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 [32] | |
| 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 [31] | ||
| 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 [30] | ||
| RU-24969 | ～ | ～ | ～ | ～ | Effect of RU-24969 on LI** | ～ | ～ | ↓ LI** at both doses: PE > NPE (p<0.001) |
Completed | https://doi.org/10.1177/026988119300700110 [30] | |
| 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 [30] | |
| 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 [33] | |
| 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 [34] | ||
| 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 [38] | |
| 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 [43] | |
| 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 [44] | |
| 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 [45] | |
| 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 [46] | |
| 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 [57] | |
| 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 [58] |
||
| 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 [36] | |
| 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 [42] | |
| 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 [48] | |
| 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 [51] | |
| 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 [24] | |
| 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 [25] | ||
| 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 | 1st week double-blind: switch OLZ to BX (up to 30 mg/day) or BX continuation at 30 mg/day From 2nd 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 [26] | ||
| 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 [27] | ||
| 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 [40] | |
| 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) [54] | |
| 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 [55] |
||
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.