Delivery systems and dosing for antipsychotics.

Schizophrenia is a devastating illness, affecting approximately 1-2 % of the world population. Age of onset is generally between 20 and 30 years of age with a chronic, unremitting course for the duration of the patient's life. Although schizophrenia is among the most severe and debilitating illnesses known to medicine, its treatment has remained virtually unchanged for over 50 years. This chapter covers several major concepts in experimental drug development and delivery: (1) the concept of "typical" vs. "atypical" classifications for antipsychotic drugs as it relates to dosing; (2) the development of depot formulations for improved medication adherence; and (3) several promising areas for future therapeutic advances related to the methods and duration of drug administration. These areas include sublingual, injectable, and implantable drug delivery strategies that have the potential to effect rapid and dramatic improvements in schizophrenia outcomes.

New insights into attention-deficit/hyperactivity disorder using structural neuroimaging.

This article reviews recent advances in structural neuroimaging in attention-deficit/hyperactivity disorder (ADHD). Observational studies have found treatment with psychostimulants to be associated more closely with dimensions of some brain structures in typically developing children than in those found in treatment-naïve children with ADHD. Novel analytic approaches allow for greater precision in the definition of brain regions that are most compromised in ADHD, with meta-analyses highlighting compromise of the basal ganglia. Cortical changes, particularly in the lateral prefrontal and parietal cortex, are also commonly reported, but with less consensus on the exact location of structural change. Anomalies in the shape of subcortical structures, specifically of the basal ganglia, hippocampus, and amygdala, implicate frontostriatal loops and the limbic system in the disorder. Finally, longitudinal data suggest that ADHD in childhood may be characterized by a delay in cortical maturation and that different clinical outcomes may be associated with different developmental trajectories in adolescence and beyond.

Ketamine exposure in adult mice leads to increased cell death in C3H, DBA2 and FVB inbred mouse strains.

BACKGROUND: Drug abuse is common among adolescents and young adults. Although the consequences of intoxication are known, sequelae of drugs emerging on campuses and in clubs nationwide are not. We previously demonstrated that ketamine exposure results in lasting physiological abnormalities in mice. However, the extent to which these deficits reflect neuropathologic changes is not known. METHODS: The current study examines neuropathologic changes following sub-anesthetic ketamine administration (5mg/kg i.p. x 5) to three inbred mouse strains. Stereologic quantification of silver stained nuclear and linear profiles as well as activated caspase-3 labeling was used to address: (1) whether or not ketamine increases excitotoxic and apoptotic cell death in hippocampal CA3 and (2) whether or not ketamine-induced cell death varies by genetic background. RESULTS: Ketamine increased cell death in hippocampal CA3 of adult C3H, DBA2 and FVB mice. Neither silver staining nor activated caspase-3 labeling varied by strain, nor was there an interaction between ketamine-induced cell death and strain. CONCLUSIONS: Ketamine exposure among young adults, even in limited amounts, may lead to irreversible changes in both brain function and structure. Loss of CA3 hippocampal cells may underlie persistent ERP changes previously shown in mice and possibly contribute to lasting cognitive deficits among ketamine abusers.

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

Antipsychotic dosing and drug delivery.

This chapter addresses the current state of affairs regarding proposed mechanism of action for antipsychotic medications and how this mechanism relates to dosing and delivery strategies. The initial portion describes the history of antipsychotic medication, including key discoveries that contribute to the dopamine hypothesis of schizophrenia and provide evidence that dopamine D2 receptor antagonism remains the most copasetic explanation for both determination of dose and degree of efficacy for current antipsychotic medications. Early observations regarding the unique properties of clozapine and how those observations led to the misconception and misnomer of atypicality are also discussed. Subsequent sections relate the dosing of available medications using chlorpromazine equivalents, with a discussion of non-D2-related mechanisms to antipsychotic effects. The balance of the chapter explores the temporal pattern of receptor occupancy as a key determinant of antipsychotic effectiveness, noting that continuous infusion would present the optimal method of treatment. In addition to the pharmacodynamic benefits of continuous long-term delivery systems, the incidence, causes, and clinical consequences of poor adherence are addressed. These observations are then discussed in the context of clinical studies and meta-analyses, demonstrating superiority of long-term depot preparations over oral administration. However, despite overwhelming evidence in favor of long-term delivery systems, few options are available to provide such ideal medication delivery profiles. Barriers to creating traditional depot preparations for a large number of antipsychotic agents, as well as efforts to address these limitations with polymer-based microspheres are described. The potential extension of current formulations to very long-term delivery implants using biodegradable and nonbiodegradable platforms is then described. Benefits as well as limitations of such systems are discussed with respect to clinical and ethical issues as well as a brief description of potential regulatory and logistic barriers to developing better delivery options. In summary, this chapter describes the basis for relating the dose of all existing antipsychotic medications to dopamine D2 receptor affinity and the potential contribution of continuous occupancy to enhanced efficacy through superior biological effects and improved adherence.

Development of cortical asymmetry in typically developing children and its disruption in attention-deficit/hyperactivity disorder.

CONTEXT: Just as typical development of anatomical asymmetries in the human brain has been linked with normal lateralization of motor and cognitive functions, disruption of asymmetry has been implicated in the pathogenesis of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD). No study has examined the development of cortical asymmetry using longitudinal neuroanatomical data. OBJECTIVE: To delineate the development of cortical asymmetry in children with and without ADHD. DESIGN: Longitudinal study. SETTING: Government Clinical Research Institute. PARTICIPANTS: A total of 218 children with ADHD and 358 typically developing children, from whom 1133 neuroanatomical magnetic resonance images were acquired prospectively. MAIN OUTCOME MEASURES: Cortical thickness was estimated at 40 962 homologous points in the left and right hemispheres, and the trajectory of change in asymmetry was defined using mixed-model regression. RESULTS: In right-handed typically developing individuals, a mean (SE) increase in the relative thickness of the right orbitofrontal and inferior frontal cortex with age of 0.011 (0.0018) mm per year (t(337) = 6.2, P < .001) was balanced against a relative left-hemispheric increase in the occipital cortical regions of 0.013 (0.0015) mm per year (t(337) = 8.1, P < .001). Age-related change in asymmetry in non-right-handed typically developing individuals was less extensive and was localized to different cortical regions. In ADHD, the posterior component of this evolving asymmetry was intact, but the prefrontal component was lost. CONCLUSIONS: These findings explain the way that, in typical development, the increased dimensions of the right frontal and left occipital cortical regions emerge in adulthood from the reversed pattern of childhood cortical asymmetries. Loss of the prefrontal component of this evolving asymmetry in ADHD is compatible with disruption of prefrontal function in the disorder and demonstrates the way that disruption of typical processes of asymmetry can inform our understanding of neurodevelopmental disorders.