AbstractThere is growing evidence for the role of glutamate in the aetiology of schizophrenia and a number of glutamatergic drugs are being developed and trialled. This systematic review finds that there is evidence for beneficial effects on symptoms in schizophrenia for both adjuvant NMDA glycine binding-site agonists and monotherapy with a type II metabotropic glutamate receptor agonist (LY2140023). LY2140023 represents the first successful placebo controlled clinical trial of non-dopamine based antipsychotic therapy for schizophrenia but the evidence for its greater efficacy over glycine binding-site agonists is tentative at best. It is unclear why the apparently antagonistic effects of post-synaptic NMDA co-agonism and reduced glutamate release via pre-synaptic inhibition from type II metabotropic agonism both appear to have beneficial effects on schizophrenic symptoms, nor why the latter is so much more successful than direct NMDA antagonism. Ongoing trials should help to clarify the promising results found to date.
IntroductionAll existing antipsychotics work via the dopamine D2 receptor (1) but this class of medication has several important limitations. Although effective at treating ‘positive’ symptoms of schizophrenia (such as hallucinations and delusions) antipsychotics have limited impact on ‘negative’ symptoms (such as emotional blunting) or cognitive deficits, and it is these that are thought to have most relevance for prognosis (2). Side-effects are significant and range from considerable weight gain and hyperprolactinaemia to movement disorders such as extra-pyramidal effects and tardive dyskinesia. Although clozapine, and the atypical antipsychotics have been considered superior to typical antipsychotics any advantages appear to be fairly marginal (3).
While pathophysiological investigations of schizophrenia have traditionally concentrated on the dopaminergic system (4, 5) there is increasing evidence from gene association and neuropathological studies for an involvement of the glutamatergic system (6). For some time there have been hopes that medications which interact with the glutamatergic system may be able to ameliorate some of the negative and cognitive deficits of schizophrenia. In this review I appraise the current clinical evidence in a narrative systematic review of double blind randomised controlled clinical trials of adjuvant or monotherapy with glutamatergic drugs in schizophrenia.
MethodsGlutamatergic drugs were defined as those primarily acting via glutamate receptors or the glutamatergic system (e.g. re-uptake inhibition). Medline was searched via PubMed using the ‘broad’ and ‘therapy’ clinical study filters and the Cochrane Central Register of Controlled Trials (CENTRAL) was also searched up to January 2009. Search terms were ‘schizophrenia’ AND either ‘glutamate*’ or the names of specific glutamatergic compounds discussed below (glycine, d-cycloserine etc.). Unpublished trials from the CENTRAL database were not included in the results because no data was available, this may produce a degree of publication bias in the studies considered. Following from previous reviews I concentrate on overall symptoms as determined by the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS), negative symptoms as determined by the PANSS negative subscale or the Scale for the Assessment of Negative Symptoms (SANS), and positive, cognitive, and general symptoms from the relevant PANSS subscales.
ResultsSearches produced 522 records from Medline and 102 records from CENTRAL with 18 trials previously covered by a Cochrane review and a further 18 new studies identified. Trials were generally of good quality although small in size and of short duration. Reporting of blinding methods was poor, and outcome measures and statistical methodology were well validated but varied between trials making comparisons difficult. The initial goal to perform a meta-analysis using the additional data from newly identified studies was abandoned due to the difficulty in extracting usable data. All trials mentioned in this review are placebo controlled unless stated otherwise.
Glutamatergic stimulationOne model for pathology in schizophrenia is a hypoglutamatergic state or N-methyl-d-aspartate (NMDA) receptor dysfunction. Consistent with this proposal blockade of the NMDA receptor with phencyclidine or ketamine produces a psychotic syndrome similar to schizophrenia, including negative and cognitive symptoms. In pre-clinical trials, the use of co-agonists at the glycine binding-site of the NMDA receptor has been shown to modify some of the effects of NMDA antagonism (7).
The genes G72 and d-amino acid oxidase (DAAO) have been implicated in the genetics of schizophrenia (8) and are involved directly in neurotransmission at the NMDA receptor glycine binding-site, with DAAO metabolising the endogenous agonist d-serine.
These findings suggest that glycine binding-site agonists may potentially act to facilitate NMDA neurotransmission and correct underlying glutamate hypofunction in schizophrenia.
There have been a number of reports that augmentation of antipsychotics with agonists at the glycine binding-site preferentially improve negative and cognitive symptoms (7). A Cochrane Review has looked at the endogenous agonists glycine and d-serine and the partial agonist d-cycloserine as adjuvant therapy in schizophrenia (9). From data published up to 2003 they found 18 double blind randomised controlled trials, all short (≤12 weeks) with small numbers (358 subjects randomised in total).
d-cycloserine appeared to be ineffective on all measures, with trends towards harm compared to placebo. Glycine and d-serine were effective on some global measures and symptom scores. These comparisons all involved few patients (<150)>
Three further adjuvant studies of daily d-cycloserine have since been published and none of these found a beneficial effect on symptoms confirming the negative findings from the Cochrane review (10-12). However, an 8-week study of once weekly d-cycloserine adjuvant therapy in 38 patients found a statistically significant effect on mean negative scores but not 20% improvement rates or mean positive or cognitive scores (13).
Several studies of full glycine binding-site agonists have also been published since the Cochrane review. A 16-week trial, with 104 patients in the glycine and placebo groups combined, looking at adjunctive glycine found no difference from placebo for mean difference or 20% improvement in negative symptom scores, or for mean differences in cognitive or positive symptom scores (12). Conversely, a cross-over study of 17 patients using high dose glycine added to atypical antipsychotics resulted in a significant decrease in mean negative, cognitive, and positive symptom scores at 6-weeks. There was not a significant increase in 20% improvement rates for overall symptoms but there was for negative symptoms (14).
Similarly, in a cross-over study of 39 patients with adjuvant d-serine and atypical antipsychotics there was a significant decrease in mean negative, cognitive, and positive symptom scores, and also extra-pyramidal side-effects at 6-weeks, with 20% improvement rates significant for overall symptoms and negative symptoms (15). However, in a trial of d-serine added to risperidone, with 44 patients with acute exacerbations of schizophrenia in the d-serine and placebo groups combined, there was no statistically significant mean difference in overall or negative symptom scores at 6-weeks (16). Another small cross-over trial of 12 patients on clozapine also found no difference in mean overall, negative, positive, or general scores at 12-weeks (17).
Finally, d-alanine, another glycine binding-site agonist, has been tested as a adjuvant therapy in a 6-week study of 32 patients which found a significant benefit in mean scores on overall, negative, positive, and cognitive symptom scales (18).
The Cochrane review and later studies suggests that the partial agonist d-cycloserine is ineffective as adjuvant treatment in schizophrenia but the balance of evidence is still equivocal for the full glycine binding-site agonists. A reasonable estimate of the NNT for a 20% improvement in symptoms would be of the order of five patients but there is an obvious need for better and more consistent reporting to facilitate comparisons between trials and meta-analysis, particularly for cross-over trials. From the evidence these drugs appear to be well tolerated but they are not very practical to use, requiring fairly high doses diluted in liquid. Most trials have been fairly short, except for one 6 month trial of d-cycloserine, so estimates of long-term efficacy and tolerability are needed.
An alternative method of promoting agonist activity at the glycine binding site is the use of glycine re-uptake inhibitors. The glycine transporter-1 inhibitor N-methyl-glycine (sarcosine) has been examined in three studies. A 6-week trial of sarcosine with 38 patients showed benefits on mean differences in overall, negative, positive, cognitive, and general symptoms. These results were dependent on the analysis method, but mean differences at 6 weeks appear robust for overall and general symptoms (19).
Another 6-week study of sarcosine added to risperidone in acute exacerbations of schizophrenia, with 44 patients in the sarcosine and placebo arms combined, found significant changes in mean overall, negative, cognitive, and general symptom scales (although these depended on the analysis method used), with a significant difference in the rates of clinical response (defined as a 30% reduction in overall symptoms) (16). However, in a 6-week study of sarcosine added to clozapine with 20 patients there was no significant effect on mean difference in overall, negative, positive, cognitive, or general symptom scales (20). Pooling 6-week mean differences from all three studies will not result in significant effects because the statistical differences in the original studies largely depends on using regression to control for baseline imbalance in severity.
There has been some suggestion that use of glycine agonists with clozapine results in lower efficacy, perhaps because clozapine already has some glutamatergic activity. The Cochrane review found no evidence of differential efficacy of these drugs when used with typical or atypical antipsychotics, or with clozapine, and later studies have not provided any strong evidence to contradict this finding.
The compound CX516 is an ‘AMPAkine’ and allosterically binds to the ionotropic α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor prolonging channel opening. It has been studied as an adjuvant therapy in schizophrenia with no significant benefit found in mean overall, negative, positive, cognitive, or general symptom scales (21, 22). A tiny trial of eight patients also failed to find evidence of benefit for CX516 as monotherapy (23).
Recently a small trial of 20 patients was published looking at 6-weeks of sarcosine monotherapy for acute exacerbation of schizophrenia. This was not placebo controlled but rather compared high and low doses of sarcosine. There were no significant benefits of a higher dose on mean overall, negative, positive, or general symptom scales, but on the dichotomous outcome of 20% improvement in overall symptom score there was a significant benefit over the lower dose, and this was found in those subjects who were antipsychotic naïve (24). Although the dichotomous data suggests a NNT under three patients, in the absence of a change in mean symptom scores it seems unlikely that this finding reflects a true clinical benefit.
In contrast to the above proposition that glutamate hypofunction contributes to the symptomatology of schizophrenia, there has been some suggestion that glutamate hyperfunction may also play a role. Although superficially contradictory there is evidence that NMDA receptor hypofunction preferentially affects inhibitory interneurons causing disinhibition of pyramidal cells and increased glutamate release in prefrontal cortex (25).
Given the known effects of NMDA receptor antagonists such as phencyclidine in producing psychotic symptoms there has been little focus on these drugs as therapy. However, memantine is an NMDA antagonist used for the treatment of the cognitive symptoms of Alzheimer’s disease and has been investigated in an 8-week clinical trial of 138 patients as an adjunct to atypical antipsychotics. This study found no significant effect of memantine on global scores, or on overall, positive, negative, or cognitive symptom scales (26). There was also no significant difference in response rates (10% reduction in overall symptom score) but an increased rate of adverse events, including 6% of patients experiencing auditory hallucinations. Another study published only in abstract form has also found no effect of adjunctive memantine on cognitive measures (27).
In 2007 a glutamate agonist trial was published that caused some considerable interest. This was a 4-week trial of 196 patients with poorly controlled chronic schizophrenia given the compound LY2140023 (versus olanzapine or placebo) (28). LY2140023 is metabolised to LY404039, a selective agonist at metabotropic mGluR2/3 glutamate receptors. The gene for mGluR3 has previously been associated with schizophrenia (6). As an agonist at type II metabotropic autoreceptors LY2140023 would be expected to antagonise rather than potentiate glutamate transmission, a mechanism that contrasts with the NMDA glycine binding-site agonists. However, LY2140023 has been shown to ameliorate the effects of NMDA antagonists in pre-clinical studies. Significant reductions were seen in mean overall, negative, and positive symptom scores for both LY2140023 and olanzapine, but LY2140023 did not show the weight gain associated with olanzapine. The reduction in symptom scores was greater for olanzapine than LY2140023, particularly with positive symptoms, but this difference was not statistically significant. With the dichotomous outcome of improvement (25% reduction) in overall symptoms there was a significant benefit to both LY2140023 and olanzapine compared to placebo suggesting a NNT of less than three patients for olanzapine and around 3.5 for LY2140023.
It is worth noting that while commentators have been quick to hail the advent of a new antipsychotic agent without the extra-pyramidal side-effects of dopamine blockade this study did not find any evidence for a difference using a variety of rating scales for these side-effects, although there was a significant difference in prolactin levels between the two drug groups. A substantial number of patients dropped out of the study (40%, primarily due to lack of efficacy), significantly more in the placebo group although the LY2140023 group also had more dropouts than the olanzapine group.
The study of LY2140023 represents the first successful placebo controlled clinical trial of non-dopamine based antipsychotic therapy for schizophrenia* and the results suggest that this and similar compounds represent a promising avenue for developing antipsychotics with a different side-effect profile to that of current medication and the potential for efficacy in patients resistant to current treatments. This study does not establish that LY2140023 is better than olanzapine for negative symptoms, an early hope for these compounds, nor that it has a lower incidence of extra-pyramidal symptoms (since there were few of these in this short study) although prolactin levels were lower and weight gain less. There is an outstanding issue regarding the optimum dosing regime with LY2140023 and it is possible that higher doses could result in a greater antipsychotic effect and more marked effect on negative symptoms. A dosing study has just been completed but the manufacturers have recently announced that this failed to show a benefit of LY2140023 over placebo with no dose response effect – this failure has been ascribed to the large placebo response in the trial and further studies are awaited with interest.
It is worth comparing the NNT in the 2007 LY2140023 study with the evidence from glycine binding-site agonists as adjuvant treatment. The Cochrane review found a NNT for 20% reduction in symptoms of three patients (including evidence from later studies a more reasonable estimate would be five) and high dose sarcosine monotherapy produced a NNT of less than three patients (compared to a low dose of sarcosine). These effects are not markedly dissimilar to the results of LY2140023 and mean differences in negative symptom scales (the main outcome used in the adjuvant studies) for glycine binding-site agonists are of a similar magnitude to LY2140023. However, the difference in mean overall symptom scores is much larger for LY2140023 than the glycine binding-site agonists, and the sarcosine monotherapy trial produced no significant differences in mean symptom scores at all.
These comparisons suggest that, while LY2140023 has evidence for somewhat greater efficacy than glycine binding-site agonists this is a tentative conclusion at best, and may prove to be premature when the results of the latest trial of LY2140023 are published. We are still awaiting the outcome of placebo controlled trials of glycine binding-site agonists as monotherapy, but it is conceivable that use as adjuvant therapy may have underestimated the full antipsychotic effect of these compounds. Similarly, trials of LY2140023 as an adjuvant therapy may show an additive therapeutic benefit over-and-above the effect of conventional antipsychotics, which may be similar to or greater than that of the glycine binding-site agonists.
It is not entirely clear why both NMDA glycine binding-site agonism and reduced glutamate release (via type II metabotropic receptor agonism) appear to have beneficial effects on schizophrenic symptoms, nor why the latter is so much more successful than direct NMDA antagonism. Presumably differential and complex effects on neural circuits underlie this apparent paradox but it highlights how poor our understanding of the glutamatergic pathology of schizophrenia still is. Glutamatergic drugs may still not prove to be the future of schizophrenia treatment, but they are currently offering some hope.
* Although the original study found no evidence that LY2140023 or LY404039 interact with dopamine receptors it has been proposed that there may be some action at high-affinity state dopamine D2 receptors (29), and there are considerable interactions between the glutamatergic and dopaminergic systems (6).
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