

    Article  CAS  Google Scholar 

  • Weisler, R. H., Keck, P. E., Jr., Swann, A. C., et al. (2005). Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: A multicenter, randomized, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry, 66, 323–330.

    Article  CAS  PubMed  Google Scholar 

  • Yatham, L. N., Grossman, F., Augustyns, I., et al. (2003). Mood stabilizers plus risperidone or placebo in the treatment of acute mania. International, double-blind, randomized controlled trial. British Journal of Psychiatry, 182, 141–147.

    Article  Google Scholar 

  • Young, A. H., McElroy, S. L., Bauer, M., et al. (2010). A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). Journal of Clinical Psychiatry, 71, 150–162.i.

    Article  CAS  PubMed  Google Scholar 

  • Zohar, J., Stahl, S., Moller, H. J., Blier, P., Kupfer, D., Yamawaki, S., … Nutt, D. (2015). A review of the current nomenclature for psychotropic agents and an introduction to the Neuroscience-based Nomenclature. European Neuropsychopharmacology, 25(12), 2318–2325.

    Google Scholar 

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Mitchell, P.B. (2023). Medications for Bipolar Disorder. In: Tasman, A., et al. Tasman’s Psychiatry. Springer, Cham. https://doi.org/10.1007/978-3-030-42825-9_135-1

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