Purinergic system in psychiatric diseases.
Cheffer A,Castillo A R G,Corrêa-Velloso J,Gonçalves M C B,Naaldijk Y,Nascimento I C,Burnstock G,Ulrich H
Molecular psychiatry
Psychiatric disorders are debilitating diseases, affecting >80 million people worldwide. There are no causal cures for psychiatric disorders and available therapies only treat the symptoms. The etiology of psychiatric disorders is unknown, although it has been speculated to be a combination of environmental, stress and genetic factors. One of the neurotransmitter systems implicated in the biology of psychiatric disorders is the purinergic system. In this review, we performed a comprehensive search of the literature about the role and function of the purinergic system in the development and predisposition to psychiatric disorders, with a focus on depression, schizophrenia, bipolar disorder, autism, anxiety and attention deficit/hyperactivity disorder. We also describe how therapeutics used for psychiatric disorders act on the purinergic system.
10.1038/mp.2017.188
The blood-brain barrier in psychosis.
The lancet. Psychiatry
Blood-brain barrier pathology is recognised as a central factor in the development of many neurological disorders, but much less is known about the role of the blood-brain barrier in psychiatric disorders. We review post-mortem, serum-biomarker, CSF-biomarker, and neuroimaging studies that have examined blood-brain barrier structure and function in schizophrenia and related psychoses. We consider how blood-brain barrier dysfunction could relate to glutamatergic and inflammatory abnormalities, which are increasingly understood to play a part in the pathogenesis of psychosis. Mechanisms by which the blood-brain barrier and its associated solute transporters moderate CNS availability of antipsychotic drugs are summarised. We conclude that the complex nature of blood-brain barrier dysfunction in psychosis might be relevant to many aspects of disrupted neuronal and synaptic function, increased permeability to inflammatory molecules, disrupted glutamate homoeostasis, impaired action of antipsychotics, and development of antipsychotic resistance. Future research should address the longitudinal course of blood-brain barrier alterations in psychosis, to determine whether blood-brain barrier dysfunction is a cause or consequence of the pathology associated with the disorder.
10.1016/S2215-0366(17)30293-6
A golden age of muscarinic acetylcholine receptor modulation in neurological diseases.
Nature reviews. Drug discovery
Over the past 40 years, the muscarinic acetylcholine receptor family, particularly the M-receptor and M-receptor subtypes, have emerged as validated targets for the symptomatic treatment of neurological diseases such as schizophrenia and Alzheimer disease. However, despite considerable effort and investment, no drugs have yet gained clinical approval. This is largely attributable to cholinergic adverse effects that have halted the majority of programmes and resulted in a waning of interest in these G-protein-coupled receptor targets. Recently, this trend has been reversed. Driven by advances in structure-based drug design and an appreciation of the optimal pharmacological properties necessary to deliver clinical efficacy while minimizing adverse effects, a new generation of M-receptor and M-receptor orthosteric agonists and positive allosteric modulators are now entering the clinic. These agents offer the prospect of novel therapeutic solutions for 'hard to treat' neurological diseases, heralding a new era of muscarinic drug discovery.
10.1038/s41573-024-01007-1
Antipsychotic Drugs: A Concise Review of History, Classification, Indications, Mechanism, Efficacy, Side Effects, Dosing, and Clinical Application.
The American journal of psychiatry
The introduction of the first antipsychotic drug, chlorpromazine, was a milestone for psychiatry. The authors review the history, classification, indications, mechanism, efficacy, side effects, dosing, drug initiation, switching, and other practical issues and questions related to antipsychotics. Classifications such as first-generation/typical versus second-generation/atypical antipsychotics are neither valid nor useful; these agents should be described according to the Neuroscience-based Nomenclature (NbN). Antipsychotic drugs are not specific for treating schizophrenia. They reduce psychosis regardless of the underlying diagnosis, and they go beyond nonspecific sedation. All currently available antipsychotic drugs are dopamine blockers or dopamine partial agonists. In schizophrenia, effect sizes for relapse prevention are larger than for acute treatment. A major unresolved problem is the implausible increase in placebo response in antipsychotic drug trials over the decades. Differences in side effects, which can be objectively measured, such as weight gain, are less equivocal than differences in rating-scale-measured (subjective) efficacy. The criteria for choosing among antipsychotics are mainly pragmatic and include factors such as available formulations, metabolism, half-life, efficacy, and side effects in previous illness episodes. Plasma levels help to detect nonadherence, and once-daily dosing at night (which is possible with many antipsychotics) and long-acting injectable formulations are useful when adherence is a problem. Dose-response curves for both acute treatment and relapse prevention follow a hyperbolic pattern, with maximally efficacious average dosages for schizophrenia of around 5 mg/day risperidone equivalents. Computer apps facilitating the choice between drugs are available. Future drug development should include pharmacogenetics and focus on drugs for specific aspects of psychosis.
10.1176/appi.ajp.20240738
Negative symptoms of schizophrenia: new developments and unanswered research questions.
Galderisi Silvana,Mucci Armida,Buchanan Robert W,Arango Celso
The lancet. Psychiatry
Negative symptoms of schizophrenia are associated with poor functional outcome and place a substantial burden on people with this disorder, their families, and health-care systems. We summarise the evolution of the conceptualisation of negative symptoms, the most important findings, and the remaining open questions. Several studies have shown that negative symptoms might be primary to schizophrenia or secondary to other factors, and that they cluster in the domains of avolition-apathy and expressive deficit. Failure to take this heterogeneity into account might hinder progress in research on neurobiological substrates and discoveries of treatments for primary or enduring negative symptoms. Improvement in recognition and routine assessment of negative symptoms is instrumental for correct management of secondary negative symptoms that are amenable to treatment. If substantial progress is to be made in the understanding and treatment of negative symptoms, then advances in concepts and assessment should be integrated into the design of future studies of these symptoms.
10.1016/S2215-0366(18)30050-6
Neuroinflammation in psychiatric disorders: PET imaging and promising new targets.
Meyer Jeffrey H,Cervenka Simon,Kim Min-Jeong,Kreisl William C,Henter Ioline D,Innis Robert B
The lancet. Psychiatry
Neuroinflammation is a multifaceted physiological and pathophysiological response of the brain to injury and disease. Given imaging findings of 18 kDa translocator protein (TSPO) and the development of radioligands for other inflammatory targets, PET imaging of neuroinflammation is at a particularly promising stage. This Review critically evaluates PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis disorders, substance use, and obsessive-compulsive disorder. We also consider promising new targets that can be measured in the brain, such as monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, colony stimulating factor 1 receptor, and the purinergic P2X7 receptor. Thus far, the most compelling TSPO imaging results have arguably been found in major depressive disorder, for which consistent increases have been observed, and in schizophrenia and psychosis, for which patients show reduced TSPO levels. This pattern highlights the importance of validating brain biomarkers of neuroinflammation for each condition separately before moving on to patient stratification and treatment monitoring trials.
10.1016/S2215-0366(20)30255-8
Inflammation-Related Functional and Structural Dysconnectivity as a Pathway to Psychopathology.
Biological psychiatry
Findings from numerous laboratories and across neuroimaging modalities have consistently shown that exogenous administration of cytokines or inflammatory stimuli that induce cytokines disrupts circuits and networks involved in motivation and motor activity, threat detection, anxiety, and interoceptive and emotional processing. While inflammatory effects on neural circuits and relevant behaviors may represent adaptive responses promoting conservation of energy and heightened vigilance during immune activation, chronically elevated inflammation may contribute to symptoms of psychiatric illnesses. Indeed, biomarkers of inflammation such as cytokines and acute phase reactants are reliably elevated in a subset of patients with unipolar or bipolar depression, anxiety-related disorders, and schizophrenia and have been associated with differential treatment responses and poor clinical outcomes. A growing body of literature also describes higher levels of endogenous inflammatory markers and altered, typically lower functional or structural connectivity within these circuits in association with transdiagnostic symptoms such as anhedonia and anxiety in psychiatric and at-risk populations. This review presents recent evidence that inflammation and its effects on the brain may serve as one molecular and cellular mechanism of dysconnectivity within anatomically and/or functionally connected cortical and subcortical regions in association with transdiagnostic symptoms. We also discuss the need to establish reproducible methods to assess inflammation-associated dysconnectivity in relation to behavior for use in translational studies or biomarker-driven clinical trials for novel pharmacological or behavioral interventions targeting inflammation or its effects on the brain.
10.1016/j.biopsych.2022.11.003
Trace Amines and Their Receptors.
Gainetdinov Raul R,Hoener Marius C,Berry Mark D
Pharmacological reviews
Trace amines are endogenous compounds classically regarded as comprising -phenylethyalmine, -tyramine, tryptamine, -octopamine, and some of their metabolites. They are also abundant in common foodstuffs and can be produced and degraded by the constitutive microbiota. The ability to use trace amines has arisen at least twice during evolution, with distinct receptor families present in invertebrates and vertebrates. The term "trace amine" was coined to reflect the low tissue levels in mammals; however, invertebrates have relatively high levels where they function like mammalian adrenergic systems, involved in "fight-or-flight" responses. Vertebrates express a family of receptors termed trace amine-associated receptors (TAARs). Humans possess six functional isoforms (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9), whereas some fish species express over 100. With the exception of TAAR1, TAARs are expressed in olfactory epithelium neurons, where they detect diverse ethological signals including predators, spoiled food, migratory cues, and pheromones. Outside the olfactory system, TAAR1 is the most thoroughly studied and has both central and peripheral roles. In the brain, TAAR1 acts as a rheostat of dopaminergic, glutamatergic, and serotonergic neurotransmission and has been identified as a novel therapeutic target for schizophrenia, depression, and addiction. In the periphery, TAAR1 regulates nutrient-induced hormone secretion, suggesting its potential as a novel therapeutic target for diabetes and obesity. TAAR1 may also regulate immune responses by regulating leukocyte differentiation and activation. This article provides a comprehensive review of the current state of knowledge of the evolution, physiologic functions, pharmacology, molecular mechanisms, and therapeutic potential of trace amines and their receptors in vertebrates and invertebrates.
10.1124/pr.117.015305
Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease.
Nanou Evanthia,Catterall William A
Neuron
Voltage-gated calcium channels couple depolarization of the cell-surface membrane to entry of calcium, which triggers secretion, contraction, neurotransmission, gene expression, and other physiological responses. They are encoded by ten genes, which generate three voltage-gated calcium channel subfamilies: Ca1; Ca2; and Ca3. At synapses, Ca2 channels form large signaling complexes in the presynaptic nerve terminal, which are responsible for the calcium entry that triggers neurotransmitter release and short-term presynaptic plasticity. Ca1 channels form signaling complexes in postsynaptic dendrites and dendritic spines, where their calcium entry induces long-term potentiation. These calcium channels are the targets of mutations and polymorphisms that alter their function and/or regulation and cause neuropsychiatric diseases, including migraine headache, cerebellar ataxia, autism, schizophrenia, bipolar disorder, and depression. This article reviews the molecular properties of calcium channels, considers their multiple roles in synaptic plasticity, and discusses their potential involvement in this wide range of neuropsychiatric diseases.
10.1016/j.neuron.2018.03.017
Severe Mental Illness and Cardiovascular Disease: JACC State-of-the-Art Review.
Journal of the American College of Cardiology
People with severe mental illness, consisting of schizophrenia, bipolar disorder, and major depression, have a high burden of modifiable cardiovascular risk behaviors and conditions and have a cardiovascular mortality rate twice that of the general population. People with acute and chronic cardiovascular disease are at a higher risk of developing mental health symptoms and disease. There is emerging evidence for shared etiological factors between severe mental illness and cardiovascular disease that includes biological, genetic, and behavioral mechanisms. This state-of-the art review will describe the relationship between severe mental illness and cardiovascular disease, explore the factors that lead to poor cardiovascular outcomes in people with severe mental illness, propose strategies to improve the cardiovascular health of people with severe mental illness, and present areas for future research focus.
10.1016/j.jacc.2022.06.017