Early intervention in anxiety disorder patients with clinical high-risk factors for bipolar disorder: A randomized controlled trial

Abstract

BACKGROUND

Anxiety disorders are highly prevalent in patients with bipolar disorder (BD) and are associated with a more severe illness course and poorer outcomes. A significant clinical challenge is the frequent initial misdiagnosis of BD as anxiety, leading to prolonged diagnostic delays and suboptimal treatment. Growing evidence suggests that early intervention in individuals at high risk for BD can improve prognosis. Established clinical high-risk factors include early onset, family history of BD, and subthreshold manic symptoms. This creates a clinical dilemma whereby the administration of first-line antidepressants (e.g., sertraline) for anxiety is debated in patients with a bipolar diathesis, given the associated risk of mood destabilization. Conversely, mood stabilizers like lithium are foundational in BD treatment, but their role in treating anxiety in high-risk populations is unproven. Therefore, we conducted this randomized controlled trial to evaluate whether early intervention with a combination of sertraline and lithium is more effective than sertraline monotherapy for anxiety disorder patients with clinical high-risk factors for BD.

AIM

To investigate whether early intervention has a more positive outcome for anxiety disorders in patients who present with clinical high risk factors for BD.

METHODS

A total of 66 patients were enrolled in this study from January 2021 and December 2022 in Huzhou Third Municipal Hospital. They were randomly assigned to two groups to receive either an antidepressant (sertraline, n = 32) or a combination therapy (sertraline and lithium, n = 34). The main variables included alterations in Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale scores from the initial assessment to the final evaluation. A thorough combined Wald test was conducted to examine the intention-to-treat differences in scale assessment across treatment and time conditions.

RESULTS

Significant differences in the change of Hamilton Anxiety Rating Scale scores were observed between the two groups at week 1, week 2, and week 4 (P < 0.05). However, after 8 weeks and 12 weeks of treatment, there were no significant different (P = 0.485 and P = 0.206). There was no significant difference in the change over time in Hamilton Depression Rating Scale scores between the treatment groups (P = 0.2), except at week 12 (P = 0.034). No significant differences were observed in the adverse effects reported between patients treated with sertraline alone (18%) and those treated with the combination therapy (21%).

CONCLUSION

This current double-blind, case-controlled study assessed the effectiveness and tolerability of combined therapy vs monotherapy for anxiety disorder in patients with clinical high-risk factors for BD. In light of the constraints associated with this initial study, the results imply that the combination of sertraline and lithium may provide a more favorable prognosis.

Keywords: Anxiety disorder; Clinical high risk factors; Bipolar disorder; Early intervention; Lithium

Core Tip: This randomized controlled trial investigated early intervention in 66 antidepressant-naive adults with anxiety disorders who also presented clinical high-risk factors for bipolar disorder. The combination of sertraline and lithium demonstrated a significantly faster reduction in anxiety symptoms within the first four weeks compared to sertraline monotherapy, with comparable safety profiles. These preliminary findings suggest that early adjunctive mood stabilization may accelerate response and potentially mitigate the risk of manic switch in this clinically complex and high-risk population, warranting further investigation in larger trials.