The DOI matches its Crossref record; 114 of the 117 references it cites were found in a registry or an index; 9 of the 54 sources its claims cite were checked for support.
Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis
Open accessAbstract
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.
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Claims the paper makes
9 of 54 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Introduction
What the sources say
- Not checked — no full text of the sourcecites Carter et al., 2020 source
- Partly supportedcites Strawbridge et al., 2019 sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites Vázquez et al., 2021 sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Supportedcites Cleare et al., 2015 source
The guideline’s augmentation recommendation (section and page unavailable in our copy) identifies quetiapine among the treatments with the best evidence of efficacy. Its discussion of a meta-analysis also reports higher response and remission rates for quetiapine than for placebo. This supports the cited point that the finding accords with clinical recommendations for MDD augmentation. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites Kennedy et al., 2016 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Abstract > Results:
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Response and remission definitions across the included trials are comparable enough to combine.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Abstract > Results:
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Response and remission definitions across the included trials are comparable enough to combine.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Abstract > Results:
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Response and remission definitions across the included trials are comparable enough to combine.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In order of decreasing efficacy, T3, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine and lisdexamfetamine were statistically significant compared to placebo, with RRs ranging from 1.18 (1.03–1.37) for lisdexamfetamine to 1.90 (1.16–3.11) for T3.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In order of decreasing efficacy, T3, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine and lisdexamfetamine were statistically significant compared to placebo, with RRs ranging from 1.18 (1.03–1.37) for lisdexamfetamine to 1.90 (1.16–3.11) for T3.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Abstract > Results:
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Response and remission definitions across the included trials are comparable enough to combine.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Abstract > Results:
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Response and remission definitions across the included trials are comparable enough to combine.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Abstract > Results:
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Response and remission definitions across the included trials are comparable enough to combine.
- Probably not a substantial claim. 25
- It may state two separate claims as one. 31
- The quote only partly states this claim. 1
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Introduction
What the sources say
- Could not verifycites Zhou et al., 2015 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites Carter et al., 2020 source
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Methods > Statistical analyses
What the sources say
- Supportedcites Krahn et al 2013 source
The Methods section defines an inconsistency statistic, Qinc, with a chi-squared reference distribution for testing consistency. The Software section says the authors provided a stand-alone R function for the net heat plot, which displays inconsistency between direct and indirect evidence. Page numbers are unavailable in our copy. (LLM, conf=0.92)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Methods > Data collection and risk of bias assessment
What the sources say
- Partly supportedcites Higgins et al., 2011 sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Partly supportedcites Zhou et al., 2015 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites Lorentzen et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Supportedcites Vázquez et al., 2021 source
The Methods describe a meta-analysis of treatment response, and the Abstract’s Conclusions report that lithium was somewhat more effective as an adjunct to antidepressants for acute major depressive episodes. This supports the cited comparison with evidence of lithium’s antidepressant efficacy, specifically as an adjunct rather than as a stand-alone treatment. No page numbers are available in our copy. (LLM, conf=0.91)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Not checked — no full text of the sourcecites Seshadri et al., 2021 source
- Partly supportedcites Strawbridge et al., 2019 sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Results
Strength:plain· not yet calibratedn = 1,450Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A total of 6322 records were retrieved of which 69 studies were included (Fig. 1).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Results
Strength:plain· not yet calibratedn = 10,701Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Abstract > Results:
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Aripiprazole and quetiapine are the two most studied AAs.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, we showed T3 to be significantly more effective than placebo and comparable to lithium.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, we should acknowledge that our results emphasize an improvement on response rates not remission.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Discontinuation data was not available for nortriptyline.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Brexpiprazole trials were of slightly shorter duration compared to cariprazine (6 and 8 weeks respectively).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Abstract > Results:
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data were extracted independently by three review authors (NAN, BJ, and MP) according to inclusion criteria.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Methods > Data collection and risk of bias assessment
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Methods > Data collection and risk of bias assessment
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A comprehensive search of several databases from each database’s inception to May 29th of 2020, any language, was conducted.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Methods > Data sources and search
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Current treatment guidelines recommend augmentation strategies after failure of two antidepressants or partial response with a primary antidepressant (Kennedy et al., 2016).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Introduction
What the sources say
- Not checked — no full text of the sourcecites Kennedy et al., 2016 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Abstract > Limitations:
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Our systematic review and NMA is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Methods
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Methods > Study selection and eligibility criteria
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Introduction
What the sources say
- Not matchedcites Berlim and Turecki, 2007a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Introduction
What the sources say
- Not checked — no full text of the sourcecites Carter et al., 2020 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Not checked — no full text of the sourcecites Cipriani et al., 2013 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The transitivity assumption holds for the network meta-analysis.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Different standards of regulations in development of clinical trials may have influenced reporting on adverse events or efficacy measures”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Results > Quality assessment and publication bias
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“An overestimation of the results for the included studies which could be attributable indeed to the natural course of illness could not be ignored”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Not checked — no full text of the sourcecites Durgam et al., 2016 source
- Not matchedcites Earley et al., 2018
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lithium and thyroid hormones constitute an important augmentation strategy in the general pharmacopeia for TRD despite being relatively underutilized.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Conclusion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Not checked — no full text of the sourcecites Kumar et al., 2021 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“There was heterogeneity in the definition of TRD in the included studies which precludes assuming a homogenous population”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Not checked — no full text of the sourcecites Nelson and Papakostas, 2009 source
- Not matchedcites Rafeyan et al., 2020
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Not checked — no full text of the sourcecites Carter et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We cannot discount a dose-effect which could also contribute to sample heterogeneity”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Thyroid hormones have shown evidence of antidepressant acceleration, particularly in women, as well as an effective augmentation strategy (Altshuler et al., 2001).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Not checked — no full text of the sourcecites Altshuler et al., 2001 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Despite decades of presence of thyroid hormones amongst the affective disorders’ pharmacopeia, clinical recommendations have varied (Gelenberg et al., 2010; Kennedy et al., 2016).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Not matchedcites Gelenberg et al., 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites Kennedy et al., 2016 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“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).”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
What the sources say
- Not checked — no full text of the sourcecites Grunze et al., 2018 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Several studies comprised small sample sizes (e.g. thyroid hormones, nortriptyline, lithium, and stimulants) and had short follow-up time.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results may vary for patients with a higher level of treatment-refractoriness.”
§ Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis☆ > Discussion
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- 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.
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.”
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
MajorOne 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.
“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.”
“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.”
Search language restriction is inconsistent
MajorThe 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.
“A comprehensive search of several databases from each database’s inception to May 29th of 2020, any language, was conducted.”
“Search was performed focused on articles with English language.”
Discontinuation outcome has conflicting definitions
MinorThe 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.
“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.”
“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.”
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Baweja, R. K., Waschbusch, D. A., Petrovic-Dovat, L., Baweja, R., Singh, B., Singh, M. K., & Waxmonsky, J. G. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2026.121967
Self-citationDrug and Physical Treatments of Depression
Williams, R. C., & Cleare, A. J. (2024) · Cambridge University Press eBooks · doi:10.1017/9781911623861.006
Brexpiprazole augmentation and mitochondrial gene expression changes in major depressive disorder
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Stereotactic Radiosurgery for Treatment Resistant Depression: Systematic Review
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The impact of levodopa on post-stroke depression: the ESTREL-depression-study
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MODERN STRATEGIES FOR THE TREATMENT OF TREATMENT-RESISTANT DEPRESSION – A LITERATURE REVIEW
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Grundlagen der Diagnostik und Therapie
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Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery
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ANTIPSYCHOTIC DRUGS: THREE GENERATIONS OF ANTIPSYCHOTICS
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Application of Optogenetic Neuromodulation in Regulating Depression
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Thyroid function and depression
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No-pharmacological treatments for mood disorders
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Depression – Konventionelle Therapien
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Increased sleep duration and emotional regulation in patients with major depressive episodes
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Metadata
- 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)
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 (medical) › 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.
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