clozapine and Developmental-Disabilities

The methionine-folate cycle-dependent one-carbon metabolism is implicated in the pathophysiology of schizophrenia. Since schizophrenia is a developmental disorder, we examined the effects that perturbation of the one-carbon metabolism during gestation has on mice progeny. Pregnant mice were administered methionine equivalent to double their daily intake during the last week of gestation. Their progeny (MET mice) exhibited schizophrenia-like social deficits, cognitive impairments and elevated stereotypy, decreased neurogenesis and synaptic plasticity, and abnormally reduced local excitatory synaptic connections in CA1 neurons. Neural transcript expression of only one gene, encoding the Npas4 transcription factor, was >twofold altered (downregulated) in MET mice; strikingly, similar Npas4 downregulation occurred in the prefrontal cortex of human patients with schizophrenia. Finally, therapeutic actions of typical (haloperidol) and atypical (clozapine) antipsychotics in MET mice mimicked effects in human schizophrenia patients. Our data support the validity of MET mice as a model for schizophrenia, and uncover methionine metabolism as a potential preventive and/or therapeutic target.

Topics: Animals; Antipsychotic Agents; Basic Helix-Loop-Helix Transcription Factors; CA1 Region, Hippocampal; Clozapine; Developmental Disabilities; Disease Models, Animal; Female; Folic Acid; Haloperidol; Humans; Male; Methionine; Mice; Neurogenesis; Neuronal Plasticity; One-Carbon Group Transferases; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Schizophrenia; Stereotyped Behavior; Tetrahydrofolates

In this case series, we describe the acute clinical impact and tolerability of rapid titration of clozapine for treatment of refractory irritability in five hospitalized youth with developmental disability. We offer this descriptive report in an effort to expand the evidence base guiding treatment of refractory aggression in this population.. Five youth with developmental disability and severe irritability were admitted to a 10-bed psychiatric crisis stabilization unit where they received thorough psychiatric and medical evaluation. Informed consent was obtained in each case, and each patient underwent rapid titration onto clozapine. Clozapine monitoring guidelines were followed for all patients throughout treatment, and clinical severity at baseline and improvement with treatment was measured by use of the Clinical Global Impressions-Severity scale (CGI-S) and the Clinical Global Impressions-Improvement scale (CGI-I).. One female and four males diagnosed with developmental disability and at least one other psychiatric diagnosis, mean age of 13.1 ± 2.1 years, and mean CGI-S at baseline of 5.8, each received clozapine treatment by rapid titration. The mean therapeutic total daily dose of clozapine was 380 ± 200 mg. All patients demonstrated acute clinical improvement with the mean final CGI-I of 2.0, or "much improved.". These initial results support the potential utility of clozapine rapid titration for treatment of severe refractory irritability in youth with developmental disability. These patients tolerated clozapine treatment in the short term. Future studies are needed to thoroughly evaluate the long-term safety of clozapine treatment in this population.

Topics: Adolescent; Antipsychotic Agents; Child; Clozapine; Developmental Disabilities; Dose-Response Relationship, Drug; Female; Hospitalization; Humans; Irritable Mood; Male; Psychiatric Status Rating Scales; Treatment Outcome

Schizophrenia was proposed as a progressive neurodevelopmental disorder. In this regard herein we attempted to determine progressive inflammatory and oxidative alterations induced by a neonatal immune challenge and its possible reversal by clozapine administration. For this end, Wistar rats at postnatal day (PN) 5-7 were administered the viral mimetic polyriboinosinic-polyribocytidilic acid (polyI:C) or saline. A distinct group of animals additionally received the antipsychotic drug clozapine (25mg/kg) from PN60 to 74. At PN35 (periadolescence), 60 (adult) and 74 (adulthood) the animals were submitted to behavioral determinations of prepulse inhibition of the startle (PPI) and Y maze task for working memory evaluation. At PN35 and 74 the animals were sacrificed and the hippocampus (HC), prefrontal cortex (PFC) and striatum (ST) immunostained for Iba-1, a microglial marker, and inducible nitric oxide synthase (iNOS). At PN74 oxidative stress parameters, such as, reduced glutathione levels (GSH) and lipid peroxidation were determined. The results showed a progressive increase of microglial activation and iNOS immunostaining from PN35 to PN74 mainly in the CA2 and CA3 regions of the HC and in the ST. At PN74 neonatal challenge also induced an oxidative imbalance. These inflammatory alterations were accompanied by deficits in PPI and working memory only in adult life that were reversed by clozapine. Clozapine administration reversed microglial activation and iNOS increase, but not the alterations of oxidative stress parameters. Taken together these results give further evidences for a neuroprogressive etiology and course of schizophrenia and that clozapine may partly alleviate this process.

Topics: Age Factors; Animals; Animals, Newborn; Antipsychotic Agents; Brain; Clozapine; Developmental Disabilities; Disease Models, Animal; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Microglia; Nitric Oxide Synthase Type II; Oxidative Stress; Poly I-C; Rats; Rats, Wistar; Reflex, Startle; Schizophrenia

22q11.2 deletion is the most common microdeletion in humans and one of the most important risk factors for schizophrenia. Nevertheless, case reports of children or adolescents with 22q11.2 deletion and schizophrenia are very rare. After a review of the current knowledge about physical, developmental, behavioural and psychiatric problems in 22q11.2 deletion, the case of a 12;10-year-old boy with schizophrenia and the microdeletion is reported. About three years after the first symptoms, and only after medication with several neuroleptics, the patient reached his pre-morbid functioning level under treatment with risperidone. Under medication with clozapine he had experienced a single event of seizures which were due to hypocalcemia. This case report illustrates the importance of serum calcium controls at regular intervals for patients with 22q11.2 deletion and schizophrenia who are on neuroleptic medication. Ideally, children and adolescents with the deletion and co-morbid psychiatric problems should be treated in child and adolescent psychiatry units specialized in problems associated with the deletion. A good cooperation with other medical services is absolutely necessary.

Topics: Adolescent; Antipsychotic Agents; Calcium; Child; Chromosome Deletion; Chromosomes, Human, Pair 22; Clozapine; Developmental Disabilities; Female; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Hypocalcemia; Male; Risperidone; Schizophrenia; Schizophrenic Psychology; Seizures

This paper reports on the pharmacotherapy and long-term follow-up of a child treated with clozapine. It is one of the earliest American experiences with this agent in children to date. Clozapine was relatively effective and safe in this patient. Additional features of the case are the early social and developmental delays preceding schizophrenia, the response of symptoms of childhood-onset schizophrenia to clozapine, and the reduction in tardive dyskinesia symptoms while taking clozapine. Compared to recommendations for dosing adults, a slower rate of increasing clozapine doses was important for this child. For future reference, the protocol and consent form used for this course of treatment are included.

Topics: Adolescent; Child; Clozapine; Developmental Disabilities; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Humans; Male; Neurologic Examination; Psychiatric Status Rating Scales; Schizophrenia, Childhood; Treatment Outcome