clozapine and Diseases-in-Twins

The increasing recognition of Tourette's syndrome is probably responsible for the broadening range of symptom severities seen in clinic patients. Greater clinical diversity also brings greater treatment challenges, particularly for children in whom the risks and benefits of medication for the developing central nervous system must be weighed against the long-term risks associated with the disorder itself. Knowledge of the natural history and pathophysiology of Tourette's syndrome is vitally important for informed clinical decision making.. A MEDLINE literature search was undertaken to identify studies of the natural history and pathophysiology of Tourette's syndrome that would be relevant to clinical psychopharmacology.. Although impossible to predict with certainty for any given patient, the natural history of Tourette's syndrome is typically characterized by an early childhood onset, a prepubertal exacerbation, postpubertal attenuation, and an adult stabilization of symptoms. Symptoms fluctuate in all phases of the illness, often in response to stress. The natural history and clinical phenotype of Tourette's syndrome are thought to have both genetic and nongenetic determinants that are mediated through their effects on basal ganglia nuclei and related neural systems. Medications used in the treatment of Tourette's syndrome are thought to modulate the functioning of these neural systems.. Although medication decisions must consider tic symptom severity, expectations of the disorder's natural history, and the child's adaptive capacities-his or her comorbid illnesses, coping mechanisms, interpersonal relatedness, impulse control, affect regulation, and family and social supports-are the most important determinants of well-being and outcome. These therefore are the most important considerations when making treatment decisions, as well.

Topics: Adolescent; Adult; Age of Onset; Antipsychotic Agents; Child; Clozapine; Disease Progression; Diseases in Twins; Dopamine; Haloperidol; Humans; Obsessive-Compulsive Disorder; Phenotype; Pimozide; Risperidone; Tourette Syndrome; Treatment Outcome

It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific signal by minimizing genetic heterogeneity. In proteomic and pathway analyses, clinical illness is associated especially with altered glycosaminoglycan, GABAergic synapse, sialylation, and purine metabolism pathways. Although only 12% of all 19,462 genes are expressed differentially between healthy males and females, up to 61% of the illness-related genes are sex specific. These results on sex-specific genes are replicated in another dataset. This implies that the pathophysiology differs between males and females, and may explain why symptoms appear after adolescence when the expression of many sex-specific genes change, and suggests the need for sex-specific treatments.

Topics: Adolescent; Antipsychotic Agents; Clozapine; Diseases in Twins; Female; Gene Expression Profiling; Humans; Male; Neurons; Pluripotent Stem Cells; Proteome; Proteomics; Schizophrenia; Sex Factors; Twins, Monozygotic

Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research.

Topics: Antipsychotic Agents; B-Lymphocytes; Biological Variation, Population; Clozapine; Diseases in Twins; Female; Gene Expression; Humans; Induced Pluripotent Stem Cells; Middle Aged; Neurons; Schizophrenia; Transcriptome; Twins, Monozygotic

Topics: Adult; Antipsychotic Agents; Bulimia; Clozapine; Diseases in Twins; Humans; Male; Obesity; Schizophrenia, Paranoid; Twins, Monozygotic; Weight Gain

Topics: Adult; Antipsychotic Agents; Clozapine; Diseases in Twins; Drug Therapy, Combination; Humans; Male; Schizophrenia; Twins, Monozygotic; Valproic Acid