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Cited by 217Treatment of Major DepressionElectroconvulsive Therapy StudiesBipolar Disorder and Treatment

Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis

Open access
Nuñez, Nicolas A, Joseph, Boney, Pahwa, Mehak, Kumar, Rakesh, Resendez, Manuel Gardea, Prokop, Larry J, Veldic, Marin, Seshadri, Ashok +4 more·2022·Journal of Affective Disorders
DOI 10.1016/j.jad.2021.12.134PMC PMC9328668
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Abstract

Objective To compare the efficacy and discontinuation of augmentation agents in adult patients with treatment-resistant depression (TRD). We conducted a systematic review and network meta-analyses (NMA) to combine direct and indirect comparisons of augmentation agents. Methods We included randomized controlled trials comparing one active drug with another or with placebo following a treatment course up to 24 weeks. Nineteen agents were included: stimulants, atypical antipsychotics, thyroid hormones, antidepressants, and mood stabilizers. Data for response/remission and all-cause discontinuation rates were analyzed. We estimated effect-size by relative risk using pairwise and NMA with random-effects model. Results A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA. Our findings from the NMA for response rates, compared to placebo, were significant for: liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine, and lisdexamfetamine. For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine). Compared to placebo, ziprasidone, mirtazapine, and cariprazine had statistically significant higher discontinuation rates. Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB. Limitations Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons. Conclusions This NMA suggests a superiority of the regulatory approved adjunctive atypical antipsychotics, thyroid hormones, dopamine compounds (modafinil and lisdexamfetamine) and lithium. Acceptability was lower with ziprasidone, mirtazapine, and cariprazine. Further research and head-to-head studies should be considered to strengthen the best available options for TRD.

Integrity signals

Registry

Crossref · 10.1016/j.jad.2021.12.134

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

9 of 54 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Earlier meta-analyses found evidence supporting atypical antipsychotics, lithium, ketamine, and esketamine.

    “Previous meta-analyses have shown evidence for the use of AAs, lithium, ketamine and esketamine (Carter et al., 2020; Strawbridge et al., 2019; Vázquez et al., 2021; Zhou et al., 2015).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Carter et al., 2020 source
    • cites Strawbridge et al., 2019 source

      The Clinical implications table reports meta-analytic results for antipsychotics, lithium and ketamine. The discussion describes aripiprazole as effective and lithium evidence as promising but less certain. Our copy does not report results for esketamine, so this source supports only part of the cited sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Vázquez et al., 2021 source

      The Results (Meta-analyses; page not provided) report efficacy for adjunctive second-generation antipsychotics, intranasal esketamine, and lithium in major depression. The paper’s analysis does not include ketamine as a separate treatment, so it does not support that part of the sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingcitation

    Quetiapine at a mean dose of 156.74 ± 97.6 mg/day showed significant benefits for both response and remission rates compared to placebo.

    “In addition, quetiapine (mean dose,156.74 ± 97.6 mg/day) showed significant benefits for both response and remission rates compared to placebo, which is in accordance with current clinical recommendations for augmentation strategies for MDD (Cleare et al., 2015; Kennedy et al., 2016).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Cleare et al., 2015 source
    • cites Kennedy et al., 2016 source
    • The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
  • Findingown data

    In the network meta-analysis, lithium augmentation produced a significantly higher response rate than placebo.

    “Our findings from the NMA for response rates, compared to placebo, were significant for: liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine, and lisdexamfetamine.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Response and remission definitions across the included trials are comparable enough to combine.
  • Findingown data

    In the network meta-analysis, risperidone augmentation produced a significantly higher remission rate than placebo.

    “For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Response and remission definitions across the included trials are comparable enough to combine.
  • Findingown data

    In the network meta-analysis, quetiapine augmentation produced a significantly higher remission rate than placebo.

    “For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Response and remission definitions across the included trials are comparable enough to combine.
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 31
  • The quote only partly states this claim. 1

  • Classified as probably not a substantial claim.

    Premisecitation

    Prior network meta-analyses have recommended atypical antipsychotics as augmentation agents.

    “Previous studies utilizing NMA approaches have suggested the use of AAs (Zhou et al., 2015; Carter et al., 2020) as augmentation agents, although number of included trials and agents have varied across studies due to different inclusion criteria.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Zhou et al., 2015 source

      The available copy contains the paper’s title, identifying it as a network meta-analysis of augmentation agents, but the retrieved passage is repository navigation rather than the paper’s findings (no section or page is available). Searches for atypical antipsychotics and specific agents found no passage showing whether the paper recommended them. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites Carter et al., 2020 source

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

    Study design and conductcitation

    Direct and indirect evidence were checked for inconsistency with a chi-square test using the netheat function.

    “Inconsistency between findings from pairwise meta-analyses (direct evidence) and NMA (indirect evidence) was evaluated by chi2 test using the “netheat” function (Krahn et al 2013) (Appendix 1, Table 2).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Krahn et al 2013 source

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

    Study design and conductcitation

    Trial methodological quality was assessed with the Cochrane Risk of Bias Tool across five domains.

    “The methodological quality of the RCTs was assessed using the Cochrane collaboration’s Risk Interventions Risk of Bias Tool (Higgins et al., 2011) reporting each of its five domains (adequate randomization and allocation, blinding, loss to follow-up, selective reporting, and other sources of potential bias) into a low risk of bias, high risk of bias, or unclear risk of bias.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Higgins et al., 2011 source

      The paper’s “The risk of bias tool” section confirms that the Cochrane tool assesses randomized trials and assigns low, high, or unclear risk judgments. But it explicitly describes six domains, not five; the citing sentence combines performance and detection bias under “blinding.” (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationown data

    The results agree with a previous network meta-analysis showing efficacy of thyroid hormones as an augmentation agent and contrast with Lorentzen and colleagues, who reported negative findings for thyroid hormones in unipolar treatment-resistant depression.

    “Our results are in concordance with a previous NMA (Zhou et al., 2015) showing efficacy of thyroid hormones as an augmentation agent and in contrast to Lorentzen and colleagues who reported negative findings for the use of thyroid hormones in unipolar TRD (Lorentzen et al., 2020).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Zhou et al., 2015 source

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

      Experimental — accuracy not yet measured
    • cites Lorentzen et al., 2020 source
    • The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.

  • May combine two claims.

    Interpretationown data

    These data provide further evidence of lithium's antidepressant efficacy, consistent with a recent meta-analysis.

    “Importantly, these data provide further evidence of lithium’s antidepressant efficacy which is consistent with the results of a recent meta-analysis (Vázquez et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Vázquez et al., 2021 source
    • The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.

  • May combine two claims.

    Findingcitation

    Aripiprazole as an augmentation agent at a mean dose of 10.68 ± 3.1 mg/day showed significant benefit and had low discontinuation rates.

    “Aripiprazole as an augmentation agent (mean dose,10.68 ± 3.1 mg/day) showed significant benefit and had low discontinuation rates, which aligns with previous studies (Seshadri et al., 2021; Strawbridge et al., 2019).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Seshadri et al., 2021 source
    • cites Strawbridge et al., 2019 source

      The 'Pharmacological interventions without high' section reports a consistent effect for aripiprazole across four studies, supporting the claimed benefit. The 'Tolerability and acceptability' section discusses dropout rates but does not give a low discontinuation rate for aripiprazole, and the copy does not substantiate the stated mean dose of 10.68 ± 3.1 mg/day. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.

  • May combine two claims.

    Findingown data

    Nine trials (N = 1,450) compared drugs head to head, with treatment lasting up to 12 weeks.

    “Nine studies (N = 1450) examined head to head drugs (Bauer et al., 2013; Cheon et al., 2017; Dorée et al., 2007; Dunner et al., 2007; Nierenberg et al., 2006; Raeisi et al., 2006; Schindler and Anghelescu, 2007; Shahal et al., 1996; Trivedi et al., 2006) with a treatment duration of up to 12 weeks.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The search retrieved 6,322 records, and 69 studies were included.

    “A total of 6322 records were retrieved of which 69 studies were included (Fig. 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fifty-one studies (52 cohorts) compared medications with placebo; their combined sample was 10,701, and treatment duration ranged from 48 hours to 16 weeks.

    “Fifty one studies (52 cohorts) evaluated medications in comparison to placebo”
    • Also stated in: § Results · plain
      “with a sample size of N = 10,701, and the treatment duration ranging from 48 hours–16 weeks”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The network meta-analysis pooled 65 trials involving 12,415 participants and 19 augmentation agents.

    “A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Findingnone given

    Aripiprazole and quetiapine are the two most studied atypical antipsychotics.

    “Aripiprazole and quetiapine are the two most studied AAs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    T3 was significantly more effective than placebo and comparable to lithium.

    “In our study, we showed T3 to be significantly more effective than placebo and comparable to lithium.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.

  • May combine two claims.

    Findingown data

    The results emphasize an improvement in response rates but not remission.

    “However, we should acknowledge that our results emphasize an improvement on response rates not remission.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.

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

    Findingnone given

    Discontinuation data were not available for nortriptyline.

    “Discontinuation data was not available for nortriptyline.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    Brexpiprazole trials were of slightly shorter duration than cariprazine trials (6 versus 8 weeks).

    “Brexpiprazole trials were of slightly shorter duration compared to cariprazine (6 and 8 weeks respectively).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Across included trials, 24% were rated low risk of bias, 63% moderate risk, and 13% high risk.

    “Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Three review authors extracted data independently.

    “Data were extracted independently by three review authors (NAN, BJ, and MP) according to inclusion criteria.”
    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 conductcitation

    Publication bias was assessed by funnel-plot symmetry, Eggers tests, regression asymmetry tests, and trim-and-fill when asymmetry was present.

    “We examined the publication bias by examining a symmetry of the funnel plot of the trials using Eggers tests and regression asymmetry tests (Begg and Mazumdar, 1994; Egger et al., 1997). In case of asymmetry we applied the trim and fill method for all outcome measures (Begg and Mazumdar, 1994).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Begg and Mazumdar, 1994 source
    • cites Egger et al., 1997 source

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

    Study design and conductown data

    A comprehensive search covered multiple databases from their inception to 29 May 2020, without language restriction.

    “A comprehensive search of several databases from each database’s inception to May 29th of 2020, any language, was conducted.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Atypical antipsychotics have been reported as effective adjuncts to antidepressants.

    “According to the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines and American Psychiatric Association Practice guidelines, atypical antipsychotics (AA) have been reported as an effective augmentation strategy to antidepressants.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Guidelines currently advise augmentation after two antidepressants fail or after partial response to a primary antidepressant.

    “Current treatment guidelines recommend augmentation strategies after failure of two antidepressants or partial response with a primary antidepressant (Kennedy et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kennedy et al., 2016 source

  • Classified as probably not a substantial claim.

    Premisenone given

    Network meta-analysis can combine direct and indirect evidence when head-to-head trials are absent.

    “Network meta-analysis (NMA) is a promising statistical method which allows to synthetize information from different clinical trials by combining direct and indirect evidence in the absence of head-to-head treatment comparisons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    The review's limitations included heterogeneity in TRD definitions, variable trial duration, methodological and clinical design issues in older studies, and few trials per comparison.

    “Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The review and network meta-analysis followed PRISMA reporting guidelines.

    “Our systematic review and NMA is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines.”
    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

    Two reviewers independently screened titles and abstracts, then separately reviewed full texts.

    “Two reviewers, (NAN, MP) working independently, screened the titles and abstracts of potentially eligible articles. Subsequently, the full texts of eligible articles were reviewed separately by the same two reviewers.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    No consensus exists on a single definition of treatment-resistant depression.

    “However, consensus has not yet been established regarding an integrated definition for TRD (i.e. after trial of one or two antidepressant of same or different classes) (Berlim and Turecki, 2007a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Berlim and Turecki, 2007a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Carter and colleagues performed a systematic review and network meta-analysis of drug and psychological augmentation for TRD, but no psychological trial met the common-comparator requirement.

    “Carter et al. recently conducted a systematic review and NMA of pharmacological and psychological augmentation interventions for TRD (defined as two adequate treatments in current episode), however, no psychological trial could be included due to the absence of a common comparator (Carter et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Carter et al., 2020 source

  • May combine two claims.

    Study design and conductown data

    Inconsistency between direct and indirect evidence was assessed in the study and found to be noncontributing.

    “For example, while conducting a NMA it allows to estimate effectiveness of different treatments in the absence of direct comparison between trials (Cipriani et al., 2013), thus, issues regarding inconsistency between either direct or indirect evidence could arise which was assessed in our study and found to be noncontributing (Appendix 1, Table 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cipriani et al., 2013 source
    • The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Different regulatory standards in clinical trial development may have influenced reporting on adverse events or efficacy measures.

    “Different standards of regulations in development of clinical trials may have influenced reporting on adverse events or efficacy measures”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The importance of dopaminergic agents in depression has been suggested in both unipolar and bipolar depression, showing promising results as augmentation strategies.

    “The importance of dopaminergic agents in depression has been suggested in both in unipolar and bipolar depression (McIntyre et al., 2017; Nunez et al., 2020; Szmulewicz et al., 2017) showing promising results as augmentation strategies.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites McIntyre et al., 2017 source
    • cites Nunez et al., 2020 source
    • cites Szmulewicz et al., 2017 source

  • May combine two claims.

    Study design and conductown data

    In the risk-of-bias assessment, 15 studies (24%) had low risk, 40 (63%) had moderate risk, and 8 (13%) had high risk.

    “Overall, 15 (24%) studies were rated as having low risk of RoB, 40 (63%) had moderate RoB and 8 (13%) had high RoB (Appendix 4, Fig. 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductreasoning

    Reporting of side effects and dosing in older trials may not have been optimal because of the trial design methodology at that time.

    “Additionally, we should consider the possibility that reporting of side effects and dosing in the older trials (ie. thyroid, lithium) was not optimal due to trial design methodology at that time.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Clinical guidelines such as CANMAT suggest caution with stimulant and stimulant-like molecules and recommend their use as second- or third-line adjunctive agents.

    “Clinical guidelines such as CANMAT suggest caution regarding the use of stimulant and stimulant like molecules and based on previous meta-analysis (Goss et al., 2013; Kennedy et al., 2016) recommend their utilization as second-third line adjunctive agents.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Goss et al., 2013 source
    • cites Kennedy et al., 2016 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    An overestimation of the results attributable to the natural course of illness could not be ignored.

    “An overestimation of the results for the included studies which could be attributable indeed to the natural course of illness could not be ignored”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cariprazine, already FDA approved for schizophrenia and bipolar I disorder, has been studied as an adjunctive agent for major depressive disorder and showed a significant reduction in MADRS scores at week 8 compared to placebo.

    “Similarly, cariprazine currently FDA approved for treatment of schizophrenia and bipolar-type I disorder has been studied as an adjunctive agent for MDD showed a significant reduction in MADRS scores at week 8 compared to placebo (Durgam et al., 2016; Earley et al., 2018).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Durgam et al., 2016 source
    • cites Earley et al., 2018

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Lithium and thyroid hormones constitute an important augmentation strategy in the general pharmacopeia for treatment-resistant depression despite being relatively underutilized.

    “Lithium and thyroid hormones constitute an important augmentation strategy in the general pharmacopeia for TRD despite being relatively underutilized.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
    • Rests on an assumption: Defining treatment-resistant depression as failure of one or more antidepressants in the current episode is adequate for identifying the TRD population.

  • May combine two claims.

    Premisecitation

    Evidence on the association between lamotrigine serum levels and response is inconclusive, which could contribute to inadequate therapeutic levels.

    “Lastly, we should also acknowledge the inconclusive evidence between association of lamotrigine serum levels and response which could contribute to inadequate therapeutic levels (Kumar et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kumar et al., 2021 source

  • May combine two claims.

    Study design and conductown data

    The study used a single all-cause discontinuation measure as a general reflection of drug acceptability and safety and did not include individualized side effects associated with dropout rates because such data were not widely available.

    “We provided a single measure of all cause discontinuation as a general reflection of drugs acceptability and safety outcomes and did not include individualized side-effects associated to dropout rates due to data not being widely available for all studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The study did not include comparisons of non-pharmacological augmentation treatments because of difficulties in standardizing comparisons, which could have overestimated the effect of a single medication or combination drug.

    “We did not include comparisons of non-pharmacological treatments associated to augmentation strategies considering difficulties to standardize comparisons; plausibly, this could have overestimated the effect of a single medication or combination drug”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    There was heterogeneity in the definition of treatment-resistant depression across included studies, which precludes assuming a homogeneous population.

    “There was heterogeneity in the definition of TRD in the included studies which precludes assuming a homogenous population”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Previous studies emphasize the use of these agents as a pivotal point to overcome treatment resistance.

    “Additionally previous studies emphasize the use of these agents as a pivotal point to overcome treatment resistance (Nelson and Papakostas, 2009; Rafeyan et al., 2020).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Nelson and Papakostas, 2009 source
    • cites Rafeyan et al., 2020

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductown data

    Three included studies reportedly included patients with bipolar disorders; the authors extracted unipolar depression data where possible and conducted a sensitivity analysis excluding the two studies without independent unipolar outcomes.

    “We included 3 studies which reportedly included bipolar disorders patients however we tried to extract data for patients with unipolar depression where possible (one study) and conducted a sensitivty analysis after excluding the two studies where independent unipolar depression outcomes were not avilable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    The study did not include comparisons with NMDA antagonists such as ketamine because those had been addressed in a previous network meta-analysis and have much faster action than conventional augmentation agents.

    “We did not include comparisons with NMDA antagonists, such as ketamine, since those have been addressed in a previous NMA (Carter et al., 2020) and has much faster action as compared to the conventional augmentation agents”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Carter et al., 2020 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Study design and conductnone given

    A dose-effect cannot be discounted and could contribute to sample heterogeneity.

    “We cannot discount a dose-effect which could also contribute to sample heterogeneity”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Thyroid hormones have shown evidence of antidepressant acceleration, particularly in women, and as an effective augmentation strategy.

    “Thyroid hormones have shown evidence of antidepressant acceleration, particularly in women, as well as an effective augmentation strategy (Altshuler et al., 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Altshuler et al., 2001 source

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

    Premisecitation

    Clinical recommendations for thyroid hormones in affective disorders have varied.

    “Despite decades of presence of thyroid hormones amongst the affective disorders’ pharmacopeia, clinical recommendations have varied (Gelenberg et al., 2010; Kennedy et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gelenberg et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Kennedy et al., 2016 source

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

    Premisecitation

    The World Federation of Societies of Biological Psychiatry Task Force recommends lithium as a first-line augmentation agent and aripiprazole and quetiapine as alternatives for unipolar treatment-resistant depression.

    “This is also congruent with current recommendations for augmentation in patients with unipolar TRD by the World Federation of Societies of Biological Psychiatry Task Force which considers lithium as first-line agent and aripiprazole and quetiapine as alternatives (Grunze et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Grunze et al., 2018 source

  • May combine two claims.

    Study design and conductown data

    Several included studies had small sample sizes and short follow-up times.

    “Several studies comprised small sample sizes (e.g. thyroid hormones, nortriptyline, lithium, and stimulants) and had short follow-up time.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The results may vary for patients with a higher level of treatment refractoriness.

    “The results may vary for patients with a higher level of treatment-refractoriness.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Defining treatment-resistant depression as failure of one or more antidepressants in the current episode is adequate for identifying the TRD population.
49 of 49

  • The paper relies on this without support.

    The trials included in the network meta-analysis are sufficiently similar for indirect comparisons to be valid.

    “Network meta-analysis (NMA) is a promising statistical method which allows to synthetize information from different clinical trials by combining direct and indirect evidence in the absence of head-to-head treatment comparisons.”

  • The paper relies on this without support.

    All-cause discontinuation is a valid proxy for overall acceptability.

    “We elected to use all cause discontinuation (proportion of patients who discontinued due to side effects) as measure of overall acceptability considering that data was not widely available for all studies.”

  • The paper relies on this without support.

    Lithium and thyroid hormones act faster than other augmentation agents, so trials shorter than four weeks can be included for them.

    “Most studies had a study duration of 4 weeks or longer, however, we also included studies with a shorter duration (< 4 weeks) for lithium and thyroid as there is data suggesting faster efficacy for these two agents.”

  • The paper relies on this without support.

    Response and remission definitions across the included trials are comparable enough to combine.

    “The primary outcome was response rates [(defined as a decrease of ≥ 50% of the validated behavioral scales for depression (e.g. HAMD or MADRS)]. Secondary outcomes included: remission rates, defined as a score below <10 for the MADRS or <7 on the HAMD or as per the study, and all cause discontinuation rates calculated for the patients who discontinued the trial.”

  • The paper relies on this without support.

    The different definitions of treatment-resistant depression used by included trials are sufficiently comparable for pooling.

    “Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons.”

  • The authors state this as an assumption.

    The transitivity assumption holds for the network meta-analysis.

    “Importantly we should also consider the plausibility of the transitivity assumption as an essential factor while controlling for the individual biases that could occur in the selection of included studies, populations and environment in which the studies were conducted (LeLorier et al., 1997).”

  • The paper relies on this without support.

    Defining treatment-resistant depression as failure of one or more antidepressants in the current episode is adequate for identifying the TRD population.

    “we defined TRD as failure of one or more antidepressants in the current episode of depression for our study. However, this definition has been used in prior systematic reviews and thus, the included patients could be less refractory than some other TRD studies requiring two failed antidepressants.”

  • The paper relies on this without support.

    Prior studies have suggested that lithium has a rapid onset of therapeutic effects for depression.

    “Prior studies have suggested a rapid onset of lithium’s therapeutic effects for depression despite variability in lithium dosages, population heterogeneity, and treatment durations among the studies.”
8 of 8

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.

  • All-cause discontinuation is defined as side-effect discontinuation

    Major

    One outcome definition counts patients who discontinued the trial, regardless of cause. The next sentence instead defines the same measure as the proportion who discontinued because of side effects.

  • Search language restriction is inconsistent

    Major

    The search is described as covering any language, but the methods later say it focused on English-language articles. The text does not clarify whether the search itself was language-restricted or only the subsequent study selection was.

  • Discontinuation outcome has conflicting definitions

    Minor

    The methods define all-cause discontinuation as discontinuation due to side effects. Later, the paper says it used all-cause discontinuation because side-effect-specific dropout data were not widely available. Those are different outcomes.

3 of 3

Cites

Flagged first, then by citations

3 of the 117 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. 2009, Study in patients with depression not responding to selective serotonin reuptake inhibitors, clinicaltrials.gov

Cited by

Sorted by citations

Related

Authors
Nuñez, N. A., Joseph, B., Pahwa, M., Kumar, R., Resendez, M. G., Prokop, L. J., Veldic, M., Seshadri, A., Biernacka, J. M., Frye, M. A., Wang, Z., & Singh, B.
Affiliations
Mayo Clinic (US)
Corresponding author
Singh, Balwinder
ORCID
Venue
Journal of Affective Disorders
Publisher
Elsevier BV
Published
2022-04
Volume
302
Pages
385-400
ISSN
0165-0327 (ISSN-L)
DOI
10.1016/j.jad.2021.12.134
PMC
PMC9328668
OpenAlex
W4206068971
Cited by
215
References
117
Citations by year
2026: 44 · 2025: 66 · 2024: 49 · 2023: 40 · 2022: 16
FWCI
6.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Affective Disorders (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of General Medical Sciences (T32GM008685)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Keywords
treatment-resistant depression, antidepressant augmentation, atypical antipsychotics, thyroid hormones, liothyronine, lithium, modafinil, lisdexamfetamine, aripiprazole, brexpiprazole, quetiapine, cariprazine, mirtazapine, ziprasidone, olanzapine, treatment discontinuation, stimulants
MeSH terms
Adult, Antidepressive Agents, Depression, Major Depressive Disorder, Humans, Antipsychotic Agents, Depressive Disorder, Treatment-Resistant

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 under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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