clozapine and Multiple-Sclerosis

The high efficacy of atypical antipsychotics (AAP) in treating diverse psychiatric disorders has been partly attributed to their capacity to curb neuroinflammation, a shared aspect of these diseases. These immunomodulatory properties of AAP have lately been explored in the context of multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS.. This study aimed to review in vivo studies reporting on the therapeutic effects of AAP both in EAE, the main animal model of MS and in cuprizone-induced demyelination. For that matter we conducted a literature search and a screening process that eventually yielded 8 eligible studies.. All studies agreed on the efficiency of AAP to dramatically reduce EAE severity and delay its onset, while suppressing the production of numerous inflammatory cytokines. Clozapine showcased similar yet more intense effects than risperidone, quetiapine and olanzapine, significantly attenuating CD4 T cell infiltration and myeloid cell activation, while upregulating Tregs. Clozapine also downregulated chemokines responsible for the migration of immune cells in the CNS and caused dopamine receptor levels in the brain of EAE mice to rise.. Taken together, these findings unanimously attest to the anti-inflammatory and immunomodulatory properties of AAP, suggesting that their therapeutic potential expands beyond their current neuropsychiatric applications. Despite the salutary effects of AAP in MS reported in vivo, a clinical trial of clozapine on MS patients failed to confirm preclinical findings due to low acceptability of AAP and early participant withdrawal.. Although preclinical evidence unquestionably supports the multifaceted beneficial properties of AAP in MS, further investigation is required to elucidate the pharmacodynamic profile of these agents and allow for their proper clinical testing on MS patients.

Topics: Animals; Antipsychotic Agents; Clozapine; Encephalomyelitis, Autoimmune, Experimental; Humans; Mice; Multiple Sclerosis; Olanzapine; Quetiapine Fumarate

Multiple sclerosis is a disease characterised by demyelination of axons in the central nervous system. The atypical antipsychotic drug clozapine has been shown to attenuate disease severity in experimental autoimmune encephalomyelitis (EAE), a mouse model that is useful for the study of multiple sclerosis. However, the mechanism of action by which clozapine reduces disease in EAE is poorly understood. To better understand how clozapine exerts its protective effects, we investigated the underlying signalling pathways by which clozapine may reduce immune cell migration by evaluating chemokine and dopamine receptor-associated signalling pathways. We found that clozapine inhibits migration of immune cells by reducing chemokine production in microglia cells by targeting NF-κB phosphorylation and promoting an anti-inflammatory milieu. Furthermore, clozapine directly targets immune cell migration by changing Ca

Topics: Animals; Anti-Inflammatory Agents; Antipsychotic Agents; Chemokines; Clozapine; Dopamine; Encephalomyelitis, Autoimmune, Experimental; Lymphocytes; Mice; Mice, Inbred C57BL; Multiple Sclerosis; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Dopamine

Multiple sclerosis is a disease characterised by axonal demyelination in the central nervous system (CNS). The atypical antipsychotic drug clozapine attenuates experimental autoimmune encephalomyelitis (EAE), a mouse model used to study multiple sclerosis, but the precise mechanism is unknown and could include both peripheral and CNS-mediated effects. To better understand where clozapine exerts its protective effects, we investigated the tissue distribution and localisation of clozapine using matrix-assisted laser desorption ionization imaging mass spectrometry and liquid chromatography-mass spectrometry. We found that clozapine was detectable in the brain and enriched in specific brain regions (cortex, thalamus and olfactory bulb), but the distribution was not altered by EAE. Furthermore, although not altered in other organs, clozapine levels were significantly elevated in serum during EAE. Because clozapine antagonises dopamine receptors, we analysed dopamine levels in serum and brain as well as dopamine receptor expression on brain-resident and infiltrating immune cells. While neither clozapine nor EAE significantly affected dopamine levels, we observed a significant downregulation of dopamine receptors 1 and 5 and up-regulation of dopamine receptor 2 on microglia and CD4+-infiltrating T cells during EAE. Together these findings provide insight into how neuroinflammation, as modelled by EAE, alters the distribution and downstream effects of clozapine.

Topics: Animals; Antipsychotic Agents; Brain; CD4-Positive T-Lymphocytes; Clozapine; Dopamine; Down-Regulation; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Mice; Microglia; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Receptors, Dopamine; Tissue Distribution; Up-Regulation

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and ultimately neuronal loss. The etiology and physiopathology of MS are still elusive, and no fully effective therapy is yet available. We investigated the role in MS of autophagy (physiologically, a controlled intracellular pathway regulating the degradation of cellular components) and of mitophagy (a specific form of autophagy that removes dysfunctional mitochondria). We found that the levels of autophagy and mitophagy markers are significantly increased in the biofluids of MS patients during the active phase of the disease, indicating activation of these processes. In keeping with this idea, in vitro and in vivo MS models (induced by proinflammatory cytokines, lysolecithin, and cuprizone) are associated with strongly impaired mitochondrial activity, inducing a lactic acid metabolism and prompting an increase in the autophagic flux and in mitophagy. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, also significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. Therefore, haloperidol and clozapine may represent additional therapeutic tools against MS.

Topics: Animals; Antipsychotic Agents; Autophagy; Autophagy-Related Proteins; Axons; Biomarkers; Clozapine; Cytokines; Demyelinating Diseases; Disease Models, Animal; Glucose; Haloperidol; Inflammation; Interleukin-1beta; Mitochondria; Mitophagy; Models, Biological; Motor Activity; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Stress, Physiological; Tumor Necrosis Factor-alpha

The atypical antipsychotic agent, clozapine, is used to treat a variety of neurological disorders including schizophrenia and Parkinson's disease and readily crosses the blood brain barrier to interact with a wide range of neuroreceptors including those for dopamine and serotonin. Recent work has shown that clozapine can reduce neuroinflammation in experimental autoimmune encephalomyelitis, a neuroinflammatory model of multiple sclerosis (MS) and mediates its effects in the central nervous system. To further characterise the protection provided by clozapine, the cuprizone model of demyelination was used to assess the effect of clozapine treatment on the cellular events surrounding demyelination and remyelination. Using this model of non-immune demyelination, we found that clozapine administration was unable to prevent demyelination, but when administered post demyelination, was able to enhance the rate of functional recovery. The more rapid improvement of clozapine-treated mice correlated with a decreased level of astrocyte and microglial activation but only modestly enhanced remyelination. Together, these studies highlight the potential of clozapine to support enhanced functional recovery after demyelination, such as that occurring during MS.

Topics: Animals; Astrocytes; Central Nervous System; Clozapine; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath

A complete atrioventricular block (CAVB) can be a lethal complication when it is not treated directly with isoprenaline and pacemaker therapy. The overall incidence of CAVB varies between 4 to 8 per cent with a mortality OR of 3.2 within 30 days if untreated. Main causes of CAVB are inferior myocardial infarction, congenital AV node malformation, mitral valve insufficiency and valve surgery, metabolic disorders and intoxications. The authors describe a case with a CAVB due to lithium-clozapine therapy and relapsing multiple sclerosis.

Topics: Antipsychotic Agents; Atrioventricular Block; Bipolar Disorder; Cardiotonic Agents; Clozapine; Female; Humans; Isoproterenol; Lithium; Middle Aged; Multiple Sclerosis; Pacemaker, Artificial; Recurrence

Severe impulsiveness in the absence of apparent neurological signs has rarely been reported as a clinical presentation of multiple sclerosis (MS). An 11-year-old female developed progressive and sustained personality disturbances including disinhibition, hypersexuality, drug abuse, aggressiveness and suicide attempts, without neurological signs. She was given several unsuccessful psychopharmacological and psychotherapeutic interventions. At age 21, a diagnosis of MS was made, confirmed by imaging, laboratory and neurophysiological studies. Although unusual, MS may produce pure neurobehavioral disturbances. In the present case, widespread demyelinization produced a complex behavioral disorder, with features compatible with orbitofrontal and Klüver-Bucy syndromes.

Topics: Adolescent; Adult; Antimanic Agents; Antipsychotic Agents; Child; Clozapine; Female; Homicide; Humans; Impulsive Behavior; Magnetic Resonance Imaging; Masturbation; Multiple Sclerosis; Personality; Psychotropic Drugs; Sex Work; Sexual Behavior; Substance-Related Disorders; Suicide; Valproic Acid

Topics: Adult; Antipsychotic Agents; Clozapine; Delusions; Female; Humans; Multiple Sclerosis; Neurocognitive Disorders; Paranoid Disorders; Psychiatric Status Rating Scales