Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options

Figures & data

Table 1 Emerging pharmacological agents for the treatment of negative symptoms in patients with schizophrenia

Class/agent	Mechanism of action	Meta-analysis?	Number of studies and major findings	Number of patients evaluated
NMDA receptor function enhancers
Glycine-site agonists
Glycine, D-cycloserine, D-serine, D-alanine	Increase in NMDA receptor activation through glycine-site binding	No	Five studies: improvement in negative symptoms^Citation88^–^Citation92	N=74
			CONSIST: no clinical benefit conferred by glycine or D-cycloserine^Citation17	N=157
		Yes	Two meta-analyses: benefit with D-serine and sarcosine for the treatment of negative symptoms^Citation81,Citation82	N=181^Citation81; N=145^Citation82
			One meta-analysis: benefit with glycine^Citation81	N=133
D-amino acid oxidase (DAAO) inhibitors Sodium benzoate	Increase D-serine by diminishing its catabolism and increase NMDA receptor activation at the glycine-binding site	No	Proof-of-concept study: improvement in negative symptoms^Citation93	N=53
Glycine reuptake inhibitors (GRIs)
Sarcosine	Naturally occurring, nonselective GRI used as a clinical research tool	Yes	Two meta-analyses: benefit with D-serine and sarcosine for the treatment of negative symptoms^Citation81,Citation82	N=181^Citation81; N=145^Citation82
		No	Four studies: improvement of negative symptoms with sarcosine^Citation83^–^Citation87	N=203 total across four studies
Bitopertin	Corrects or compensates for potential NMDA receptor hypofunction by boosting synaptic availability of glycine (NMDA receptor coagonist with glutamate)	No	Phase II study: bitopertin (10 mg or 30 mg once daily) added to stable antipsychotic regimen significantly improved the PANSS negative symptoms factor score in patients completing the trial according to protocol^Citation80	N=323
Metabotropic glutamatergic receptor 2 (mGluR2)
Pomaglumetad methionil (LY2140023)	Agonism of mGluR2/3; decreases amount of glutamate released in the synapse	No	Adjunctive therapy trial: negative results; development program terminated^Citation94	N=167
JNJ-40411813/ADX-71149	Positive allosteric modulator (PAM) of mGluR2	No	Phase IIa adjunctive therapy trial: trend toward separation from placebo after 1 month at moderate doses^Citation95	N=92
Nicotinic acetylcholine receptors
EVP-6124	Alpha-7 nicotinic receptor agonism	No	Phase IIb study: demonstrated improvement of negative symptoms (secondary end point)^Citation96	N=319
TC-5619	Alpha-7 nicotinic receptor agonism	No	Phase IIb study: negative results; development program terminated^Citation133	N=477
			Proof-of-concept study: promising results on cognitive end points and negative symptoms^Citation97	N=185
Galantamine	Dual alpha-7 nicotinic receptor PAM and cholinesterase inhibitor	No	Small study: galantamine failed to show any benefit on negative symptoms or cognition but demonstrated significant treatment effects for global functioning and free verbal recall^Citation98	N=43
Donepezil	Cholinesterase inhibitor	Yes	Meta-analysis of five adjunctive therapy studies (two studies with galantamine; three studies with donepezil): greater effect on negative symptoms than cognition^Citation99	N=103
Psychostimulants
Lisdexamfetamine dimesylate	Prodrug of dextroamphetamine with CNS stimulant activity; blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases their release into the extraneuronal space^Citation100	No	Open-label trial: potential benefit for negative symptoms without aggravating positive symptoms^Citation101,Citation102	N=69
Modafinil, armodafinil	CNS stimulants with wake-promoting actions similar to amphetamine; both also bind in vitro to the dopamine transporter and inhibit dopamine reuptake	No	Available study data do not conclusively support use of modafinil/armodafinil as add-on treatment^Citation102,Citation103	N=970
Other drugs
N-acetyl cysteine (NAC)	Putative anti-inflammatory agent in schizophrenia	No	Placebo-controlled trial: NAC added to routine care for 6 months improved negative symptoms and akathisia^Citation104	N=140
Minocycline	Putative anti-inflammatory agent in schizophrenia	No	Two placebo-controlled studies: benefit in early-phase schizophrenia, especially on negative symptoms, but no benefit on overall psychopathology^Citation105,Citation106	N=54^Citation106; N=144^Citation105
Ondansetron, granisetron, tropisetron	Serotonin 5-HT3 receptor antagonism; may be active in schizophrenia through their affinity for nicotinic and GABA receptors	Yes	Systematic review and meta-analysis: greater benefit for improvement of negative symptoms than positive symptoms when used as add-on therapy^Citation107	N=311
Lamotrigine	Anticonvulsant; inhibition of voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and modulating presynaptic transmitter release of excitatory amino acids (eg, glutamate, aspartate)	Yes	Meta-analysis of five trials: superiority in overall symptom improvement and improvement in positive and negative symptoms^Citation108	N=161
Memantine	NMDA receptor antagonism	Yes	Meta-analysis: adjunctive therapy may improve overall symptoms and negative symptoms^Citation109	N=186
		No	Randomized, placebo-controlled trial: no benefit conferred^Citation110	N=138
Pregnenolone	Neurosteroid	No	Proof-of-concept trial: significantly greater improvement in negative symptoms as adjunctive therapy (500 mg/day)^Citation111 Two small studies: benefit in schizophrenia^Citation112	N=21
Sildenafil	Phosphodiesterase 5 (PDE5) inhibition	No	Small study: no benefits on any symptom domains^Citation113	N=17
			Trial in patients with prominent negative symptoms: significant separation from placebo^Citation114	N=40
Folic acid/vitamin B12	Increase blood folate levels, particularly in patients homozygous for the 484T allele of FOLH1 (rs202676)	No	Randomized, placebo-controlled study: effective in a subgroup of patients homozygous for the 484T allele; response influenced by genetic variation in folate absorption^Citation115	N=140

Abbreviations: CNS, central nervous system; CONSIST, cognitive and negative symptoms in schizophrenia trial; NMDA, N-methyl-D-aspartate; PANSS, Positive and Negative Syndrome Scale; GABA, gamma-amino butyric acid.

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