NMDA receptor modulators (glutamate modulators) are a new form of antipsychotic that are in Phase II FDA studies. The first compound studied was glycine which was hypothesized by Daniel Javitt after observation that people with phencyclidine(PCP)-induced psychosis were lacking in glutamate transmission. [1] (PCP is an NMDA receptor antagonist that blocks glutamate.) In giving glycine to people with PCP-induced psychosis a recovery rate was noted. From there, it was hypothesized that people with psychosis from schizophrenia would benefit from increased glutamate transmission and glycine was added with strong recovery rates noted especially in the area of negative and cognitive symptoms. Glycine, however, sporadic results aside (dose 60 g/day or 0.8 g/kg, [2] [3] approximately the amount in 300 g of gelatin powder or two kilograms of sunflower seeds [4] ) remains an adjunct antipsychotic and an unworkable compound. However, the Eli Lilly and Company study drug LY-2140023 is being studied as a primary antipsychotic and is showing strong recovery rates, especially in the area of negative and cognitive symptoms of schizophrenia. Tardive dyskinesia, diabetes and other standard complications have not been noted:
Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P = 0.001 at week 4). Notably, patients treated with LY-2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia. [5]
Other NMDA receptor modulators are being studied and this modality of treatment may once approved as antipsychotic medications gradually replace the current (dopaminergic) antipsychotics.
Psychosis is a condition of the mind or psyche that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are disorganized thinking and incoherent speech and behavior that is inappropriate for a given situation. There may also be sleep problems, social withdrawal, lack of motivation, and difficulties carrying out daily activities. Psychosis can have serious adverse outcomes.
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptions of sounds, and violent behavior. As a recreational drug, it is typically smoked, but may be taken by mouth, snorted, or injected. It may also be mixed with cannabis or tobacco.
Schizophrenia is a mental disorder characterized variously by hallucinations, delusions, disorganized thinking and behavior, and flat or inappropriate affect. Symptoms develop gradually and typically begin during young adulthood and are never resolved. There is no objective diagnostic test; diagnosis is based on observed behavior, a psychiatric history that includes the person's reported experiences, and reports of others familiar with the person. For a diagnosis of schizophrenia, the described symptoms need to have been present for at least six months or one month. Many people with schizophrenia have other mental disorders, especially mood disorders, anxiety disorders, and obsessive–compulsive disorder.
Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations from alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks for people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.
The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.
The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model that attributes the positive symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia. Rather, the overactivation of D2 receptors, specifically, is one effect of the global chemical synaptic dysregulation observed in this disorder.
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.
The management of schizophrenia usually involves many aspects including psychological, pharmacological, social, educational, and employment-related interventions directed to recovery, and reducing the impact of schizophrenia on quality of life, social functioning, and longevity.
The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms of schizophrenia linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.
Tardive psychosis is a hypothetical form of psychosis caused by long-term use of neuroleptics. It was first proposed in 1978 but was questioned by the late 1980s. It was hypothesized that psychosis could arise as neuroleptic medication become decreasingly effective, requiring higher doses, or when not responding to higher doses.
Pomaglumetad (LY-404,039) is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3. Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. Pomaglumetad is intended as a treatment for schizophrenia and other psychotic and anxiety disorders by modulating glutamatergic activity and reducing presynaptic release of glutamate at synapses in limbic and forebrain areas relevant to these disorders. Human studies investigating therapeutic use of pomaglumetad have focused on the prodrug LY-2140023, a methionine amide of pomaglumetad (also called pomaglumetad methionil) since pomaglumetad exhibits low oral absorption and bioavailability in humans.
LY-379,268 is a drug that is used in neuroscience research, which acts as a potent and selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).
Bitopertin is a glycine reuptake inhibitor which was under development by Roche as an adjunct to antipsychotics for the treatment of persistent negative symptoms or suboptimally controlled positive symptoms associated with schizophrenia. Research into this indication has been largely halted as a result of disappointing trial results. As of 2024, it is under development for the management of erythropoietic protoporphyria.
Brilaroxazine, also known as oxaripiprazole, is an investigational atypical antipsychotic which is under development by Reviva Pharmaceuticals for the treatment of neuropsychiatric and inflammatory disorders. It has currently completed the first of two phase III clinical trials for schizophrenia. Reviva Pharmaceuticals also intends to investigate brilaroxazine for the treatment of bipolar disorder, major depressive disorder, attention deficit hyperactivity disorder (ADHD), irritability in autism, tics, psychosis/agitation associated with Alzheimer's disease, Parkinson's disease psychosis, as well as the inflammatory disorders pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and psoriasis. The FDA granted brilaroxazine orphan drug designation for the treatment of PAH and IPF.
ADX-71149, also known as JNJ-40411813 and JNJ-mGluR2-PAM, is a selective positive allosteric modulator of the mGlu2 receptor. It is being studied by Addex Therapeutics and Janssen Pharmaceuticals for the treatment of schizophrenia. It was also researched by these companies for the treatment of anxious depression, but although some efficacy was observed in clinical trials, it was not enough to warrant further development for this indication. As of 2015, ADX-71149 is in phase II clinical trials for schizophrenia.
Neboglamine, formerly known as nebostinel, is a positive allosteric modulator of the glycine site of the NMDA receptor which is under investigation for Rottapharm for the treatment of schizophrenia and cocaine dependence. It shows cognition- and memory-enhancing effects in animal models. As of June 2015, it is in phase II clinical trials for both schizophrenia and cocaine abuse.
Immuno-psychiatry, according to Pariante, is a discipline that studies the connection between the brain and the immune system. It differs from psychoneuroimmunology by postulating that behaviors and emotions are governed by peripheral immune mechanisms. Depression, for instance, is seen as malfunctioning of the immune system.
Pesampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Pfizer for the treatment of cognitive symptoms in schizophrenia. In March 2018, the development of the drug was transferred over from Pfizer to Biogen. It was also under development for the treatment of age-related sensorineural hearing loss, but development for this indication was terminated due to insufficient effectiveness. In July 2022, Biogen discontinued the development of pesampator for cognitive symptoms in schizophrenia due to ineffectiveness.
Ulotaront is an investigational antipsychotic that is undergoing clinical trials for the treatment of schizophrenia and Parkinson's disease psychosis. The medication was discovered in collaboration between PsychoGenics Inc. and Sunovion Pharmaceuticals using PsychoGenics' behavior and AI-based phenotypic drug discovery platform, SmartCube. Ulotaront is in Phase III of clinical development.
Iclepertin is an investigational nootropic to enhance the cognition and functional capacity in schizophrenia developed by Boehringer Ingelheim. As of May 2020, it is in phase III of clinical trial under the code name CONNEX-3. BI 425809 is an inhibitor of glycine transporter 1 (Gly-T1) that in phase II improved cognition after 12 weeks in patients with schizophrenia. Doses of 10 mg and 25 mg showed the largest separation from placebo. If these encouraging results are confirmed in phase 3 trials, BI 425809 could provide an effective treatment for cognitive impairment associated with schizophrenia. Schizophrenia is characterized by abnormalities in glutamatergic pathways related to NMDA receptor hypofunction. Inhibition of GlyT1 on the presynaptic membrane or astrocytes is hypothesized to increase glycine levels within the synapse. The NMDA receptor function may be enhanced by increasing levels of its co-agonist, glycine, within the synaptic cleft, which may lead to improvements in cognitive function.