Medications for Bipolar Disorder

Bipolar disorder, also known as manic depression, is a chronic mental illness that causes unusual shifts in mood, energy and activity levels.[1] These changes can range from a period of extremely elated, “up” and energized behavior (a manic episode) to a very sad, “down” or hopeless period (a depressive episode). Sometimes a mood state includes both manic and depressive symptoms at the same time (a mixed episode). Moods also may quickly swing from low to high and back again over a few days or hours (rapid cycling). Another possible state that is different from the stable state is called a hypomanic episode, in which the individual feels good and functions well, but only his or her family or friends may recognize abnormal behavioral signs.

Recent studies have estimated there are 5.4 million people in the U.S with bipolar disorder, of whom about one-third were untreated.[2]

Medications for bipolar disorder have two goals: to control the “up” or “down” mood episodes in patients in acute manic, depressive, or mixed episodes, and to prevent or reduce these mood episodes among patients in stable or hypomanic states, thereby improving their functioning (maintenance treatment).[3]

Yet choosing the right bipolar disorder medication for each patient can be challenging. Some medications can help with one treatment goal but not the other, and all of them carry side effects. Additionally, some drugs have been illegally promoted for bipolar disorder, although they were not approved by the Food and Drug Administration (FDA) for this condition.[4],[5]

Drugs Approved for Bipolar Disorder

*Limited Use
**Do Not Use for Seven Years (until Oct. 28, 2017 for lurasidone and Sept. 17, 2022 for cariprazine)
***Do Not Use

Lithium (LITHOBID)

Lithium is a mood-stabilizing medication that has been around for many decades.[6] It remains the best and most well-established medication for bipolar disorder, so it is prescribed for life in many patients.[7] It is approved and shown to be the drug of choice both for controlling symptoms in acute manic episodes and in preventing or decreasing the intensity of future manic episodes.[8],[9] It is also known to reduce suicide risk.[10] However, bipolar patients experiencing mixed episodes or rapid-cycling states may not benefit from lithium.[11] Additionally, there is no strong evidence supporting this drug’s effectiveness in preventing depressive episodes.[12],[13]

Lithium has disadvantages[14]: It may take one to three weeks before it works, it carries a black-box warning (the strongest warning the FDA can require) because it can cause severe toxicity at higher than prescribed doses, it requires regular monitoring for its levels in the blood, and its abrupt cessation causes withdrawal symptoms (such as nausea and vomiting). Lithium has numerous side effects, including heart problems in newborns of mothers who have taken the drug during pregnancy, abnormal functioning of the thyroid and parathyroid glands, kidney damage, and increased blood calcium levels. It also can affect the body’s ability to adjust to heat, causing heat stress (inability of the body to adjust to increased heat).

Divalproex (DEPAKOTE)

Divalproex is an anti-seizure drug that is also approved for treating acute manic episodes of bipolar disorder (the drug’s extended release form [DEPAKOTE ER] is also approved for mixed episodes).[15] It is recommended as a first-line solo medication for acute manic, but not depressive, episodes.[16] There is currently no strong evidence from clinical trials to support divalproex’s use for mania for more than three weeks.[17] Therefore, it is not suited to be a maintenance treatment for bipolar disorder.

Divalproex carries a black-box warning because it can cause potentially fatal liver toxicity and inflammation of the pancreas, as well as major birth defects if used during pregnancy. The FDA recommends against the use of this drug in pregnant women and women of child-bearing age, unless it is essential for treatment. The agency also issued a safety warning in 2008 about increased risks for suicidal thoughts and behaviors in patients taking divalproex or other anti-seizure drug.[18]

Lamotrigine (LAMICTAL)

Lamotrigine, another anti-seizure drug, has been approved as a maintenance treatment of bipolar disorder.[19] Evidence supports its effectiveness on its own or with lithium in reducing the risk of recurrence of bipolar episodes, particularly in patients who tend to experience depressive states. [20] However, it is not approved for the treatment of acute manic or mixed episodes.[21]

It carries a black-box warning for life-threatening rashes, including Stevens-Johnson syndrome (painful blistering and rash of the skin and mucous membranes) and toxic epidermal necrolysis (abnormal skin peeling). The dose of lamotrigine needs to be carefully adjusted over a minimum of six weeks to minimize the risk of these serious skin reactions.[22]

Lamotrigine, like divalproex, is associated with an increased risk for suicidal thoughts and behaviors.[23] The FDA also issued a safety warning in 2010 regarding an increased risk of aseptic meningitis (inflammation of the brain and spinal cord membranes) associated with this drug.[24]

Extended-release carbamazepine (EQUETRO)

Extended-release carbamazepine is a third anti-seizure drug approved for treating acute manic or mixed episodes in adults.[25] It is not usually a first-choice drug, because it is less effective than lithium.[26] However, it sometimes works for bipolar patients with rapid-cycling situations. It may have greater benefit if taken in combination with lithium than if taken alone.

It carries a black-box warning for serious side effects, including failure of the bone marrow to produce new blood cells, and for skin reactions, such as Stevens-Johnson syndrome.[27] Carbamazepine is not recommended for use during pregnancy because it increases the risk of major birth defects.

Atypical antipsychotics

Eight atypical antipsychotics (see table) have been approved for treating acute manic, depressive or mixed episodes, either as solo treatments or in combination with lithium or divalproex. These drugs are the most potent medications that are used in acute mania.[28] For example, some patients respond to quetiapine (SEROQUEL, SEROQUEL ER) after approximately one week of therapy.[29] Although some of these drugs are also approved as a maintenance treatment for bipolar disorder, research supporting their long-term use is limited.[30]

Like all antipsychotics, these medications carry black-box warnings for increased risk of death in elderly patients with dementia-related psychosis.[31] They have been linked to stroke (and other adverse cardiovascular effects), metabolic complications (such as diabetes)[32],[33] and weight gain. They are also associated with various movement disorder side effects, including akathisia (restlessness and the inability to sit still),[34] parkinsonism (rigidity of muscles and masked face [reduced ability to make facial expressions])[35] and tardive dyskinesia (involuntary movements of the face, arms and legs).[36] Other side effects for these drugs include anticholinergic reactions, including increased heart rate, blurred vision, dry mouth and decreased sweating,[37] which are especially problematic in older adults. There is limited evidence about the safety of these medications in pregnancy.[38]

Antidepressants

There is controversy about the use of antidepressants in bipolar disorder, because they can trigger a manic episode or rapid-cycling situations.[39] However, in treatment-resistant patients with depressive episodes, the selective serotonin reuptake inhibitor fluoxetine (PROZAC, SELFEMRA) may be used in combination with olanzapine.[40] The FDA has approved a combination pill containing these two drugs (brand name SYMBYAX) for the short-term treatment of depressive episodes associated with bipolar disorder.

What You Can Do

If you have bipolar disorder, discuss the various medications presented in this article with your doctor and ask him or her to balance the benefits and risks of these medications to help find the ones that suit you best. Never discontinue your medications suddenly without medical supervision. Follow up periodically with your doctor and tell him or her if you experience any mood changes and medication side effects. Seek psychological therapy as well, because medications alone are not enough to manage bipolar disorder. If you think about harming yourself, call the toll-free National Suicide Prevention Lifeline at 800-273-8255 immediately.

References

[1] National Institutes of Health. Bipolar disorder. April 2016. https://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml. Accessed December 16, 2016.

[2] Treatment Advocacy Center. Research weekly: Prevalence of treated and untreated severe mental illness by state. May 17, 2016. http://www.treatmentadvocacycenter.org/fixing-the-system/features-and- news/3076-research-weekly-prevalence-of-treated-and-untreated-severe-mental-illness-by-state. Accessed January 25, 2017.

[3] Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-1682.

[4] Department of Justice. Justice news. Pharmaceutical companies to pay $214.5 million to resolve allegations of off-label promotion of Zonegran. December 15, 2010. https://www.justice.gov/opa/pr/pharmaceutical-companies-pay-2145-million-resolve-allegations-label-promotion- zonegran. Accessed January 3, 2017.

[5] Food and Drug Administration. Office of Criminal Investigations. Novartis Pharmaceuticals Corporation to pay $422.5 million for off-label drug marketing. September 30, 2010. http://www.fda.gov/ICECI/CriminalInvestigations/ucm228104.htm. Accessed January 3, 2017.

[6] Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-1682.

[7] Malhi GS, Outhred T. Therapeutic mechanisms of lithium in bipolar disorder: recent advances and current understanding. CNS Drugs. 2016;30(10):931-949.

[8] ANI Pharmaceuticals, Inc. Label: lithium (LITHOBID). June 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=f7f5b69a-c2a1-4586-a189-1475d41387c0&type=pdf&name=f7f5b69a- c2a1-4586-a189-1475d41387c0. Accessed January 11, 2017.

[9] Oruch R, Elderbi MA, Khattab HA, et al. Lithium: A review of pharmacology, clinical uses, and toxicity. Eur J Pharmacol. 2014;740:464-473.

[10] Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-1682.

[11] Price A, Marzani-Nissen G. Bipolar disorder: a review. Am Fam Physician. 2012;85(5):483- 493.

[12] Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161(2):217-22.

[13] Oruch R, Elderbi MA, Khattab HA, Pryme IF, Lund A. Lithium: A review of pharmacology, clinical uses, and toxicity. Eur J Pharmacol. 2014;740:464-473.

[14] WorstPills.org. Drug profile: Lithium (LITHOBID). Updated July 2016. /monographs/view/75. Accessed January 11, 2017.

[15] AbbVie Inc. Label: divalproex (DEPAKOTE ER). November 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac&type=pdf&name=0dc024ce- efc8-4690-7cb5-639c728fccac. Accessed January 11, 2017.

[16] Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2009;15(1):1-44.

[17] AbbVie Inc. Label: divalproex (DEPAKOTE, DEPAKOTE ER). November 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac&type=pdf&name=0dc024ce- efc8-4690-7cb5-639c728fccac. Accessed January 11, 2017.

[18] Food and Drug Administration. Information for healthcare professionals: Suicidal behavior and ideation and antiepileptics drugs. December, 2008. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm100192.htm. Accessed January 11, 2017.

[19] Alembic Pharmaceuticals Limited. Label: lamotrigine. Updated November 2015. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=ae6522d4-d824-44aa-afe0-70cdcbd845af&type=pdf&name=ae6522d4- d824-44aa-afe0-70cdcbd845af. Accessed December 16, 2016. \

[20] Malhi GS, McAulay C, Das P, Fritz K. Maintaining mood stability in bipolar disorder: A clinical perspective on pharmacotherapy. Evid Based Ment Heal. 2015;18(1):1-6.

[21] Alembic Pharmaceuticals Limited. Label: lamotrigine. Updated November 2015. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae6522d4-d824-44aa-afe0-70cdcbd845af. Accessed January 11, 2017.

[22] Price A, Marzani-Nissen G. Bipolar disorder: A review. Am Fam Physician. 2012;85(5):483- 493.

[23] Food and Drug Administration. Information for healthcare professionals: Suicidal behavior and ideation and antiepileptics drugs. December 2008. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm100192.htm. Accessed January 11, 2017.

[24] Food and Drug Administration. FDA drug safety communication: Aseptic meningitis associated with use of Lamictal (lamotrigine). August 2010. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm221847.htm. Accessed January 11, 2017.

[25] Validus Pharmaceuticals LLC. Label: carbamazepine ER (EQUETRO). October 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=be478f3c-40f6-47cc-8ab9-f420a9372b1c&type=pdf&name=be478f3c- 40f6-47cc-8ab9-f420a9372b1c. Accessed January 11, 2017.

[26] Malhi GS, McAulay C, Das P, Fritz K. Maintaining mood stability in bipolar disorder: A clinical perspective on pharmacotherapy. Evid Based Ment Heal. 2015;18(1):1-6.

[27] Validus Pharmaceuticals LLC. Label: carbamazepine ER (EQUETRO). October 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=be478f3c-40f6-47cc-8ab9-f420a9372b1c&type=pdf&name=be478f3c- 40f6-47cc-8ab9-f420a9372b1c. Accessed January 11, 2017.

[28] Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-1682.

[29] Price A, Marzani-Nissen G. Bipolar disorder: A review. Am Fam Physician. 2012;85(5):483- 493.

[30] Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-1682.

[31] Food and Drug Administration. FDA requests boxed warnings on older class of antipsychotic drugs. June 2008. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116912.htm. Accessed January 12, 2017.

[32] Price A, Marzani-Nissen G. Bipolar disorder: A review. Am Fam Physician. 2012;85(5):483- 493.

[33] Orsolini L, Tomasetti C, Valchera A, et al. An update of safety of clinically used atypical antipsychotics. Expert Opin Drug Saf. 2016;15(10):1329-1347.

[34] Drug-induced acute akathisia (restlessness). Worst Pills, Best Pills News. April 2011. /newsletters/view/737. Accessed January 12, 2017.

[35] Drug-induced parkinsonism. Worst Pills, Best Pills News. October 2010. /newsletters/view/711. Accessed January 12, 2017.

[36] Price A, Marzani-Nissen G. Bipolar disorder: A review. Am Fam Physician. 2012;85(5):483- 493.

[37] Lieberman J III. Managing anticholinergic side effects. Prim Care Companion J Clin Psychiatry. 2004;6(Suppl 2):20-23.

[38] Drugs for bipolar disorder. Med Lett Drugs Ther. 2016;58(1501):103-106.

[39] Drug treatment of bipolar disorder. Harv Ment Health Lett. 2006;22(11):1-4.

[40] Malhi GS, McAulay C, Das P, Fritz K. Maintaining mood stability in bipolar disorder: A clinical perspective on pharmacotherapy. Evid Based Ment Heal. 2015;18(1):1-6.