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Cited by 11Treatment of Major DepressionAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesMental Health Treatment and Access

Relapse prevention with levomilnacipran ER in adults with major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study

Open access
Durgam, Suresh, Chen, Changzheng, Migliore, Raffaele, Prakash, Chandran, Thase, Michael E.·2019·Depression and Anxiety
DOI 10.1002/da.22872PMC PMC6590342
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Abstract

BACKGROUND: Levomilnacipran extended release (ER) is a serotonin and norepinephrine reuptake inhibitor approved for major depressive disorder (MDD) in adults. This study was designed to evaluate relapse prevention with levomilnacipran ER in patients with MDD. METHODS: Patients (≥18 years) with MDD (N = 644) received 20 weeks of open-label treatment with levomilnacipran ER 40, 80, or 120 mg/d (8 weeks flexible dosing; 12 weeks fixed dosing). Patients with a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤12 from the end of week 8 to week 20 were randomized to 26 weeks of double-blind treatment with levomilnacipran ER (same dosage; n = 165) or placebo (n = 159). The primary efficacy endpoint was time to relapse, defined as insufficient therapeutic response (≥2-point increase from randomization in Clinical Global Impression of Severity score, risk of suicide, need for hospitalization due to worsening of depression, or need for alternative antidepressant treatment as determined by the investigator) or an MADRS total score ≥18 at 2 consecutive visits. RESULTS: In the double-blind intent-to-treat population, levomilnacipran ER-treated patients had a significantly longer time to relapse compared with placebo (hazard ratio = 0.56; 95% CI, 0.33-0.92; P = 0.0212). Crude relapse rates were 14.5% (levomilnacipran ER) and 24.5% (placebo). Double-blind treatment-emergent adverse events (AEs) were reported for 58.8% and 56.0% of levomilnacipran ER and placebo patients, respectively; 3.0% and 1.3% discontinued due to AEs, and 1.2% and 0.6% had serious AEs, respectively. CONCLUSION: Levomilnacipran ER (40-120 mg/d) was effective in preventing relapse in patients with MDD. Safety and tolerability results were consistent with levomilnacipran ER acute studies.

AI snapshot

Written from the paper’s full text.

TL;DR

In adults with MDD who responded to 20 weeks of open-label levomilnacipran ER, continuing levomilnacipran ER for 26 weeks significantly prolonged time to relapse versus placebo. Safety and tolerability were consistent with levomilnacipran ER acute studies.

Key findings

  • Time to relapse was significantly longer with levomilnacipran ER than placebo: HR = 0.56 (95% CI, 0.33–0.92; P = 0.0212). Crude relapse rates were 14.5% (24/165) with levomilnacipran ER and 24.5% (39/159) with placebo.
  • The most common relapse reason was insufficient therapeutic response, defined as ≥2-point increase from randomization in CGI-S score: 70.8% (17/24) in the levomilnacipran ER group and 79.5% (31/39) in the placebo group. No patients relapsed due to suicide risk or hospitalization for worsening depression.
  • Double-blind treatment-emergent AEs occurred in 58.8% of levomilnacipran ER patients and 56.0% of placebo patients; discontinuations due to AEs were 3.0% vs 1.3%, and serious AEs were 1.2% vs 0.6%, respectively. Nausea was the only TEAE reported in ≥5% of levomilnacipran ER patients and at twice the placebo rate (7.9% vs 3.1%).
  • Additional efficacy measures worsened more in the placebo group than in the levomilnacipran ER group at the end of double-blind treatment, including MADRS total score (LS mean change +5.3 vs +3.0; LSMD −2.3 [95% CI, −4.3 to −0.4]) and CGI-S, SDS total, and SDS subscale scores (P < 0.05 for all LOCF outcomes).

Methods

  • Multicenter, randomized, double-blind, placebo-controlled relapse-prevention study (NCT02288325) conducted at 44 US centers from 2014 to 2016. The study was up to 53 weeks: 8-week open-label flexible-dose run-in, 12-week open-label fixed-dose stabilization, 26-week double-blind treatment, and down-taper.
  • Patients were adults ≥18 to ≤70 years with DSM-5 MDD, ongoing major depressive episode, ≥3 lifetime depressive episodes, and MADRS total score ≥26. A total of 644 entered open-label treatment; 324 were randomized to double-blind treatment (165 levomilnacipran ER, 159 placebo).
  • Primary endpoint was time to first relapse, analyzed using the log-rank test with Cox proportional hazards model for HR and 95% CI, and Kaplan–Meier curves. Additional efficacy used ANCOVA with LOCF; safety was summarized descriptively.

Limitations

  • The authors state that the long open-label treatment period, including the 12-week stabilization phase, may have limited the number of observed relapse events; the open-label initial phases could be considered a limitation; the double-blind phase had no active comparator; because doses were optimized for each patient, no conclusions can be drawn about specific doses; strict eligibility criteria limit generalizability; and the MADRS ≥18 relapse cutoff may have lacked sensitivity given the low mean MADRS baseline score at randomization (∼5).
  • The authors also note the randomized withdrawal design raises the possibility that placebo-arm relapses could reflect withdrawal symptoms rather than true relapse, but they report low and similar early relapse rates and a post hoc analysis censoring relapses during the first 28 days that maintained the significant levomilnacipran ER advantage.
  • Evident from the text: the double-blind phase was 26 weeks, and the study enrolled a selected population that had already responded to and tolerated open-label levomilnacipran ER, which may limit applicability to broader MDD populations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/da.22872

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 54 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    At the end of the 26-week double-blind treatment phase, greater worsening of rating scale scores was noted in the placebo group relative to the levomilnacipran ER group on all additional efficacy measures.

    “At the end of the 26‐week double‐blind treatment phase, greater worsening of rating scale scores was noted in the placebo group relative to the levomilnacipran ER group on all additional efficacy measures.”
    Quote in the paperSubstantial claim
  • Findingown data

    Relapse rates for levomilnacipran ER and placebo in the current study were lower than the average rates reported in the meta-analyses.

    “The relapse rates for levomilnacipran ER and placebo in the current study were lower than the average rates reported in the meta‐analyses.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Geddes et al., 2003 source

      Not checked in the free run.

    • cites Borges et al., 2014 source

      Not checked in the free run.

  • Findingown data

    At the end of double-blind treatment, increases in MADRS total score, CGI-S score, SDS total, and subscale scores were significantly greater in the placebo group than in the levomilnacipran ER group.

    “At the end of treatment, increases in MADRS total score, CGI‐S score, SDS total, and subscale scores were significantly greater in the placebo group than in the levomilnacipran ER group”
    Quote in the paperSubstantial claim
  • Findingown data

    3.0% and 1.3% of levomilnacipran ER and placebo patients discontinued due to AEs, respectively.

    “Double‐blind treatment‐emergent adverse events (AEs) were reported for 58.8% and 56.0% of levomilnacipran ER and placebo patients, respectively; 3.0% and 1.3% discontinued due to AEs, and 1.2% and 0.6% had serious AEs, respectively.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The treatment group differences were statistically significant using LOCF analyses (P < 0.05, all outcomes).

    “The treatment group differences were statistically significant using LOCF analyses (P < 0.05, all outcomes).”
    Quote in the paperSubstantial claim
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 20

  • May combine two claims.

    Findingown data

    SAEs were reported in 9 patients; no preferred term for an SAE was reported in >1 patient.

    “SAEs were reported in 9 patients; no preferred term for an SAE was reported in > 1 patient.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the end of open-label treatment with levomilnacipran ER, decreases (improvement) were observed in MADRS total score, CGI-S score, SDS total score, and SDS subscale scores.

    “At the end of open‐label treatment with levomilnacipran ER, decreases (improvement) were observed in MADRS total score, CGI‐S score, SDS total score, and SDS subscale scores (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The relapse rates observed in the current study were similar to those reported in recently completed studies with desvenlafaxine versus placebo (13.6% vs. 28.3%) and vortioxetine versus placebo (13% vs. 26%).

    “the relapse rates observed in the current study were similar to those reported in recently completed studies with desvenlafaxine versus placebo (13.6% vs. 28.3%; Rosenthal, Boyer, Vialet, Hwang, & Tourian, 2013) and vortioxetine versus placebo (13% vs. 26%; Boulenger, Loft, & Florea, 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rosenthal, Boyer, Vialet, Hwang, & Tourian, 2013 source

      Not checked in the free run.

    • cites Boulenger, Loft, & Florea, 2012 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The relapse rates for levomilnacipran ER were similar in the current (14.5%) and previous (13.9%) studies, while the rates for placebo were higher in the current study (24.5%) than in the previous one (20.5%).

    “Results showed that the relapse rates for levomilnacipran ER were similar in the current (14.5%) and previous (13.9%) studies (Shiovitz et al., 2014), while the rates for placebo were higher in the current study (24.5%) than in the previous one (20.5%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shiovitz et al., 2014

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Rates of relapse were low and similar (~5%) for both levomilnacipran ER- and placebo-treatment arms in the first few weeks following randomization.

    “When evaluating whether early relapse events were related to withdrawal symptoms, it was noted that rates of relapse were low and similar (∼5%) for both levomilnacipran ER‐ and placebo‐treatment arms in the first few weeks following randomization (Figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    AEs that led to premature discontinuation in >2 patients were nausea (n = 11), headache (n = 6), anxiety and tachycardia (n = 4 each), erectile dysfunction and testicular pain (n = 3 each [male patients only]), and hyperhidrosis (n = 3).

    “AEs that led to premature discontinuation in > 2 patients were nausea (n = 11), headache (n = 6), anxiety and tachycardia (n = 4 each), erectile dysfunction and testicular pain (n = 3 each [male patients only]), and hyperhidrosis (n = 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Overall, relapse occurred in 24.5% (39/159) of patients in the placebo group and 14.5% (24/165) of patients in the levomilnacipran ER group.

    “Overall, relapse occurred in 24.5% (39/159) of patients in the placebo group and 14.5% (24/165) of patients in the levomilnacipran ER group.”
    • Also stated in: § Results · plain
      “Crude relapse rates were 14.5% (levomilnacipran ER) and 24.5% (placebo).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The relapse rate was 14.5% in the levomilnacipran ER group compared with 24.5% in the placebo group, yielding an absolute difference of 10 points.

    “The relapse rate was 14.5% in the levomilnacipran ER group compared with 24.5% in the placebo group, yielding an absolute difference of 10 points.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Weight gain ≥7% from baseline was reported in 3.3% of patients during open-label treatment and in 10.1% and 13.9% of placebo- and levomilnacipran ER-treated patients, respectively, during double-blind treatment.

    “Weight gain ≥7% from baseline was reported in 3.3% of patients during open‐label treatment and in 10.1% and 13.9% of placebo‐ and levomilnacipran ER‐treated patients, respectively, during double‐blind treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SAEs were reported in one patient in the placebo group (suspected overdose Tylenol PM) and two patients in the levomilnacipran ER group (transient ischemic attack [related] and Escherichia pyelonephritis [not related]); all SAEs resolved.

    “SAEs were reported in one patient in the placebo group (suspected overdose Tylenol PM) and two patients in the levomilnacipran ER group (transient ischemic attack [related] and Escherichia pyelonephritis [not related]); all SAEs resolved.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the end of the double-blind treatment phase, patients in the levomilnacipran ER group had greater mean increases relative to placebo in systolic blood pressure, diastolic blood pressure, and pulse rate.

    “At the end of the double‐blind treatment phase, patients in the levomilnacipran ER group had greater mean increases relative to placebo in systolic blood pressure, diastolic blood pressure, and pulse rate (Table 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During the open-label treatment phase, C-SSRS-assessed suicidal ideation and behavior were reported in 180 (28.1%) and 12 (1.9%) patients, respectively.

    “During the open‐label treatment phase, C‐SSRS‐assessed suicidal ideation and behavior were reported in 180 (28.1%) and 12 (1.9%) patients, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No patient had >60 msec change in QTcF, a clinically significant shift from a normal to abnormal ECG reading, or QTc values >500 msec during double-blind treatment.

    “No patient had >60 msec change in QTcF, a clinically significant shift from a normal to abnormal ECG reading, or QTc values >500 msec during double‐blind treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Long-term treatment with levomilnacipran ER was generally well tolerated; no new or unexpected TEAEs were reported.

    “Long‐term treatment with levomilnacipran ER was generally well tolerated; no new or unexpected TEAEs were reported.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    During the double-blind down-taper phase, NEAEs were reported in 7 placebo- and 10 levomilnacipran ER-treated patients; NEAEs were considered treatment-related in one placebo patient and three levomilnacipran ER patients (diarrhea, headache, initial insomnia, cold sweat, and hot flush).

    “During the double‐blind down‐taper phase, NEAEs were reported in 7 placebo‐ and 10 levomilnacipran ER‐treated patients; NEAEs were considered to be treatment‐related in one placebo patient and three levomilnacipran ER patients (diarrhea, headache, initial insomnia, cold sweat, and hot flush).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    The most common TEAEs in the open-label phase appear to have been transient with lower incidences in the double-blind phase.

    “The most common TEAEs in the open‐label phase appear to have been transient with lower incidences in the double‐blind phase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Suicidal ideation was reported as a TEAE in two patients.

    “Suicidal ideation was reported as a TEAE in two patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The more acute treatment regimens a patient requires, the higher the risk of relapse.

    “In addition, the STAR*D trial showed that the more acute treatment regimens a patient requires, the higher the risk of relapse (Rush et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rush et al., 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One study had numerically greater improvement with levomilnacipran ER versus placebo.

    “while one study had numerically greater improvement with levomilnacipran ER versus placebo (Gommoll et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gommoll et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Clinical guidelines recommend an additional 4 to 9 months of antidepressant treatment after initial response is achieved and at least 3 years of continual treatment for maintenance therapy, especially in patients who experience recurrent MDD.

    “Clinical guidelines recommend an additional 4 to 9 months of antidepressant treatment after initial response is achieved and at least 3 years of continual treatment for maintenance therapy, especially in patients who experience recurrent MDD (APA, 2010; Bauer et al., 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites APA, 2010

      Not checked in the free run.

    • cites Bauer et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antidepressants are effective in decreasing depressive symptoms and reducing the risk of relapse in patients with MDD.

    “Antidepressants are effective in decreasing depressive symptoms and reducing the risk of relapse in patients with MDD (Geddes et al., 2003; Glue, Donovan, Kolluri, & Emir, 2010; Sim, Lau, Sim, Sum, & Baldessarini, 2015).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Geddes et al., 2003 source

      Not checked in the free run.

    • cites Glue, Donovan, Kolluri, & Emir, 2010 source

      Not checked in the free run.

    • cites Sim, Lau, Sim, Sum, & Baldessarini, 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    To attain 308 randomized patients, it was estimated that approximately 640 patients would be needed for enrollment, based on an assumption that response rates during the RIP and the SP would be 65% and 75%, respectively.

    “To attain 308 randomized patients, it was estimated that approximately 640 patients would be needed for enrollment, based on an assumption that response rates during the RIP and the SP would be 65% and 75%, respectively.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    All patients, investigators, and the study sponsor were blinded to treatment assignment.

    “All patients, investigators, and the study sponsor were blinded to treatment assignment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The protocol and amendments were approved by the institutional review board at each study center, and all patients provided written informed consent.

    “The protocol and amendments were approved by the institutional review board at each study center, and all patients provided written informed consent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a prior relapse-prevention study of levomilnacipran ER 40-120 mg, time to relapse was slower for levomilnacipran ER than for placebo, but the treatment effect was not statistically significant for the primary parameter, time to relapse (HR = 0.68; relapse rates: levomilnacipran ER = 13.9%, placebo = 20.5%).

    “Although analysis of relapse rates showed that the time to relapse was slower for levomilnacipran ER than for placebo, the treatment effect was not statistically significant for the primary parameter, time to relapse (HR = 0.68; relapse rates: levomilnacipran ER = 13.9%, placebo = 20.5%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shiovitz et al., 2014

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Randomization codes were generated electronically and implemented using an interactive web response system; identical packaging was used for all study medications.

    “Randomization codes were generated electronically and implemented using an interactive web response system; identical packaging was used for all study medications.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    A total of 429 patients entered the SP, and 331 (77.2%) patients completed.

    “A total of 429 patients entered the SP, and 331 (77.2%) patients completed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Meta-analyses yielded relapse rates of 18% for antidepressant treatment and 37% to 41% for placebo, with absolute drug-placebo differences in rates ranging from 10 to 31 points.

    “These meta‐analyses yielded relapse rates of 18% for antidepressant treatment and relapse rates of 37% to 41% for placebo, with absolute drug–placebo differences in rates ranging from 10 to 31 points.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Geddes et al., 2003 source

      Not checked in the free run.

    • cites Borges et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These analyses found no notable impact of total duration of treatment prior to randomization.

    “These analyses found no notable impact of total duration of treatment prior to randomization”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Geddes et al., 2003 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    During the study, it was not necessary to unblind any treatment code.

    “During the study, however, it was not necessary to unblind any treatment code.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    A total of 324 patients entered double-blind treatment (159 placebo, 165 levomilnacipran ER); 274 (84.6%) completed the study.

    “A total of 324 patients entered double‐blind treatment (159 placebo, 165 levomilnacipran ER); 274 (84.6%) completed the study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was conducted from 2014 to 2016 at 44 study centers in the United States in full compliance with the International Council on Harmonisation guideline for Good Clinical Practice and the principles of the Declaration of Helsinki.

    “The study was conducted from 2014 to 2016 at 44 study centers in the United States in full compliance with the International Council on Harmonisation guideline for Good Clinical Practice and the principles of the Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The study was multicenter, randomized, double-blind, placebo-controlled.

    “This was a multicenter, randomized, double‐blind, placebo‐controlled, relapse‐prevention study with levomilnacipran ER in patients with MDD (NCT02288325).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    A total of 644 patients entered the RIP, and 499 patients completed (77.5%).

    “A total of 644 patients entered the RIP, and 499 patients completed (77.5%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    Actual relapse rates in the prior levomilnacipran ER study were lower than the anticipated rates in the statistical analysis plan (levomilnacipran ER = 20%; placebo = 38%), compromising the projected power to demonstrate a difference between groups.

    “actual relapse rates were lower than the anticipated rates in the statistical analysis plan (levomilnacipran ER = 20%; placebo = 38%), compromising the projected power to demonstrate a difference between groups.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shiovitz et al., 2014

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Sample size and power calculations were based on historical relapse data, with assumed relapse rates at the end of double-blind treatment of 30% in the placebo group and 15% in the levomilnacipran ER group, and a common discontinuation rate of 20% for both groups.

    “Sample size and power calculations were based on historical relapse data, with assumed relapse rates at the end of double‐blind treatment of 30% in the placebo group and 15% in the levomilnacipran ER group, and a common discontinuation rate of 20% for both groups.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Efficacy analyses used the intent-to-treat (ITT) population, defined for each treatment phase as patients in safety population who had ≥1 available postbaseline (open-label) or postrandomization (double-blind) MADRS assessment.

    “Efficacy analyses used the intent‐to‐treat (ITT) population, defined for each treatment phase as patients in safety population who had ≥1 available postbaseline (open‐label) or postrandomization (double‐blind) MADRS assessment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Patient characteristics in the double-blind safety population were generally similar between treatment groups and consistent with characteristics in the open-label safety population.

    “Patient characteristics in the double‐blind safety population were generally similar between treatment groups and consistent with characteristics in the open‐label safety population (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Breaking the blind at the study center level disqualified the patient from further study participation.

    “Breaking the blind at the study center level disqualified the patient from further study participation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Long-term treatment with levomilnacipran ER was generally safe and well tolerated, and side effects were consistent with those found in shorter studies.

    “Long‐term treatment with levomilnacipran ER was generally safe and well tolerated, and side effects were consistent with those found in shorter studies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The initial open-label phases may have provided some descriptive measures of drug effectiveness.

    “they may have provided some descriptive measures of drug effectiveness”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The double-blind phase did not include an active comparator.

    “the double‐blind phase did not include an active comparator.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The initial phases of the study were open-label, which could be considered a limitation.

    “although the initial phases of the study were open‐label, which could be considered a limitation”
    Quote in the paperNot a substantial claim
43 of 43

  • The paper relies on this without support.

    Withdrawal symptoms from levomilnacipran ER, if they occur, would be expected during the first few weeks after randomization.

    “an excess of relapse events would be expected in the placebo arm during the first few weeks of treatment when withdrawal symptoms are likely to occur.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • One double-blind randomized placebo-controlled trial reported that levomilnacipran outperformed placebo in relapse rate at study-endpoint, while another did not report the statistical result; one trial investigating milnacipran also did not report statistical results.

    “One DBRPCT reported that levomilnacipran outperformed placebo in terms of relapse rate at the study-endpoint [22], while another DBRPCT did not report the statistical result of the outcome [49]; one trial investigating milnacipran also did not report the statistical results [47].”

    From Antidepressants for the treatment of adults with major depressive disorder in the maintenance phase: a systematic review and network meta-analysis (2023) · cites this paper as [22]

    Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • 20 articles define relapse with psychometric measures (Hamilton Depression Rating Scale, Beck Depression Inventory, Montgomery-Asberg Depression Rating Scale, Goldberg Anxiety and Depression Scale, Clinical Global Impression).

    “20 do so with psychometric measures (Hamilton Depression Rating Scale, Beck Depression Inventory, Montgomery-Asberg Depression Rating Scale, Goldberg Anxiety and Depression Scale, Clinical Global Impression) (4, 7, 9, 13–18, 33, 34, 42–49)”

    From Administrative criteria in the relapse of depressive disorder: a critical appraisal (2026) · cites this paper as [15]

  • The second most used scale is the Montgomery-Asberg Depression Rating Scale (MADRS), with 7 studies establishing the definition of relapse based on it, with varying criteria: 15+, 18+, 21 or 50% increase, and >=22 for 2 consecutive weeks.

    “The second most used scale is the Montgomery-Asberg Depression Rating Scale (MADRS), with 7 studies establishing the definition of relapse based on it, although again the criteria vary; for Verwijk et al. (16) and van Diermen et al. (46) a score of 15 or more would be sufficient, for Durgam et al. (15), 18 or more”

    From Administrative criteria in the relapse of depressive disorder: a critical appraisal (2026) · cites this paper as [15]

  • 4 studies use the Clinical Global Impression (CGI-S), 2 use the Beck's Depression Inventory, and 1 uses the Goldberg Anxiety and Depression Scale (GADS).

    “Finally, 4 studies use the Clinical Global Impression (CGI-S) (15, 33, 43, 48), 2 use the Beck`s Depression Inventory (4, 9) and 1 uses the Goldberg Anxiety and Depression Scale (GADS) (20).”

    From Administrative criteria in the relapse of depressive disorder: a critical appraisal (2026) · cites this paper as [15]

  • 40 articles define relapse based on administrative criteria.

    “and 40 define it based on what we will establish as administrative criteria (1, 4, 7, 9, 11–13, 15–29, 33, 34, 38, 39, 42–50, 52–55).”

    From Administrative criteria in the relapse of depressive disorder: a critical appraisal (2026) · cites this paper as [15]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • CGI-I confidence interval conflicts with stated significance

    Major

    The reported 95% confidence interval for the CGI-I treatment difference includes zero, but the table marks that difference as significant at P < 0.05.

1 of 1

Cites

Flagged first, then by citations

1 of the 33 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. APA, 2010, Practice guidelines for the treatment of patients with major depressive disorder (3rd ed

Cited by

Sorted by citations

Related

Authors
Durgam, S., Chen, C., Migliore, R., Prakash, C., & Thase, M. E.
Affiliations
  • Allergan (United States) (US)
  • University of Pennsylvania Health System (US)
Corresponding author
Durgam, Suresh
ORCID
Venue
Depression and Anxiety
Publisher
Wiley
Published
2019-01-23
Volume
36
Issue
3
Pages
225-234
ISSN
1091-4269 (ISSN-L)
DOI
10.1002/da.22872
PMC
PMC6590342
OpenAlex
W2912878867
Cited by
11
References
33
Citations by year
2026: 1 · 2025: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2017: 1
FWCI
0.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Depression and Anxiety (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
Allergan
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Social Sciences › Psychology › Social Psychology › Mental Health Treatment and Access
Keywords
levomilnacipran, major depressive disorder, relapse prevention, sustained-release formulation, serotonin-norepinephrine reuptake inhibitors, time to relapse, antidepressant efficacy, treatment-emergent adverse events, tolerability
MeSH terms
Serotonin and Noradrenaline Reuptake Inhibitors, Levomilnacipran, Adolescent, Adult, Aged, Antidepressive Agents, Major Depressive Disorder, Double-Blind Method, Female, Humans, Male, Middle Aged, Recurrence, Suicide, Treatment Outcome, Secondary Prevention, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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