Bipolar disorders are usually treated with mood stabilizers, atypical antipsychotics, or a combination. Medications are often given for acute symptoms upon initial presentation and then changed or adjusted, if needed, for maintenance therapy. Bipolar disorders can be difficult to treat because all medications have significant potential adverse effects, drug interactions are common, and no medication is universally effective. Selection should be based on authoritative guidelines (1), as well as on medications that were previously effective and well tolerated in a given patient. If the patient was not previously treated with medications for bipolar disorder (or medication history is unknown), choice is based on the patient’s medical history (ie, which mood stabilizer's adverse effect profile is most compatible with the patient's medical history) and the severity of symptoms.
(See also Bipolar Disorders: Treatment.)
General reference
1. Keramatian K, Chithra NK, Yatham LN. The CANMAT and ISBD Guidelines for the Treatment of Bipolar Disorder: Summary and a 2023 Update of Evidence. Focus (Am Psychiatr Publ). 2023;21(4):344-353. doi:10.1176/appi.focus.20230009
Mood Stabilizers
Medications used as mood stabilizers in bipolar disorders include lithium and certain antiseizure medications. Medications used as mood stabilizers in bipolar disorders include lithium and certain antiseizure medications.
Whether lithium or another mood stabilizer is being used, recurrent symptoms are more likely in patients who have mixed episodes, rapid-cycling forms of bipolar disorder (usually defined as ≥ 4 episodes/year), comorbid anxiety, substance use disorder, or a neurologic disorder (1, 2).
Lithium
Lithium attenuates bipolar mood swings but has no effect on normal mood. Patients with a family history of typical bipolar disorders are more likely to respond to Lithium attenuates bipolar mood swings but has no effect on normal mood. Patients with a family history of typical bipolar disorders are more likely to respond tolithium than those without such a family history (2).
Because lithium takes 4 to 10 days to achieve a therapeutic effect, a medication that works more rapidly, such as an antiseizure medication or atypical antipsychotic, is often given to control acute symptoms of excited thought and activity.
Lithium carbonate is typically titrated based on blood levels, tolerance, and response. Higher maintenance levels are more protective against manic (but not depressive) episodes but have more adverse effects. Adolescents, whose glomerular function is excellent, need higher doses; older patients need lower doses.
Lithium can cause sedation and cognitive impairment directly or indirectly (by causing hypothyroidism) and often exacerbates acne and psoriasis. The most common acute, mild adverse effects are fine tremor, fasciculation, nausea, diarrhea, polyuria, polydipsia, and weight gain (partly attributed to an increased urge to drink high-calorie beverages). These effects are usually transient and often respond to decreasing the dose slightly, dividing the dose (eg, 3 times a day), or using slow-release forms. A beta-blocker can control severe tremor; however, some beta-blockers (eg, propranolol) may worsen depression. . The most common acute, mild adverse effects are fine tremor, fasciculation, nausea, diarrhea, polyuria, polydipsia, and weight gain (partly attributed to an increased urge to drink high-calorie beverages). These effects are usually transient and often respond to decreasing the dose slightly, dividing the dose (eg, 3 times a day), or using slow-release forms. A beta-blocker can control severe tremor; however, some beta-blockers (eg, propranolol) may worsen depression.
The minimal effective dose for effective prophylaxis should be used because cumulative dose is a risk factor for renal toxicity.
dosage is established, the entire dose should be given after the evening meal. This once-daily dosing may improve adherence and possibly reduce renal toxicity. A beta-blocker (eg, atenolol 25 to 50 mg orally once a day) can control severe tremor; however, some beta-blockers (eg, propranolol) may worsen depression.dosage is established, the entire dose should be given after the evening meal. This once-daily dosing may improve adherence and possibly reduce renal toxicity. A beta-blocker (eg, atenolol 25 to 50 mg orally once a day) can control severe tremor; however, some beta-blockers (eg, propranolol) may worsen depression.
Acute lithium toxicityAcute lithium toxicity is manifested initially by gross tremor, increased deep tendon reflexes, persistent headache, vomiting, and confusion and may progress to stupor, seizures, and arrhythmias. Toxicity is more likely to occur in the following:
Older patients
Patients with decreased creatinine clearance
Those with sodium loss (eg, due to fever, vomiting, diarrhea, or use of diuretics)
Thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin may contribute to hyperlithemia. Thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin may contribute to hyperlithemia.
Potential long-term adverse effects of lithium include:
Hypothyroidism, particularly when there is a family history of hypothyroidism
Renal damage involving the distal tubule that appears after ≥ 15 years of lithium treatment15 years of lithium treatment
Thyroid-stimulating hormone (TSH) levels should be measured whenever symptoms suggest thyroid dysfunction (including when mania recurs) because hypothyroidism may require treatment and may blunt the effect of mood stabilizers.
Routine monitoring of patients taking lithiumRoutine monitoring of patients taking lithium includes measuring the following serum levels (3–5):
Lithium : Every 6 months and whenever the dose is changed
TSH: Before lithium is started and then every other year or annually thereafter (in patients with a family history of thyroid dysfunction) TSH: Before lithium is started and then every other year or annually thereafter (in patients with a family history of thyroid dysfunction)
Blood urea nitrogen (BUN) and creatinine: Before lithium is started and then 2 or 3 times during the first 6 months of therapy. These tests should then be repeated once or twice a year. nitrogen (BUN) and creatinine: Before lithium is started and then 2 or 3 times during the first 6 months of therapy. These tests should then be repeated once or twice a year.
Calcium and parathyroid hormone: Annually
Antiseizure medications
Antiseizure medications that are effective as mood stabilizers, especially valproate and carbamazepine, are often used for acute mania and for mixed states (mania and depression) in patients with bipolar disorders. The precise mechanism of action for antiseizure medications in bipolar disorder is unknown but may involve gamma-aminobutyric acid mechanisms and ultimately G-protein signaling systems. Their main advantages over lithium include a wider therapeutic window and lack of renal toxicity. Antiseizure medications that are effective as mood stabilizers, especially valproate and carbamazepine, are often used for acute mania and for mixed states (mania and depression) in patients with bipolar disorders. The precise mechanism of action for antiseizure medications in bipolar disorder is unknown but may involve gamma-aminobutyric acid mechanisms and ultimately G-protein signaling systems. Their main advantages over lithium include a wider therapeutic window and lack of renal toxicity.
For valproate, the initial dose and route of administration may vary, but it requires adjustment based on target serum levels. A loading-dose protocol based on weight (20 to 30 mg/kg) may result in earlier symptom improvement. Adverse effects include nausea, headache, sedation, dizziness, and weight gain; rare serious effects include hepatotoxicity and pancreatitis.
For carbamazepineFor carbamazepine a loading dose should not be given; dose should be increased gradually to achieve a target serum level. Adverse effects include nausea, dizziness, sedation, and unsteadiness. Very severe effects include aplastic anemia and agranulocytosis.
For lamotrigineFor lamotrigine, the initial dose and titration vary depending on possible interactions with concomitant medications. Dosage is lower for patients taking valproate and higher for patients taking carbamazepine. Lamotrigine can cause rash and, rarely, the life-threatening , the initial dose and titration vary depending on possible interactions with concomitant medications. Dosage is lower for patients taking valproate and higher for patients taking carbamazepine. Lamotrigine can cause rash and, rarely, the life-threateningStevens-Johnson syndrome, particularly if the dosage is increased more rapidly than recommended. While taking lamotrigine, patients should be encouraged to report any new rash, hives, fever, swollen glands, sores in the mouth and on the eyes, and swelling of the lips or tongue. Lamotrigine is effective for mood-cycling and for depression., particularly if the dosage is increased more rapidly than recommended. While taking lamotrigine, patients should be encouraged to report any new rash, hives, fever, swollen glands, sores in the mouth and on the eyes, and swelling of the lips or tongue. Lamotrigine is effective for mood-cycling and for depression.
Mood stabilizers references
1. Woo YS, Yoon BH, Song JH, et al. Clinical correlates associated with the long-term response of bipolar disorder patients to lithium, valproate or lamotrigine: A retrospective study. . Clinical correlates associated with the long-term response of bipolar disorder patients to lithium, valproate or lamotrigine: A retrospective study.PLoS One. 2020;15(1):e0227217. Published 2020 Jan 10. doi:10.1371/journal.pone.0227217
2. Hui TP, Kandola A, Shen L, et al. A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder. . A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder.Acta Psychiatr Scand. 2019;140(2):94-115. doi:10.1111/acps.13062
3. Pawar AS, Kattah AG. Lithium-induced nephropathy. . Lithium-induced nephropathy.N Engl J Med. 378 (11):1042, 2018. doi: 10.1056/NEJMicm1709438
4. McKnight RF, Adida M, Stockton S, et al. Lithium toxicity profile: A systematic review and meta-analysis. . Lithium toxicity profile: A systematic review and meta-analysis.Lancet. 379 (9817):721-728, 2012. doi: 10.1016/S0140-6736(11)61516-X
5. Meyer JM, Stahl SM. The Lithium Handbook. In: . The Lithium Handbook. In:The Lithium Handbook: Stahl’s Handbooks. Stahl’s Essential Psychopharmacology Handbooks.The Lithium Handbook: Stahl’s Handbooks. Stahl’s Essential Psychopharmacology Handbooks. Cambridge University Press; 2023:i-i.
Antipsychotics
Mania, including acute manic psychosis, may be managed with second-generation antipsychotics:
Aripiprazole Aripiprazole
AsenapineAsenapine
Cariprazine Cariprazine
LumateperoneLumateperone
Lurasidone Lurasidone
Olanzapine Olanzapine
PaliperidonePaliperidone
Quetiapine Quetiapine
Risperidone Risperidone
Ziprasidone Ziprasidone
Some of these medications are used as monotherapy and some as adjunctive or combination therapy, both during and after the acute phase of treatment (1). In addition, certain atypical antipsychotics (eg, quetiapine) are used for bipolar depression.). In addition, certain atypical antipsychotics (eg, quetiapine) are used for bipolar depression.
Although any of these medications may have extrapyramidal adverse effects and cause akathisia, risk is lower with more sedating medications such as quetiapine and olanzapine. Less immediate adverse effects include substantial weight gain and development of the Although any of these medications may have extrapyramidal adverse effects and cause akathisia, risk is lower with more sedating medications such as quetiapine and olanzapine. Less immediate adverse effects include substantial weight gain and development of themetabolic syndrome (including weight gain, excess abdominal fat, insulin resistance, and dyslipidemia); risk may be lower with the least sedating second-generation antipsychotics, lurasidone, ziprasidone, and aripiprazole. resistance, and dyslipidemia); risk may be lower with the least sedating second-generation antipsychotics, lurasidone, ziprasidone, and aripiprazole.
For extremely hyperactive psychotic patients with poor food and fluid intake, an antipsychotic, including haloperidol, given IM plus supportive care in addition to lithium or an antiseizure medication may be appropriate.For extremely hyperactive psychotic patients with poor food and fluid intake, an antipsychotic, including haloperidol, given IM plus supportive care in addition to lithium or an antiseizure medication may be appropriate.
Antipsychotics reference
1. Keramatian K, Chithra NK, Yatham LN. The CANMAT and ISBD Guidelines for the Treatment of Bipolar Disorder: Summary and a 2023 Update of Evidence. Focus (Am Psychiatr Publ). 2023;21(4):344-353. doi:10.1176/appi.focus.20230009
Antidepressants
Specific antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs]) are sometimes given to patients with bipolar disorders who have severe depression, but their effectiveness is controversial; they are generally not recommended as monotherapy for depressive episodes, though there is evidence that an SSRI (specifically sertraline) may be safe and effective as monotherapy for bipolar II depression ([SSRIs]) are sometimes given to patients with bipolar disorders who have severe depression, but their effectiveness is controversial; they are generally not recommended as monotherapy for depressive episodes, though there is evidence that an SSRI (specifically sertraline) may be safe and effective as monotherapy for bipolar II depression (1, 2). A series of small studies have indicated that tranylcypromine may be more effective than other antidepressants in the treatment of bipolar depression (). A series of small studies have indicated that tranylcypromine may be more effective than other antidepressants in the treatment of bipolar depression (3).
Antidepressants references
1. Gitlin MJ. Antidepressants in bipolar depression: An enduring controversy. Int J Bipolar Disord. 6:25, 2018. doi: 10.1186/s40345-018-0133-9
2. Keramatian K, Chithra NK, Yatham LN. The CANMAT and ISBD Guidelines for the Treatment of Bipolar Disorder: Summary and a 2023 Update of Evidence. Focus (Am Psychiatr Publ). 2023;21(4):344-353. doi:10.1176/appi.focus.20230009
3. Heijnen WT, De Fruit J, Wiersma AI, et al. Efficacy of tranylcypromine in bipolar depression: A systematic review. . Efficacy of tranylcypromine in bipolar depression: A systematic review.J Clin Psychopharmacol. 35: 700-705, 2015. doi: 10.1097/JCP.0000000000000409
Precautions During Pregnancy
Patients with bipolar disorders who are planning to become pregnant or are pregnant should be counseled about the risks of congenital malformations caused by antiseizure medications. Treatment decisions are complicated by the fact that with unplanned pregnancy, teratogenic effects may already have taken place by the time patients and clinicians consider medication safety. In all cases, discussing the risks and benefits of treatment with patients is important, and medications should be changed or adjusted as needed to achieve the highest level of safety for the fetus while also effectively managing the pregnant patient's bipolar disorder.
Review of treatment of bipolar disorder in pregnancy typically requires a consultation with a maternal fetal medicine specialist and/or a perinatal psychiatrist.
Among mood stabilizers, valproate is the most likely to be teratogenic and should be avoided in all pregnant patients (1, 2). Carbamazepine is also typically avoided or combined with high-dose folate supplementation. ). Carbamazepine is also typically avoided or combined with high-dose folate supplementation.
Valproateis associated with a 1 to 4% risk of neural tube defects (3, 4). It is also associated with craniofacial, limb, and cardiovascular anomalies as well as adverse cognitive outcomes (eg, low IQ scores) and autism spectrum disorders. Its use during pregnancy to treat bipolar disorder is banned in some countries.
CarbamazepineCarbamazepine increases the risk of neural tube defects. Patients with bipolar disorder taking this medication are usually transitioned to another medication before pregnancy or as soon as pregnancy is diagnosed. However, in certain circumstances carbamazepine is continued combined with folate supplementation at 4 mg daily (increases the risk of neural tube defects. Patients with bipolar disorder taking this medication are usually transitioned to another medication before pregnancy or as soon as pregnancy is diagnosed. However, in certain circumstances carbamazepine is continued combined with folate supplementation at 4 mg daily (3).
LamotrigineLamotrigine is associated with a lower risk of teratogenicity compared to carbamazepine and valproate (eg, in one meta-analysis, the risk was not significantly different than in the general population) (is associated with a lower risk of teratogenicity compared to carbamazepine and valproate (eg, in one meta-analysis, the risk was not significantly different than in the general population) (2).
LithiumLithium use during pregnancy has been associated with an increased risk of cardiovascular malformations (particularly Ebstein anomaly). However, the absolute risk of this particular malformation is quite low (5, 6), and lithium is sometimes continued at the lowest possible dose during pregnancy. Patients taking lithium during the first trimester of pregnancy should have a detailed ultrasound examination during the second trimester. ), and lithium is sometimes continued at the lowest possible dose during pregnancy. Patients taking lithium during the first trimester of pregnancy should have a detailed ultrasound examination during the second trimester.
Some evidence suggests that atypical (second-generation) antipsychotics are safe in pregnancy, though quetiapine, aripiprazole, olanzapine, and risperidone may carry a modest increase in risk (are safe in pregnancy, though quetiapine, aripiprazole, olanzapine, and risperidone may carry a modest increase in risk (7, 8).
The risk of teratogenicity also appears to be low for selective serotonin reuptake inhibitors (SSRIs) (9, 10). Some studies suggest there may be a small absolute increased risk of congenital heart defects with paroxetine (). Some studies suggest there may be a small absolute increased risk of congenital heart defects with paroxetine (11), but the data are inconsistent. (See also Antidepressants During Pregnancy.)
Precautions during pregnancy references
1. Carvalho AF, Firth J, Vieta E. Bipolar Disorder. N Engl J Med. 2020;383(1):58-66. doi:10.1056/NEJMra1906193
2. Battino D, Tomson T, Bonizzoni E, et al. Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy. JAMA Neurol. 2024;81(5):481-489. doi:10.1001/jamaneurol.2024.0258
3. Treatment and Management of Mental Health Conditions During Pregnancy and Postpartum: ACOG Clinical Practice Guideline No. 5. Obstet Gynecol. 2023;141(6):1262-1288. doi:10.1097/AOG.00000000000052023.
4. Anmella G, Pacchiarotti I, Cubała WJ, et al. Expert advice on the management of valproate in women with bipolar disorder at childbearing age. Eur Neuropsychopharmacol. 2019;29(11):1199-1212. doi:10.1016/j.euroneuro.2019.09.007
5. Fornaro M, Maritan E, Ferranti R, et al. Lithium exposure during pregnancy and the postpartum period: A systematic review and meta-analysis of safety and efficacy outcomes. . Lithium exposure during pregnancy and the postpartum period: A systematic review and meta-analysis of safety and efficacy outcomes.Am J Psychiatry. 177(1):76-92,2020. doi: 10.1176/appi.ajp.2019.19030228
6. Wang E, Liu Y, Wang Y, et al. Comparative Safety of Antipsychotic Medications and Mood Stabilizers During Pregnancy: A Systematic Review and Network Meta-analysis of Congenital Malformations and Prenatal Outcomes. CNS Drugs. 2025;39(1):1-22. doi:10.1007/s40263-024-01131-x
7. Cohen LS, Viguera AC, McInerney KA, et al. Reproductive Safety of Second-Generation Antipsychotics: Current Data From the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics. Am J Psychiatry. 2016;173(3):263-270. doi:10.1176/appi.ajp.2015.15040506
8. Huybrechts KF, Straub L, Karlsson P, et al. Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US. JAMA Psychiatry. 2023;80(2):156-166. doi:10.1001/jamapsychiatry.2022.4109
9. Lebin LG, Novick AM. Selective Serotonin Reuptake Inhibitors (SSRIs) in Pregnancy: An Updated Review on Risks to Mother, Fetus, and Child. Curr Psychiatry Rep. 2022;24(11):687-695. doi:10.1007/s11920-022-01372-x
10. Gao SY, Wu QJ, Sun C, et al. Selective serotonin reuptake inhibitor use during early pregnancy and congenital malformations: a systematic review and meta-analysis of cohort studies of more than 9 million births. BMC Med. 2018;16(1):205. Published 2018 Nov 12. doi:10.1186/s12916-018-1193-5
11. Bérard A, Iessa N, Chaabane S, et al. The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: A systematic review and meta-analysis. . The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: A systematic review and meta-analysis.Br J Clin Pharmacol. 81(4):589-604, 2016. doi: 10.1111/bcp.12849
Drugs Mentioned In This Article
