TABLE 3.
Summary of preclinical and clinical studies of histamine receptor modulators in neuropsychiatric disease.
| Drug | Mechanism of action | Study design | Finding | References |
| Hydroxyzine | H1 receptor antagonist | Case report: male patient with a rare, mis-sense mutation in HNMT associated with a severe intellectual disability. | Hydroxyzine and a low histidine diet reduced aggression, improving speech development and sleep disturbance. | Verhoeven et al., 2020 |
| Famotidine | H2 receptor antagonist | Randomized, double-blind, placebo-controlled, cross-over design of 9 children with ASD. | Four of 9 children randomized had evidence of behavioral improvement. Children with marked stereotypy did not respond. | Linday et al., 2001 |
| Famotidine | H2 receptor antagonist | Double-blind, placebo-controlled, parallel-group, randomized trial of famotidine in treatment-resistant schizophrenia. | Famotidine did not lead to a significant improvement in Scale for the Assessment of Negative Symptoms score. However, the Positive and Negative Syndrome scale total score and the Clinical Global Impression scale showed significantly greater change in the famotidine group than in the placebo group. No significant adverse effects were observed. | Meskanen et al., 2013 |
| Famotidine | H2 receptor antagonist | Three-week, open-label study of famotidine (20 mg twice a day) was added as an adjunctive medication in people with schizophrenia and schizoaffective disorder. | Total Brief Psychiatric Rating Scale and Clinical Global Impression scores were significantly lower during the 3 weeks with famotidine compared with the week before and after its administration. Negative symptoms as measured by the Schedule for the Assessment of Negative Symptoms were not significantly different during famotidine treatment. | Deutsch et al., 1993 |
| ABT-239 and A-431404 | H3 receptor antagonists | Preclinical study using rats administered ketamine or MK-801 to induce cognitive impairments as a model of schizophrenia. | Chronic, but not acute, treatment with ABT-239 significantly improved spontaneous alternation impairments, suggesting that H3 receptor antagonists may have the potential to ameliorate cognitive deficits in schizophrenia. | Brown et al., 2013 |
| ABT-288 | H3 receptor antagonist | Preclinical study: in vitro and in vivo pharmacological profile of ABT-288 in rats (P20–24) | ABT-288 improved social recognition, spatial learning and reference memory with good pharmacokinetics and oral bioavailability of 37–66%. There was a wide central nervous system and cardiovascular safety margin. | Esbenshade et al., 2012 |
| ABT-288 | H3 receptor antagonist | A multicenter, randomized, double-blind, placebo-controlled, parallel-group 12-week study of ABT-288 (10 or 25 mg) vs. placebo in clinically stable subjects with schizophrenia (n = 214). | Study medication was tolerated. There was an increased incidence of psychosis-related and sleep-related adverse events associated with ABT-288. Neither dose of ABT-288 resulted in cognitive improvement in clinically stable adults with schizophrenia. | Haig et al., 2014 |
| ABT-288 | H3 receptor antagonist | Randomized, double-blind, placebo- and active-controlled (donepezil) phase 2 study of ABT-288 in subjects with mild-to-moderate Alzheimer’s disease (n = 242) | ABT-288 did not have pro-cognitive efficacy in subjects with mild-to-moderate Alzheimer’s Disease, but was safe and well tolerated. | Haig et al., 2012 |
| ABT-288 | H3 receptor antagonist | Randomized, double-blind, placebo-controlled, dose-escalating study designs of the safety and tolerability ABT-288 in young adults and in elderly subjects. | Single doses up to 40 mg and doses up to 3 mg once-daily taken over 12 (for elderly subjects) or 14 days (for younger subjects) were generally safe and well tolerated. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer’s patients. | Othman et al., 2013 |
| ABT-288 | H3 receptor antagonist | Randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic (n = 67). | ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. | Othman et al., 2014 |
| Bavisant (JNJ-31001074) | H3 receptor antagonist | Randomized, double-blind, placebo- and active-controlled, parallel-group, multicenter study evaluated three dosages of bavisant (1, 3, or 10 mg/day) and two active controls in adults with ADHD. | Bavisant, a highly selective, wakefulness-promoting H3 antagonist, did not display significant clinical effectiveness in the treatment of adults with ADHD. | Weisler et al., 2012 |
| Ciproxifan | H3 receptor antagonist | Preclinical study of mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA). | VPA animals presented a significantly higher nociceptive threshold. Ciproxifan was not able to modify this parameter but was able to attenuate sociability deficits and stereotypies present in the VPA model of autism. | Baronio et al., 2015 |
| Ciproxifan | H3 receptor antagonist | Preclinical study using MK-801 to mimic the hypoglutamatergic state suspected to exist in schizophrenia. | H3 antagonists can alleviate the impact of NMDA receptor hypofunction on some forms of memory, but may exacerbate its effect on other behaviors. | Bardgett et al., 2010 |
| DL77 | H3 receptor antagonist | Preclinical study of mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA). | DL77 improved sociability and social novelty preference and attenuated the release of proinflammatory cytokines following lipopolysaccharide challenge. | Eissa et al., 2018b |
| GSK207040 | H3 receptor antagonist | Preclinical study using rats with deficits in novel object recognition memory and pre-pulse inhibition induced by isolation rearing, and hyperlocomotor activity induced by amphetamine. | GSK207040 significantly enhanced object recognition memory and attenuated isolation rearing-induced deficits in pre-pulse inhibition but did not reverse amphetamine-induced increases in locomotor activity. | Southam et al., 2009 |
| GSK239512 | H3 receptor antagonist | Phase II randomized controlled trial of GSK239512 vs. placebo in cognitive impairment in 50 stable outpatients with schizophrenia. | GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology of H3 receptor antagonists. There was no evidence of overall beneficial effects of GSK239512 for cognitive impairment in this population. | Jarskog et al., 2015 |
| GSK239512 | H3 receptor antagonist | Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomized, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients. | GSK239512 displayed a satisfactory level of tolerability in patients with Alzheimer’s disease with evidence for positive effects on attention and memory. | Nathan et al., 2013 |
| JNJ-10181457 | H3 receptor antagonist | Preclinical study to evaluate the behavioral and neurochemical effects of JNJ-10181457 in rats. | Selective blockade of H3 receptor might have therapeutic utility for the treatment of working memory deficits and learning disorders, especially those associated with reduced cholinergic neurotransmission. | Galici et al., 2009 |
| SAR110894 | H3 receptor antagonist | Preclinical study evaluating the ability of SAR110894 to inhibit tau pathology and prevent cognitive deficits in a tau transgenic mouse model (THY-Tau22) | SAR110894 treatment for 6 months decreased tau hyperphosphorylation in the hippocampus and the formation of neurofibrillary tangles in the cortex, hippocampus, and amygdala. SAR110894 also prevented episodic memory deficits, and this effect was still detected after treatment washout. | Delay-Goyet et al., 2016 |
| Thioperamide | H3 receptor antagonist | Preclinical study investigating the effect of thioperamide on memory consolidation and recall mechanisms in rats. | H3 receptor antagonism improves memory retention and reverses the cognitive deficit induced by scopolamine in a two-trial place recognition task | Orsetti et al., 2001 |
| Thioperamide and ciproxifan | H3 receptor antagonists | Preclinical study using mice with natural deficits in pre-pulse inhibition as a model of schizophrenia. | Thioperamide and ciproxifan both improved natural deficits in pre-pulse inhibition in mice suggesting that they may have therapeutic potential in the treatment of schizophrenia. | Browman et al., 2004 |
| E100 | Dual-active H3 receptor antagonist and AChE inhibitor | Preclinical study of mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA). | E100 dose-dependently ameliorated repetitive and compulsive behaviors. Pretreatment with E100 attenuated anxiety levels, microglial activation, proinflammatory cytokine release and expression of NF-κB, iNOS, and COX-2 in the cerebellum. | Eissa et al., 2019 |
| E100 | Dual-active H3 receptor antagonist and AChE inhibitor | Preclinical study of mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA). | E100 dose-dependently attenuated sociability deficits and mitigated oxidative stress status by increasing the levels of decreased glutathione, superoxide dismutase, and catalase in VPA mice. | Eissa et al., 2020a |
| E100 | Dual-active H3 receptor antagonist and AChE inhibitor | Preclinical study of BTBR mice, a confirmed model of autism | E100 dose-dependently attenuated social deficits of BTBR mice, repetitive/compulsive behaviors and reduced the number of activated microglial cells compared to the saline-treated BTBR mice. Numbers of activated microglial cells were entirely reversed by co-administration of an H3 receptor agonist. | Eissa et al., 2020b |
| JNJ7777120 | H4 receptor antagonist | Preclinical study of BTBR mice, a confirmed model of autism | Decreased expression of the pro-inflammatory cytokines IL-17 and IL-22 and increased Foxp3-producting CD8+ T cells, suggesting that H4 receptor antagonism may block inflammatory signaling in the brain. | Ahmad et al., 2019 |
AChE, acetylcholinesterase; ASD, autism spectrum disorder; BTBR, BTBR T+Itpr3tf/J mouse; COX-2, cyclo-oxygenase-2; HNMT, histamine N-methyltransferase; H1, histamine 1; H2, histamine 2; H3, histamine 3; H4, histamine 4; IL-17, interleukin-17; IL-22, interleukin-22; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor-κB; VPA, valproic acid.