Experimental Serotonergic Agents for the Treatment of Schizophrenia

Figures & data

Figure 1 PRISMA diagram for reviews.

Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.⁷⁰

Table 1 Experimental Serotonergic Agents in Schizophrenia

Serotonergic Agent	Properties	Other Binding Sites	References
Bifeprunox (DU-127090)	- Partial agonist at presynaptic 5-HT1ARs (pKi=8.2) - Partial agonist at presynaptic D2Rs (pKi=8.5)	− 5HT2A, 5HT2CRs (pKi<6) - M and H1Rs (pKi<6)	- Bruins et al, 2005 [^Citation21] - Tadori et al, 2007 [^Citation22] - Stahl, 2002 [^Citation23]
8-OH-DPAT	- Agonist at presynaptic 5-HT1ARs (pKi=9.0)	−5-HT1B (pKi=6.2), 5-HT1D (pKi=6.8), 5-HT7Rs (pKi=6.4) - D2, α1,α2Rs (pKi≤6)	- Assié and Koek, 2000 [^Citation29]
LASSBio-579	- Agonist at presynaptic 5-HT1ARs (Ki=0.22 μM) - Antagonist at postsynaptic D2-like (Ki=0.39 μM) and D4Rs (Ki=0.18 μM)	− 5-HT2A, 5-HT2CRs (Ki around 7 μM) - MRs (Ki>30 μM), α1B and α2Rs (Ki=2.6 μM)	- Pompeu et al, 2013 [^Citation33] - Neves et al, 2013 [^Citation34]
SB-773812	-Antagonist at postsynaptic 5-HT2ARs (pKi=8.5) - Antagonist at D3Rs (pKi=9.0)*	- D2Rs (pKi=7)	- Catafau et al, 2011 [^Citation35]
AM-831	- Antagonist at postsynaptic 5-HT2ARs** - Antagonist at postsynaptic D2Rs(antagonist)**	- M1Rs**	ACADIA Pharmaceuticals Advances, 2011 [^Citation37]
Zicronapine (Lu 31–130)	- Antagonist at postsynaptic 5-HT2ARs (Ki=4.2 nM) -Antagonist at postsynaptic D1 and D2Rs (Ki=19 nM)	N/A	- Citrome, 2013 [^Citation39]
Vabicaserin (SCA-136)	-Agonist at postsynaptic 5-HT2CRs (Ki=3 nM)	− 5HT1A (Ki=112 nM), 5-HT2BRs (Ki=14nM) - More than 50-fold selective on Receptors such as other 5-HT, D and α1Rs (Ki≥152nM)	- Liu et al, 2014 [^Citation41]
AS2030680	- Antagonist at presynaptic 5-HT5ARs (Ki=0.58 ± 0.17 nM)	−5-HT1A (Ki=20.7 nM), 5-HT2B (Ki= 22.0 nM), 5-HT6 (Ki=39.3 nM), 5HT7Rs (Ki=10.3 nM), other 5-HTRs (Ki>300 nM)	Yamazaki et al, 2015 [^Citation43]
AS2674723	- Antagonist at presynaptic 5-HT5ARs (Ki=0.75 ± 0.03 nM)	− 5-HT1A (Ki=83.8 nM), 5-HT7Rs (Ki=7.3 nM); other 5-HTRs (Ki>300 nM)	Yamazaki et al, 2015 [^Citation43]
ASP5736	-Antagonist at presynaptic 5-HT5ARs (Ki=3.6 ± 0.66 nM)	− 5-HT2CR (Ki=286.8 nM); other 5-HTRs (Ki > 1000 nM)	Yamazaki et al, 2015 [^Citation43,44]
SB699551	- Antagonist at presynaptic 5-HT5ARs (pKi=8.5)	− 5-HT1A and 5-HT7Rs (pKi<5.5); 5-HT1B,5-HT1D, 5-HT2A and 5-HT2C (pKi<6)	Thomas et al, 2006 [^Citation46]
AVN-211	Antagonist at postsynaptic 5-HT6Rs (Ki=2.1 nM)	− 5-HT2BRs (Ki=125nM); within the other 5-HTRs group the compound showed about 100-fold less than 5-HT6R selectivity.	-Ivachtchenko et al, 2016 [^Citation47]
Idalopirdine (Lu-AE58054)	- Antagonist at postsynaptic 5-HT6Rs (Ki=0.83±0.12 nM)	−5-HT2A (Ki=83±17nM), 5-HT2CRs (Ki=250±23nM); other 5-HTRs: over 400-fold less affinity than for 5-HT6Rs - α1ARs (Ki=21 nM), α1BRs (Ki=22nM)	- Arnt et al, 2010 [^Citation50]
RU-24969	- Agonist at pre-synaptic 5-HT1A (pKi=9) and 5-HT1BRs (pKi=8.1)	− 5-HT1D (pKi=7.7), 5HT2B (pKi=6.9), 5HT2A (pKi=6.9), 5HT2C (pKi=6.8),5HT5A (pKi=6), 5HT6 (pKi=6.2), 5HT7Rs (pKi=6.9)	- Cassaday et al, 1993 [^Citation30]
Ritanserin	Antagonist at postsynaptic 5-HT2AR (pKi=9.2) and 5-HT2CRs (pKi=8.2–9.6)	− 5-HT2BRs (pKi=8.3); other 5-HTRs (pKi≦7.8) - D2 (pKi=5.8), H1 (pKi<5), α1 (pKi=6.6–7.1) and α2Rs (pKi=6.5–7)	- Leysen et al, 1985 [^Citation53]
LuAF-35700	- Antagonist at postsynaptic 5-HT2A and 5-HT6Rs** - Antagonist at postsynaptic D1>D2Rs**	N/A	https://clinicaltrials.gov/ct2/show/NCT03230864 [^Citation54]
Brilaroxazine (RP5063)	- Partial agonism at presynaptic 5-HT1A (Ki=1.5nM) and postsynaptic 5-HT2A (Ki=2.5 nM); - Antagonism at presynaptic 5-HT2B (Ki=0.19 nM), postsynaptic 5-HT6**, and 5-HT7Rs (Ki=2.7 nM) - Partial agonism at D2, D3 and D4Rs**	-SERT and nAChRα4β2**	- Cantillon et al, 2017 [^Citation56]

Notes: *Unspecified pre or post-synaptic targets; **Unspecified degree of affinity binding.

Abbreviations: 5-HTR, 5-hydroxytryptamine receptor; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino) tetralin; αR, adrenoreceptor; DR, dopamine receptor; H, histamine; Ki, the inhibitory constant; LASSBio-579, [1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine]; MR, muscarinic receptor; μM, micromole; nAChRs, Nicotinic acetylcholine receptors; nM, nanomole; pKi, the negative log (base 10) of the Ki value eg pKi, -log10(Ki); SERT, serotonin transporter; N/A, not available.

Table 2 Summary of Animal and Human Studies About Experimental Serotonergic Agents Under Study for SCZ Treatment

Serotonergic Agent	Study	Phase	Duration		N	Aim	Study Design and Drug Doses	Primary Outcomes	Results	Status	Ref
Animal studies
8-OH-DPAT	Comparative experiment	Preclinical	7 days		26 male, Lister Hooded rats	Involvement of 5-HT1A and 5-HT2A in mPFC on 5CSRT	Training on 5CSRT. Intra-mPFC infusion through bilateral cannulae. Experimental (8-OH-DPAT or M100907) vs vehicle	Percentage of correct responses on 5CSRT (stimulus duration = 0.5 s)	8-OH-DPAT and M100907 enhanced attention and impulse control in every experiment (p<0.05)	Completed	https://doi.org/10.1007/s00213-003-1398-x [^Citation32]
	Comparative experiment	Preclinical	3 days		39 male Sprague –Dawley rats	Contribution of pre- or post-synaptic 5-HT1A receptors in PPI* disruption, caused by 8-OH-DPAT	Experiment 1- Central DRN microinjections: 7 sham-operated male rats vs 10 castrated Experiment 2- DRN lesions: 12 sham-operated male rats vs 10 rats which received a selective serotonergic lesion of the DRN	Experiment 1: Body and seminal vesicle weight, startle amplitude, PPI* Experiment 2: 5HT-content, startle amplitude, PPI*	DRN lesion: ↓ 5-HT content in frontal cortex (↓70%), striatum (↓69%), ventral hippocampus (↓76%) Activation of post-synaptic 5-HT1A → PPI* disruption	Completed	https://doi.org/10.1016/j.pbb.2005.05.007 [^Citation31]
	Comparative experiment	Preclinical	3 days		72 male Sprague-Dawley rats 2 groups of 6 for each treatment	Effect of 8-OH-DPAT on attentional processes (LI**)	Treatment: pre-exposed vs not pre-exposed. Experiment 1 Ritanserin 0.67 and 2.0 mg/kg in saline. Experiment 2 RU 24969 0.5 and 10.0 mg/kg in saline Experiment 3 8-OH-DPAT 0.19 and 0.38 mg/kg in saline	Time to complete a preset number of licks (Test: suppression of drinking procedure)	↓ LI**for all the three active compounds with a statistical significance for ritanserin and RU 24969	Completed	https://doi.org/10.1177/026988119300700110 [^Citation30]
RU-24969	～	～	～		～	Effect of RU-24969 on LI**	～	～	↓ LI** at both doses: PE > NPE (p<0.001)	Completed	https://doi.org/10.1177/026988119300700110 [^Citation30]
Ritanserin	～	～	～		～	Effect of Ritanserin on LI**	～	～	↓ LI**: - at low dose (p<0.001) - at high dose (p>0.05)	Completed	https://doi.org/10.1177/026988119300700110 [^Citation30]
LASSBio-579	Comparative experiment	Preclinical	N/A		Adult male CF1 mice	To increase the affinity of LASSBio-579 for 5-HT2A receptor synthesizing 5 new N-phenylpiperazine derivatives	In-vivo pharmacological evaluation: intraperitoneally and orally (10 mL/kg) or subcutaneously (5 mL/kg) administration of compounds	Classical competition assays; GTP-shift assay; climbing behavior in mice	↑ 3–10-fold affinity for 5-HT2A (p<0.001) = affinity for the D2-like and 5-HT1A	Completed	https://doi.org/10.1016/j.ejmech.2013.05.027 [^Citation33]
	Comparative experiment	Preclinical	N/A		Adult male CF1 mice	Pharmacological evaluation LASSBio-579, −580 and −581 to investigate potential APS activity	Mice received a combination of sub-effective dose of LASSBio- 579 + haloperidol, LASSBio-579 + clozapine or haloperidol + clozapine	Climbing behavior in mice; apomorphine-induced climbing and apomorphine-induced hypothermia in mice; motor parameter; PPI* of startle reflex	- ↓ locomotor activity (p<0.022) - effect on apomorphine-induced climbing test at 5 mg/kg (p=0.758) - effective on preventing PPI* (80 dB) at 0.5 mg/kg (p<0.02) - effective on preventing PPI* (8085 dB) at 1 and 5 mg/kg (p<0.022)	Completed	https://doi.org/10.1016/j.bbr.2012.09.016 [^Citation34]
AM-831	N/A	Preclinical	N/A		N/A	N/A	N/A	N/A	AM-831 did not meet predetermined criteria for further development in Phase I testing	Interruption of the development of the compound	https://adisinsight.springer.com/drugs/800016551 [^Citation38]
ASP5736, AS2030680 and AS2674723	In vitro and in vivo (comparative experiments)	Preclinical	N/A		Groups of 10 (mice), 5 (young rats) or 3 (aged rats)	To investigate the relationship between the 5-HT5A receptor and cognitive function	In-vitro analysis: - 5-HT5A receptors expression in cell membranes - affinity of ASP5736, AS2030680 and AS2674723 for 5-HT5A receptors In-vivo analysis: - drug concentrations in biological samples - 5-HT5A influence on cognitive function	Spatial working memory: - Y-maze test after scopolamine administration - Morris water maze test Ex-vivo receptor occupancy for 5-HT5A rat receptor	- high affinity for 5-HT5A of each species - low affinity for 5-HT2B and 5-HT7 - Each of the three compounds ameliorated scopolamine-induced working memory deficit (p<0.05)	Completed	https://doi.org/10.1016/j.jphs.2015.02.006 [^Citation43]
ASP5736	In vitro and in vivo (comparative experiments)	Preclinical	N/A		Groups of 10 mice	Evaluation of: - in-vitro inhibitory effects of ASP5736 on 5-HT5A - ASP5736 affinity for various receptors - ASP5736 pharmacokinetics - ASP5736 efficacy on positive -like and cognitive symptoms - efficacy and safety of ASP5736 + OLZ	In-vitro analysis: - 5-HT5A expression in cell membranes - affinity of ASP5736 for 5-HT5A In-vivo analysis: - working memory deficit in MK-801-treated mice and visual learning deficit in neonatally PCP-treated mice - MK-801- and MAP-induced hyperactivity	Y-maze test; NORT	↓ MK-801- and PCP-induced cognitive deficit (p<0.001) Addition of OLZ was safe and did not compromise ASP5736 efficacy on cognitive deficits	Completed	https://doi.org/10.1016/j.euroneuro.2014.07.009 [^Citation44]
ASP5736 and SB699551	Dose–response determination experiments	Preclinical	N/A		13 male Sprague Dawley rats	To test the involvement of 5-HT5A in LSD behavioural effects	- Intraperitoneal administration of LSD (0.08 mg/kg) or sterile water - 10 training sessions - Drug discrimination tests	Response rate and numbers of rats completing the test	↓ subjective effects of LSD in rats (p<0.012)	Completed	https://doi.org/10.1177/0269881119867603 [^Citation45]
SB699551	In vitro and in vivo	Preclinical	N/A		Male Dunkin Hartley guinea pigs	Receptorial affinity, pharmacokinetics and action of SB699551	- In vitro: fast cyclic voltammetry - In-vivo pharmacokinetic analysis; microdialysis (animals were treated with either vehicle (NaCl) or SB699551/WAY-100365***)	Mean discharge frequency during the final 2 min of exposure to each concentration of drug	- high affinity for guinea pig 5-HT5A receptor - antagonist profile on 5-HT5A receptors - in association with WAY-100635***: ↑ extracellular levels of cortical 5-HT	Completed	https://doi.org/10.1016/j.neuropharm.2006.04.019 [^Citation46]
Human studies
Brilaroxazine (RP5063)	RCT	I	10 days	19 male pts with stable disease in 4 cohorts		- Safety in healthy volunteers - safety and initial clinical activity in stable SCZ pts	Ascending-dose, double-blind - single‐dose in healthy volunteers: 10, 15 mg -multiple‐dose in SCZ pts: 10, 20, 50, 100 mg	PANSS, CG-I, CGI-S, CDSS	↓ PANSS positive subscale in pts with PANSS ≥ 50 at BL: RP5063>PBO (p<0.05)	Completed	https://doi.org/10.1111/cts.12545 [^Citation57]
	RCT	II	57 days	234 SCZ pts		Safety and efficacy in acute SCZ	Double-blind, multi-centric Brilaroxazine (15, 30 or 50 mg) vs ARI (15 mg) or PBO once daily	PANSS	↓ PANSS: Brilaroxazine 15 or 50 mg > PBO (p<0.05)	Completed	https://clinicaltrials.gov/ct2/show/NCT01490086 [^Citation58]
SB-773812	RCT	II	12-week treatment 2 years extension	338 SCZ pts		Efficacy, safety and tolerability of SB-77381	Double-blind, multi-centric 3 arms: - SB-773812 (60 or 120 mg) - OLZ (15 mg) - PBO	PANSS, BPRS, CGI-S. CGI-I, CDSS	↓ PANSS: - SB-773812 60 mg=PBO (p>0.05) - SB-773812 60 and 120 mg = OLZ > PBO (p<0.05)	Completed	https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-002883-27/results [^Citation36]
Vabicaserin (SCA-136)	RCT	II	4 weeks	202 SCZ pts 37 PBO 43 RIS 122 Vabicaserin		Efficacy, safety, and tolerability in acute SCZ	Double-blind, multi-centric RIS: 4 mg/day Vabicaserin: 50, 100, 150, 200, 300, 400, 600 mg/day)	PANSS, CGI-S, CGI-I, CDSS	↓ PANSS: - Vabicaserin at all doses = PBO (p>0.05)	Recruitment status completed	https://clinicaltrials.gov/ct2/show/NCT00563706 [^Citation42]
AVN-211	RCT	II	4 weeks	42 SCZ pts 17 AVN-211 25 PBO		Efficacy on clinical and cognitive symptoms in SCZ pts on APS medications	Double-blind AVN-211: 4 mg	PANSS, CGI-S, CGI-I, CDSS, NSA-16, WAIS, 5 attention tests	↓ PANSS positive subscale: AVN-211>PBO (p=0.058) WAIS: AVN-211>PBO (p=0.02) AVN-211 ↓ PANSS positive subscale: p=0.007 AVN-211 ↓ CGI-S: p=0.048 AVN-211 ↓ CDSS: p<0.05	Completed	https://doi.org/10.1017/S1092852913000394 [^Citation48]
Idalopirdine (Lu-AE58054)	RCT	II	12 weeks	122 SCZ pts 58 RIS+Lu-AE58054 64 RIS+PBO		Efficacy as augmentation therapy to RIS	2-week, prospective run-in period → double-blind Lu-AE58054 (120 mg/day) or PBO (12 weeks) RIS: 4–8 mg/day	PANSS, BACS, CGI-I, CGI-S, SQoL	↓ PANSS: RIS+Lu-AE58054 = RIS+PBO (p>0.05)	Interruption of the development of the compound	https://www.clinicaltrialsregister.eu/ctr-search/trial/2008-001441-26/IT [^Citation51]
Bifeprunox (DU-127090)	RCT	III	12 months: 6-month treatment period + 6-month extension period	93 acute SCZ pts 35 BX 58 RIS		Long-term safety, tolerability and efficacy of BX vs RIS flexible doses	Double-blind 2 arms: - BX: 30–40 mg/day - RIS: 4–6 mg/day	PANSS; BPRS; CGI-S; CGI-I; CDSS	- ↓ PANSS, BPRS, CGI-S, CGI-I: RIS > BX (p<0.05) - ↓ CDSS: RIS = BX (p>0.05)	Recruitment completed. End of trial ongoing	https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-002185-38/results [^Citation24]
	RCT	III	12 months	223 SCZ pts 79 BX 76 QUE 68 PBO		Efficacy of fixed doses BX vs PBO Efficacy, safety, tolerability, functional outcomes, quality of life, and treatment compliance BX vs QUE	Multi-national, multi-centric, double-blind 3 arms: -BX: 20 mg/day -QUE: 600 mg/day -PBO - lead-in period (4 weeks) -PBO-controlled (12 weeks) - QUE-controlled period (9 months)	PANSS, CGI-S score, CGI-I score, and CDSS	- ↓ PANSS at week 12: BX=QUE > PBO (p<0.05)	Prematurely ended	https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001097-90/GR [^Citation25]
	Open-label	N/A	40 weeks	153 SCZ pts 73 OLZ → BX 80 BX → BX		Long-term safety, tolerability and maintenance of therapeutic effects of BX flexible doses vs OLZ	1^st week double-blind: switch OLZ to BX (up to 30 mg/day) or BX continuation at 30 mg/day From 2^nd week: BX flexible dose (20, 30, or 40 mg/day) OLZ: 15 mg/day	PANSS, CGI-S, CDSS	BX → BX: - ↓ PANSS during lead-in, ↑ during continuative OLZ → BX - ↑ PANSS at Week 40	Completed	https://www.cliicaltrialsregister.eu/ctr-search/trial/2004-000707-18/IT [^Citation26]
	Open-label	N/A	14–531 days	11 SCZ pts		Efficacy, long-term safety and tolerability	BX flexible doses (20, 30, or 40 mg/day)	CGI-S	No efficacy results (small sample of pts)	Completed	https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-000497-50/IT [^Citation27]
Zicronapine (Lu 31–130)	RCT	III	6 months	160 SCZ pts		Efficacy, safety and tolerability of ZIC vs RIS	Double-blind 2 arms: - ZIC 7.5 mg/day - RIS 5 mg/day	PANSS; CGI-S, GAF	↓ PANSS and CGI-S: ZIC=RIS (p>0.05)	Completed	https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-022181-28/EE [^Citation40]
LuAF-35700	RCT	III	16 weeks	1098 TRS pts 401 did not complete PC 235 LuAF-35700 10 mg 232 LuAF-35700 20 mg 232 continued PC treatment		Efficacy in TRS pts	- Screening Period (3 weeks) - PC: 6-week, patient-blinded treatment with RIS (4–6 mg/day) or OLZ (15–20 mg/day) - DBT (10 weeks): LuAF-35700 10 mg or 20 mg or continued PC treatment (1:1:1) - Safety Follow-up Period (6 weeks)	PANSS, PSP, CGI-S	↓ PANSS: LuAF-35700 = RIS or OLZ (p>0.05)	Recruitment status completed	https://investor.lundbeck.com/news-releases/news-release-details/lundbeck-updates-clinical-phase-iii-study-lu-af35700-treatment (Valby, Oct. 25, 2018) [^Citation54]
	RCT	III	34 weeks	119 TRS pts 68 RIS 51 OLZ 51 Non randomized 35 LuAF-35700 10 mg 33 continued PC treatment		Testing the efficacy on symptoms of SCZ	- PC: 6-week, patient-blinded treatment with RIS (4–6 mg/day) or OLZ (15–20 mg/day) - DBT (8 weeks): LuAF-35700 10 mg or continued PC treatment (1:1) - observation period for AEs (20 weeks)	PANSS, CGI-S, NSA-16	Waiting for results on patients randomized in the DBT period.	Terminated (New data; the study was terminated based on new efficacy data from another study)	https://clinicaltrials.gov/ct2/show/NCT03230864 [^Citation55]

Notes: *PPI is a measure of sensorimotor gating that is deficient in schizophrenia; **Latent inhibition is the delay in responding to a stimulus which has no consequences in the first exposures. For example, when animals were exposed to a stimulus without implications they are impaired in learning that this stimulus could predict an important event such as footshocks. The impairment in comprehending danger stimulus is called pre-exposition. Amphetamine disrupts LI while antipsychotics have an opposite effect; ***WAY-100635: 5-HT1A receptor-selective antagonist.

Abbreviations: ～, The same information as the box above; 5CSRT, five-choice serial reaction time task; AEs, adverse events; APS, antipsychotic; ARI, aripiprazole; BL, baseline; BACS, Brief Assessment of Cognition in Schizophrenia; BPRS, Brief Psychiatric Rating Scale; BX, bifeprunox; CAT, Continuous Attention Task; CF1 mouse, obtained with outbreeding by Carworth Farms; CGI-S, Clinical Global Impression – Severity of Illness; CGI-I, Clinical Global Impression – Global Improvement; CDSS, Calgary Depression Scale for Schizophrenia; CSRT choice serial reaction time task; DAI-30, Drug Attitude Inventory; DBT, Double-Blind Treatment; DRN, dorsal raphe nucleus; GAF, Global Assessment of Functioning; GTP, nucleotide guanosine triphosphate; LSD, D-lysergic acid diethylamide; MAP, methamphetamine; MK-801, dizocilpine; mPFC, medial Prefrontal Cortex; N/A, not applicable; NPE, not pre-exposed; NORT, Novel object recognition test; NSA-16, Negative Symptom Assessment; OLZ, olanzapine; PBO, placebo; PC, prospective confirmation; PCP, phencyclidine; PE, pre-exposed; pts, patients; PSP, Personal and Social Performance Scale; QUE, quetiapine; RIS, risperidone; RU 24969, (5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl); SCZ, schizophrenia; S-QoL, Schizophrenia Quality of Life; PANSS,Positive and Negative Syndrome Scale; TRS, treatment-resistant SCZ; WAIS, Wechsler Adult Intelligence Scale; ZIC, zicronapine; PPI, Prepulse inhibition; LI, latent inhibition.

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