Table 1.

Definitions of Treatment Resistance in Bipolar Depression

Author / Study / Guideline	Definition/Criteria
Sachs, 19969	Depression without remission despite two adequate trials of standard antidepressant agents (six weeks each), with or without augmentation strategies.
Yatham et al, 200310	Non-response to a six-week trial with lithium at serum levels of ≥ 0.8 mmol ⁄L.
Nierenberg et al (STEP-BD study), 200611	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, 200612	Criteria used for treatment-resistant unipolar depression would apply, with the proviso that failure to respond to mood stabilizers, as well as antidepressants.
Gajwani, 200913	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, 200914	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, 201015	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, 201216	Failure to reach remission despite two or three adequate trials of first-line medication, such as a mood stabilizer.
Poon et al, 201217	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, 201918	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), 202019	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.