Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. (2015)

Unfortunately, a recent systematic review and meta-analysis has found no pro-cognitive benefits from glutamate modulators in schizophrenia:

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials.

Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

” …this is the first comprehensive meta-analysis to examine the effects of glutamate positive modulators on cognitive deficits in patients with schizophrenia. As a whole, glutamate positive modulators were not found to be superior to placebo as an adjunctive therapy to antipsychotics although 5 out of 17 individual studies have demonstrated their procognitive effects”

cognition glu
Effects of glutamate positive modulators on overall cognitive function. There were no significant differences in effects on overall cognitive function between glutamate positive modulators and placebo in patients with schizophrenia. CI, confidence interval; DCS, D-cycloserine; IV, inverse variance; SE, standard error; Std, standard.

“As a whole, glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, CI=−0.06 to 0.23, P=0.57) and each of eight cognitive domains in patients with schizophrenia.”

  • Minocycline was effective for attention/vigilance (SMD=0.42, CIs=0.02 to 0.82, P=0.04)*
  • DCS had negative effects on visual learning (SMD=−0.48, CIs=−0.86 to −0.09, P=0.01)*
    *These results, however, did not survive after adjusting for multiple comparison testing (the significance level was set at a Bonferroni corrected P-value of<0.05/(10 × 8) (10 compounds and 8 cognitive domains).
  • Glycine allosteric site of NMDA receptors: “There were no differences between the drugs (benzoate, DCS, d-serine, glycine, and Org25935) and placebo in terms of overall cognitive function.”
  • AMPA receptors: “Beneficial effects of the drugs (CX516 and minocycline) on attention/vigilance were found compared to placebo (four studies, n=205, SMD=0.32, CIs=0.01 to 0.64, P=0.05); the statistical significance did not survive after adjusting for multiple comparison testing in two subgroups and eight cognitive domains (a significance level of P<0.05/2 × 8)”
  • By concomitant antipsychotics: “No difference was found in subjects on non-clozapine antipsychotics between the drugs and placebo with respect to overall cognitive function (no data for overall cognition available for those on clozapine).”
  • By diagnosis of schizophrenia: “Among the studies that included subjects with schizophrenia only, we found beneficial effects of glutamate positive modulators on attention/vigilance (seven studies, n=460, SMD=0.20, CIs=0.01 to 0.39, P=0.04), which, however, was not confirmed after adjusting for multiple comparisons in 8 cognitive domains (significance level of P<0.05/8)”
  • Meta-regression analyses: “It was found that the higher the proportion of males in studies, the lower the SMDs of effects of glutamate modulators on overall cognitive function (11 studies, n=858, slope=−0.01, 95% CI: −0.03 to −0.002, P=0.03). There were no associations between the SMDs and age, duration of illness, concomitant antipsychotic dose, baseline PANSS total score, and baseline Clinical Global Impression score”

Some of the research is in its infancy:

“Notably, in the past several years, a number of compounds have been identified to enhance glutamatergic signaling. Minocycline, a tetracycline with broad-spectrum antimicrobial activity, has been suggested to increase GluR1 subunit phosphorylation and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiation. l-carnosine, a co-localized dipeptide with glutamate,and N-acetylcysteine, a precursor of glutathione, may enhance NMDA signaling via the redox site of the NMDA receptor. Pregnenolone, a neurosteroid, elevates serum pregnenolone sulfate, which in turn positively modulates NMDA receptors via a non-canonical G protein, phospholipase C, and a Ca2+ dependent mechanism. These promising compounds were not included in the previous studies. Therefore, it is critically important to include those new drugs and conduct a more comprehensive meta-analysis in order to provide robust evidence on the effects of glutamate positive modulators on cognitive functions in patients with schizophrenia.”

The limitations of the above study provide some hope and guidance for future research:

“The present report must be considered in light of various limitations. First, the number of included subjects and individual studies was still small. Second, we did not examine the long-term effects of glutamate positive modulators since duration of individual studies did not exceed 36 weeks. Third, the total number of subjects and studies varied across cognitive domains, as not all studies examined all cognitive domains. The results for specific cognitive domains that are based on a small number of studies or subjects need to be considered as preliminary. Fourth, it is worth noting that many of the drugs included in this study have different mechanisms of action even though each involves the glutamatergic system. As such, combining compounds with different glutamate-influencing mechanisms represents a limitation of our study. To somewhat address this limitation, we conducted subgroup analyses by the pathway of drugs to enhance the glutamatergic neurotransmission in which drugs were divided into the glycine allosteric site of NMDA receptor and AMPA receptor groups. However, the aforementioned limitation still exists for this subgroup analysis. Further research is necessitated to examine the relationships between procognitive effects and specific glutamate-influencing mechanisms of action. Fifth, some of the included compounds have been reported to have other mechanisms of action such as glutamatergic signal enhancers, anti-inflammation, or neuroprotection. Sixth, 15 out of 17 studies enrolled subjects within the chronic stage of the illness. It remains unclear whether these compounds have effects on subjects in the early stage of the illness (for example, FEP). Seventh, influences of concomitant antipsychotics are not clear. For example, 5 out of 17 studies did not discriminate between those taking clozapine, which has been reported to modulate glutamatergic signaling, and those taking non-clozapine antipsychotics. Eighth, although we included only double-blind randomized placebo-controlled trials, only 24% of the studies had a ‘low risk’ of bias, which should be carefully taken into account. Ninth, a possibility of publication bias should not be dismissed. Finally, we did not examine adverse events, which clearly hinders us from making a balanced risk-and-benefit decision.”

Some direction towards future research avenues is provided:

“…further research is needed to elucidate optimal dose ranges and route of administration of the drugs acting on glycine allosteric site in an effort to derive procognitive effects in schizophrenia.”

“Given that attention/vigilance has a crucial role in predicting favorable outcomes in patents with schizophrenia, AMPA positive modulators in particular, which may have beneficial effects on attention/vigilance, might have a role in improving functional outcome. …future studies are necessitated to investigate this relationship, given that there was a tendency that AMPA positive modulators might improve attention/vigilance.”

To conclude:

“The findings from this meta-analysis indicate that glutamate positive modulators were not effective for overall cognitive deficits in patients with schizophrenia. Further research is required to elucidate the role of the glutamatergic system on the cognitive dysfunction observed in schizophrenia. Going forward, it is necessary to characterize a subgroup of patients for which glutamate modulators are specifically procognitive within this heterogeneous population.”

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