Treatment-Resistant Bipolar Depression: Therapeutic Trends, Challenges and Future Directions

Figures & data

Table 1 Definitions of Treatment Resistance in Bipolar Depression

Author / Study / Guideline	Definition/Criteria
Sachs, 1996^Citation9	Depression without remission despite two adequate trials of standard antidepressant agents (six weeks each), with or without augmentation strategies.
Yatham et al, 2003^Citation10	Non-response to a six-week trial with lithium at serum levels of ≥ 0.8 mmol ⁄L.
Nierenberg et al (STEP-BD study), 2006^Citation11	Bipolar disorder type I or II with a current DSM-IV major depressive episode of at least 8 weeks, and had not responded to treatment in first 12 weeks of treatment (according to the protocol) or had a well-documented failure to respond to at least two trials of antidepressants or an antidepressant and mood stabilizer.
Gitlin, 2006^Citation12	Criteria used for treatment-resistant unipolar depression would apply, with the proviso that failure to respond to mood stabilizers, as well as antidepressants.
Gajwani, 2009^Citation13	Stage I: Failed monotherapy trial of lithium, anticonvulsant, or atypical antipsychotic (quetiapine or olanzapine-fluoxetine combination) of adequate dose and for adequate duration. Stage II: Stage I plus failed trial of combination of two above mentioned medications. Stage III: Stage II plus failed trial of several different evidence-based adjunctive pharmacological compounds. Stage IV: Stage III plus neurostimulation (ie, ECT or VNS).
Pacchiarotti et al, 2009^Citation14	A depressive episode within bipolar disorder that fails to reach remission with adequately dosed lithium (0.8 mEq⁄l in the plasma) or to other adequate ongoing mood-stabilizing treatment, plus lamotrigine (50–200 mg⁄day) or with full dose (≥ 600 mg⁄day) of quetiapine as monotherapy (Additional definitions are provided for refractory, intractable, and involutional depression in bipolar disorder, indicating an increase in the degree of unresponsiveness.)
Lipsman et al, 2010^Citation15	Nonresponse to adequate trials of monotherapy with lithium or lamotrigine, as well as lithium or lamotrigine in combination with at least one anticonvulsant or antipsychotic. The addition of a third agent, if necessary, should be an antidepressant only.
Malhi et al, 2012^Citation16	Failure to reach remission despite two or three adequate trials of first-line medication, such as a mood stabilizer.
Poon et al, 2012^Citation17	Clinically unsatisfactory response following at least two, presumably adequate (by dose and duration), trials of dissimilar treatments within a specific phase of the illness (ie, depression), excluding patients who have responded, but are intolerant of the treatment regime.
Hidalgo-Mazzei et al, 2019^Citation18	Failure to reach sustained remission or tolerate at least two different adequate treatment trials, for at least 8 weeks at therapeutic doses with acceptable adherence, of monotherapy (quetiapine, lurasidone, lamotrigine, or olanzapine/ fluoxetine combination), or at least one of these as monotherapy and one of these in combination with lamotrigine, valproate, or lithium. Additional definition is provided for multi-therapy resistant bipolar depression.
Fountoulakis et al (CINP Guideline), 2020^Citation19	No significant reduction in MADRS/HDRS scores or significant increase in YMRS/MRS scores or YMRS and MRS scores exceed 5 and their recommended duration of treatment is 10–12 weeks.

Abbreviations: CINP, International College of Neuropsychopharmacology; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; fourth edition; ECT, Electroconvulsive therapy; HDRS, Hamilton Depression Rating Scale; MADRS, Montgomery–Asberg Depression Rating Scale; MRS, Mania Rating Scale; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder; VNS, Vagal nerve stimulation; YMRS, Young Mania Rating Scale.

Table 2 Conventional Psychotropic Pharmacotherapy Studies for the Treatment of TRBD

Author, Year	Study Design	Intervention	Sample Size (n)	Outcome measure	Key Outcome
Nierenberg et al, 2006^Citation11	3-arm RCT	Lamotrigine	66	Rate of recovery	No significant difference between groups.
		Inositol			Post-hoc analysis suggest lamotrigine may be superior.
		Risperidone
Goldberg et al, 2004^Citation32	RCT	Placebo	22	Response (HDRS improvement >50%)	67% of pramipexole responded vs 20% of placebo group.
		Pramipexole (flexible dose)		CGI	Mean improvement in HDRS and CGI better in pramipexole group.
Frye et al, 2007^Citation35	RCT	Modafinil 177 mg/d	85	IDS	Significantly greater IDS change in treatment group compared with placebo.
		Placebo		Response/remission	Response and remission were significant.
Murphy et al, 2014^Citation33	RCT	Naltrexone 50 mg/d	30	MADRS	No significant difference.
		Placebo		HDRS

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, 2022^Citation40	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,^Citation39 Murata S et al, 2020^Citation70	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 2020^Citation39)
Edberg et al, 2020^Citation47	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, 2020^Citation45	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.
					No difference between BD groups after treatment.
			32 HC		Baseline VEGF was a poor predictor of treatment response.
Edberg et al, 2018^Citation46	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.
			32 HC

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.

Table 4 Ketamine Studies for the Treatment of TRBD

Author, Year	Study Design	Intervention	Sample Size (n)	Outcome measure	Key Outcome
Unique RCTs Identified
Diazgranados et al, 2010^Citation62	RCT	Mood stabilizer+ Ketamine hydrochloride (0.5mg/kg)	18	MADRS	Significant improvement in depressive symptoms in ketamine group
		Mood stabilizer +Placebo			Onset of action within 40 minutes.
Zarate et al, 2012^Citation63	RCT	Mood stabilizer+ Ketamine hydrochloride (0.5mg/kg)	15	MADRS	Significant improvement in depressive symptoms in ketamine group
		Mood stabilizer +Placebo			Onset in 40 min, effect lasted up to 3 days.
Post-hoc analyses of the two previously mentioned RCTs
Lally et al, 2014^Citation65	Post-hoc on 2 RCTs	Mood stabilizer + Ketamine hydrochloride (0.5mg/kg)	36	Level of anhedonia	Reduction of anhedonia independent of the reductions in general depressive symptoms
		Mood stabilizer +Placebo
Saligan et al, 2016^Citation66	Post-hoc on 2 RCTs	Mood stabilizer + Ketamine hydrochloride (0.5mg/kg)	36	Fatigue scores	Significantly lower fatigue scores in ketamine vs placebo at day 2
		Mood stabilizer +Placebo
Xu et al, 2015^Citation64	Post-hoc on 2 RCTs	Lithium +Ketamine 0.5 mg/kg	36	MADRS	No statistically significant difference between mood stabilizer groups
		Valproate + Ketamine 0.5 mg/kg
Villasenor et al, 2014^Citation67	Post-hoc analysis	Ketamine	22	Metabolomic patterns	The metabolomic patterns were significantly different between the patients maintained on lithium and those maintained on valproate
		Placebo

Figure 1 The study flow chart showing the study identification and selection.

Abbreviations: RCT, randomized controlled trial; TRBD, treatment-resistant bipolar depression.

Table 5 Randomized Controlled Trials of Electroconvulsive therapy

Author, Year	Study Design	Intervention	Sample Size (n)	Outcome Measure	Key Outcomes
Unique RCTs Identified
Sienaert et al, 2009^Citation75	RCT	Unilateral ECT 6 times threshold	64 (13=Bipolar depression; 51=Unipolar depression)	HRSD	No difference between bipolar and unipolar depression in response or remission
		Bifrontal ECT 1.5 times threshold		CGI	No difference in response to unilateral or bifrontal ECT
					Patients with bipolar disorder showed more rapid response
Bailine et al, 2010^Citation76	RCT	Right unilateral, bifrontal or bitemporal ECT	220 (50=Bipolar depression; 170=Unipolar depression)	Remission/response rates	No difference between the groups
Schoeyen et al, 2015^Citation72	RCT	ECT vs algorithm-based pharmacological treatment	73	MADRS	ECT was more effective than algorithm-based pharmacotherapy.
Bjoerke-Bertheussen et al, 2018^Citation74	RCT follow-up study of Schoeyen et al^Citation72	6-months follow-up after: ECT vs Algorithm-based pharmacological treatment	73	MATRICS Consensus Cognitive Battery AMI-SF	MATRICS improved significantly in both groups No difference between groups
Post-hoc of the above mentioned RCT (Schoeyen H et al^Citation72)
Kessler et al, 2014^Citation73	Post-hoc	ECT 3/week up to 6 weeks Algorithm-based pharmacological treatment	73	MATRICS Consensus Cognitive Battery AMI-SF	MATRICS improved significantly in both groups No difference between groups

Abbreviations: AMI-SF, Autobiographical Memory Interview-Short Form; CGI, Clinical Global Impression Scale; ECT, Electroconvulsive therapy; HRSD, Hamilton Rating Scale for Depression; MADRS, Montgomery-Asberg Depression Rating Scale; MATRICS, Measurement and Treatment Research to Improve Cognition in Schizophrenia; RCT, Randomized controlled trial.

Table 6 Ongoing Bipolar Depression Trials Registered on ClinicalTrials.gov

	Bipolar Depression	Treatment Resistant Bipolar Depression
Conventional drugs	Lumateperone (mixed depression)^Citation85 Vortioxetine^Citation86 Aripiprazole (adjunct)^Citation101 Perospirone (in adolescents)^Citation90 Scopolamine IV^Citation95 Bezafibrate (add-on)^Citation98	Brexpiprazole^Citation88 Extended-release capsule of mixed salts of a single-entity amphetamine (Mydayis ^®)^Citation87
Psychedelic drugs	Xenon^Citation97 Psilocybin (for BD II)^Citation112,Citation118	Ketamine^Citation89,Citation91,Citation117
Dietary supplement	Creatine monohydrate (add-on)^Citation104 Trehalose (add-on)^Citation92	-
Neuromodulation	Magnetic Seizure Therapy (for rapid response)^Citation105,Citation123	Transcranial Electric Stimulation Therapy^Citation96 Intensive intermittent theta-burst stimulation (iTBS)^Citation106 Theta Burst Transcranial Magnetic Bilateral Stimulation^Citation93 Magnus Transcranial Magnetic Neuromodulation System (MNS) with SAINT^® (Stanford Accelerated Intelligent Neuromodulation Therapy)^Citation111
Other non-invasive interventions	Bright light therapy (adjunct)^Citation100
Psychotherapy	Electronic CBT (for BD II)^Citation113
Biological agents	Low Dose IL-2 Therapy^Citation103 Allogenic Fecal Microbiota Transplantation^Citation108	Allogeneic Bone Marrow-Derived Multipotent Mesenchymal Stromal Cells^Citation109
Novel drugs	JNJ-55308942 (P2X7 antagonist)^Citation99 NRX-101 (a fixed dose combination of D-cycloserine + lurasidone)^Citation102 SEP-4199 (non-racemic ratio of amisulpride enantiomers)^Citation107 OSU6162 (a partial agonist at both dopamine D2 and 5-HT2A receptors)^Citation110

Abbreviations: BD II, bipolar disorder type II; CBT, Cognitive Behavioral Therapy; IL-2, Interleukin-2; IV, intravenous.

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