Self-Reported History of Manic/Hypomanic Switch Associated With Antidepressant Use: Data From the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study investigated treatment-emergent risk factors associated with manic and hypomanic episodes in patients with bipolar disorder. The results of this study provide insights into the prevalence of manic/hypomanic switch in patients undergoing antidepressant therapy and may help guide decisions on appropriate management.

Janelle Hoaglund, MSN, PMHNP-BC

“Bipolar patients can often be misdiagnosed with major depressive disorder, given the overlapping depressive symptoms in the disease course, and may be prescribed antidepressant monotherapy. The STEP-BD study reminds nurse practitioners to be mindful when using antidepressants to treat the depressive episodes of bipolar disorder, and the need for careful, appropriate, and informed prescribing.”

NP Psych Navigator contributors are paid consultants of AbbVie Inc.

Bipolar disorder, characterized by alternating manic and depressive episodes, is a lifelong mental health condition.1 In managing bipolar depression, antidepressant monotherapy is often prescribed despite its potential increased risk of precipitating a manic switch, also known as treatment-emergent affective switch (TEAS).2 The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study was a landmark study that identified risk factors associated with antidepressant-triggered manic or hypomanic episodes in bipolar disorder.3 We now have further evidence that the use of antidepressant monotherapy in bipolar depression comes with potential risks, including TEAS.2 These study findings can aid nurse practitioners in recognizing risk factors and developing a patient-specific plan to help appropriately manage this condition.

Why was the research needed?

The use of antidepressants in treating bipolar depression is a subject of controversy due to concerns about their safety and effectiveness in bipolar disorder.3 The use of these drugs can lead to the emergence of TEAS, which has been recognized to occur in 15% to 20% of patients.4 Previous studies have suggested several potential triggers for these episodes, including a history of antidepressant-induced mania, bipolar I disorder (BP-1), substance abuse,4,5 and a younger age or earlier onset of illness.3 Some studies have also noted that specific antidepressants may carry a higher risk of treatment-emergent mania.3 Although a meta-analysis conducted by Gijsman et al in 2004 did not find a higher incidence of switching to mania associated with antidepressant use,6 this study included trials with uneven sample sizes and noncontrolled study designs.3 The STEP-BD trial sought to fill gaps in the knowledge by conducting a large-scale investigation, inclusive of the real-world patient experience, to characterize the risk factors for TEAS in patients with bipolar disorder.3

What did the researchers do?

STEP-BD was a large, multi-site investigation combining prospective naturalistic research with randomized controlled trials. The retrospective cohort study examined the first 500 participants enrolled and included patients of all bipolar subtypes.3 Diagnoses were established through screening interviews led by certified clinical investigators, utilizing diagnostic instruments such as the Mini-International Neuropsychiatric Interview (MINI) and the standardized Affective Disorder Evaluation (ADE). The ADE collected information on various characteristics such as illness onset, previous episodes, treatment history, family history, childhood psychopathology, comorbidities, and substance use. Treatment history was recorded using a yes/no format and covered exposure to various standard treatment options for bipolar disorders. Histories of manic/hypomanic switches were obtained through direct subject reports during the baseline interview, which were recorded as yes/no responses for each treatment.3

What were the key results of the study?

Study demographics at baseline showed that 62.0% of patients were female and 91.0% of patients had a family history of bipolar illness. With regards to diagnosis, 71.6%, 25.1%, and 3.3% of patients had BP-1, bipolar II disorder (BP-2), and other bipolar clinical features, respectively. These baseline characteristics were similar across comparison groups.3

The STEP-BD study revealed that 44.4% of patients who had at least 1 antidepressant trial reported experiencing at least 1 manic switch.3 The study identified potential risk factors, including a younger age, a history of lifetime rapid cycling, and exposure to multiple antidepressant medications. Among patients with a history of manic switch, 36% encountered a switch with 2 or more antidepressant medications, and 15% reported a switch with 3 or more antidepressants.3 Additionally, the study indicated that patients might be more prone to affective switch with tricyclic antidepressants (TCAs), most selective serotonin reuptake inhibitors (SSRIs), or a norepinephrine and dopamine reuptake inhibitor (NDRI). Two factors were identified as predictors of antidepressant-associated switch into manic/hypomanic episodes in the stepwise logistic regression model; these included shorter duration of illness (odds ratio [OR] = 1.02; 95% confidence interval [CI] = 1.01 to 1.04) and a history of multiple antidepressant trials (OR = 1.73, 95% CI = 1.38 to 2.16).3

Limitations of the STEP-BD study

The STEP-BD study, which relied on self-reported data from patients, may not accurately reflect the actual occurrence of manic/hypomanic switch events due to potential recall bias.3 Additionally, its retrospective observational nature raises concerns about the accuracy of the historical count of antidepressant trials. The noncontrolled and nonrandomized design of the study further limits the ability to establish a causal relationship between antidepressant use and TEAS.3

Why are these results important?

The STEP-BD study provides critical insights for nurse practitioners regarding the use of antidepressants in patients with bipolar disorder. These findings are helpful in making informed decisions, particularly by highlighting factors that increase the risk of a manic/hypomanic switch, such as a shorter duration of illness and a history of multiple antidepressant trials. This information may assist providers in identifying patients who may be at higher risk of TEAS with antidepressant use.3

Additional evidence about TEAS

Building on the STEP-BD study, the 2015 study by Viktorin et al observed an increase in the risk of mania during the acute period with antidepressant monotherapy (hazard ratio [HR] = 2.83; 95% CI = 1.12 to 7.19; p = 0.028).7 The same study presented data suggesting that the addition of a mood stabilizer to an antidepressant regimen does not increase the risk of mania. Further analysis showed that, for patients receiving a mood stabilizer concurrently, the risk of mania did not change in the acute period following the initiation of antidepressant treatment (HR = 0.79; 95% CI = 0.54 to 1.15) and appeared to decrease over a longer duration (HR = 0.63; 95% CI = 0.42 to 0.93; p = 0.020). Therefore, the study suggested that antidepressant monotherapy is associated with an increased risk of a switch to mania in the absence of a concurrent mood stabilizer.7 A 2021 meta-analysis by McGirr et al found that while the short-term use of an antidepressant combined with a mood stabilizer or a second-generation antipsychotic did not increase the risk of TEAS, long-term use was associated with a higher risk of TEAS.1 The authors confirmed the International Society of Bipolar Disorders (ISBD) expert consensus position on discouraging antidepressant monotherapy use due to the increased risk of TEAS.1

What’s next?

The results of the STEP-BD study and the subsequent studies reviewed contribute to the existing body of knowledge on the use of antidepressants in bipolar disorder, including on the increased risk of TEAS with antidepressant monotherapy, and can inform future research in this area. The findings may prompt further investigation into the development of more targeted and personalized management approaches for bipolar disorder. Due to the limitations of the STEP-BD study design, it will be important to conduct prospective trials to draw additional conclusions.


  1. McGirr A, Vöhringer PA, Nassir Ghaemi S, et al. Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in acute bipolar depression: randomised systematic review and meta-analysis of a placebo-controlled trials. Focus. 2021;19(1):129-137. doi:10.1176/appi.focus.19102
  2. Mousavi Z, Johnson S, Li D. Does recent mania affect response to antidepressants in bipolar disorder? A re-analysis of STEP-BD data. J Affect Disord. 2018;236:136-139. doi:10.1016/j.jad.2018.04.097
  3. Truman CJ, Goldberg JF, Ghaemi SN, et al. Self-reported history of manic/hypomanic switch associated with antidepressant use: data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). J Clin Psychiatry. 2007;68(10):1472-1479. doi:10.4088/jcp.v68n1002
  4. Goldberg JF, Whiteside JE. The association between substance abuse and antidepressant-induced mania in bipolar disorder: a preliminary study. J Clin Psychiatry. 2002;63(9):791-795. doi:10.4088/jcp.v63n0907
  5. Altshuler LL, Suppes T, Black DO, et al. Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second-generation antidepressants. Am J Psychiatry. 2006;163(2):313-315. doi:10.1176/appi.ajp.163.2.313
  6. Gijsman HJ, Geddes JR, Rendell JM, et al. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry. 2004;161(9):1537-1547. doi:10.1176/appi.ajp.161.9.1537
  7. Viktorin A, Lichtenstein P, Thase ME, et al. The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am J Psychiatry. 2014;171(10):1067-1073. doi:10.1176/appi.ajp.2014.13111501

This resource is intended for educational purposes only and is intended for US healthcare professionals. Healthcare professionals should use independent medical judgment. All decisions regarding patient care must be handled by a healthcare professional and be made based on the unique needs of each patient.   

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