Journal of Psychiatric Research 108 (2019) 57–83 Contents lists available at ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/jpsychires The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review T ∗ Ragy R. Girgis ,1, Anthony W. Zoghbi1, Daniel C. Javitt, Jeffrey A. Lieberman The New York State Psychiatric Institute, Columbia University Irving Medical Center, New York, N.Y, USA ARTICLE INFO ABSTRACT Keywords: Since the discovery of chlorpromazine in the 1950's, antipsychotic drugs have been the cornerstone of treatment Schizophrenia of schizophrenia, and all attenuate dopamine transmission at the dopamine-2 receptor. Drug development for Experimental treatments schizophrenia since that time has led to improvements in side effects and tolerability, and limited improvements Clinical trials in efficacy, with the exception of clozapine. However, the reasons for clozapine's greater efficacy remain unclear, Dopamine despite the great efforts and resources invested therewith. We performed a comprehensive review of the lit- Glutamate erature to determine the fate of previously tested, non-dopamine-2 receptor experimental treatments. Overall we Novel therapeutics included 250 studies in the review from the period 1970 to 2017 including treatments with glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormone-based, dopaminergic, metabolic, vitamin/naturopathic, histaminergic, infection/inflammation-based, and miscellaneous mechanisms. Despite there being several pro- mising targets, such as allosteric modulation of the NMDA and α7 nicotinic receptors, we cannot confidently state that any of the mechanistically novel experimental treatments covered in this review are definitely effective for the treatment of schizophrenia and ready for clinical use. We discuss potential reasons for the relative lack of progress in developing non-dopamine-2 receptor treatments for schizophrenia and provide recommendations for future efforts pursuing novel drug development for schizophrenia. 1. Introduction and cognitive deficits, along with better tolerability. However, there has been relatively little progress in the development of new treatments Since the serendipitous discovery of chlorpromazine in the 1950's, since the introduction of antipsychotic medications. antipsychotic drugs (APDs) have been the cornerstone of treatment of First generation APDs had high affinity and were full antagonists at schizophrenia (Lehmann and Ban, 1997). However, 30% of all schizo- D-2 receptors, while second generation APDs were D-2 receptor an- phrenia subjects do not respond to currently available treatments, and tagonists and possessed higher affinity for other neuro-receptors in- 60% have partial response with residual symptoms persisting (Barbui cluding the 5-HT2A receptors (Miyamoto et al., 2012). More recently, et al., 2009). Moreover, antipsychotic medications have very limited compounds have been developed that represent variations on this D-2 effects on negative symptoms (Breier et al., 1994; Kasper et al., 2003; receptor super-family and include partial agonists at the D-2 receptor Marder et al., 1997; Meltzer et al., 1998; Miyamoto et al., 2005) and (aripiprazole and brexpiprazole), D-3 selective compounds (cariprazine cognitive deficits (e.g., working memory, verbal memory, attention, [Allergan] and F1764 [Pierre Fabre]) and ITI-007 (Intracellular executive functioning) (Davidson et al., 2009; Green et al., 1997, 2002; Therapies) which acts intra and extracellularly and at multiple neu- Keefe et al., 1999, 2004, 2006, 2007; Kern et al., 1998; Miyamoto et al., roreceptors including D-2 (Lieberman et al., 2016; Durgam et al., 2014; 2005), and no medications are currently approved for the treatment of Rakhit et al., 2014). residual psychotic, negative or cognitive symptoms. In addition, me- Landmark comparative effectiveness studies such as CATIE, tabolic disturbances such as hyperglycemia, hyperlipidemia, obesity CUTLASS, and EUFEST showed that older and newer medications were and diabetes can add to the morbidity of schizophrenia and decrease more similar than different (with the greatest exception being cloza- patient adherence to the required long-term treatment regimens pine), with the greatest differences being in side effects (Jones et al., (Marder et al., 2004). New therapies are needed that provide rapid 2006; Kahn et al., 2008; Lieberman et al., 2005). Clozapine is unique in improvement in active psychotic symptomatology, negative symptoms, that it is an effective antipsychotic medication and exhibits therapeutic ∗ Corresponding author. New York State Psychiatric Institute, Columbia University Medical Center, 1051 Riverside Drive, Unit 31, New York, N.Y10032. USA. E-mail address: [email protected] (R.R. Girgis). 1 These authors contributed equally. https://doi.org/10.1016/j.jpsychires.2018.07.006 Received 15 January 2018; Received in revised form 13 June 2018; Accepted 12 July 2018 0022-3956/ © 2018 Elsevier Ltd. All rights reserved. R.R. Girgis et al. Table 1 Clinical trials of experimental medications with glutamatergic mechanisms. Name (Mechanism) Reference Design Sample Length Treatment Conditions Primary Outcome Results Comment Sarcosine (Glycine (Lin et al., 2017b) RCT, Add-on, 63 12 weeks Sarcosine 2 g/day + Benzoate 1 g/day, PANSS total, global Improvement in global and Taiwanese inpatients, transporter-1 inhibitor) Double Blind Sarcosine 2 g/day, Placebo and neurocognitive neurocognitive composite scores in required PANSS > 60, small and Sodium Benzoate (D- composite of Chinese Sarcosine + Benzoate over both sample amino acid oxidase) MCCB equivalent Sarcosine and placebo groups, no difference in PANSS total Sarcosine (Glycine (Lane et al., RCT, Add-on, 60 6 weeks Sarcosine 2 g/day, D-Serine 2 g/day, PANSS, SANS, QOL, Improvement with Sarcosine on Han Chinese inpatients transporter-1 inhibitor) 2010) Double Blind Placebo GAF PANSS total, SANS, QOL, and GAF, and D-Serine no differences for D-serine Sarcosine (Glycine (Lane et al., RCT, Add-on, 20 6 weeks Sarcosine 1 g/day, Sarcosine 2 g/day PANSS, SANS, QOL No differences Acutely ill Han Chinese transporter-1 inhibitor) 2008) Double Blind inpatients Sarcosine (Glycine (Lane et al., RCT, Add-on, 20 6 weeks Sarcosine 2 g/day, Placebo PANSS No differences Add-on to clozapine, transporter-1 inhibitor) 2006) Double Blind hypothesized negative result Sarcosine (Glycine (Lane et al., RCT, Add-on, 65 6 weeks Sarcosine 2 g/day, D-Serine 2 g/day, PANSS, SANS Sarcosine superior to D-Serine and Add on to risperidone transporter-1 inhibitor) 2005) Double Blind Placebo Placebo on PANSS total, general, and D-Serine cognitive, depressive, SANS Sarcosine (Glycine (Tsai et al., 2004) RCT, Add-on, 38 6 weeks Sarcosine 2 g/day, Placebo PANSS, SANS, BPRS Improvement on BPRS, SANS, and Add on to non-clozapine transporter-1 inhibitor) Double Blind PANSS positive, cognitive, general, antipsychotics and total Bitopertin (Glycine (Bugarski-Kirola RCT, 301 4 weeks Bitopertin 10 mg/day, Bitopertin PANSS No differences Failed active comparator, transporter-1 inhibitor) et al., 2014a,b) Monotherapy, 30 mg/day, Olanzapine 15 mg/day, multicenter phase II/III trial, Double Blind Placebo used LOCF Bitopertin (Glycine (Arango et al., RCT, Add-on, 605 24 weeks Bitopertin 5 mg/day, Bitopertin 10 mg/ PANSS negative No differences Multicenter phase III transporter-1 inhibitor) 2014) Double Blind day, Placebo symptoms factor score DayLyte study, stable patients 58 Bitopertin (Glycine (Umbricht et al., RCT, Add-on, 323 8 weeks Bitopertin 10 mg/day, 30 mg/day, PANSS Improvement in PANSS negative Phase II multicenter trial transporter-1 inhibitor) 2014a) Double Blind 60 mg/day, Placebo symptoms at 10 mg/day and 30 mg/ day, no differences at 60 mg/day Bitopertin (Glycine (Blaettler et al., RCT, Add-on, 627 24 weeks Bitopertin 10 mg/day, Bitopertin PANSS negative No differences Multicenter phase III transporter-1 inhibitor) 2014) Double Blind 20 mg/day, Placebo symptoms factor score FlashLyte study, stable patients, used ITT Sodium Benzoate (D-amino (Lin et al., 2017a) RCT, Add-on, 60 6 weeks Sodium Benzoate 1 g/day, 2 g/day, PANSS Total, SANS- Improvement on SANS-20 for both Taiwanese inpatients, acid oxidase inhibitor) Double Blind Placebo 20, QOL, GAF doses, QOL and PANSS total for 2 g resistant to clozapine, dose, no difference in GAF for either PANSS > 70, SANS > 40, dose change in catalase correlated with improvement in PANSS total/positive scores Sodium Benzoate (D-amino (Lane et al., RCT, Add-on, 52 6 weeks Sodium Benzoate 1 g/day, Placebo PANSS Total Improvement on PANSS total, Taiwanese outpatients, acid oxidase inhibitor) 2013) Double Blind negative, general, positive, SANS, required PANSS > 60, large CGI, GAF, QOLS, processing speed, effect sizes Journal ofPsychiatricResea visual learning memory, MCCB composite score LY2140023 (mGlu 2/3 (Kinon et al., RCT, 667 4 weeks LY2140023 5 mg, 20 mg, 40 mg, or PANSS total No differences Failed active comparator, receptor agonist) 2011) Monotherapy, 80 mg BID, Olanzapine 15 mg/day, multicenter phase II trial, Double Blind Placebo four seizures in treatment group, LY2140023 (mGlu 2/3 (Patil et al., 2007) RCT, 196 4 weeks LY2140023 40 mg BID, Olanzapine PANSS total Improvement on total, negative, and Active comparator, receptor agonist) Monotherapy, 15 mg/day, Placebo positive subscales multicenter trial, placebo Double Blind group worsened rch 108(2019)57–83 significantly Sodium Nitroprusside