Neuropsychiatry of Histaminergic Circuits: Potential Role of Novel H3 Receptor Selective Antagonist/Inverse Agonist Pitolisant in Prader-Willi Syndrome

Dear Editor

Histamine and its receptors have been implicated in several neuropsychiatric conditions including Gilles de la Tourette syndrome, schizophrenia, attention deficit hyperactivity disorder, narcolepsy, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, epilepsy, and substance use disorders.^1–3

Histaminergic brain circuitry is involved in multiple complex neurological functions including the arousal system, sensory and motor functions, attentional processes, memory, learning and reward.² Histamine is synthesized from the amino acid histidine which is taken up into histamine neurons and converted by histidine decarboxylase into histamine.² The histaminergic neurons are located in the tuberomammillary nucleus of the posterior hypothalamus, with widespread projections innervating most areas of the brain.² There are 4 different types of histamine receptors (H1R-H4R), all of them are part of the rhodopsin-like family of G protein-coupled receptors.^4,5 H1R and H2R have predominantly excitatory activity and H4R have predominantly peripheral expression in immune system cells involved in immunomodulation and inflammatory response.⁴ H3R receptors differ from other histamine receptors in that they are mostly inhibitory presynaptic autoreceptors promoting the reuptake of histamine thereby decreasing histamine in the synapse.⁵ Blocking these H3R promotes the release of histamine.⁶ There receptors are located on tuberomammillary neurons and are mainly expressed in cerebral cortex, hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum, thalamus, and hypothalamus.⁵ H3 heteroreceptors, present in different neuronal populations, inhibit the release of other neurotransmitters including acetylcholine, dopamine, serotonin, noradrenaline, GABA, and glutamate.⁴ Histaminergic brain circuits have long been a subject of interest in neuropsychiatry with wide direct and indirect evidence of their involvement in several neurological and psychiatric symptoms.^1,4,7

Postsynaptic H1R and H2R play a key role in attention regulation with blockade of presynaptic H3 auto-receptors indirectly enhancing histamine-mediated attention in disorders such as ADHD and Alzheimer’s disease.⁷ Besides controlling histamine release through the presynaptic H3R, ligands may also control the release of other neurotransmitter systems involved in cognitive processes.⁷ Regarding schizophrenia, in addition to the histaminergic and dopaminergic hyperactivity, postsynaptic H3R shows additive activation with striatal dopamine D2 receptors in generating some symptoms, thus supporting the interest of H3R inverse agonists as antipsychotics.⁷

Selective ligands targeting the H3R auto-receptor have been shown to be modulators of sleep and associated disorders. Drugs acting on H3R include agonists (e.g., N-methylhistamine, R-methylhistamine, imetit), protean agonists that may function as full or partial agonists, neutral antagonists, partial or full inverse agonists (e.g., proxyfan) and inverse agonists (e.g., thioperamide, ciproxifan, pitolisant).

Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder resulting from abnormal expression of genes on the chromosome region 15q11.2–q13.⁸ Most cases result from genetic errors with de novo paternal deletions with the remaining cases resulting from maternal uniparental disomy, imprinting center defects and other atypical mutations.^8,9 PWS clinical presentation differs according to the stage of development of the individual but includes several developmental delays with skeletal anomalies, dysmorphic features, endocrinological disorders (e.g., growth hormone deficiency, hypogonadism) and neuropsychiatric symptoms.^8,10,11 Neuropsychiatric symptoms include delayed cognitive development and learning disabilities, muscular hypotonia, autonomic instability and seizures. Other neurobehavioral symptoms include agitation, anger, temper tantrums, hyperphagia with food stealing, self-harm, skin picking, and hoarding.^8,11 According to Glasson and colleagues’ systematic review among children with different neurodevelopmental syndromes, PWS presents the highest scores of psychiatric symptoms.¹² According to this study, most prevalent DSM 5 diagnosis in PWS included oppositional defiance disorder (20%), anxiety disorders (10%), conduct disorder (5%) and psychotic disorders (3%).¹²

Treatment of PWS involves a multidisciplinary integrated approach to achieve optimal monitoring of disease progression, comorbidities, prevention of complications ultimately improving quality of life and prognosis.⁸ The protean neuropsychiatric presentation of PWS with behavioral symptoms that are often challenging to manage effectively with unspecific pharmacological interventions mean that there is a constant search for additional agents that might be suitable to manage these in some patients.

Pitolisant is a novel H3 selective antagonist and inverse agonist.^6,13,14 Acute H3R manipulation has shown to mainly affect general motor activity levels in novel environments with small changes in stereotyped behaviors observed but probably driven by altered general activity levels in animal models of autism spectrum disorders.¹⁵ Pitolisant was FDA approved in 2019 for narcolepsy type 1 and 2 with similar efficacy to modafinil. Ongoing phase 2 clinical trial intend to establish safety and efficacy in the treatment of daytime sleepiness in Prader-Willi syndrome which includes as secondary outcomes the evaluation of its impact in behavioral symptoms and cognitive rigidity (ClinicalTrials.gov Identifier: NCT04257929). Excessive daytime sleepiness treatment with pitolisant proved better tolerated than modafinil.¹⁶

Preclinical studies have demonstrated the potential efficacy of pitolisant in addressing neurobehavioral symptoms of PWS. Studies have found that pitolisant improved cognitive flexibility and reduced repetitive behaviours as well as improved social behaviour and reduced anxiety-like behaviour in animal models of PWS.^13,17 In a small case series of patients aged 10–15 years old impact in cognitive function has been reported in Prader-Willi syndrome with improvements in processing speed and mental clarity.¹⁸

Clinical trials of pitolisant in PWS patients have also shown promising results. In the phase 2 trial mentioned earlier (ClinicalTrials.gov Identifier: NCT04257929), pitolisant improved scores on the Adaptive Behavior Assessment System (ABAS), which measures social skills, daily living skills, and academics, compared to placebo. It also improved scores on the Vineland Adaptive Behavior Scale (VABS), which measures adaptive behaviour and socialization. Safety of pitolisant has also been studied in real world settings outside clinical trials. A recent pharmacovigilance study revealed the most common adverse drug reactions reported are neuropsychiatric and gastointestinal.¹⁹

Complex neuropsychiatric conditions such as PWS present a wide range of cognitive and behavioural symptoms that are frequently difficult to manage as there are no optimal or targeted pharmacological interventions. Commonly used strategies include the non-specific use of antidopaminergic and serotoninergic agents, anticonvulsants, psychostimulants, and even intranasal oxytocin. Considering PWS is amongst the neurodevelopmental conditions with the most neuropsychiatric symptoms,¹² novel agents such as pitolisant should be considered as they may prove useful to improve cognitive and behavioural manifestations of this syndrome. Although the management of these conditions goes far beyond a single pharmacological intervention, these may be vital as part of an integrated management plan involving multidisciplinary teams that enables optimization of clinical outcomes.