Histamine schizophrenia

The neurotransmitter histamine receives less attention compared with other biogenic amines, because of its moderate action in the central nervous system (CNS). However, recent evidence suggests that histamine plays an important role in multiple CNS disorders including insomnia, narcolepsy, Parkinson's diseases, schizophrenia, Alzheimer's disease, and cerebral ischemia. New insights are emerging into the potential roles of histamine receptors as targets for the treatment of these diseases. Although some histamine related agents have failed in clinical trials, current preclinical studies suggest that this neurotransmitter may still have extensive applications in treating CNS disorders, however, advanced studies are warranted...

The basal ganglia have a central role in motor patterning, habits, motivated behaviors, and cognition as well as in numerous neuropsychiatric disorders. Receptors for histamine, especially the H3 receptor (H3R), are highly expressed in the striatum, the primary input nucleus of the basal ganglia, but their effects on this circuitry have been little explored. H3R interacts with dopamine (DA) receptors ex vivo; the nature and functional importance of these interactions in vivo remain obscure. We found H3R activation with the agonist R-(-)-α-methylhistamine to produce a unique time- and cell type-dependent profile of molecular signaling events in the striatum...

The potential contributions of dysregulation of the brain's histaminergic modulatory system to neuropsychiatric disease, and the potential of histamine-targeting medications as therapeutic agents, are gradually coming into focus. The H3R receptor, which is expressed primarily in the central nervous system, is a promising pharmacotherapeutic target. Recent evidence for a contribution of histamine dysregulation to Tourette syndrome and tic disorders is particularly strong; although specific mutations in histamine-associated genes are rare, they have led to informative studies in animal models that may pave the way for therapeutic advances...

In spite of almost 60 years of experience with the pharmacological treatment of schizophrenia, there is still a large unmet medical need for better control of especially the negative and cognitive symptoms of schizophrenia. One potential new avenue is the selective blockade of histamine H3 receptors (H3R). Based on a large basis of preclinical data, H3R antagonists or inverse agonists have been suggested to improve cognition in a variety of neurological and psychiatric indications. The aim of the present paper is to review the potential usefulness of H3R antagonists for the treatment of schizophrenia...

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0...

Histamine H3 receptor therapeutics have been proposed for several diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease and obesity. We set out to evaluate the novel compound, [125I]WYE-230949, as a potential radionuclide imaging agent for the histamine H3 receptor in brain. [125I]WYE-230949 had a high in vitro affinity for the rat histamine H3 receptor (Kd of 6.9 nM). The regional distribution of [125I]WYE-230949 binding sites in rat brain, demonstrated by in vitro autoradiography, was consistent with the known distribution of the histamine H3 receptor...

Although histamine H3 receptors are predominantly known as presynaptic receptors, regulating the release of neurotransmitters such as dopamine, acetylcholine, and histamine, in the striatal complex the vast majority of these receptors are actually located on the other side, in other words postsynaptically. Given their strategic location, they can crucially affect signaling throughout the basal ganglia. We describe the anatomy and function of H3 receptors within the basal ganglia with a specific focus on their colocalization with dopamine D1 and D2 receptors...

INTRODUCTION: ABT-288 is a highly potent histamine-3 receptor antagonist that has demonstrated pro-cognitive effects in preclinical models relevant to schizophrenia. This study evaluated the efficacy and safety of two doses of ABT-288 in the treatment of cognitive impairment associated with schizophrenia. METHODS: A randomized, double-blind, placebo-controlled, parallel-group 12-week study was conducted at 23 centers in the United States. Clinically stable subjects with schizophrenia were randomized in an equal ratio to ABT-288 10 mg, ABT-288 25 mg, or placebo once daily while continuing their antipsychotic regimen...

Histamine has important functions as regulator of several other key neurotransmitters. Patients with schizophrenia have lower histamine H1 receptor levels. Since a case report in 1990 of an effect of the H2 antagonist famotidine on negative symptoms in schizophrenia, some open-label trials have been performed, but no randomized controlled trial. Recently, it was shown that clozapine is a full inverse agonist at the H2 receptor. We performed a researcher-initiated, academically financed, double-blind, placebo-controlled, parallel-group, randomized trial with the histamine H2 antagonist famotidine in treatment-resistant schizophrenia...

BACKGROUND: Current antipsychotic treatments have little impact on the cognitive deficits associated with schizophrenia. It has been proposed that agents which promote histamine release may enhance cognition. We evaluated whether the H3 inverse agonist MK-0249 might improve cognitive deficits in patients with schizophrenia. METHODS: Outpatients (N=55) with schizophrenia between ages 21 and 55 who were clinically stable, experienced no more than mild to moderate overall symptoms (PANSS score total 36-75), and were taking a stable dose of antipsychotic medication were randomized to MK-0249 10mg and placebo in a multi-center, randomized, double-blind, 2-period (4-weeks per period), cross-over study...

OBJECTIVE: To evaluate the use and potential benefit of famotidine in the management of schizophrenia. DATA SOURCES: Clinical literature accessed through MEDLINE (February 1998-October 1998). Key search terms included famotidine, schizophrenia, and histamine. DATA SYNTHESIS: Schizophrenia is a complicated disorder associated with high morbidity if left unmanaged. Histamine2 (H2)-antagonists may be an alternative to conventional treatments...

The usefulness of the histamine-2 (H2) antagonist famotidine as an adjunct to conventional antipsychotic treatments of idiopathic psychotic disorders (i.e., schizophrenia and schizoaffective disorder) was investigated in an open-label study. After stabilization for at least 1 week with their conventional antipsychotic medication regimen, 10 patients completed a 3-week study period in which famotidine (20 mg twice a day) was added as an adjunctive medication. The 10 patients were all somewhat treatment refractory and had spent a mean of 230 days of the previous 2 years in the hospital...

Famotidine (Pepcid, a histamine-2 receptor blocker, is marketed for the treatment of peptic ulcer disease, gastroesophageal reflux, and the treatment of pathological hypersecretory conditions, including the Zollinger-Ellison syndrome. Recent reports indicate that it is also effective in relieving the deficit (or withdrawal) symptoms of adults with schizophrenia. Autism, a neuropsychiatric disorder which presents within the first few years of life, is defined by deficient social interaction, communication, language, play, and a markedly restricted repertoire of activities and interests...

Histaminergic projections innervate brain areas implicated in the pathophysiology of schizophrenia. In a previous open-label study, there was the suggestion that famotidine, and H2 histamine-receptor antagonist, possessed adjuvant therapeutic properties when added to the stable neuroleptic medications regimens of 10 treatment-refractory patients. In that study, the maximal dosage of famotidine was limited to 40 mg/day, the recommended maximal dosage for the treatment of peptic ulcer disease. In this study, we examined 18 patients fulfilling DSM-III-R criteria for schizophrenia and schizoaffective disorder who had famotidine (100 mg/day) added to their stable neuroleptic medication regimen...

The first indication that histamine might be important in the functioning of the brain was the finding that the centrally penetrating histamine H1 antagonists had marked sedative properties. Subsequently with the development of more specific compounds and drugs for the H1, H2 and H3 receptors a greater understanding of the neurotransmitter/modulator role of histamine in the CNS has been possible. Histamine is now associated with wakefulness, suppression of seizures, hypothermia and emesis. The histamine H1 antagonists have been shown to potentiate opioid-induced analgesia, and modify eating and drinking patterns as well as endocrine secretions from the pituitary gland...

Smooth pursuit eye movements (SPEM) are often abnormal in schizophrenic patients and have been proposed as a trait marker of the disorder. We explored the use of SPEM as an outcome measure in an open-label clinical trial of famotidine, an H-2 antagonist, in patients with schizophrenia; famotidine has been proposed as an adjunctive medication, particularly for negative symptoms. Prior studies using SPEM as an outcome measure have not found a significant effect with "typical" neuroleptic medication, and one study found greater SPEM dysfunction with clozapine treatment...

Recent reports suggest some utility for famotidine, a histamine type 2 (H2) antagonist, in the treatment of schizophrenia. The current report describes a treatment-resistant patient with chronic undifferentiated schizophrenia whose most dramatic symptomatic improvements were temporarily related to the open-label addition of famotidine (40-100 mg/day) to conventional neuroleptic treatment (molindone 150-200 mg/day) over the course of approximately 10 months. During one 2-week interval, his symptoms were controlled with famotidine (40 mg/day) alone...

Some patients suffering from schizophrenia fail to respond to or tolerate adequate doses of available antipsychotic medications. Thus, innovative pharmacotherapeutic approaches, such as augmentation strategies, play an important role in the management of these treatment-resistant patients. A recent case report suggested that the administration of famotidine to a patient suffering from schizophrenia with peptic ulcer disease was associated with improvement in the deficit symptoms of schizophrenia. Famotidine is a potent highly selective H2 receptor antagonist which crosses the blood-brain barrier...

Involvement of histamine H1 receptor in the brains of schizophrenic patients was investigated using 3H-mepyramine as a ligand. The specific 3H-mepyramine binding in the frontal cortex was saturable with the dissociation constant (Kd) of about 0.6 nM and the maximum number of binding sites (Bmax) of 64 fmol/mg protein. Specific H1 antagonists, mepyramine (Ki = 1.4 nM), promethazine (Ki = 1.4 nM), diphenylpyraline (Ki = 4.1 nM), triprolidine (Ki = 5.3 nM), diphenylhydramine (Ki = 35 nM), but not the specific H2 antagonist, cimetidine (Ki greater than 10(5) nM), strongly inhibited the 3H-mepyramine binding...