Antidepressant-Induced Mania: Ongoing Debate and Concerns
Ann Millermental health

Bipolar disorder (BD) is a complex and often debilitating mental health condition characterized by extreme mood fluctuations, including episodes of mania or hypomania that oscillate or occur alongside depressive states (American Psychiatric Association, 2013; GBD, 2019). These mood episodes can significantly disrupt daily functioning and quality of life, making effective management crucial for individuals affected by this disorder.

Research indicates that depressive symptoms are often more prevalent in individuals with BD, presenting a greater overall burden compared to episodes of elevated mood (Judd et al., 2002; Judd et al., 2003; Miller et al., 2014). Despite the challenges of managing these depressive episodes, the use of antidepressants in treating bipolar depression remains a contentious topic, as their safety and efficacy in this context are still under scrutiny (McGirr et al., 2016; Pacchiarotti et al., 2013; Sachs et al., 2007).

In a blog post by Prof Joseph Hayes featured on Mental Elf, insights into the National Institute for Health and Care Excellence (NICE) 2014 guidelines for BD (NICE, 2014) suggest that fluoxetine may be a more suitable option compared to other antidepressants for treating bipolar depression. Additionally, recommendations from the British Association for Psychopharmacology in 2016 emphasize that antidepressants may yield positive outcomes only when combined with mood stabilizers (Goodwin et al., 2016), highlighting the importance of a multimodal treatment approach.

Evidence from various studies indicates that the potential risk of inducing a manic episode may be higher with tricyclic antidepressants (TCA) than with selective serotonin reuptake inhibitors (SSRIs) (Goodwin et al., 2016; Tondo et al., 2010). Although randomized controlled trials (RCTs) have shown conflicting results, some studies suggest that prolonged treatment with antidepressants may exacerbate manic or hypomanic symptoms in individuals with BD (Ghaemi et al., 2021; McGirr et al., 2016; Yatham et al., 2023).

A contemporary study by Rohde et al. (2024) aimed to provide clarity regarding the risks associated with antidepressant-induced mania in patients suffering from bipolar depression through a method known as target trial emulation.

An image of a hand holding some yellow pills.

There is no clear consensus on the use of antidepressants for bipolar depression, but some evidence suggests they may worsen manic symptoms.

Understanding the Research Methodology Behind Target Trial Emulation

The study conducted by Rohde et al. (2024) employed a method known as a ‘target trial emulation’ model (Matthews et al., 2022), which allowed researchers to utilize comprehensive data from Danish national registers while adhering to the core principles of evidence-based medicine found in randomized controlled trials (RCTs).

In a target trial emulation, researchers compile and manipulate existing observational data to uphold the principles that govern traditional RCTs. Participants are meticulously identified and screened according to strict criteria, and the data is stratified to serve as a proxy for randomization. For this study, the authors assessed occurrences of mania by analyzing psychiatric admissions with a primary diagnosis of either a manic or hypomanic episode.

Key Findings and Statistical Outcomes from the Study

The final cohort for this study comprised 979 patients diagnosed with bipolar depression, of whom 36.6% (n = 358) received treatment involving antidepressants. Notably, the demographic characteristics, including age and sex, were comparable between those who were treated with antidepressants and those who were not.

Interestingly, among the patients receiving antidepressants, only 62.6% were treated in conjunction with mood stabilizers. Within this antidepressant group, approximately 50.5% (n=181) were prescribed an SSRI, 14.3% (n=51) were given a TCA, and 11.5% (n=41) received serotonin and norepinephrine reuptake inhibitors (SNRIs). The remaining 85 patients were treated with other types of antidepressants.

Rohde et al. (2024) assert that based on a hazard ratio effect size of 1.77 stemming from a previous meta-analysis (McGirr et al., 2016), their study achieved a statistical power of 90%.

  • When analyzing fully adjusted models that included the entire sample, no statistically significant associations were found between antidepressant treatment and the occurrence of mania or hypomania, with a hazard rate ratio of 1.08 (95% CI=0.72 to 1.61), indicating no association.
  • Furthermore, antidepressant treatment did not show significant association with the risk of mania or hypomania:
    • Among patients who received mood stabilizers (hazard rate ratio=1.16, 95% CI=0.63 to 2.13)
    • Or among individuals who did not receive a mood stabilizer (hazard rate ratio=1.16, 95% CI=0.65 to 2.07).
  • Secondary analyses revealed that the occurrence of bipolar depression relapse was not linked to the use of antidepressants (hazard ratio=0.91, 95% CI=0.65 to 1.27).
Rohde et al’s (2024) findings indicated that treatment with an antidepressant was not significantly associated with the risk of mania in people with bipolar depression.

These findings indicated that treatment with an antidepressant was not significantly associated with the risk of mania.

Insights and Implications from the Research Findings

The study executed by Rohde et al. represents a target trial emulation that utilized observational data from Danish health registers to investigate the potential risk of mania in patients with bipolar depression following the use of antidepressants over a one-year period.

The authors concluded that their findings suggest the risk of developing antidepressant-induced mania is negligible, while also emphasizing the necessity for ongoing research in this area. However, other studies indicate that extended treatment with antidepressants may correlate with an increased risk of manic or hypomanic symptoms in bipolar disorder (McGirr et al., 2016; Yatham et al., 2023; Tondo et al., 2010).

While the research conducted by Rohde and colleagues (2024) enhances our understanding of the complexities surrounding the “mood switch” phenomenon often seen with antidepressant treatment in bipolar disorder, the methodological limitations highlighted in their study necessitate further exploration in this crucial area.

Although Rohde et al (2024) provided some evidence on the risk of antidepressant-induced mania in bipolar depression, further long-term RCTs are needed to draw definite conclusions.

Further long-term RCTs are needed to draw definite conclusions on the safety of antidepressants for bipolar.

Evaluating the Strengths and Limitations of the Study

Rohde et al.’s application of a target trial emulation model provided several notable methodological advantages:

  • Large sample size: Utilizing Danish national registers, the study comprised a final cohort of 979 participants, which the authors noted was larger than any previous trials examining antidepressant effects in bipolar depression.
  • Extended follow-up period: This study monitored patients for one year, unless they were readmitted or passed away. This duration represents one of the longest follow-up intervals pertaining to this research topic.

Despite the various strengths of this study design, several limitations and drawbacks remain. While target trial emulations strive to emulate the scientific rigor of RCTs by applying their principles to observational data, they are not a perfect substitute for rigorously controlled live studies.

  • Restricted management of participants: While Rohde et al. managed to assign participants to conditions, they could not control the courses of treatment. In fact, more than a quarter of those initially assigned to the non-antidepressant group ultimately began taking antidepressants.
  • Restricted applicability of findings: The data utilized in Rohde et al.’s analysis did not allow for differentiation between bipolar I and II disorders. Consequently, the study could not ascertain whether rates of antidepressant-induced [hypo]mania differ between these two types.
  • Reduced generalizability: The study’s eligibility criteria excluded participants who experienced episodes without hospitalization, which limits the findings’ relevance to individuals with at least one prior admission.
Being a target trial emulation study, Rohde et al. sought a balance between the combined benefits of RCTs and observational data (e.g., large sample size, rigorous analysis), and their attendant drawbacks (e.g., restricted management of participants).

This trial emulation sought a balance between the combined benefits of RCTs and observational data and their attendant drawbacks.

Practical Implications for Clinicians

The authors elucidate how their findings suggest that the risk of antidepressants triggering mania in patients with bipolar disorder is negligible. The occurrence of manic episodes in these patients, often observed in those treated with antidepressants, may simply be an outcome of the recurrent nature of the disorder rather than a direct side effect of the medication. Furthermore, the results derived from their emulation study support the idea that antidepressants do not inherently cause mania.

As more data accumulates in this field, we may see a shift in clinical perceptions regarding the prescription of antidepressants for treating bipolar depression, particularly in the short-term context. However, current clinical guidelines for managing bipolar disorder do not advocate for the monotherapy of antidepressants (Goodwin et al., 2016). As noted by Rohde et al., there is a prevailing caution among clinicians when considering the prescription of antidepressants for bipolar disorder patients, largely due to concerns about the potential for inducing mania. This cautious approach may be reflected in their findings, which showed that patients who were not treated with antidepressants experienced a more severe clinical course, with an increased average of hospital admissions, outpatient consultations, and episodes of mania when compared to their antidepressant-using counterparts.

While the findings presented by Rohde et al. contribute to a growing body of evidence challenging the belief that antidepressants are solely responsible for increased rates of manic episodes, the results are not definitive. This uncertainty arises, in part, from the study’s limitations previously discussed. Therefore, further research is essential to comprehensively understand whether:

  • Participants who abstain from taking antidepressants throughout a future study (including follow-up) experience better or worse outcomes than those who are prescribed antidepressants for the trial’s duration;
  • Distinctions between bipolar I and II are further reflected in their responses to antidepressant treatment;
  • The severity of manic symptoms is, on average, greater among those on antidepressants, regardless of whether they have been hospitalized due to bipolar episodes.

Addressing these critical questions will not only enhance our understanding of the overall impact of antidepressant treatment within the bipolar disorder context but will also empower clinicians with more informed insights regarding whether a specific patient could benefit from such treatment based on their individual circumstances, including the type of bipolar disorder and the severity of recent symptoms.

Rohde et al.’s study was informative as to the potential effects of antidepressants in the context of bipolar disorder, but more work needs to be done to fill in the gaps.

This study adds to our understanding of the effects of antidepressants for bipolar, but more evidence is needed.

Disclosures of Conflicts of Interest

Paul Leeks declares no conflicts of interest. Michail Kalfas has received honoraria from Neurocentrx Pharma.

Accessing Further Resources and References

Primary Research Paper

Rohde C, Østergaard SD, Jefsen OH. (2024). A Nationwide Target Trial Emulation Assessing the Risk of Antidepressant-Induced Mania Among Patients With Bipolar Depression. The American Journal of Psychiatry 181(7) 630–638. https://doi.org/10.1176/appi.ajp.20230477

Additional References for Context

American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders (5th ed.).

Bobo WV. (2017) The Diagnosis and Management of Bipolar I and II Disorders: Clinical Practice Update. Mayo Clinic proceedings, 92(10), 1532–1551. https://doi.org/10.1016/j.mayocp.2017.06.022

GBD 2019 Mental Disorders Collaborators. (2022) Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry 9(2) 137-150.

Ghaemi SN, Whitham EA, Vohringer PA. et al (2021) Citalopram for Acute and Preventive Efficacy in Bipolar Depression (CAPE-BD): A Randomized, Double-Blind, Placebo-Controlled Trial. The Journal of clinical psychiatry 82(1) 19m13136.

Goodwin GM, Haddad PM, Ferrier IN. et al (2016) Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. Journal of psychopharmacology (Oxford, England) 30(6) 495–553.

Judd LL, Akiskal HS, Schettler PJ. et al (2003) A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Archives of general psychiatry 60(3) 261–269.

Judd LL, Akiskal HS, Schettler PJ. et al (2002) The long-term natural history of the weekly symptomatic status of bipolar I disorder. Archives of general psychiatry 59(6) 530-537.

Matthews A A, Danaei G, Islam N. et al (2022) Target trial emulation: applying principles of randomised trials to observational studies BMJ 378:e071108 doi:10.1136/bmj-2022-071108

McGirr A, Vöhringer PA, Ghaemi SN. et al (2016) Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in acute bipolar depression: a systematic review and meta-analysis of randomised placebo-controlled trials. Lancet Psychiatry 3(12) 1138-1146.

Miller S, Dell’Osso B, Ketter TA. (2014) The prevalence and burden of bipolar depression. Journal of affective disorders 169(1) S3-11.

National Institute for Health and Care Excellence [NICE] (2014) Bipolar Disorder: assessment and guidance. NICE clinical guideline CG185.

Pacchiarotti I, Bond DJ, Baldessarini RJ. et al (2013) The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. The American

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