TABLE 1

Effects of atypical antipsychotic drugs and drugs modulating targets modulating the glutamatergic system on positive and negative symptoms of schizophrenia and preclinical behavioral paradigms relevant to these symptom domains in addition to cognitive dysfunction

Behavioral Measure	D2/5HT2A Antagonists	mGlu2/3 Agonists	mGlu2 PAMs	GlyT1 Inhibitors	mGlu5 PAMs
Positive symptoms (clinic)	Yes	Yes	N.T.	N.R.^{^a}	N.T.
NMDA receptor antagonist-induced hyperlocomotion	Yes^{^b}	Yes^{^c}	Yes^{^d}	Yes^{^e}	Yes^{^f}
Amphetamine-induced hyperlocomotion	Yes^{^b}	Yes^{^g}	Yes^{^h}	Yes^ⁱ/No^{^j}	Yes^{^k}
Serotonergic hallucinogen-induced head shakes/twitches	Yes^{^l}	Yes^{^m}	Yes^ⁿ	N.R.	N.R.
Conditioned avoidance response	Yes^{^b}	Yes^{^o}	N.R.	N.R.	Yes^{^p}
Negative symptoms (clinic)	Yes	Yes	N.T.	N.T.^{^a}	N.T.
PCP-induced social interaction deficits	Yes^{^q}	N.R.	N.R.	N.R.	N.R.
Improve cognition^{^r} (preclinical)	No	Yes/No	Yes	Yes	Yes

N.R., not reported; N.T., not tested.
↵a Results of double-blind, placebo-controlled studies not yet reported for a number of GlyT1 inhibitors tested (phase 1/2 studies), including GSK1018921, ORG 25935 (SCH900435), RG1678, and R231857.
↵b For review, see Geyer and Ellenbroek (2003).
↵c Moghaddam and Adams, 1998; Cartmell et al., 1999; Rorick-Kehn et al., 2007.
↵d Galici et al., 2005; Johnson et al., 2005.
↵e Harsing et al., 2003; Depoortere et al., 2005; Boulay et al., 2008; Singer et al., 2009.
↵f Chan et al, 2008; Homayoun and Moghaddam, 2008; Liu et al., 2008.
↵g Gallici et al., 2005; Rorick-Kehn et al., 2007.
↵h Gallici et al., 2005.
↵i See Depoortere et al. (2005) for positive results in rats treated with PCP as neonates.
↵j See Singer et al. (2009) for GlyT1 inhibitor potentiation.
↵k Kinney et al., 2005; Liu et al., 2008.
↵l Sánchez and Arnt, 2000.
↵m Gewirtz and Marek, 2000; Klodzinska et al., 2002; Benneyworth et al., 2007.
↵n Benneyworth et al., 2007.
↵o Takamori et al., 2003; Rorick-Kehn et al., 2007.
↵p Liu et al., 2008.
↵q Nilsson et al., 2006.
↵r See text for discussion of improvement from baseline cognitive performance or provocation-induced impairment of cognition/executive function.