| Study | Population | Intervention | Comparison | Details of inadequate response/treatment resistance | Comments |
|---|---|---|---|---|---|
|
RCT Australia, Canada, Europe & South Africa |
N=493 Mean age (years): 45.4 Gender (% female): 68 Ethnicity (% BME): 2 Baseline severity: HAMD 24.6 (more severe) | Quetiapine 150mg/day or 300mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Inadequate response during the current episode to amtitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine, which were given for ≥6 weeks at adequate doses (minimum effective dose according to label and including at least 1 dose increase as permitted by label) |
Treatment length (weeks): 6 Outcomes:
|
|
RCT 16 countries in Asia, Europe, Latin America, & North America |
N=886 Mean age (years): 46.8 Gender (% female): 69 Ethnicity (% BME): 4 Baseline severity: MADRS 25.85 (more severe) | Brexpiprazole 1-3mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Insufficient response to 1-3 adequate antidepressants (including the treatment a patient was taking at screening) for the current MDE; and insufficient response (defined as <50% improvement in MADRS; MADRS score ≥18; CGI-I score ≥3) to open-label antidepressants and double-blind augmentation during the 8 week prospective treatment phase |
Treatment length (weeks): 24 Outcomes:
|
|
RCT US |
N=362 Mean age (years): 45.4 Gender (% female): 63 Ethnicity (% BME): 10 Baseline severity: MADRS 26 (more severe) | Aripiprazole 2-20mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | TRD: Inadequate response to 1-3 adequate antidepressant trials (>6 weeks duration at adequate doses) at entry into trial and inadequate response (failing to meet criteria of <50% reduction in symptoms, HAMD≥15 and CGI-I≥3) to prospective treatment phase (8-week treatment with escitalopram [10/20mg/day], fluoxetine [20/40mg/day], paroxetine CR [37.5/50mg/day], sertraline [100/150mg/day] or venlafaxine [150/225mg/day]) |
Treatment length (weeks): 6 Outcomes:
|
|
RCT US |
N=349 Mean age (years): 45.4 Gender (% female): 73 Ethnicity (% BME): 13 Baseline severity: MADRS 26.9 (more severe) | Aripiprazole 2-20mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | TRD: Inadequate response to a previous antidepressant (as defined by <50% reduction in severity of depressive symptoms-determined by the MGH ATRQ) in 1-3 antidepressant trials of at least 6 weeks duration at entry into trial and inadequate response (failing to meet criteria of <50% reduction in HAMD from baseline, HAMD≥14 and CGI-I≥3) to prospective treatment phase (8-week treatment with escitalopram [10/20mg/day], fluoxetine [20/40mg/day], paroxetine CR [37.5/50mg/day; paroxetine 30/40m/day if paroxetine CR unavailable], sertraline [100/150mg/day] or venlafaxine [150/225mg/day]) |
Treatment length (weeks): 6 Outcomes:
|
|
RCT US |
N=64 Mean age (years): 44.0 Gender (% female): 52 Ethnicity (% BME): 11 Baseline severity: MADRS 29.95 (more severe) | Ziprasidone 80mg/day or 160mg/day + sertraline 100-200mg/day | Sertraline 100-200mg/day | TRD: Failure to respond to ≥1 previous course of treatment of ≥4 weeks’ duration with a clinically appropriate dose of an SSRI or non-SSRI antidepressant (based on self-report), and failure to respond (<30% improvement in MADRS score and continued to have a CGI-S score ≥4 and meet DSM-IV criteria for MDD) to an initial 6-week open-label prospective treatment phase with sertraline |
Treatment length (weeks): 8 Outcomes:
|
|
RCT US & Europe |
N=819 Mean age (years): 45.7 Gender (% female): 71 Ethnicity (% BME): 13 Baseline severity: MADRS 29.1 (more severe) | Cariprazine 1-2mg/day or 2-4.5mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Inadequate response during the current episode to antidepressant treatment for at least 6 weeks at recommended doses |
Treatment length (weeks): 8 Outcomes:
|
|
RCT US |
N=527 Mean age (years): 44.0 Gender (% female): 65 Ethnicity (% BME): 28 Baseline severity: MADRS 25.3 (more severe) | Cariprazine 1.5-4.5mg/day + any antidepressant | Placebo + any antidepressant | TRD: previously failed to respond to 1 or 2 adequate antidepressant trials, and inadequate response (HAMD score improved <50%, HAMD score <15, or CGI-I score <3) to prospective open-label 8 week prospective antidepressant treatment |
Treatment length (weeks): 8 Outcomes:
|
|
RCT US |
N=446 Mean age (years): 45.5 Gender (% female): 72 Ethnicity (% BME): 10 Baseline severity: HAMD 24.1 (more severe) | Quetiapine 150mg/day or 300mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Inadequate response (continuing depressive symptoms) during their current depressive episode to one of the following antidepressants: amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, or venlafaxine for at least 6 weeks at adequate doses (minimum effective dose according to US label and including ≥1 dose increase as permitted by label) |
Treatment length (weeks): 6 Outcomes:
|
|
RCT China |
N=90 Mean age (years): NR Gender (% female): NR Ethnicity (% BME): NR Baseline severity: NR (more severe) | Risperidone 2mg/day + paroxetine 20mg/day | Paroxetine 20mg/day | TRD: Inadequate response to ≥2 adequate treatments from different classes of antidepressants in the current depressive episode (adequate dosages of antidepressants for ≥3-month duration) determined through medical records and/or prospective treatment |
Treatment length (weeks): 8 Outcomes:
|
|
RCT US |
N=225 Mean age (years): 45 Gender (% female): 68 Ethnicity (% BME): 19 Baseline severity: MADRS 31.1 (more severe) | Aripiprazole 2mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Inadequate response (< 50% reduction in depressive symptom severity, as assessed by the MGH ATRQ) to 1-3 antidepressant trials with an adequate dose of SSRIs/SNRIs during the current episode for ≥8 weeks |
Treatment length (weeks): 4 Outcomes:
|
|
RCT US |
N=231 Mean age (years): 45.4 Gender (% female): 71 Ethnicity (% BME): 81 Baseline severity: MADRS 26.4 (more severe) | Cariprazine 0.1–0.3mg/day or 1–2mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | TRD: failed to respond to 1-2 adequate trials of antidepressants (<50% reduction in depressive symptoms using the MGH ATRQ) and failed to respond (achieved <50% improvement in HAMD, HAMD score >14, or CGI-I score ≥3) to 8-week prospective open-label antidepressant treatment phase |
Treatment length (weeks): 8 Outcomes:
|
|
RCT US |
N=207 Mean age (years): NR Gender (% female): 73 Ethnicity (% BME): 28 Baseline severity: HAMD 22.23 (more severe) | Pimavanserin 34mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Inadequate response to 1 or 2 antidepressant treatments (including SSRI/SNRI) during the current depression episode |
Treatment length (weeks): 5 Outcomes:
|
|
RCT US, Germany, Poland, Slovakia, & Hungary |
N=394 Mean age (years): 42.9 Gender (% female): 74 Ethnicity (% BME): 15 Baseline severity: MADRS 26.64 (more severe) | Brexpiprazole 2mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | TRD: Inadequate response (<50% improved according to the MGH ATRQ) to 1-3 prior antidepressants (on a therapeutic dose for an adequate duration) during the current episode; and inadequate response (<50% improvement in HAMD and MADRS, HAMD score >14, and CGI-I score ≥3) to 8-week prospective open-label antidepressant treatment |
Treatment length (weeks): 6 Outcomes:
|
|
RCT US, Russia, Poland, France, Serbia, Germany, & Canada |
N=503 Mean age (years): 43.1 Gender (% female): 68 Ethnicity (% BME): 10 Baseline severity: MADRS 25.44 (more severe) | Brexpiprazole 2-3mg/day or quetiapine 150-300mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | TRD: Inadequate response (defined as <50% improved on the MGH ATRQ) during the current episode to 1-3 antidepressants at a therapeutic dose and for an adequate duration (>6 weeks); inadequate response (<50% reduction in MADRS total score between the start of prospective treatment and each 2-weekly visit; CGI-I score>3 at each 2-weekly visit; and MADRS total score≥ 18) to open-label 8-10 week prospective antidepressant treatment phase |
Treatment length (weeks): 6 Outcomes:
|
|
RCT Japan |
N=586 Mean age (years): 38.7 Gender (% female): 42 Ethnicity (% BME): NR Baseline severity: MADRS 25.3 (more severe) | Aripiprazole fixed dose 3mg/day or flexible dose 3-15mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | TRD: Previous inadequate response to 1–3 antidepressant trials of at least 6-weeks’ duration (64% 1 trial; 27% 2 trials; 10% 3 trials); and inadequate response (<50% reduction in HAMD from baseline to the end of the screening phase; HAMD score≥14; or CGI-I score≥3) to an 8-week, single-blind, prospective treatment phase |
Treatment length (weeks): 6 Outcomes:
|
|
RCT Japan, Korea, Malaysia, Taiwan, & Australia |
N=412 Mean age (years): 38.9 Gender (% female): 37 Ethnicity (% BME): 99 Baseline severity: MADRS 25.05 (more severe) | Aripiprazole 3-12mg/day + sertraline 100mg/day | Placebo + sertraline 100mg/day | TRD: inadequate response to 1-3 previous antidepressant treatments (75% 1 previous adequate antidepressant treatments) and inadequate response (<50% reduction in HAMD from baseline to the end of the prospective treatment period; HAMD score≥14 at the end of the prospective treatment period; and a constant CGI-I score≥3 throughout the prospective treatment period) to 8-week prospective treatment phase with sertraline |
Treatment length (weeks): 6 Outcomes:
|
|
RCT US |
N=97 Mean age (years): 45.2 Gender (% female): 59 Ethnicity (% BME): 10 Baseline severity: MADRS 25.7 (more severe) | Risperidone 0.5-3mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Inadequate response to open-label treatment trial with antidepressant monotherapy (the particular antidepressant used was based on clinician choice) lasting for ≥5 weeks |
Treatment length (weeks): 4 Outcomes:
|
|
RCT US & Canada |
N=181 Mean age (years): 66.0 Gender (% female): 57 Ethnicity (% BME): 12 Baseline severity: MADRS 23 (more severe) | Aripiprazole 2-15mg/day + venlafaxine 300mg/day | Placebo + venlafaxine 300mg/day | Inadequate response (failure to remit; MADRS>10) to venlafaxine 150-300mg/day (for ≥12 weeks of treatment with ≥4 weeks at the highest tolerated dose). 74% previous history of at least 1 adequate antidepressant trial during the present episode |
Treatment length (weeks): 12 Outcomes:
|
|
RCT China |
N=95 Mean age (years): 42.2 Gender (% female): 52 Ethnicity (% BME): NR Baseline severity: HAMD 25.9 (more severe) | Quetiapine 200-400mg/day + venlafaxine 225mg/day (antidepressant switch) | Venlafaxine 225mg/day (antidepressant switch) | TRD: Inadequate response (<50% reduction of initial HAMD and HAMD score ≥20) to ≥2 different antidepressant therapies with clinically-appropriate dosage and time-course |
Treatment length (weeks): 8 Outcomes:
|
|
RCT US |
N=274 Mean age (years): 46.1 Gender (% female): 74 Ethnicity (% BME): 24 Baseline severity: HAMD 24.6 (more severe) | Risperidone 0.25-2mg/day + any antidepressant | Placebo + any antidepressant | Inadequate response (defined as CGI-S score≥4 and a Carroll Depression Scale score≥20) to a 4-week prospective open-label run-in period with current antidepressant monotherapy at the dosages recommended in product labelling |
Treatment length (weeks): 6 Outcomes:
|
|
RCT US |
N=381 Mean age (years): 44.5 Gender (% female): 67 Ethnicity (% BME): 11 Baseline severity: MADRS 26.1 (more severe) | Aripiprazole 2-20mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | TRD: Inadequate response to 1-3 previous antidepressant trials of >6 weeks’ duration (>3 weeks for combination treatments) at a minimum acceptable dose as determined by the MGH ATRQ and inadequate response (defined as failure to achieve ≥50% reduction in the HAMD total score from baseline to the end of the prospective treatment phase, a HAMD>14, or a CGI-I score >3) to 8-week single-blind prospective treatment phase with standard antidepressant in accordance with current product labelling |
Treatment length (weeks): 6 Outcomes:
|
|
RCT Canada |
N=58 Mean age (years): 44.5 Gender (% female): 62 Ethnicity (% BME): NR Baseline severity: HAMD 23.3 (more severe) | Quetiapine 50-600mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Inadequate response to treatment for their current episode with a single SSRI/venlafaxine at a therapeutic dose for ≥6 weeks |
Treatment length (weeks): 8 Outcomes:
|
|
RCT Romania |
N=72 Mean age (years): 39.8 Gender (% female): 75 Ethnicity (% BME): NR Baseline severity: HAMD 23.39 (more severe) | Quetiapine 150mg/day + duloxetine 60mg/day | Duloxetine 60mg/day | Inadequate response (HAMD≥14) to the antidepressant therapy (the use of minimal doses accepted as effective for a period of at least 4 - 6 weeks), for the current depressive episode |
Treatment length (weeks): 8 Outcomes:
|
|
RCT US |
N=372 Mean age (years): 43.5 Gender (% female): 68 Ethnicity (% BME): NR Baseline severity: NR (unclear severity) | Brexpiprazole 1-3mg/day + any antidepressant | Placebo + any antidepressant | TRD: history for the current depressive episode of an inadequate response to 1-3 adequate antidepressant treatments; incomplete response to prospective open-label treatment with commercially available antidepressant for 8 weeks at maximally tolerated doses |
Treatment length (weeks): 6 Outcomes:
|
|
RCT US |
N=429 Mean age (years): 43.7 Gender (% female): 67 Ethnicity (% BME): NR Baseline severity: NR (unclear severity) | Brexpiprazole 1-4mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | TRD: report a history for the current depressive episode of an inadequate response to 1-3 adequate antidepressant treatments; incomplete response to prospective open-label treatment with a commercially available antidepressant for 8 weeks at maximally tolerated doses |
Treatment length (weeks): 6 Outcomes:
|
|
RCT US |
N=139 Mean age (years): 44.5 Gender (% female): 71 Ethnicity (% BME): NR Baseline severity: HAMD 20 (more severe) | Ziprasidone 40-160mg/day + escitalopram 10-30mg/day | Placebo + escitalopram 10-30mg/day | Inadequate response (continued to meet DSM-IV criteria and had a QIDS-SR score≥10) to 8-week open-label prospective phase of escitalopram treatment. Mean number of past unsuccessful trials of antidepressants during the current major depressive episode was 0.94 (SD=0.76) |
Treatment length (weeks): 8 Outcomes:
|
|
RCT US |
N=23 Mean age (years): 44.0 Gender (% female): 70 Ethnicity (% BME): NR Baseline severity: MADRS 35.5 (more severe) | Risperidone 0.25-2mg/day + any antidepressant | Placebo + any antidepressant | Inadequate response to 1-2 antidepressants for 3 or more weeks |
Treatment length (weeks): 8 Outcomes:
|
|
RCT China |
N=120 Mean age (years): 44.0 Gender (% female): 50 Ethnicity (% BME): NR Baseline severity: HAMD 28 (more severe) | Risperidone 0.5-2mg/day + venlafaxine 50-250mg/day | Venlafaxine 50-250mg/day | TRD: inadequate response to at least 2 antidepressants at adequate dose |
Treatment length (weeks): 6 Outcomes:
|
|
RCT US & Canada |
N=406 Mean age (years): 44.5 Gender (% female): 64 Ethnicity (% BME): 13 Baseline severity: MADRS 30 (more severe) | Olanzapine 6, 12 or 18mg/day + fluoxetine 50mg/day | Fluoxetine 50mg/day | TRD: Documented history of failure to achieve a satisfactory response (based on investigator’s clinical judgement) to an antidepressant (except fluoxetine) after ≥6 weeks of therapy at a therapeutic dose, and failure to respond (<25% decrease in HAMD) to an 8-week, open-label prospective fluoxetine (25-50mg/day) therapy lead-in |
Treatment length (weeks): 8 Outcomes:
|
|
RCT US, Poland, France, & Slovakia |
N=379 Mean age (years): 44.7 Gender (% female): 70 Ethnicity (% BME): 13 Baseline severity: MADRS 26.85 (more severe) | Brexpiprazole 0.5-2mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Inadequate response during the current episode, defined as <50% reduction in symptoms via patient self-reports on the MGH ATRQ to an adequate trial of 1-3 antidepressants including the most recent drug treatment. During the current episode, 82% had 1 prior antidepressant failure |
Treatment length (weeks): 6 Outcomes:
|
|
RCT US, Germany, Ukraine, Russia, Hungary, Canada, & Romania |
N=677 Mean age (years): 45.6 Gender (% female): 68 Ethnicity (% BME): 13 Baseline severity: MADRS 26.47 (more severe) | Brexpiprazole 1mg/day or 3mg/day + SSRI/SNRI | Placebo + SSRI/SNRI | Inadequate response during the current episode, defined as <50% reduction in MGH ATRQ score to an adequate trial of 1-3 antidepressants. 78% 1 prior antidepressant treatment |
Treatment length (weeks): 6 Outcomes:
|
BME: black and minority ethnic; CGI-I: clinical global impression-improvement; CGI-S: clinical global impression-severity; CR: controlled release; DSM: diagnostic statistical manual; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; MDD: major depressive disorder; MDE: major depressive episode; MGH ATRQ: Massachusetts General Hospital antidepressant treatment response questionnaire; NR: not reported; QIDS-SR: quick inventory of depressive symptomatology-self report; RCT: randomised controlled trial; SD: standard deviation; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression
From: Further-line treatment
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