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Are There Weight Gain and Metabolic Differences in Agents Used for Bipolar Depression?

Manish Jha, MD

Assistant Professor
Center for Depression Research and Clinical Care
Department of Psychiatry
UT Southwestern Medical Center
Dallas, Texas

Manish Jha, MD, has disclosed that he has received consulting fees from Eleusis Therapeutics and Guidepoint Global and funds for research support from Acadia and Janssen.

View ClinicalThoughts from this Author

Released: November 15, 2021

Differences in FDA-Approved Medications for Bipolar Depression
Significant weight gain and metabolic differences exist among FDA-approved medications for bipolar depression (Table 1).

Table 1. FDA-Approved Medications for Bipolar Depression


Longitudinal Course of Bipolar Disorder
Because duration of treatment may impact weight gain and metabolic dysregulation with these medications, any conversation about treatment of bipolar disorder should start with its naturalistic course. Judd and colleagues1,2 have shown that patients with bipolar disorder remain symptomatic for more than one half of their follow-up period, and depressive symptoms are more frequent than manic/hypomanic symptoms or cycling/mixed symptoms (Table 2). Therefore, depressive symptoms often are the active focus of treatment for patients with bipolar disorder and warrant chronic long-term treatment.

Table 2. Natural History of Symptomatic Status of Patients With Bipolar Disorder


Healthcare practitioners often rely on prescribing labels and have used them to evaluate the weight gain and metabolic differences among cariprazine,3 lurasidone,4 olanzapine and fluoxetine combination (OFC),5 quetiapine,6 and quetiapine extended release (XR).7

Differences in Weight Gain
In acute-phase studies of adults, clinically significant weight gain (ie, ≥7% increase) over baseline was highest with OFC (22%), followed by quetiapine, including the XR formulation (8%); cariprazine (3%); and lurasidone (2.4% with monotherapy and 3% as adjunctive treatment). In pediatric studies, clinically significant weight gain was much higher with OFC (52%) than either quetiapine XR (15%) or lurasidone (4%). Longer-term duration of treatment may result in further weight gain. In studies of OFC that lasted ≥48 weeks, 66% of patients gained ≥7% of their weight, which was 3 times higher than the rate observed in acute-phase studies.

Differences in Impaired Glycemic Control
Rates of impaired glycemic control (ie, shift from normal or borderline blood glucose to high blood glucose) were 8-10 times higher with OFC compared with placebo in adult studies of up to 12 weeks. In contrast, rates of impaired glycemic control with cariprazine, lurasidone, and quetiapine were similar to placebo in short-term adult studies of up to 12 weeks. Rates of treatment-emergent increases in blood glucose levels were lower in pediatric studies compared with adult studies. Yet, treatment with OFC was associated with 3-4 times higher rates of impaired glycemic control compared with placebo. Use of quetiapine (including the XR formulation) in the long term was associated with significantly higher rates of impaired glycemic control compared with placebo. Therefore, healthcare professionals should consider obtaining A1C levels from their patients prior to initiating either OFC or quetiapine to estimate blood glucose levels over 2-3 months.

Differences in Dyslipidemia
In short-term studies of OFC, nonfasting triglyceride levels increased by ≥50 mg/dL in 67.8% of patients, and nonfasting total cholesterol levels increased by ≥40 mg/dL in 35% of patients. In longer-term studies (up to 47 weeks), fasting total cholesterol levels increased from normal to high levels in 19.3% of patients, and fasting triglycerides increased from normal to high levels in 72.5% of patients. Acute-phase studies of quetiapine found a clinically significant increase in triglycerides and total cholesterol in 14% and 9% of patients. Rates of clinically significant increases in triglycerides and total cholesterol with acute-phase treatment with quetiapine XR, lurasidone, and cariprazine were similar to placebo in adult studies. Magnitude of dyslipidemia with OFC in pediatric patients was significantly greater than in adult patients. In an 8-week study, fasting triglyceride levels increased by ≥50 mg/dL in 70.3% of pediatric patients, and fasting total cholesterol levels increased by ≥40 mg/dL in 52.5% of pediatric patients. Changes in total cholesterol and triglyceride levels with lurasidone were similar to placebo in a 6-week pediatric study.

Future Considerations
Given the paucity of evidence-based treatments for bipolar depression, there is an urgent need to develop new treatments. In a recent phase III study, D’Souza and colleagues8 reported greater reduction in depressive symptoms with lumateperone compared with placebo in adults with bipolar depression. A recent phase III study of lumateperone failed to meet the primary endpoint, likely related to high placebo response,9 and another is currently recruiting patients (NCT04285515). Weight gain and metabolic changes with lumateperone were similar to placebo in previous short-term studies,10 and it may emerge as a treatment for bipolar depression if future studies support its efficacy. Although the addition of samidorphan and metformin has been shown to attenuate weight gain associated with olanzapine,11,12 the effect of these medications on weight gain and metabolic dysregulation with OFC has not been evaluated yet. For patients with antipsychotic-related weight gain and diabetes, glucagon-like peptide-1 receptor agonists may be considered in consultation with endocrinologist given emerging evidence for significant weight loss and A1C reduction with their use.13

Patients with bipolar disorder experience frequent and disabling depressive symptoms that may warrant chronic treatment. Among the currently approved medications for bipolar depression, OFC should be avoided due to high rates of weight gain and metabolic dysregulation. Quetiapine, including the XR formulation, has numerically higher rates of weight gain compared with both cariprazine and lurasidone and is associated with impaired glycemic control with long-term treatment. Rates of weight gain and metabolic changes with cariprazine and lurasidone were comparable with placebo. Therefore, cariprazine and lurasidone may be considered as first-line options for treatment of bipolar depression when avoiding clinically significant weight gain and metabolic dysregulation.


  1. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60:261-269.
  2. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530-537.
  3. Cariprazine [prescribing information]. Forest Laboratories Ireland Limited, Dublin, IE: Allergan USA; 2019.
  4. Lurasidone [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals; 2017.
  5. Olanzapine and fluoxetine [prescribing information]. Indianapolis, IN: Lilly USA; 2020.
  6. Quetiapine [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2019.
  7. Quetiapine extended release [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2020.
  8. D'Souza I, Durgam S, Satlin A, et al. Lumateperone (ITI-007) in the treatment of bipolar depression: results from a randomized clinical trial. CNS Spectr. 2021;26:150.
  9. Intra-Cellular Therapies. Intra-Cellular Therapies announces positive top-line results from a phase 3 trial of lumateperone in patients with bipolar depression. ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-positive-top-line-results-0. Accessed November 2, 2021.
  10. Lumateperone [prescribing information]. New York, NY: Intra-Cellular Therapies; 2019.
  11. Correll CU, Newcomer JW, Silverman B, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry. 2020;177:1168-1178.
  12. Praharaj SK, Jana AK, Goyal N, Sinha VK. Metformin for olanzapine‐induced weight gain: a systematic review and meta‐analysis. Br J Clin Pharmacol. 2011;71:377-382.
  13. Siskind D, Hahn M, Correll CU, et al. Glucagon-like peptide-1 receptor agonists for antipsychotic-associated cardio-metabolic risk factors: a systematic review and individual participant data meta-analysis. Diabetes Obes Metab. 2019;21:293-302.

Your Thoughts?
Tell us about your thought process when you see a patient with bipolar depression. What techniques have you used to differentiate between agent treatment choices in relation to weight gain and metabolic differences? Please share your experiences and thoughts by posting a comment.

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