Objective To compare the risk of negative mental and physical health outcomes in people with bipolar disorder taking commonly prescribed psychotropic medications Study Design Design Element Description Design Observational: cohort study Population 1.3 million people with bipolar disorder (any type) Interventions/ Comparators Individual or combination treatments for bipolar disorder (analyses included 67–102 regimens), including mood-stabilizing anticonvulsants, first- and second-generation antipsychotics, and 5 classes of antidepressants Lithium alone (comparator for primary outcomes) No medication regimen (comparator for secondary outcomes) Outcomes Primary: psychiatric hospitalization, self-harm Secondary: kidney disorders, diabetes mellitus Timeframe Up to 13-year follow-up for primary outcomes (2003–2016) In these retrospective observational cohort studies, researchers used administrative claims data from 2003 to 2016 for 1.3 million people with bipolar disorder. For each outcome, researchers compared time periods when patients with bipolar disorder received one or multiple medications against periods when patients received lithium alone or against periods with no medications. They examined the risk of Psychiatric hospitalizations among 852,063 patients, comparing time periods on different medications and medication combinations versus lithium alone Self-harm among 529,359 patients, comparing time periods on different medications and medication combinations versus lithium alone Kidney disorders among 591,052 patients, comparing time periods on different medications and medication combinations versus medication-free periods Type 2 diabetes among 565,253 patients, comparing time periods on different medications and medication combinations versus medication-free periods Researchers did not study people with other serious mental health conditions or, for secondary outcomes, people who had kidney disease or diabetes prior to starting medication. Researchers examined outcomes for up to 13 years after treatment initiation. An advisory council of people with bipolar disorder, patient advocates, family members, and physicians was part of the study team. To identify outcomes of interest and interpret the findings, researchers conducted focus groups with people with bipolar disorder and their family members. Results For each outcome, use of the following treatments had the lowest and highest risk estimates relative to their comparators. These differences were statistically significant and clinically meaningful. Psychiatric hospitalization. Compared with use of lithium alone, lamotrigine and bupropion—either alone or with a mood stabilizing anticonvulsant (MSA)—had a lower risk of hospitalization. MAOI antidepressants and antipsychotics had a higher risk. Taking three or more medications generally had a higher risk of hospitalization. Self-harm. Compared with use of lithium alone, MSAs, second-generation antipsychotics, bupropion, and SSRI and SNRI antidepressants, plus a combination of SSRIs and bupropion, had a lower risk of self-harm, while first-generation antipsychotics as well as combinations of second-generation antipsychotics and other medications had a higher risk. Kidney disorders. Compared with medication-free periods, use of MAOIs and medication combinations that included lithium, MSAs, or antipsychotics had a higher risk of kidney disorders. Diabetes. Compared with medication-free periods, use of lithium, bupropion, MSAs, and SSRI antidepressants had a lower risk of diabetes. Some antipsychotics and many medication combinations had a higher risk. Limitations Patients were not randomly assigned to medications; unmeasured participant characteristics, such as mental illness severity or medical history, may have affected the findings. Researchers did not control for medication dosage, administration route, or adherence to prescribed regimen. Conclusions and Relevance Some medications and medication combinations for bipolar disorder may have fewer negative side effects than seen with lithium or medication-free periods. Taking multiple medications for bipolar disorder may bring additional risks for physical health compared with taking only one medication. Future Research Needs Future research could randomly assign participants to medications and combinations and track medication adherence.