Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders.

Rationale: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain.

Objective: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays.

Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: Results from a randomized placebo-controlled clinical trial.

Objective: This phase 3, randomized, double-blind, placebo-controlled study (NCT02600507) evaluated the efficacy and safety of lumateperone adjunctive therapy to lithium or valproate in patients with bipolar depression.

Methods: Patients (18-75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (MDE), with inadequate therapeutic response to lithium or valproate, were randomized 1:1:1 to 6 weeks adjunctive therapy with lumateperone 28 mg (n = 176), lumateperone 42 mg (n = 177), or placebo (n = 176). The primary and key secondary efficacy endpoints were change from baseline to Day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score and the Clinical Global Impression Scale-Bipolar Version-Severity Scale (CGI-BP-S) depression subscore.

Single doses of a highly selective inhibitor of phosphodiesterase 1 (lenrispodun) in healthy volunteers: a randomized pharmaco-fMRI clinical trial.

Lenrispodun is a potent and highly selective inhibitor of phosphodiesterase (PDE) type 1, which is thought to prolong intracellular second messenger signaling within cortical and subcortical dopaminergic brain regions. This is the first study of a PDE1 inhibitor in healthy volunteers using behavioral and neuroimaging approaches to examine its effects on neural targets and to provide a safety and tolerability assessment. The primary objectives were to determine whether lenrispodun induces changes in BOLD fMRI signals in the inferior frontal gyrus (IFG) during the stop signal task, and the dorsal anterior insula (dAI) during the extinction phase of a fear conditioning/extinction task.

Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial.

Objective: In a phase 3 randomized double-blind placebo-controlled study, the authors investigated the efficacy and safety of 42 mg/day of lumateperone in patients with bipolar I or bipolar II disorder experiencing a major depressive episode.

Methods: Patients 18-75 years old with a clinical diagnosis of bipolar I or bipolar II disorder and experiencing a major depressive episode were eligible for the study. Patients were randomized in a 1:1 ratio to receive 42 mg/day of lumateperone (N=188) or placebo (N=189), administered orally once daily in the evening for 6 weeks.

Safety and tolerability of lumateperone for the treatment of schizophrenia: a pooled analysis of late-phase placebo- and active-controlled clinical trials.

Lumateperone, an antipsychotic that is US Food and Drug Administration-approved for the treatment of schizophrenia, has a novel mechanism of action that may confer beneficial effects with improved tolerability. This pooled analysis of three randomized, double-blind, placebo-controlled trials was conducted to evaluate the safety and tolerability of lumateperone 42 mg. The pooled population comprised 1073 patients with an acute exacerbation of schizophrenia randomized to placebo (n = 412), lumateperone 42 mg (n = 406) or risperidone 4 mg (n = 255).

A review of the pharmacology and clinical profile of lumateperone for the treatment of schizophrenia.

Schizophrenia is associated with a tremendous individual and societal burden. The disease is characterized by a complex set of symptoms including psychosis, hallucinations, delusions and related positive symptoms combined with social function deficits, cognitive disturbances and, often, devastating mood disorder, such as comorbid depression. Management of the disease often requires lifelong pharmacotherapy.

Safety and tolerability of lumateperone 42 mg: An open-label antipsychotic switch study in outpatients with stable schizophrenia.

Background: Lumateperone is a mechanistically novel agent FDA-approved for the treatment of schizophrenia. Efficacy and favorable tolerability of lumateperone were demonstrated in 2 short-term placebo-controlled studies in patients with schizophrenia. This open-label study investigated the short-term safety/tolerability of lumateperone in outpatients with stable schizophrenia switched from previous antipsychotic treatment.

Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial.

Importance: Individuals living with schizophrenia are affected by cardiometabolic, endocrine, and motor adverse effects of current antipsychotic medications. Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects.

Objective: To examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia.

Dopamine D receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia.

Dopamine D receptor occupancy (DRO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high DRO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders.

PDE Inhibitors for the Treatment of Schizophrenia.

Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world's population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems.

Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats.

Rationale: Therapeutic agents for memory enhancement in psychiatric disorders, such as schizophrenia, are urgently needed.

Objective: The aim of this study is to characterize the preclinical profile of ITI-214, a potent inhibitor of phosphodiesterase 1 (PDE1).

Methods: ITI-214 was assayed for inhibition of PDE1 versus other PDE enzyme families using recombinant human PDE enzymes and for off-target binding to 70 substrates (General SEP II diversity panel; Caliper Life Sciences).

Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future.

Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the world's population. This disease is associated with considerable morbidity placing a major financial burden on society. Antipsychotics have been the mainstay of the pharmacological treatment of schizophrenia for decades.

Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.

A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo.

ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial.

Background: An urgent need exists for new treatments of schizophrenia that are effective against a broad range of symptoms and free of limiting safety issues. ITI-007 is a new molecular entity with a pharmacologic profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins.

Methods: A phase II randomized, double-blind, placebo-controlled, and active-controlled trial was conducted at eight sites in the United States with randomization of 335 acutely psychotic adults with schizophrenia.

ITI-007 demonstrates brain occupancy at serotonin 5-HT₂A and dopamine D₂ receptors and serotonin transporters using positron emission tomography in healthy volunteers.

Rationale: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders.

Objectives: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers.

Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.

Rationale: Schizophrenia remains among the most prevalent neuropsychiatric disorders, and current treatment options are accompanied by unwanted side effects. New treatments that better address core features of the disease with minimal side effects are needed.

Objectives: As a new therapeutic approach, 1-(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) is currently in human clinical trials for the treatment of schizophrenia.

Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders.

We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT(2A) and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT(2A) antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo.

Intracellular signaling and approaches to the treatment of schizophrenia and associated cognitive impairment.

Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world's population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems.

Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans.

Antiinflammatory drugs achieve their therapeutic actions at least in part by regulation of cytokine formation. A "cytokine hypothesis" of depression is supported by the observation that depressed individuals have elevated plasma levels of certain cytokines compared with healthy controls. Here we investigated a possible interaction between antidepressant agents and antiinflammatory agents on antidepressant-induced behaviors and on p11, a biochemical marker of depressive-like states and antidepressant responses.

Pimavanserin tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers.

Objective: Determine the effects of pimavanserin tartrate [ACP-103; N-(4-flurophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide], a selective serotonin 5-HT(2A) receptor inverse agonist, on slow wave sleep (SWS), other sleep parameters, and attention/vigilance.

Methods: Forty-five healthy adults were randomized to pimavanserin (1, 2.5, 5, or 20 mg) or placebo in a double-blind fashion (n=9/group).

Role of 5-HT2A receptor antagonists in the treatment of insomnia.

Insomnia encompasses a difficulty in falling asleep (sleep-onset insomnia) and/or a difficulty in staying asleep (SMI). Several selective serotonin-2A (5-HT2A) receptor antagonists have been in development as potential treatments for SMI. However, none have shown a sufficiently robust benefit-to-risk ratio, and none have reached market approval.

A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model.

A potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonist and antagonist, ACP-103 [N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1, active:salt)], was evaluated for its ability to reduce the primary motor symptom of tremor using tacrine-induced tremulous jaw movements in rats, which is an animal model of parkinsonian tremor. Furthermore, ACP-103 was evaluated for its ability to reduce levodopa-induced dyskinesias in monkeys rendered parkinsonian with MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]. ACP-103 reduced tacrine-induced tremulous jaw movements in rats.

Antipsychotic-like behavioral effects and cognitive enhancement by a potent and selective muscarinic M-sub-1 receptor agonist, AC-260584.

AC-260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one) is a potent and selective muscarinic M-sub-1 receptor agonist. AC-260584 was evaluated in animal models: antipsychotic-like effects were tested by the ability to reduce amphetamine- and MK-801-induced hyperactivity and apomorphine-induced climbing; catalepsy was assessed by measuring step-down latency; spatial memory was tested by using the Morris water maze. AC-260584 reduced amphetamine- and MK-801-induced hyperactivity and apomorphine-induced climbing.

PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain.

The mechanisms underlying the clinical properties of atypical antipsychotics have been postulated to be mediated, in part, by interactions with the 5-HT2A receptor. Recently, it has been recognized that clinically effective antipsychotic drugs are 5-HT2A receptor inverse agonists rather than neutral antagonists. In the present study, which is part of the clinical development of the novel, selective 5-HT2A receptor inverse agonist ACP-103, we applied positron emission tomography (PET) with the radioligand [11C]N-methylspiperone ([11C]NMSP) to study the relationship between oral dose, plasma level, and uptake of ACP-103 in living human brain.