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International Journal of Health Sciences, Qassim University, Vol. 10, No. 4 (Oct-Dec 2016)

Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect: a current preclinical & clinical perspective

Danish Mahmood Department of Pharmacology & Toxicology, Unaizah College of Pharmacy, Qassim University

Abstract

Histamine H3 receptors are present as on and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key in the brain. H3 antagonism may be a novel approach to develop a new class of antipsychotic given the gathering evidence reporting therapeutic efficacy in several disorders. Several medications such as , lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of . These medications works through diverse mechanisms which include agonism at metabotropic (mGluR2/3), partial agonism at D2, D3 and 5-HT1A receptors, antagonism at D2, 5-HT2A, 5-HT2B and 5-HT7 receptors, combined dopamine antagonism with GABA agonist activity, inhibition of monoamine oxidase-B, modulation of oestrogen receptor, and activation of nuclear retinoid X receptor. However, still specific safe therapy for psychosis remains at large. Schizophrenia is a severe neuropsychiatric disorder result both from hyper- and hypo- dopaminergic transmission causing positive and negative symptoms, respectively. Pharmacological stimulation of dopamine release in the prefrontal cortex has been a viable approach in treating negative symptoms and cognitive deficits of schizophrenia symptoms that are currently not well treated and continue to represent significant unmet medical challenges. Administration of H3 antagonists/inverse agonists increase extracellular dopamine concentrations in rat prefrontal cortex, but not in the striatum suggesting that antagonism via H3 receptor may be a potential target for treating negative symptoms and cognitive deficits associated with schizophrenia. Further, insights are emerging into the potential role of histamine H3 receptors as a target of antiobesity therapeutics which is one of the limiting adverse effects of second generation schizophrenia medications. The recent failures of two promising H3 compounds in clinical trial dampened the interest in seeking antipsychotic like activities of H3 receptor antagonists. However, due to the inconclusive nature of many of these studies, the development of H3 compounds via H3 antagonism/inverse agonism approach still hold lot of promises and may be developed as a novel class of drugs for schizophrenia and its related complications e.g. weight gain

Key words: Schizophrenia, , H3 antagonist/inverse agonist, cognitive deficits

Correspondence:

Danish Mahmood Department of Pharmacology & Toxicology, Unaizah College of Pharmacy, Qassim University Mobile #: +966594016751 Email: [email protected]

565 Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect

Introduction behaviours and cognitive impairments in Schizophrenia, a life-time debilitating healthy humans and exacerbate symptoms in neuropsychiatric disorder, is accompanied by a schizophrenia patients indicating involvement significant deficit in social functions and of glutamate in schizophrenia. (14-21) A recent retardation in the quality of life. As many as 51 report has demonstrated reduction in both the million people worldwide suffer from positive and negative symptoms with a schizophrenia, with the developing nations. (1-4) metabotropic glutamate 2/3 (mGlu2/3) receptor According to the Saudi Arabian Ministry of agonist. (22, 23) Animal studies have reported Health (2008), 22.4% of outpatient of mental reduced density of neurones releasing γ- health services were suffering from mental and aminobutyric acid (GABA) and also the behavioural disorders caused by schizophrenia abnormalities in receptors and reuptake sites or schizotypal and delusional disorders. (5) The in several cortical and subcortical GABA presence of delusions, hallucinations, systems, and also the use of adjunctive GABA suspiciousness, disorganized thinking marks agonists have shown greater improvement in the positive symptoms of the disorder, and core schizophrenia symptoms. (24) Over the impoverished speech and thinking, lack of past decade, several basic and clinical studies social drive, flatness of emotional expression, have reported the involvement of brain apathy represents the negative symptoms of histamine in the pathophysiology of schizophrenia. Also, majority of patients with schizophrenia. (25, 26) Increased histamine schizophrenia report memory and decrement release has been recorded in several in cognitive functioning. (2, 3) The first established experimental models of generation or the drugs schizophrenia. (26, 27) In clinical studies, the (APD) have been successful in treating levels of N-tele-methylhistamine, a major brain positive symptoms but they cause severe histamine metabolite, and marker of brain limiting side-effects, while the second histamine turnover, was found to be elevated generation (atypical) APDs ameliorated in the cerebrospinal fluid of patients, and a negative symptoms and positive symptoms in decrease in binding sites most patients but they had no or only moderate was also reported. Many atypical APDs were effects on cognition and also have adverse reported to increase histamine turnover in the effects for example disturbance of metabolic brain, indicating that an abnormality in the profiles and weight gain. (6) Therefore, histamine system has a role in the presently there is a significant unmet clinical extradopaminergic brain dysfunction of needs for schizophrenia treatment especially, schizophrenia. Additionally, treatment of negative symptoms and cognitive neurodevelopmental disturbances occurring deficits associated with schizophrenia. during birth or genetic defects play critical role in schizophrenia development. (28-32) Pathophysiology An increase of subcortical mesolimbic Limitations of the Current Antipsychotic dopamine release has been reported to cause Agents hyperstimulation of dopamine D2 receptors Typical APDs have been effective in the which produces the positive symptoms, while treatment of positive symptoms and prevented reduced mesocortical dopamine release in the psychotic relapse, but they showed only prefrontal cortex causes lowering in the modest or no efficacy in improving negative dopamine D1 receptors activation which symptoms and accompanying cognitive produces the negative symptoms and cognitive deficits, and frequently caused intolerable side- impairment. (7-12) More recently, involvement of effects including extrapyramidal symptoms and presynaptic dopamine receptors has also been tardive dyskinesia. The advent of the second reported, which affects the dopamine synthesis generation, atypical APDs, significantly capacity, baseline synaptic dopamine levels, improved the pharmacologic treatment of and dopamine release.(13) N-methyl D- schizophrenia, and caused lesser side effects. aspartate (NMDA) receptor antagonists, These APDs showed superior clinical ketamine or MK-801, induce schizophrenia-like outcomes, exceptional tolerability and efficacy behavioural disturbances and impaired in refractory cases, and considerably reduced neurocognition in rodents, produce psychotic psychotic symptoms, relapse rate, and Danish Mahmood 566 improved cognitive deficits. The disadvantages Moreover, LY2140023 do not cause weight of APDs were reported to be weight gain, gain associated with instead a changes in glucose and lipid metabolism, risk modest weight loss has been reported. of diabetes, coronary disease, and However, a double-blind, placebo-controlled hypertension on prolonged use. (33) Atypical comparator study in patients with APDs also reported to have little efficacy in schizophrenia, LY2140023 treatment reversing cognitive impairments or show only demonstrated no efficacy. But the treatment modest efficacy in the treatment of negative with LY2140023 was generally well tolerated and mood symptoms, and higher incidence of with no new adverse safety findings were agranulocytosis especially with . recorded compared to previous trials. Thus, Therefore, clozapine and other second further understanding of the role of glutamate generation APDs are now reserved for patients as a therapeutic target in schizophrenia is who are unresponsive to, or intolerant of, needed. (37) Rasagiline, raloxifene and conventional APDs. Thus, there is an urgent Bexarotene are other schizophrenic need for newer for schizophrenia medications being developed as adjunct that is effective against a broad range of therapies. Rasagiline is a selective monoamine symptoms and free of such limiting safety oxidase inhibitor-B which is expected to be issues. According to a document, over 36 new added to standard antipsychotic medication to medications for schizophrenia are being treat cognitive impairment and negative developed by different biopharmaceutical symptoms associated with schizophrenia. research companies. (34) Cariprazine, a Raloxifene is a selective modulator of dopaminergic agent, is a novel atypical APD oestrogen receptor, modulating the effects of which has been currently approved by US oestrogen in the central nervous system which Food and Drug Administration (FDA). It differs could improve emotional symptoms, memory from all the current second generation APDs, and information processing in psychotic which, with the exception of amisulpride, bind patients. BL-1020 is a new GABA-enhanced to D2 and 5-HT2A receptors. It displays partial antipsychotic which combines dopamine agonism at D2, D3 and 5-HT1A receptors and antagonism with GABA agonist activity. The antagonism at 5-HT2B receptors. The data from findings of a 6-week, randomized, double- animal studies suggest low that D2 and D3 blind, controlled, efficacy and safety study receptors activity and high agonistic activity at reported it to be an effective new APD with 5-HT1A. It is believed that cariprazine besides, possible procognitive effects which is further providing an antipsychotic benefit, would being tested for short- and long-term effects. mitigate some of the cognitive deficit that is (38) Antitumor agent bexarotene act via nuclear often associated with schizophrenia. retinoid X receptor (RXR) activation and has Lurasidone is another atypical APD which been reported to modulate numerous received approval at the end of 2010 by FDA. metabolic pathways involved in the Lurasidone has high antagonistic activity at D2, pathogenesis of schizophrenia and 5-HT2A and 5-HT7 receptors and display partial schizoaffective disorder. A 6-week, agonism at 5-HT1A receptor. It is well tolerated randomized, double-blind, placebo-controlled and has few of side effects. (35) A randomized, multicenter trial evaluating bexarotene reported double-blind, placebo- and active-controlled it to be a potential novel adjuvant therapeutic trial has reported the efficacy and safety of strategy for schizophrenia, particularly for the lurasidone 80 mg/day and 160 mg/day in the reduction of positive symptoms. (39) treatment of schizophrenia. (36) A potential new ITI-007 is a new molecular entity with a class of treatments for schizophrenia that pharmacologic profile which combines dose- operate via a novel mechanism is LY2140023. related monoamine modulation with It is a prodrug of the orthosteric agonist (LY- phosphorylation of intracellular signalling 404039), which operates at the mGluR2/3 and proteins. The in vitro and in vivo activities of remains active as long as bound to the ITI-007 have supported its development for the receptor. It is believed that it exerts its effects treatment of schizophrenia and other by modulation of the dopaminergic system psychiatric and neurologic disorders. (40) ITI- because mGluR2/3 agonists have been 007 was reported as a potent 5-HT2A receptor observed to inhibit dopamine release. having strong affinity for dopamine D2

567 Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect

receptors and the serotonin transporter but cortex, thalamus, hippocampus, amygdala, negligible binding to receptors such histamine cerebellum, brain stem and spinal cord. (45-48) H1, 5-HT2C, and muscarinic receptors TMN receives afferent neuronal inputs from associated with cognitive and metabolic side preoptic area of the hypothalamus, septum, effects of antipsychotic drugs. In vivo it is a 5- prefrontal cortex, subiculum and dorsal HT2A antagonist having dual properties at D2 tegmentum. Afferent neurons in the receptors. It blocks postsynaptic D2 receptor hippocampus release either glutamate or and also acts as a partial agonist at GABA and can stimulate or inhibit TMN (40) presynaptic striatal D2 receptors. In a neurons. Cortical afferents release glutamate phase II randomized, double-blind, placebo- and stimulate TMN neurons, via both AMPA controlled, and active-controlled trial which was and NMDA receptors. (48) Histamine in the brain conducted at eight sites in the United States elicit its response through 4 subtypes of reported ITI-007 to be an effective for the receptors, H1, H2, H3 and H4 receptors and are treatment of schizophrenia and possess a coupled to specific G-proteins. (45, 48, 49) comparable efficacy with placebo on safety Histamine H4 receptors are expressed in the measures, and improve negative and immune system but are also present in the depression symptoms. Thus, it has been brain. (50) reported that ITI007 could have an expanded Histamine H1 receptors modulate many therapeutic efficacy in schizophrenia treatment physiological functions such as maintaining in comparison with the current APDs. (41) wakefulness, sleep-wake cycle, learning and Despite all the developments in schizophrenia memory, stress, seizures, emotions and (45, 48, 51) treatment, specific medication to treat all of the appetite control. Histamine H2 negative symptoms and cognitive impairments receptors in the central nervous system (CNS) remains to be developed. Thus, histamine H3 are linked to processes of learning and ligands may be regarded as one step further in memory, motor control, and thermoregulation, this context. however, their functions are not clear. (52, 53) Histamine H3 receptors are the third histamine Histamine Neurotransmission in Brain receptor, and are presynaptic autoreceptors, Histamine was first discovered in ergot which negatively regulate its synthesis and extracts and subsequently isolated from release. They are mostly restricted in the CNS, tissues and shows its physiological effect on and have a wide distribution across the brain; variety of cell types (including smooth muscle the highest densities of H3 receptors have cells, neurons, endocrine and exocrine cells, been reported in the striatum, hippocampus blood cells and cells of the immune system and . (54-58) and later demonstrated as chemical Histamine H3 receptors also act as messenger in cell to cell communication, which heteroreceptors which regulate the release of is released from tissues () producing several key neurotransmitters. (48-57) Activation bronchoconstriction during anaphylactic of H1 and H2 receptor leads to excitation, reactions. In 1970s, using radio-isotopes of whereas H3 receptor activation causes histamine and its synthetic enzyme, l- inhibition of histaminergic neurons, thus, H3 decarboxylase, it was confirmed that histamine receptors play an important role in regulating acted as a and there exists a brain histaminergic neuron. well-defined histaminergic neuronal system in (42) mammalian brain. Role of Histamine H3 Receptors and Their Histamine has been reported to act as a Antagonism in Schizophrenia: Preclinical neurotransmitter and neuromodulator in the Status mammalian brain, and is involved critically in Histamine H3 receptors are known to the regulation of memory, cognition, emotion function as auto- and hetero-receptors to and sleep. (43, 44) The cell bodies of brain modulate the synthesis and release of multiple histamine neurons are located in the neurotransmitters critical for cognition, tuberomammillary nucleus (TMN) of the including histamine, dopamine and hypothalamus. The efferents of histamine- . (58) Histaminergic neurons releasing neurons of the TMN innervate containing H3 receptors innervate prefrontal extensively to brain regions such as cerebral cortex (PFC) and hippocampus, the brain Danish Mahmood 568 areas involved in learning and memory striatopallidal neurons of the indirect-pathway processes, and H3 receptor antagonists have which in turn indicate potential interest in been reported to enhance multiple cognition developing histamine H3-receptor domains in naive animals. (59) Further, antagonists/inverse agonists in symptomatic microdialysis and in vivo electrophysiological treatment of schizophrenia. (63) In Dilute Brown studies have found decrease in histamine Non-Agouti (DBA)/2 mouse model, impaired neuronal firing following treatment with prepulse inhibition (PPI) was enhanced after (63) , a selective H3 receptor agonist. Also, treating with and . In increase in histamine neuronal firing and 2006, one of the studies reported that histamine release in TMN and PFC was histamine neuronal activity increased following demonstrated with the treatment of the administration of MK-801, a NMDA thioperamide, a H3/H4 receptor agonist. , further, suggests a role of Furthermore, local perfusion of immepip into histamine neurons in schizophrenia and the TMN elevated histamine levels which was treatment of mice with ciproxifan was reported lowered by thioperamide in TMN but not in the to decrease hyperlocomotion induced by MK- PFC. However, it was observed that immepip 801. (64) The same year, Akhtar et al. reported perfused locally into the PFC lowered the antipsychotic-like activities of thioperamide in extracellular level of histamine in both TMN several preclinical models of schizophrenia. (65) and PFC. (61) The findings of the study A recent study by Mahmood et al. also suggested that histamine H3 receptors in the reported the antipsychotic and antioxidative brain, and particularly those expressed in the activities of ciproxifan and in PFC, play key role in the regulation of experimental studies. (66, 67) Reduced dopamine histamine neurotransmission in the brain. release in PFC has been linked to negative Thus, it was suggested that histaminergic symptoms and cognitive impairment, and neuronal system of the brain may be critically treatment with H3 antagonist/inverse agonist involved in the pathophysiology of psychotic, enhanced the release of dopamine in PFC, (68) affective and cognitive disorders among other which resulted in improvement of the negative disorders of brain. Histamine H3 receptors by symptoms and cognitive impairment in presynaptic feedback mechanism regulate schizophrenia. (68-70) Antagonism/inverse- histamine synthesis and release and thereby agonism via histamine H3 receptor has been control brain histamine system. Hence, it may suggested to have a dopamine sparing-effect be expected that histamine H3 receptor could on prefrontal function and may have an potentially serve as a therapeutic target for advantage over typical APDs. They may also novel medications for the treatment of various have advantage over atypical APDs which central nervous system disorders including produce side-effects including weight gain. (45, 47, 61, 62) schizophrenia. Histamine H3 receptor antagonists/inverse In 2002, in a preclinical study, Pilot et al. agonist might improve cognitive deficit leading showed that striatopallidal neurons of indirect to poor quality of life and functioning in pathway express H3 receptors and over 70% of schizophrenics and current APDs have shown striatal enkephalin neurons express H3 poor or low efficacy in amelioration of this receptor messenger RNAs (mRNA). Acute domain of schizophrenia. In the past, several administration of ciproxifan, a histamine H3 studies investigated histamine H3 antagonists receptor antagonist/inverse agonist, strongly in several experimental models involving potentiated the -induced expression cognitive deficits of schizophrenia. (65-75) of enkephalin, c-fos and neurotensin mRNA However, most of the preclinical studies including behavioural activities e.g. locomotor involving models of cognitive deficits mostly hypoactivity and catalepsy which were reduced utilised mostly the imidazole-based by (R)-α-methylhistamine, a histamine H3 compounds (e.g. thioperamide or ciproxifan) receptor agonist. The potentiation of this effect which could not reach clinical development was also found in the caudate–putamen and stage because of undesirable effects. (75) Non- nucleus accumbens. The strong expression of imidazole based compounds have renewed the H3-receptor mRNA in enkephalin neurons interest in further pursuing H3 compounds for indicated a direct H3/D2-receptor interactions possible efficacy in the amelioration of resulting from enhanced activation of cognitive deficits. In 2007, Ligneau et al.

569 Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect

investigated the role of BF2.649, a high affinity, long-term treatment of histamine H3 selective non-imidazole histamine H3 receptor antagonists. antagonist/inverse agonist in schizophrenia. (70) ABT-239 and A-431404 are other two BF2.649 exhibited a dose-dependent cortical potent non-imidazole-based H3 receptor activation, wakening effect, in mice which antagonists which have been studied and their probably resulted from selective activation of a efficacy compared to atypical antipsychotics sub-population of dopaminergic neurons. and olanzapine, in animal model BF2.649 per se reduced locomotor with impaired cognition. (78) In spontaneous hyperactivity mediated by methamphetamine alternation in cross-maze and inhibitory or MK-801 without significantly affecting the avoidance (IA) models of working-memory and spontaneous locomotor activity and abolished long-term memory retention, respectively, apomorphine-induced deficit in PPI. ABT-239 and A-431404, but not risperidone Accumulating evidence suggests that and olanzapine attenuated MK-801-induced antagonism with non-imidazole based H3 deficits on spontaneous alternation in cross- compounds could prove to be a new class of maze. ABT-239 and A-431404 on their own did APDs with pro-cognitive properties. In 2009, not attenuate the alternation performance and Southam et al. reported preclinical study with IA but they ameliorate the MK-801-induced another non-imidazole based H3 receptor impairments in IA. It was observed that antagonist, GSK207040, in a series of risperidone and olanzapine did not decrease behavioural and neurochemical paradigms to MK-801-induced deficits in IA. The two typical evaluate its antipsychotic potential. (77) The APDs produced dose-dependent impairments acute oral dose of GSK207040 was explored when given alone. Methylazoxy-methanol for its efficacy on several preclinical models acetate (MAM), a methylating agent, is a which included reversal of deficit in novel widely recognized neurodevelopmental model object recognition memory and PPI, and to study prenatal pharmacological insult, hyperlocomotor activity induced by disruption of neurogenesis and neural amphetamine, and acute neurochemical development in rats. (79) ABT-239 significantly effects in rat anterior cingulate cortex by using improves spontaneous alternation impairments microdialysates for dopamine, noradrenaline, in MAM treated rats in cross-maze model. (78) and acetylcholine. GSK207040 at a dose of 3 Another study, in 2013, reported that histamine mg/kg showed significant increase in object H3-receptor inverse agonist, BF2.649 recognition memory, and decrease in isolation (), was effective in improving rearing-induced deficits in PPI at the dose of consolidation processes in fear-condition task 1.0 and 3.2 mg/kg. However, it failed to model in rats. (80) In a study, treatment with reverse the amphetamine-induced increase in ciproxifan at the dose of 3 mg/kg increased the locomotor activity, and did not show any working memory in sleep restricted mice evidence of interaction with haloperidol. At through specific modulation of prefrontal cortex dose of 3.2 mg/kg, it increased the areas. (81) A recent published study by extracellular dopamine, noradrenaline, and Mahmood et al. have supported acetylcholine levels in the anterior cingulate antischizophrenic activities of ciproxifan and cortex and enhanced c-fos expression in the clobenpropit on MK-801-induced schizophrenia nucleus accumbens at doses of 3.2 and 10.0 like behaviours in rodents. (82) Another mg/kg, respectively. (77) From the behavioural published report by Mahmood et al. reported and neurochemical profile of GSK207040, it the decrease in MK-801-induced may be suggested that antagonism of hyperlocomotor behaviours and the modulation histamine H3 receptor could be a promising of dopamine and histamine levels following approach to treat the cognitive deficits and subchronic dosing of ciproxifan and impaired sensory motor gating which typically clobenpropit indicating some antipsychotic-like (83) observed in patients with schizophrenia. The activities of these H3 compounds. inability of GSK207040 to reverse The study by Burban et al, in year 2010, amphetamine-induced locomotor hyperactivity reported total absence of antipsychotic effect in indicate that positive symptoms could not be several validated animal models of psychosis (77) treated with acute doses, but may require a and rejected antipsychotic-like properties of H3 receptor antagonists/inverse agonists. Danish Mahmood 570

However, they have supported their role in the effects associated with chronic medication of treating cognitive deficits of SCZ as adjunct schizophrenia. (88) medication. (84) In 2014, Suven Life Sciences, In light of the present and past studies, at Alzheimer's Association International histamine H3-receptor antagonism/inverse Conference reported positive data on agonism could be a promising therapeutic exposure, safety, pharmacokinetics, and approach to treat schizophrenia behavioral assays in rats. The poster claimed symptomatically, and the development of H3 an increase in cortical histamine and compounds acting via H3 antagonism/inverse acetylcholine levels as well as reversal of agonism hold lot of promise but may warrant memory deficits. (85) Further preclinical data advance studies. were presented at AAIC in 2015. (86) SUVN- G3031 was reported as a novel and potent Histamine H3 Receptors and their histamine developed for Antagonism in Schizophrenia: Current potential treatment of cognitive deficits. The Clinical Perspectives novel compound was shown to have a receptor In post-mortem analysis of brain samples affinity of 8.7 nM and displays more than 100 from schizophrenic patients, hippocampal CA2 fold selectivity against the related G-protein region of medicated patients and prefrontal coupled receptors. The molecule was reported cortices show lower and higher H3 receptor to exhibit desired pharmacokinetic properties binding, respectively compared to controls. and brain penetration and display an excellent This indicates a correlation with psychotic separation between H3 affinity and human symptoms suggesting that H3 receptors have a hERG potassium channel inhibition. Thus, the role in the modulation of cognition. (89) development of such novel H3 compound Histamine H3 compounds which were reported having desired efficacy, safety, with almost drug-like properties included pharmacokinetic and metabolic profiles further tiprolisant, ABT-239, GSK189254, and JNJ- (90) suggest that H3 compounds still have vast 10181457. therapeutic potential which need to be fully Weight gain is a common side effect tapped using sophisticated drug discovery associated with some prominent antipsychotic (85) methods. agents affecting compliance. Histamine H3 Additionally, H3 compounds could have an antagonists have been reported as an added advantage and edge over other pipeline alternative to olanzapine to lower weight gain. drugs for schizophrenia by the fact that In clinical studies, histamine H3 antagonists preclinical data have provided insights into the have attenuated weight gain by the long-term potential role of histamine H3 receptors as a use of antipsychotic medication e.g. target of antiobesity therapeutics. (87) Studies olanzapine. A recent double-blind placebo- on animals have revealed that brain releases controlled study reported reduced weight gain histamine during the appetitive phase to caused by olanzapine in patients with (91) provide a high level of arousal in preparation to schizophrenia following H3 antagonist use. feeding, but also mediates satiety. In human patients on antipsychotic medication, Furthermore, histamine is reported to regulate the combined 4mg dose of reboxetine (a peripheral mechanisms such as glucose selective reuptake inhibitor), uptake and insulin function. Researches on and 48 mg dose of (a potent H3 animals have indicated that activation of H1 receptor antagonist), administered daily and H3 receptors is important for the regulation significantly reduced weight compared to the of the diurnal rhythm of food consumption. placebo group. (91) A Phase II clinical trial These receptors have been specifically assessed the efficacy of BF2.649 in patients recognized as mediators of energy intake and suffering from APD medication induced weight- expenditure. However, no brain penetrating gain and found it to be effective following co- drugs acting H1 receptor agonism could be treatment with APD medication. identified as yet which could have anti- (WO2006084833A1). Another study assessed effects. However, interesting results have the procognitive potential of BF2.649 in emerged from clinical trials which have schizophrenic patients and affective disorder, assessed the ameliorating effect of betahistine and is currently underway (NCT-ID (an H1 agonist/H3 antagonist) on metabolic side NCT00690274). A Phase1b, placebo

571 Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect

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