Early Antidepressant Treatment Linked to Higher Negative Affect and Impulsivity in Bipolar Euthymia

TL;DR: A 2026 cross-sectional study in PLOS One found that euthymic bipolar disorder patients with early systematic antidepressant treatment had higher negative affect and higher attentional, non-planning, and total impulsivity scores than matched patients without that early antidepressant history.

Source: PLOS One (2026) | Han et al.

Bipolar disorder often begins with depression, which can delay recognition of later mania or hypomania. When the first presentation resembles unipolar depression, patients may receive antidepressants before bipolar disorder is diagnosed.

This study focused on euthymia, meaning patients were not currently in a depressive, manic, or hypomanic episode by rating-scale criteria. The question was whether early systematic antidepressant exposure was linked to later differences in affect and impulsivity even during a stable mood period.

Early Systematic Antidepressant Treatment Meant At Least 6 Weeks

The researchers recruited Han Chinese patients with bipolar disorder from Tianjin Anding Hospital between September 2020 and May 2023. All patients had bipolar disorder diagnosed by DSM-IV-TR structured interview and had first presented with a depressive episode.

The antidepressant-treatment group had received systematic antidepressant therapy during the early stage between first depressive onset and bipolar diagnosis. The definition required an adequate dose of a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor for at least 6 weeks.

Eligible antidepressants included sertraline, fluoxetine, paroxetine, citalopram, escitalopram, venlafaxine, and duloxetine within standard dose ranges. Benzodiazepines and sleep medications were allowed as adjuncts.

• AT group: 62 patients had early systematic antidepressant treatment.
• NT group: 62 patients had no systematic early antidepressant treatment.
• Balanced clinical state: Groups did not significantly differ by age, sex, diagnostic delay, mood stabilizer use, MADRS score, or YMRS score.

Negative Affect Was Higher Despite Euthymic Mood Ratings

Positive and negative affect were measured with the Positive and Negative Affect Scale (PANAS). Positive affect did not significantly differ between groups.

Negative affect did differ. The antidepressant-treatment group averaged 24.9 on negative affect, compared with 22.1 in the no-treatment group.

The difference remained statistically significant after adjustment for sex, age, years of delayed diagnosis, and mood stabilizer use.

Euthymia on depression and mania scales can coexist with residual mood-related differences. A person can meet euthymic criteria while still showing more negative affect on a separate affect scale.

Attentional and Non-planning Impulsivity Were Higher

Impulsivity was measured with the Barratt Impulsiveness Scale 11-A (BIS-11A). Total impulsivity was higher in the antidepressant-treatment group, with a mean score of 61.4 versus 57.2.

The subscale pattern was not uniform. Attentional impulsivity and non-planning impulsivity were significantly higher, while motor impulsivity did not significantly differ.

• Attentional impulsivity: AT 13.3 vs NT 12.1; P = 0.035.
• Non-planning impulsivity: AT 25.0 vs NT 22.7; P = 0.010.
• Motor impulsivity: AT 23.1 vs NT 22.4; P = 0.156, not statistically significant.

The finding is associative. The study cannot prove that antidepressants caused later impulsivity, because treatment history was not randomized and the design was cross-sectional.

Still, the subscale pattern is clinically relevant. Attentional and non-planning impulsivity can affect concentration, planning, and risk evaluation even when motor impulsivity is not clearly elevated.

Negative Affect Did Not Explain the Impulsivity Difference

The researchers tested whether positive or negative affect mediated the relationship between early antidepressant treatment and impulsivity. Mediation analysis did not support that pathway.

Antidepressant use correlated with negative affect and with several impulsivity measures. However, negative affect did not form a statistically significant indirect pathway from early antidepressant exposure to impulsivity.

The two differences may be partly separate: early antidepressant history was associated with higher negative affect and higher impulsivity, but the measured negative affect score did not explain the impulsivity score difference.

Cross-sectional Design Limits Causal Interpretation

The main limitation is the design. Because the study measured patients after the fact, it cannot separate medication effect from illness course, initial diagnostic uncertainty, depression severity before diagnosis, treatment selection, or other clinical factors.

The sample was also narrow: Han Chinese patients from one hospital system, aged 18 to 50, with no psychotic symptoms, substance dependence, or major physical disease. The strict criteria improve internal consistency but limit generalization.

• No random assignment: Early antidepressant exposure reflected clinical history, not a randomized intervention.
• Recall and records: Treatment history was confirmed from medical records and guardians, but retrospective classification still has limits.
• Medication detail: The analysis grouped several SSRIs and SNRIs under one systematic antidepressant category.

The clinical interpretation should stay cautious: bipolar patients who first present with depression may carry later affective and impulsivity differences if early treatment is antidepressant-focused, but longitudinal studies are needed to test timing, causality, and treatment-specific effects.