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Cited by 138Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorDementia and Cognitive Impairment Research

Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far?

Open access
Keefe, Richard S. E., Buchanan, Robert W., Marder, Stephen R., Schooler, Nina R., Dugar, Ashish, Zivkov, Milana, Stewart, Michelle·2013·Schizophrenia Bulletin
DOI 10.1093/schbul/sbr153PMC PMC3576170
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Abstract

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website "www.clinicaltrials.gov" using the terms "schizophrenia AND cognition," "schizophrenia AND neurocognition," "schizophrenia AND neurocognitive tests," "schizophrenia AND MATRICS," "schizophrenia AND MCCB," "schizophrenia AND BACS," "schizophrenia AND COGSTATE," and "schizophrenia AND CANTAB" and "first-episode schizophrenia AND cognition." The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia.

AI snapshot

Written from the paper’s full text.

TL;DR

This review of 118 registered trials of potential cognitive-enhancing drugs in schizophrenia found that most completed trials were underpowered, short (≤8 weeks), and conducted in chronic stable patients, while ongoing trials are larger, longer, and more likely to use the MCCB. The authors conclude that completed studies cannot confidently rule out efficacy for most agents, and that younger patients in earlier illness phases may be more likely to benefit.

Key findings

  • Among 118 identified trials, add-on placebo-controlled parallel-group designs predominated: 55.7% of completed and 63.9% of ongoing trials used this design.
  • Only 17.6% of completed and 35.9% of ongoing add-on trials had sample sizes sufficient to detect a medium effect size (d = 0.5, requiring 71 subjects per group); only one of 17 completed trials with available results had sufficient power for a medium effect.
  • Completed add-on trials were mostly ≤8 weeks (58.8%), recruited chronic stable patients (mean age generally 40–49 years; 68% male), and used inconsistent cognitive outcome measures; ongoing trials were longer (66.7% >8 weeks) and 53.8% of ongoing add-on trials used the MCCB as the primary outcome versus 14.7% of completed trials.
  • No completed crossover trials with available results reported significant drug effects on cognition, and only 2 of 6 completed monotherapy trials were published but without neurocognitive results; the early-phase minocycline trial was reported as significantly superior to placebo for cognitive functioning and negative symptoms.

Methods

  • Trials were identified by searching clinicaltrials.gov with terms including “schizophrenia AND cognition,” “schizophrenia AND MATRICS,” “schizophrenia AND MCCB,” and related terms, with a cutoff date of 20 April 2011; included trials were in people with schizophrenia, had cognition as a primary or secondary outcome, and examined a pharmacologically active substance, while drug challenge, pharmacokinetic, pharmacodynamic, and prodrome studies were excluded.
  • Identified trials were grouped as completed, ongoing, or terminated and classified by design; data were manually extracted from registry entries and supplemented with PubMed, Google, and Google Scholar searches for public results, then summarized descriptively, with power calculations assuming 2-tailed alpha = .05, beta = .80, ICC = .90, and effect sizes d = 0.5 and d = 0.8.

Limitations

  • The paper states that clinicaltrials.gov is only one of many national and international registries, so the data are informative but not exhaustive; older trials may not be registered or may have been missed, and lack of available results for many trials precluded assessment of the most promising mechanisms of action.
  • The paper states that most completed trials had inadequate statistical power, short duration, chronic stable and mostly male samples, and inconsistent cognitive outcome measures, limiting conclusions about overall success.
  • Evident from the text: the review is descriptive rather than a meta-analysis, relies heavily on registry entries and public-domain results, and reports 118 included studies alongside 11 terminated, 61 completed, and 57 ongoing trials, a numerical inconsistency that further complicates synthesis.

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

Integrity signals

Registry

Crossref · 10.1093/schbul/sbr153

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 105 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    In the Lieberman et al memantine trial, a similar outcome was observed for all secondary measures.

    “• A similar outcome was observed for all secondary measures.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Lieberman, 2009, A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia, Neuropsychopharmacology source

      Not checked in the free run.

  • Findingcitation

    In the Lieberman et al memantine trial, at endpoint total PANSS scores did not differ between the memantine and the placebo group.

    “• At endpoint, total PANSS scores did not differ between the memantine and the placebo group”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Lieberman, 2009, A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia, Neuropsychopharmacology source

      Not checked in the free run.

  • Findingown data

    The only outlier with respect to the age inclusion criterion was a trial of minocycline, which included subjects with recent onset schizophrenia between 18 and 35 years.

    “The only outlier with respect to the age inclusion criterion was a trial of minocycline, 29 which included subjects with recent onset schizophrenia between 18 and 35 years.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Memantine was associated with a higher incidence of adverse events than placebo in the Lieberman et al trial.

    “• Memantine showed no efficacy as an adjunctive therapy in schizophrenia patients with residual psychopathology and was associated with a higher incidence of AEs than placebo.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Lieberman, 2009, A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia, Neuropsychopharmacology source

      Not checked in the free run.

  • Findingown data

    The trial duration was ≤8 weeks in 58.8% of completed trials.

    “While the trial duration was ≤8 weeks in the majority of completed trials (58.8%)”
    Quote in the paperNot a substantial claim
  • May combine two claims. 33
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 26

  • May combine two claims.

    Findingown data

    In 79.5% (N = 31) of the ongoing add-on trials and in 88.9% (N = 16) of ongoing trials using other designs, recruitment began since 2007.

    “In 79.5% (N = 31) of the ongoing add-on trials and in 88.9% (N = 16) of ongoing trials using other designs, recruitment began since 2007.”
    • Also stated in: § Characteristics of Completed and Ongoing Add-on Trials · plain
      “In 79.5% of the ongoing add-on trials, recruitment began since the development of the MCCB.18,19”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Other neuropsychological batteries (eg, BACS or CANTAB) were used in 20.6% of completed trials and various cognitive domain-specific tests in 35.3% of completed trials.

    “Other neuropsychological batteries (eg, BACS23 or CANTAB24) were used in 20.6% trials and various cognitive domain-specific tests in 35.3% of completed trials.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Participants of both sexes were recruited in the completed studies; male subjects were in a clear majority, with 68% men across all study samples.

    “Participants of both sexes were recruited in the completed studies; male subjects were in a clear majority, with 68% men across all study samples.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among the 57 ongoing trials, 31 (68.4%) are add-on trials; 5 (8.8%) are crossover trials, 7 (12.3%) are open label, and 6 (10.5%) are monotherapy trials.

    “Among the 57 ongoing trials, 31(68.4%) are add-on trials; 5(8.8%) are crossover trials, 7(12.3%) are open label, and 6(10.5%) are monotherapy trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Results of 50.0% of add-on trials and 22.0% of trials using other designs were available in the public domain.

    “Results of 50.0% of add-on trials and 22.0% of trials using other designs were available in the public domain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In the Buchanan et al trial, there was no difference between D-cycloserine vs placebo or glycine vs placebo in changes from baseline on the cognitive domain z score.

    “• No difference between D-cycloserine vs placebo or glycine vs placebo in changes from baseline on the cognitive domain z score”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Buchanan, 2007, The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments, Am J Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    55.7% of all completed and 63.9% of all ongoing CIAS trials used a randomized, double-blind placebo-controlled add-on design.

    “and is the primary design used in CIAS trials (55.7% of all completed and 63.9% of all ongoing trials) (figure 2).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Mean age ranged between 25.1 and 52.7 across the treatment groups; in the majority of studies it was between 40 and 49 years.

    “Mean age ranged between 25.1 and 52.7 across the treatment groups; in the majority of studies it was between 40 and 49 years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among the 61 completed trials, 34 (55.7%) used double-blind, randomized, placebo-controlled add-on design; 7 (11.5%) used randomized, double-blind, placebo-controlled crossover design; 3 (4.9%) used add-on open-label design; and 17 (27.9%) were monotherapy trials.

    “Among the 61 completed trials (figure 2), 34(55.7%) used double blind, randomized, placebo-controlled add-on design; 7(11.5%) used randomized, double-blind, placebo-controlled crossover design; 3(4.9%) used add-on open-label design; and 17(27.9%) were monotherapy trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In the Buchanan et al trial, there was no difference between D-cycloserine vs placebo or glycine vs placebo in changes from baseline on the SANS.

    “• No difference between D-cycloserine vs placebo or glycine vs placebo in changes from baseline on the SANS”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Buchanan, 2007, The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments, Am J Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The MCCB (either alone or in combination with another neurocognitive assessment battery) is the primary outcome measure in 53.8% (N = 21) of ongoing add-on trials and in 38.9% (N = 7) of ongoing trials using other designs.

    “The MCCB18,19 (either alone or in combination with another neurocognitive assessment battery) is the primary outcome measure in 53.8% (N = 21) of ongoing add-on trials and in 38.9% (N = 7) of ongoing trials using other designs.”
    • Also stated in: § Characteristics of Completed and Ongoing Add-on Trials · plain
      “In 53.8% of ongoing add-on trials, the MCCB (alone or in combination with other neurocognitive test batteries such as BACS,23 CANTAB,24 or CogState Schizophrenia Battery—CSSB25) is the primary outcome measure”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The exceptions are 5 trials (8.8%), 3 of which included subjects ≤35 years old, one between 18 and 45 years and one between 18 and 50 years.

    “The exceptions are 5 trials (8.8%), 3 of which included subjects ≤35 years old, one between 18 and 45 years and one between 18 and 50 years.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Ongoing add-on trials are recruiting subjects of both sexes.

    “Ongoing add-on trials are recruiting subjects of both sexes (see online supplementary table 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In trials that reported a functional outcome, the University of California San Diego Performance Skills Assessment was the most frequently used functional capacity measure; it was included in 4/11.8% of the completed and 4/10.3% of the ongoing trials.

    “In those that reported a functional outcome, the University of California San Diego Performance Skills Assessment26 was the most frequently used functional capacity measure; it was included in 4/11.8% of the completed and 4/10.3% of the ongoing trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Only 17.6% of completed and 35.9% of ongoing trials report a sample size that was or is anticipated to be sufficient to produce statistical power to detect a medium (d = 0.5) effect size.

    “However, only 17.6% of completed and 35.9% of ongoing trials report a sample size that was or is anticipated to be sufficient to produce statistical power to detect a medium (d = 0.5) effect size”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In the Honer et al trial, the verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group (P = .02 for the comparison between the 2 groups in the change from baseline).

    “• The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group (P = .02 for the comparison between the 2 groups in the change from baseline).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Honer, 2006, Clozapine alone versus clozapine and risperidone with refractory schizophrenia, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Among 17 completed studies, the mean age of illness onset was reported in only 2 studies and mean duration of illness in 7 studies.

    “Among these 17 completed studies, the mean age of illness onset was reported in only 2 studies (11%–8%; onset at 22.7–25.9 y of age across the treatment groups) and mean duration of illness in 7 studies (41.2%; ranging between 13.0 and 25.5 y across the treatment groups).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Only 2 of 6 completed monotherapy trials are currently published but without results of neurocognitive testing.

    “Only 2 of 6 completed monotherapy trials are currently published49,50 but without results of neurocognitive testing.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Kane, 2010, Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia, J Clin Psychopharmacol source

      Not checked in the free run.

    • cites [50] Kinon, 2011, A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia, J Clin Psychopharmacol source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the Buchanan et al MK0777 trial, there were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment-2 and Schizophrenia Cognition Rating Scale total scores.

    “• There were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment-2 and Schizophrenia Cognition Rating Scale total scores.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Buchanan, 2011, A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The studies included pharmacological treatments with many diverse mechanisms of action, though agents acting at the NMDA receptor have been examined most frequently.

    “The studies included pharmacological treatments with many diverse mechanisms of action, though agents acting at the NMDA receptor have been examined most frequently.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In the Freudenreich et al trial, modafinil did not reduce negative symptoms or wakefulness/fatigue or improve cognition compared with placebo.

    “• Modafinil did not reduce negative symptoms or wakefulness/fatigue or improve cognition compared with placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Freudenreich, 2009, Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial, J Clin Psychiatry source

      Not checked in the free run.

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

    Findingnone given

    The level of baseline cognitive impairment was defined in few ongoing trials.

    “The level of baseline cognitive impairment was defined in few ongoing trials.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Most of the studies reviewed recruited participants aged between 18 and 55/60/65 years.

    “Most of the studies reviewed recruited clinically stable people with schizophrenia, aged between 18 and 55/60/65 years with a mean age between 40 and 49 years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Some of the studies included in this analysis were conducted in the early phases of drug development and involved small sample sizes.

    “Some of the studies included in this analysis were conducted in the early phases of drug development and in keeping with their exploratory nature, involved small sample sizes.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    Ongoing trials generally allow for recruitment of subjects aged between 18 and 55-65 years.

    “The ongoing trials generally allow for recruitment of subjects aged between 18 and 55–65 years, and it is likely that the actual age range will be comparable to the completed studies.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    It is still not confirmed whether the MCCB is sensitive to change during pharmacological treatment.

    “However, it is still not confirmed whether the MCCB is sensitive to change during pharmacological treatment.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    Few data are available that address empirically whether younger patients with greater potential neuroplasticity are optimal candidates for pharmacological intervention.

    “It is reasonable to expect that younger patients with greater potential neuroplasticity may be optimal candidates for pharmacological intervention, but surprisingly, few data are available that address this question empirically.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our search revealed the use of neuropsychological test batteries other than the MCCB (e.g., BACS, CANTAB, and CSSB), though their use is somewhat limited in the ongoing trials.

    “Our search revealed the use of neuropsychological test batteries other than the MCCB (eg, BACS,23 CANTAB,24 and CSSB25), though their use is somewhat limited in the ongoing trials.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] Keefe, 2004, The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery, Schizophr Res source

      Not checked in the free run.

    • cites [24] Robbins, 1994, Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers, Dementia

      Not checked in the free run.

    • cites [25] Maruff, 2003, Abnormalities of motor imagery associated with somatic passivity phenomena in schizophrenia, Schizophr Res source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    Half of the completed trials do not have results in the public domain.

    “Since half of the completed trials do not have results in the public domain and even fewer in the peer-reviewed literature, it is unfortunately challenging to make any reliable appraisals of the factors that may be associated with negative trial results.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    Ongoing studies appear to have greater statistical power than completed studies.

    “Ongoing studies appear to have greater statistical power and the opportunity for positive results is greater.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The MATRICS initiative created the MATRICS Consensus Cognitive Battery (MCCB) for measuring cognitive treatment outcomes in schizophrenia.

    “and created the MATRICS Consensus Cognitive Battery (MCCB)18,19 for measuring cognitive treatment outcomes in schizophrenia.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Nuechterlein, 2008, The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity, Am J Psychiatry source

      Not checked in the free run.

    • cites [19] Kern, 2008, The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization, Am J Psychiatry source

      Not checked in the free run.

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

    Premisecitation

    Based on experience from early studies that used the MATRICS clinical trial guidelines, the MATRICS investigators recommended revision of the inclusion criteria to enhance recruitment while maintaining sufficient methodological rigor.

    “Based on experience from early studies that used the MATRICS clinical trial guidelines, the MATRICS investigators recommended revision of the inclusion criteria to enhance recruitment while maintaining sufficient methodological rigor.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Buchanan, 2011, The FDA-NIMH-MATRICS Guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later?, Schizophr Bull source

      Not checked in the free run.

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

    Premisecitation

    A randomized, double-blind placebo-controlled add-on design was recommended by the MATRICS panel.

    “A randomized, double-blind placebo-controlled add-on design was recommended by the MATRICS panel17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Buchanan, 2005, A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia, Schizophr Bull source

      Not checked in the free run.

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

    Study design and conductreasoning

    The power calculation assumptions were not strictly met in some cases, especially for studies using outcome measures with lower reliability and study designs with multiple treatment arms.

    “Note that these assumptions were not strictly met in some cases, especially for studies using outcome measures with lower reliability and study designs with multiple treatment arms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The Goff et al study, as the first study of once-weekly dosing in schizophrenia, was exploratory, so its results must be considered preliminary.

    “• As the first study of once weekly dosing in schizophrenia, this study was exploratory and so results must be considered preliminary.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Goff, 2008, Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study, Schizophr Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Galantamine may have selective benefits for aspects of processing speed and verbal memory but interferes with practice effects during the performance of an attention task.

    “• Galantamine may have selective benefits for aspects of processing speed and verbal memory but interferes with practice effects during the performance of an attention task.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Buchanan, 2008, Galantamine for the treatment of cognitive impairments in people with schizophrenia, Am J Psychiatry source

      Not checked in the free run.

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

    Study design and conductcitation

    In the Buchanan et al MK0777 trial, it was planned to enroll 30 participants/group, which would have enabled detecting an effect size of .73 with power .80.

    “Planned toenroll 30 participants/group, which would have enabled detecting an effect size _ .73 with power _ .80.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Buchanan, 2011, A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    In the Buchanan et al MK0777 trial, actual recruitment was only approximately 20 participants/group, but the observed R of approximately .9 suggested power to detect an effect size of .49.

    “The actual recruitment was only approximately 20 participants/group, but the observed R approximately_.9, suggesting power to detect an effect size of .49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Buchanan, 2011, A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia, Biol Psychiatry source

      Not checked in the free run.

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

    Study design and conductcitation

    In the Buchanan et al MK0777 trial, the sample size was determined with the ANCOVA power formula using z of 2.24, z of .842 (power .80), an estimated baseline-to-endpoint correlation of .6 for the MCCB composite score, the between-group difference, and the SD of the primary outcome.

    “The sample size was determined with the ANCOVA power formula, n_2(z__z_)2 s2 (1_R 2)/d2, with z__ 2.24, z__.842 (corresponding to power_.80), R_the correlation between baseline and end of study measures of the primary outcome (estimated to equal .6 for the MCCB composite score), d the difference between groups, and s the SD of the primary outcome.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Buchanan, 2011, A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia, Biol Psychiatry source

      Not checked in the free run.

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

    Study design and conductcitation

    In the Lieberman et al memantine trial, the required sample size was determined using the assumption that a clinically meaningful difference between the 2 treatment groups would be 8.5 points in total PANSS score with a pooled SD of 14.7.

    “The required sample size was determined using the assumption that a clinically meaningful difference between the 2 treatment groups would be 8.5 points in total PANSS score with a pooled SD of 14.7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Lieberman, 2009, A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The Freudenreich et al trial had limited power to detect a treatment effect, with a clear possibility of a type II error.

    “• Given the limited power to detect a treatment effect and the clear possibility of a type II error, larger trials are needed to resolve or refute a potential therapeutic effect of uncertain magnitude”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Freudenreich, 2009, Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial, J Clin Psychiatry source

      Not checked in the free run.

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

    Study design and conductreasoning

    Some older trials may not be registered at www.clinicaltrials.gov, or some trials may not have been identified in the search and therefore omitted from the analysis.

    “In addition, some older trials may not be registered at www.clinicaltrials.gov, or some trials may not have been identified in the search and therefore omitted from this analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Worse recall of material in episodic memory, changes in select time-based measures of problem solving, and fine motor dexterity have been associated with greater length of illness in schizophrenia.

    “Larger deficits in working memory have been shown to exist in elderly vs first-episode people with schizophrenia, while worse recall of material in episodic memory, changes in select time-based measures of problem solving and fine motor dexterity have all been associated with greater length of illness.61,62”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Zanello, 2009, Working memory impairments in first-episode psychosis and chronic schizophrenia, Psychiatry Res source

      Not checked in the free run.

    • cites [62] Sponheim, 2010, Cognitive deficits in recent-onset and chronic schizophrenia, J Psychiatr Res source

      Not checked in the free run.

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

    Premisecitation

    The MCCB has been translated into a range of languages to accommodate the needs of multinational trials.

    “To accommodate the needs of multinational trials, the MCCB has been translated into a range of languages.67”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Harvey, 2010, Latest developments in the MATRICS process, Psychiatry (Edgmont)

      Not checked in the free run.

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

    Interpretationreasoning

    Younger patients with greater potential neuroplasticity may be optimal candidates for pharmacological intervention.

    “It is reasonable to expect that younger patients with greater potential neuroplasticity may be optimal candidates for pharmacological intervention, but surprisingly, few data are available that address this question empirically.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The actual age range in ongoing trials will likely be comparable to the completed studies.

    “The ongoing trials generally allow for recruitment of subjects aged between 18 and 55–65 years, and it is likely that the actual age range will be comparable to the completed studies.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The MATRICS recommendation for a phase 3 registration trial to be at least 6 months remained unchanged in the recent revision.

    “The original MATRICS guidelines17 specify that a phase 3 registration trial should be of sufficient duration to show an enduring effect on cognition (ie, at least 6 months), and this recommendation remained unchanged in their recent revision.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Buchanan, 2011, The FDA-NIMH-MATRICS Guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later?, Schizophr Bull source

      Not checked in the free run.

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

    Interpretationcitation

    Large samples imply multi-site trials, which present investigators and sponsors with specific challenges.

    “Such large samples imply multi-site trials, which present investigators and sponsors with specific challenges (for review, see ref.54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Leon, 2008, Implications of clinical trial design on sample size requirements, Schizophr Bull source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MCCB has excellent reliability, minimal practice effects, and significant correlations with measures of functional capacity.

    “It has been demonstrated that the MCCB18,19 has excellent reliability, minimal practice effects, and significant correlations with measures of functional capacity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Nuechterlein, 2008, The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity, Am J Psychiatry source

      Not checked in the free run.

    • cites [19] Kern, 2008, The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization, Am J Psychiatry source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The original MATRICS guidelines specify that a phase 3 registration trial should be of sufficient duration to show an enduring effect on cognition (at least 6 months).

    “The original MATRICS guidelines17 specify that a phase 3 registration trial should be of sufficient duration to show an enduring effect on cognition (ie, at least 6 months), and this recommendation remained unchanged in their recent revision.20”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Buchanan, 2005, A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia, Schizophr Bull source

      Not checked in the free run.

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

    Premisecitation

    The MATRICS guidelines noted that in general, it is not necessary to exclude subjects with a high level of cognitive functioning in whom further improvement in cognition would not be expected to be demonstrated because with a properly constructed cognitive test battery, this level of performance is very rare.

    “The MATRICS guidelines17 noted that in general, it is not necessary to exclude subjects with a high level of cognitive functioning in whom further improvement in cognition would not be expected to be demonstrated because with a properly constructed cognitive test battery, this level of performance is very rare.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Buchanan, 2005, A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia, Schizophr Bull source

      Not checked in the free run.

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

    Interpretationcitation

    The initial findings on genetic mediation of improvements in neurocognitive deficits will require replication and functional validation.

    “Although the possibility of genetic mediation of improvements in neurocognitive deficits is intriguing, the initial findings to date will require replication and functional validation.70”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] McClay, 2011, Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia, Neuropsychopharmacology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Older, chronic, mostly male patients with schizophrenia may be the least likely to benefit from cognitive enhancement.

    “Further, the predominant patient population in these studies has been older, chronic, and mostly male patients with schizophrenia, who may be the least likely to benefit from cognitive enhancement.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The recent VIM study suggests that there are no optimal co-primary measures, although several of them have reasonable psychometric characteristics.

    “The recent VIM study68 suggests that there are no optimal co-primary measures, although several of them have reasonable psychometric characteristics.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Green, 2011, Evaluation of functionally meaningful measures for clinical trials of cognition enhancement in schizophrenia, Am J Psychiatry source

      Not checked in the free run.

54 of 54

  • The paper relies on this without support.

    The trials listed on clinicaltrials.gov are representative of the clinical trials of cognitive-enhancing drugs in schizophrenia.

    “A review of the trials listed on www.clinicaltrials.gov suggests that a substantial number of clinical trials of potential treatments for cognitive enhancement in schizophrenia are currently ongoing.”
1 of 1

Claims other papers make about this one

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

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.

  • Armodafinil baseline MCCB minimum differs from Table 1

    Minor

    The text gives the lowest armodafinil-group baseline MCCB score as 20.8, while Table 1 gives 20.6 with the same SD of 8.5.

  • Ongoing add-on count does not match its percentage

    Minor

    Of 57 ongoing trials, 31 would be 54.4%, not 68.4%. The listed design counts also total only 49 rather than 57.

    Reported 68.4 · recomputed 54.385965

  • Age-range exceptions use the wrong denominator

    Minor

    This passage describes ongoing add-on trials, for which the paper elsewhere gives a total of 39. Five of 39 is 12.8%, whereas the reported 8.8% uses all 57 ongoing trials as its denominator.

    Reported 8.8 · recomputed 12.820513

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. American Psychiatric Association, Global Assessment of Functioning Scale. Diagnostic and Statistical Manual—III rd Edition, Revised.

Cited by

Sorted by citations

Related

Authors
Keefe, R. S. E., Buchanan, R. W., Marder, S. R., Schooler, N. R., Dugar, A., Zivkov, M., & Stewart, M.
Affiliations
  • Duke University (US)
  • University of Maryland, Baltimore (US)
  • University of California, Los Angeles (US)
  • SUNY Downstate Health Sciences University (US)
  • Pfizer (United States) (US)
Corresponding author
Keefe, Richard S. E.
ORCID
Venue
Schizophrenia Bulletin
Publisher
Oxford University Press (OUP)
Published
2011-11-22
Volume
39
Issue
2
Pages
417-435
ISSN
  • 0586-7614 (ISSN-L)
  • 1745-1701
DOI
10.1093/schbul/sbr153
PMC
PMC3576170
OpenAlex
W2135288411
Semantic Scholar
8baab6b3820c5bf9696759a7f192bf328d605acc
Cited by
138
References
67
Citations by year
2026: 2 · 2025: 3 · 2024: 8 · 2023: 2 · 2022: 7 · 2021: 9 · 2020: 6 · 2019: 11 · 2018: 11 · 2017: 11 · 2016: 15 · 2015: 13 · 2014: 15 · 2013: 22 · 2012: 3
FWCI
1.68
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Schizophrenia Bulletin (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
Funders
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Sanofi
  • Sunovion
  • Astellas Pharma
  • H. Lundbeck A/S
  • Medical Research Council
  • National Institute of Mental Health
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
schizophrenia, cognitive impairment
MeSH terms
Adolescent, Adult, Aged, Clinical Trials as Topic, Cognition Disorders, Female, Humans, Male, Middle Aged, Schizophrenia, Schizophrenic Psychology, Nootropic Agents, Young Adult

About these checks

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

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

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

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