Differential diagnosis of bipolar II disorder and major depressive disorder: Integrating multimodal approaches to overcome clinical challenges

Table 1 Key biomarkers in differentiating bipolar II disorder from major depressive disorder

Biomarker/category	MDD	BD-II	Ref.
Inflammatory cytokines: IL-6, TNF-α	Lower or normal compared to BD	Generally elevated compared to MDD	[19]
Neurotransmitter metabolites: Serotonin, norepinephrine	Levels relatively stable or altered without clear episodic pattern	Fluctuations associated with mood episodes	[20]
Neutrophil-to-lymphocyte ratio	Lower than BD and close to healthy controls	Significantly elevated; correlated with frequency and severity of depressive episodes	[21,22]
Anti-inflammatory cytokine: IL-10	Consistently reduced; linked to impaired suppression of inflammation	Marked variability: Lower during depressive episodes, higher or normalized during hypomanic episodes	[23,24]
Inflammatory cell counts	Leukocyte and NLR within normal or slightly elevated range	Leukocyte and NLR significantly elevated	[25]
Oxidative stress markers: ROS, antioxidant enzymes (SOD, CAT)	ROS low/normal; antioxidant enzyme activity preserved or slightly elevated	ROS elevated; antioxidant enzyme activity reduced	[26]
Cortisol levels	Less pronounced fluctuation; moderate increase under stress	Greater fluctuation; significantly elevated during depressive episodes; distinct pattern from other depression types	[27-29]

MDD: Major depressive disorder; BD-II: Bipolar II disorder; ROS: Reactive oxygen species; NLR: Neutrophil-to-lymphocyte ratio; TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; IL-10: Interleukin-10; SOD: Superoxide dismutase; CAT: Catalase; BD: Bipolar disorder.