. 2022 Dec 16;18:2927–2943. doi: 10.2147/NDT.S273503

Table 3.

Nonconventional Pharmacotherapy Studies for the Treatment of TRBD

Author, Year	Study Design	Intervention	Sample Size (n)	Outcome Measure	Key Outcome
Unique RCTs Identified.
Calkin et al, 2022⁴⁰	RCT	Metformin 2000 mg/qd	45	MADRS	Significantly more IR-converters in metformin group. Converters experienced significant improvement in MADRS and GAF.
		Placebo		GAF
				CGI-BP
				IR converters
Halaris et al, 2020,³⁹ Murata S et al, 2020⁷⁰	RCT	Escitalopram (10–40 daily) + Celecoxib (200 mg twice daily) vs Escitalopram (10–40 daily) + placebo (twice daily)	47	HDRS HAM-A IL-1β	Significantly more responders and remitters in Celecoxib group. Responders in the celecoxib group had a trend towards lower IL-1β. Significant decreases in HDRS and HAM-A scores at week 1. Celecoxib was well tolerated.
Post-hoc analyses of the above mentioned RCT (Halaris A et al 2020³⁹)
Edberg et al, 2020⁴⁷	Post-hoc analysis	Escitalopram (10–40 daily) + Celecoxib (200 mg twice daily) vs Escitalopram (10–40 daily) + placebo (twice daily)	47	Plasma MCP-1 levels	MCP-1 levels were not different in BDD vs HC subjects.
Castillo et al, 2020⁴⁵	Post-hoc analysis	Escitalopram (10–40 daily) + Celecoxib (200 mg twice daily) vs Escitalopram (10–40 daily) + placebo (twice daily) 32 HC	47 BD	VEGF levels	VEGF was significantly higher at baseline in BD patients compared to HC.
			47 BD		No difference between BD groups after treatment.
			32 HC		Baseline VEGF was a poor predictor of treatment response.
Edberg et al, 2018⁴⁶	Post-hoc analysis	Escitalopram (10–40 daily) + Celecoxib (200 mg twice daily) vs Escitalopram (10–40 daily) + placebo (twice daily) 32 HC	47 BD	Plasma CRP	No significant difference in CRP levels between the groups (celecoxib and placebo) at baseline. Significant decrease in CRP levels among celecoxib group (versus placebo) by week 8.
Edberg et al, 2018⁴⁶	Post-hoc analysis		32 HC	Plasma CRP

Abbreviations: CGI, Clinical Global Impression Scale; CGI-BP, Clinical Global Impression Scale – Bipolar Version; CRP, C-reactive protein; GAF, Global Assessment of Functioning; HAM-A, Hamilton Rating Scale for Anxiety; HC, Healthy control; HDRS, Hamilton Depression Rating Scale; IDS, Inventory of Depressive Symptoms; IL-1β, Interleukin-1 beta; IR, Insulin Resistance; MADRS, Montgomery-Asberg Depression Rating Scale; MCP-1, Monocyte chemoattractant protein-1; RCT, Randomized controlled trial; TRBD, Treatment-resistant bipolar depression; VEGF, Vascular Endothelial Growth Factor.