clozapine and Brain-Diseases

Early-onset psychotic illnesses in children and adolescents are not as rare as is commonly believed. These disorders, which include schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, and major depression with psychotic features, often have a chronic and severe course and poor long-term outcome. Many patients with early-onset schizophrenia have greater functional impairments than most patients with adult-onset schizophrenia. Magnetic resonance imaging studies show that patients with early-onset schizophrenia experience substantial gray matter loss during adolescence, which is not observed in studies of patients with adult-onset schizophrenia. The chronic course, severe functional impairments, and poor prognosis of early-onset psychosis create a great need to identify effective and safe treatments for youth with psychosis. Although atypical anti-psychotics have been considered superior to traditional antipsychotics, there has been little controlled information to inform clinical decisions until recently. Over the past 5 years, several studies have been initiated to address these questions. The results of the studies completed to date are reviewed.

Topics: Adolescent; Adult; Age of Onset; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Brain Diseases; Child; Chronic Disease; Clozapine; Comorbidity; Disease Progression; Humans; Magnetic Resonance Imaging; Olanzapine; Piperazines; Prognosis; Psychotic Disorders; Quinolones; Schizophrenia; Thiazoles; Treatment Failure

Topics: Brain; Brain Diseases; Clozapine; Corpus Striatum; Functional Laterality; Humans; Receptors, Dopamine; Receptors, Dopamine D2; Schizophrenia

Schizophrenia is the most prevalent of the major psychoses, but the underlying neurobiology of this debilitating disorder remains mysterious. Recent developments in molecular biology, neuroanatomic pathology, neurochemistry, and functional imaging suggest that a number of factors converge to produce schizophrenia. Specifically, an early neurodevelopmental "lesion," possibly within the mesial temporal lobe, may contribute to later temporolimbic-prefrontal dysfunction as the nervous system matures. Genetic factors appear to facilitate liability to schizophrenia, and dopaminergic and possibly other neurotransmitter systems may mediate clinical expression of the illness through newly recognized receptor subtypes.

Topics: Brain; Brain Diseases; Clozapine; Female; Frontal Lobe; Humans; Magnetic Resonance Imaging; Male; Neurobiology; Radiography; Receptors, Dopamine D2; Schizophrenia; Temporal Lobe

Fahr's syndrome is a rare disorder characterized by abnormal deposits of calcium in areas of the brain that control movement, including the basal ganglia and the cerebral cortex associated with many neurological and psychiatric abnormalities such as a rigid hypokinetic syndrome, mood disorders and cognitive impairment. Fahr's syndrome is secondary to some disorders, such as hypoparathyroidism.. We report the case of a 56 year-old man, with a history of cataract, who was admitted to our psychiatric hospital for the first time in his life because of psychotic symptoms associated with irritability and aggressiveness. Since the age of 38 the patient had become nervous, 10 years later he developed tonic-clonic seizures. Two months ago, he began expressing delusions of persecution against his wife and sons and making fugues. According to his family during this period, he was agitated, aggressive, and suffered from insomnia and anorexia. The general and psychiatric examination showed an upright and bronzed patient with neglected hygiene. He was indifferent to his environment and expressed poor mimics and gestures. He was anxious, suspicious and not very talkative. He was conscious but his attention was slightly decreased. Moreover, he was not aware of his problems. The neurological examination showed extrapyramidal syndrome with postural tremor and cerebellar ataxia. A cranial computed tomography brain scan found bilateral, symmetric basal ganglia calcifications, in favour of Fahr's syndrome. Phosphocalcic investigations revealed low concentration of serum calcium at 1.01mmol/L (normal 2.15 to 2.57mmol/L) and hyperphosphoremia at 2.69mmol/L (normal 0.81 to 1.55mmol/L). He also had low concentrations of 25-OH vitamin as well as decreased urinary levels of phosphate and calcium. The blood level of parathyroid hormone was 0ng/L. The diagnosis of Fahr's syndrome, revealing a hypoparathyroidism was posed. He was supplemented with calcium and alpha cholecalciferol and treated with clozapine (100mg per day). After four weeks, psychotic symptoms responded well to this treatment without expressing any side effects, notably seizures.. Psychotic symptoms seen in Fahr's disease include auditory and visual hallucinations, complex perceptual distortions, delusions, and fugue state. Some of them were manifest in this patient. It is likely that the psychosis in both Fahr's disease and schizophrenia share a similar pathology. Positive psychotic symptoms, hallucinations, and paranoia are not necessarily generated by the classical hypothesis of dopamine-mediated attachment of salience to internally generated stimuli. Still, there is some evidence that disruption of the cortex involved in the pathophysiology of schizophrenia is also seen in Fahr's disease, particularly in areas of the limbic system.. Psychiatrists should consider Fahr's syndrome as a differential diagnosis in the evaluation of psychosis associated with seizures. This case, along with others in the literature, further emphasizes the importance of the role of neuro-imaging and the search for disrupted phosphocalcic metabolism in patients with atypical psychotic symptoms. Moreover, further research should focus on pharmacologic interventions. The efficacy and risks of neuropharmacologic and psychopharmacologic interventions in Fahr's syndrome, and correlates of good and poor outcome with these interventions remain to be defined.

Topics: Basal Ganglia; Basal Ganglia Diseases; Brain Diseases; Calcinosis; Calcium; Cholecalciferol; Clozapine; Humans; Hypoparathyroidism; Male; Middle Aged; Neurocognitive Disorders; Neurodegenerative Diseases; Tomography, X-Ray Computed

Dyke-Davidoff-Masson syndrome, or cerebral hemiatrophy, is a pre- or perinatally acquired entity characterized by predominantly neurologic symptoms, such as seizures, facial asymmetry, contralateral hemiplegia, and mental retardation. Psychiatric symptoms are rarely reported. We report the first case of left cerebral hemiatrophy and a late onset of treatment-resistant schizoaffective disorder after a stressful life event. The patient finally responded well to clozapine. The clinical history and results from structural neuroimaging are highlighted to discuss the possible developmental bias for psychotic disorders.

Topics: Adult; Antipsychotic Agents; Atrophy; Brain; Brain Diseases; Clozapine; Facial Asymmetry; Hemiplegia; Humans; Magnetic Resonance Imaging; Male; Psychotic Disorders; Syndrome; Treatment Outcome

Schizophrenia is a neuropsychiatric disorder of a neurodevelopmental origin manifested symptomatically after puberty. Structural neuroimaging studies show that neuroanatomical aberrations occur before onset of symptoms, raising a question of whether schizophrenia can be prevented. Treatment with atypical antipsychotic drugs before the development of the full clinical phenotype might reduce the risk of transition to psychosis, but it remains unknown whether neuroanatomical abnormalities can be prevented. We used a neurodevelopmental animal model of schizophrenia to assess the efficacy of the atypical antipsychotic clozapine to prevent neuroanatomical deterioration.. Pregnant rats received injection on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (PolyI:C) or saline. Structural brain changes in the male offspring were assessed at adolescence and adulthood (35 days and 120 days) with structural neuroimaging. In the second part, male offspring of PolyI:C- and saline-treated dams received daily clozapine (7.5 mg/kg) or saline injection in adolescence (days 34-47) and underwent behavioral testing and imaging at adulthood (from 90 days onward).. In utero exposure to maternal infection led in the offspring to postpubertal emergence of hallmark structural abnormalities associated with schizophrenia, enlarged ventricles, and smaller hippocampus. These abnormalities were not observed in the offspring of mothers who received PolyI:C that were treated with clozapine in adolescence. This was paralleled by prevention of behavioral abnormalities phenotypic of schizophrenia, attentional deficit, and hypersensitivity to amphetamine.. This is the first demonstration that pharmacological intervention during adolescence can prevent the emergence of brain structural changes resulting from in-utero insult.

Topics: Abnormalities, Drug-Induced; Age Factors; Amphetamine; Animals; Antipsychotic Agents; Attention; Brain Diseases; Cerebral Ventricles; Clozapine; Disease Models, Animal; Hippocampus; Inhibition, Psychological; Male; Motor Activity; Poly I-C; Rats; Rats, Wistar; Schizophrenia

Antipsychotic drugs increase expression of the immediate early gene, c-fos, in the striatum, nucleus accumbens and prefrontal cortex of rat brain. Since intracerebro-ventricular (i.c.v.) infusion of kainic acid (KA) produces loss of limbic-cortical neurons that project to these brain areas, we postulated that the c-fos responses to antipsychotics in these brain areas would be altered following i.c.v. KA administration. To produce limbic-cortical lesions, rats received i.c.v. infusions of either KA (4.5 nmol) or vehicle. Then, 25 28 days later, rats received 0.13, 0.35, or 1.5 mg/kg haloperidol, 6.3, 17.5, or 30.0 mg/kg clozapine, or saline. In both KA-lesioned and control animals, haloperidol produced greater increases in Fos protein immunoreactivity in the striatum than in limbic-cortical areas, while clozapine produced greater increases in Fos protein immunoreactivity in limbic-cortical areas than in the striatum. In both KA-lesioned and control animals, haloperidol and clozapine administration also produced similar dose-dependent increases in Fos protein immunoreactivity in the striatum and nucleus accumbens. However, the ability of clozapine to increase Fos protein immunoreactivity in the infralimbic prefrontal cortex was significantly enhanced in KA-lesioned rats compared to controls. Since limbic-cortical pathology has been implicated in the negative symptoms of schizophrenia, the enhanced effect of clozapine on limbic-cortical expression of c-fos in KA-lesioned rats may be relevant to understanding clozapine's unusual therapeutic actions in patients with schizophrenia.

Topics: Animals; Antipsychotic Agents; Brain; Brain Diseases; Cell Count; Clozapine; Dose-Response Relationship, Drug; Gene Expression; Genes, fos; Haloperidol; Kainic Acid; Limbic System; Male; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley

Topics: Adult; Age Factors; Brain Diseases; Child; Clozapine; Drug Therapy, Combination; Haloperidol; Humans; Magnetic Resonance Imaging; Schizophrenia