Glutamatergic agents
Many drugs that target and co-activate glutamatergic pathways have been of interest as a non-dopaminergic approach to improve antipsychotic treatment in schizophrenia. Strategies to improve glutamate NMDA receptor hypoactivity on GABAergic interneurons have targeted extracellular binding sites on the receptor. The glycine modulatory site has been investigated as a target to improve NMDA receptor hypofunction in schizophrenia and several agonists or partial agonists of this binding site on the NMDA receptor have been studied in clinical trials (138).
The amino acid glycine is a co-agonist of the NMDA receptor and it is required along with glutamate to activate the NMDA ion channel (139, 140). The binding site for glycine (located on the NR1 subunit) of the NMDA receptor was first discovered by Johnson and Ascher (1987) by preclinical electrophysiology studies using the outside-out patch clamp method. The NMDA receptor response was then observed to be potentiated by glycine. The distinct binding site (glycine B receptor) was separate from the strychnine-sensitive glycine inhibitory receptor as NMDA receptor potentiation by glycine was not blocked by strychnine (139). In clinical studies, reduced plasma concentrations of glycine have been found in patients with schizophrenia and have been correlated with a greater number of negative symptoms (141, 142), supporting the use of glycine as a strategy to improve NMDA receptor functioning in those patients identified as having treatment resistance specific to the negative symptom domain (138).
Glycine was first used as an augmenting treatment in schizophrenia close to 30 years ago in a few small open-label clinical trials used at doses between 5 and 25 g per day (138, 143–145). In subsequent controlled trials, 60 g of glycine augmented with first-generation or second-generation antipsychotic medication was reported to improve not only the negative symptoms (146–150), but also cognitive symptoms (147, 148, 150) and the depressive symptoms of the illness (148). Glycine is not able to cross the blood-brain barrier easily as it has no specific amino acid transporter, so higher doses must be used that impacts patients' tolerability to glycine. The benefits reported of using glycine as an augmenting treatment to antipsychotic medications to improve the cognitive and negative symptoms domains of the illness has since been disputed. In a subsequent review, glycine was found to have moderate effect in reducing negative symptoms and it was uncertain whether it had any benefit at improving cognitive symptoms (151). The multicentre Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST), found no significant differences between glycine and placebo at improving the negative or cognitive symptom domains of the illness (152). Overall, glycine may be beneficial for those patients that have treatment resistance specific to the negative and cognitive symptom domains; (153) however it has not been a beneficial augmenting strategy in patients with TRS on clozapine (154).
An alternative approach to increasing endogenous brain glycine concentrations has been to block its reuptake and thus improve glutamatergic tone. The amino acid sarcosine, a GlyT1 inhibitor, has also been demonstrated to improve the negative, cognitive and depressive symptom domains of schizophrenia (155, 156). Unfortunately, significant side-effects have since been reported including ataxia, hypoactivity and respiratory depression with the use of sarcosine, perhaps in relation to mechanisms involved in the overstimulation of the strychnine-sensitive glycine inhibitory glycine receptor (157, 158). When used as an augmenting strategy in patients with TRS, sarcosine was also not effective (159). This may be related to clozapine's glutamatergic effects and known GlyT1 antagonist properties (136, 138). Bitopertin, a non-sarcosine-based selective GlyT1 inhibiting drug, has also been investigated as an adjunct to antipsychotics (at doses of 10 and 30 mg per day) to mainly target the negative symptom domain of the illness (160). In subsequent phase III trials (SearchLyte trial programme), bitopertin was unsuccessful at improving the primary outcome measure of Positive and Negative Syndrome Scale (PANSS) (161) negative symptom scores over placebo which led the manufacturer Hoffmann-La Roche to discontinue the programme prematurely (138).
D-serine, an allosteric modulator at the glycine co-agonist binding site, has also been investigated as an augmenting strategy primarily for improving the deficit symptoms of schizophrenia. D-serine may be more effective than glycine as it has a greater affinity for the glycine/serine binding site and also has an increased ability to cross the blood-brain barrier (162–164). Serum concentrations of D-serine have also been found to be reduced in schizophrenia (165). D-serine selectively binds to synaptic NMDA receptors and may strengthen circuit connectivity and have more of a neuroprotective effect as compared to glycine, which binds to both synaptic and extrasynaptic NMDA receptors (138, 166). The therapeutic effects of D-serine to improve refractory negative symptoms in schizophrenia have been demonstrated when added to antipsychotic therapy in patients with acute (156), chronic (167), and treatment-resistant illness (168). D-serine is well-tolerated and has been reported to be safe and effective used at dosages up to 120 mg/kg per day (169). D-cycloserine, a drug that was initially used to treat tuberculosis and an anolog of D-serine, is also active at the glycine site and has been reported to benefit the negative symptom domain of schizophrenia (170–172). Unfortunately, in patients with TRS, glycine, D-serine, and D-cycloserine have all been reported to be less effective at improving the negative and cognitive symptom domains in those patients receiving clozapine therapy (138, 152, 154, 172, 173).
Drugs that can downregulate presynaptic disinhibited glutamate release on secondary downstream glutamate neurons have also been explored in patients with TRS and may also work to modulate circuit connectivity. Lamotrigine, an anticonvulsant drug that suppresses presynaptic glutamate release by the blockade of voltage-sensitive sodium channels has been shown to improve clinical response when used as an adjunct to clozapine treatment in ultra-resistant schizophrenia (138, 174–178). The beneficial effects may be associated with clozapine's low affinity to the D2-receptor and involvement with the glutamate system (in comparison to other antipsychotic drugs) which may be further enhanced by lamotrigine (138, 175). More recent clinical trials have studied the efficacy between the metabotropic glutamate 2/3 (mGlu2/3) receptor agonist pomaglumetad methionil (also known as LY2140023) and atypical antipsychotics (138, 179, 180). In a phase II study, it was found to be less effective than the comparator atypical antipsychotic (180) and Eli Lilly subsequently stopped a phase III trial investigating the compound as it failed to meet its primary endpoint.