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).