Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

<p>Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by damage to the myelin sheaths that surround nerve axons. Inflammatory damage to the myelin sheath leads to severe physical disability in patients. Whereas approved disease modifying treatments are available for relapsing-remitting forms of MS, there are no approved treatments for the progressive stages, leaving approximately 50% of MS sufferers without treatment. Therefore, there is an urgent need for development of effective alternatives. Atypical antipsychotic agents used for treating schizophrenia have recently been recognized for their immune-modifying properties and our laboratory has shown previously that treating mice with risperidone or clozapine reduces the severity of disease in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Although atypical antipsychotic agents like clozapine have been used in the clinic for almost 60 years, there is very little experimental data that describes the mechanism by which atypical antipsychotic agents like clozapine are able to modify the immune response. This thesis aimed to describe the immunological mechanisms by which clozapine is able to reduce EAE disease and to determine the underlying cellular signalling alterations that occur during treatment to facilitate immune modifying properties. In vitro experiments showed that clozapine can impair induction of Th1 and Th17 cells while promoting the differentiation of iTreg and increasing Foxp3 expression. However, although clozapine effectively delayed disease onset and reduced the severity of EAE, the therapeutic effect of clozapine was not associated with impaired capacity to induce antigen specific Th1 or Th17 responses in the periphery. Moreover, Treg function was dispensable for disease protection by clozapine. Instead, disease protection by clozapine was associated with a suppressed state of activation in CNS resident microglia and infiltrating monocytes assessed by flow cytometric measurement of activation associated receptor expression. In vitro experiments using primary macrophage cell culture revealed that clozapine can alter the activation of activated macrophages towards a less inflammatory state directly. Interestingly, the altered state of activation in primary macrophages was not associated with detectable changes in cell signalling pathways known to mediate activation. This thesis demonstrated that clozapine treatment protects from EAE by a multi-faceted immunological mechanism that likely involves modifying multiple pathways and cell types during EAE and may be of therapeutic benefit to MS patients in the progressive stages of disease. Finally, this thesis also has relevance to psychiatry as it demonstrates that clozapine has potential to alter cellular immune responses.</p>

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

<p>Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by damage to the myelin sheaths that surround nerve axons. Inflammatory damage to the myelin sheath leads to severe physical disability in patients. Whereas approved disease modifying treatments are available for relapsing-remitting forms of MS, there are no approved treatments for the progressive stages, leaving approximately 50% of MS sufferers without treatment. Therefore, there is an urgent need for development of effective alternatives. Atypical antipsychotic agents used for treating schizophrenia have recently been recognized for their immune-modifying properties and our laboratory has shown previously that treating mice with risperidone or clozapine reduces the severity of disease in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Although atypical antipsychotic agents like clozapine have been used in the clinic for almost 60 years, there is very little experimental data that describes the mechanism by which atypical antipsychotic agents like clozapine are able to modify the immune response. This thesis aimed to describe the immunological mechanisms by which clozapine is able to reduce EAE disease and to determine the underlying cellular signalling alterations that occur during treatment to facilitate immune modifying properties. In vitro experiments showed that clozapine can impair induction of Th1 and Th17 cells while promoting the differentiation of iTreg and increasing Foxp3 expression. However, although clozapine effectively delayed disease onset and reduced the severity of EAE, the therapeutic effect of clozapine was not associated with impaired capacity to induce antigen specific Th1 or Th17 responses in the periphery. Moreover, Treg function was dispensable for disease protection by clozapine. Instead, disease protection by clozapine was associated with a suppressed state of activation in CNS resident microglia and infiltrating monocytes assessed by flow cytometric measurement of activation associated receptor expression. In vitro experiments using primary macrophage cell culture revealed that clozapine can alter the activation of activated macrophages towards a less inflammatory state directly. Interestingly, the altered state of activation in primary macrophages was not associated with detectable changes in cell signalling pathways known to mediate activation. This thesis demonstrated that clozapine treatment protects from EAE by a multi-faceted immunological mechanism that likely involves modifying multiple pathways and cell types during EAE and may be of therapeutic benefit to MS patients in the progressive stages of disease. Finally, this thesis also has relevance to psychiatry as it demonstrates that clozapine has potential to alter cellular immune responses.</p>

A History of the Pharmacological Treatment of Bipolar Disorder

In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade’s experiments with lithium and the beginning of the so-called “Psychopharmacological Revolution” in the 1950s. We also describe the clinical studies and development processes, enabling the therapeutic introduction of pharmacological agents currently available for the treatment of bipolar disorder in its different phases and manifestations. Those drugs include lithium salts, valproic acid, carbamazepine, new antiepileptic drugs, basically lamotrigine and atypical antipsychotic agents (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine, cariprazine and lurasidone). Finally, the socio-sanitary implications derived from the clinical introduction of these drugs are also discussed.

Improving Adherence to Atypical Antipsychotic Agent Screening Guidelines in Pediatric Patients: A Quality Improvement Project Within an Integrated Community Mental Health Setting

Background: Approximately 14% to 20% of children and adolescents have a mental health problem. Atypical antipsychotic agents are used to treat behavioral, emotional, and mental health problems in children and adolescents. A discrepancy between best practices and actual practices exists. Objective: The purpose of this quality improvement project was to increase adherence above baseline, through implementation of a checklist, to recommended screening guidelines in children, ages 4 to 18, prescribed atypical antipsychotic agents over 12 weeks. Design/Results: Aggregate comparison of the mean ranks of scores were tested with the Mann–Whitney U test, U = 1,087.5, n1 = n2 = 70, total N =140, p < .001. Variables of body mass index, blood pressure, waist circumference, fasting glucose, fasting lipids, personal history, and family history were observed and tested using the chi-square with Fisher’s exact tests and are significant at or above 99% confidence level ( p < .01). Conclusion: Educating mental health providers, child and adolescent psychiatrists, and psychiatric mental health nurse practitioners on recommended screening guidelines and implementing a checklist had a measurable effect on increasing adherence to the recommended screening guidelines in a community mental health setting.