Presynaptic norepinephrine transporters (NETs) mediate the rapid clearance of norepinephrine from synaptic spaces. NET is a member of the Na+ and Cl− -coupled neurotransmitter transporter gene family, which also includes the serotonin and dopamine transporters. Recent studies reveal that these transporter molecules might be a dynamic component of synaptic plasticity, rather than a constitutive determinant of neurotransmitter levels in synaptic spaces. Recognition that cellular signaling molecules and transporter ligands, including cocaine, amphetamines, and antidepressants, can modify transporter intrinsic activity, trafficking, phosphorylation, and protein levels suggests opportunities for revealing unknown mechanisms of drug action. Control of these properties of transporter function may allow for the development of new strategies to modulate monoaminergic neurotransmission and identify regulatory pathways that may be compromised in psychiatric, neurologic, and neurodegenerative disorders.

The growth of gambling across the United States over the past decade has created significant difficulties for pathological gamblers. The rise in problem gambling, coupled with an increasing strain on social and health care services for treatment of gamblers and their families, has resulted in an urgent need for innovative interventions that target patients, health care providers, educational institutions, government, media, and the gambling industry. This article describes the impact of gambling from a consumer-protection perspective, and offers approaches to promoting public awareness of compulsive gambling as a pervasive problem that affects multiple areas of society.

This manuscript summarizes presentations by an international panel of experts, representing Brazil, Israel, Italy, Mexico, Portugal, Spain, and the United States, at a symposium on obsessive-compulsive disorder (OCD) and its possible subtypes. Presentations concerned both OCD proper, as well as putative obsessive-compulsive-spectrum disorders (autistic disorders, eating disorders, pathological gambling, and schizo-obsessive disorder). Projects discussed included a study assessing impulsive temperament in eating disorder patients, a study on serotonin receptor sensitivity in autism, a study of sleep EEG abnormalities in OCD, a study of dissociation in pathological gamblers, papers on aspects of schizo-obsessive patients, a study addressing biological alterations in OCD, data from a new family study on OCD, data from a molecular genetic study of OCD, a factor analytic study of Tourette disorder, a study hypothesizing the existence of an OCD continuum, and, finally, a paper on early- vs late-onset OCD. General discussion followed leading to a consensus that 1) OCD is likely heterogeneous with multiple subtypes; 2) division of patients by age-at-onset probably represents a robust and valid subtyping scheme; 3) the presence of schizophrenic features probably identifies a valid subtype; 4) the validation of subtypes in the future will be informed by both family-genetic studies, as well as studies of biological alterations in OCD; and 5) the study of obsessive-compulsive spectrum disorders adds to our understanding of the OCD phenomenon, and helps in our search to identify valid subtypes.

In 1992, the Food and Drug Administration (FDA) issued new guidelines governing stereoisomerism in new-drug development. The guidelines strongly encourage the development of single isomers and discourage stereoisomeric (eg, racemic) mixtures. As a result, most new chiral drugs are being developed as single enantiomers (ie, single isomers). There are three mechanisms for the identification and development of new single-isomer drugs: chiral switches (CS), chiral metashifts (CM), and new single-isomer chemical entities (NSICEs). In a CS, one of the two enantiomers of an established racemate is developed as a new drug, with the expectation that the single-isomer form has advantages over the racemic parent in terms of efficacy and/or adverse effects. Many new CS drugs are in development, eg, (S)-oxybutynin for urinary incontinence and escitalopram for depression. In a CM, a chiral metabolite of a drug is developed, in single-isomer form, as an agent with advantages over the parent. Among the current CM drugs in development are (+)-norcisapride (safer GI prokinetic agent than the racemic parent cisapride) and (S)-desmethylzopiclone (antianxiety agent, metabolite of the sedative-hypnotic zopi-clone). Many NSICEs are in development, eg, rosuvastatin as an antihypercholesterolemic, posaconazole as an antifungal, sitafloxacin as a fluoroquinolone antibacterial, pregabalin as an anticonvulsant, abarelix as an antineoplastic, etc. As in the development of any new drug, not every single-isomer candidate will reach the clinic, but there is no doubt that the move to single-isomer agents is an important step forward in the search for better and safer drugs.

A summary of the Third International Obsessive Compulsive Disorder Conference proceedings on neuroimaging research and neurocircuitry models of obsessive-compulsive disorder (OCD) is presented. This survey of recent and ongoing research indicates that a wide range of modern techniques and experimental strategies are being employed in a complementary fashion to enhance our understanding of OCD. Imaging studies in animal models of OCD are helping to elaborate relevant normal anatomy and neuro-chemistry. Functional imaging methods are being employed in conjunction with behavioral, pharmacologic, and cognitive challenge paradigms. Magnetic resonance spectroscopy as well as radiotracer methods are being utilized to measure neurochemical and neuropharmacologic indices in OCD. Transcranial magnetic stimulation has emerged as a tool for probing neurocircuitry that may also have therapeutic potential. Experimental designs and data-analytic methods are evolving to help elucidate the pathophysiology of OCD and related disorders, delineate neurobiologically meaningful subtypes of OCD, and identify potential predictors of treatment response. Collectively, these efforts promise important advances as we approach the new millennium.

Research in children and adolescents with obsessive-compulsive disorder (OCD) is increasing in both quantity and quality. This session will focus on new and exciting research findings regarding family genetic studies, infectious and immune etiologies, pediatric psychopharmacology, and cognitive behavioral treatment.

The present investigation examined factors that predict physical aggression in children with attention-deficit/hyperactivity disorder (ADHD). Stepwise, multiple regression-analyses were used to examine predictors of children's physical aggression as rated by parents at a 1-year follow-up point and by teachers at both 1- and 2-year follow-up points. Early parent and teacher ratings of verbal aggression (ie, cursing, teasing, and threatening) accounted for the greatest proportion of the variance in physical aggression ratings obtained at follow-up. None of the other predictor variable, including early ratings of physical aggression and ADHD behaviors, contributed significant additional variance beyond that accounted for by early verbal aggression ratings. Temporal and cross-informant analyses revealed that the relationship between verbal aggression and later physical aggression was situation-specific for teacher ratings but no parent ratings. Although physical aggression may emerge early in development, these data suggest that verbal aggre sion represents a stable, temperamental characteristic that may be of greater value than early physical aggression for predicting later physically aggressive acts.

Social phobia is a common psychiatric disorder that is often associated with significant psychiatric comorbidity and disability. In the past, clinicians have underutilized pharmacotherapy as a treatment option for this disorder. This article provides a review of current pharmacotherapeutic options for social phobia, including a review of the results to date of numerous controlled trials, a description of the recent results of open trials of new and promising agents, and a summary of the information available on the use of pharmacotherapy in the treatment of children and adolescents.

This issue of CNS Spectrums represents a milestone for both those affected by autism and related disorders and for clinicians and researchers who provide help and support to these individuals. In order to improve the lives of a rapidly increasing number of patients with this diagnosis, it is critical for the medical and research community to apply a collaborative and consistent strategy for clinical studies in autism.

The five articles that follow are a synopsis of the five subcommittees of the Autism Clinical Trials Task Force (ACTTF), a collaborative panel of experts convened by the Cure Autism Now (CAN) foundation in the spring of 2002. These subcommittees focused on key issues in clinical trials of autism, including subject selection, outcome measures, study design, biological measures, and governmental issues. CAN brought together this panel of participants from academia, government, and industry for the ACTTF think tank. The panel was organized and chaired by Eric Hollander, MD, and Ricki Robinson, MD, MPH. The overarching goal was to clarify what was known about the state of the art of the field in this area, what key information was still unknown, and to implement specific approaches and suggestions for studies which would provide information to fill in the missing gaps in our knowledge base.

Suicide is a global public health issue, with behavior differing across genders, age groups, places, and sociopolitical settings. Emile Durkheim characterized anomic suicide as occurring when social standards fail, resulting in purposelessness and directionlessness. Young people who are experiencing social issues are in danger, even if they do not voice suicidal ideas. Prevention interventions should target these people by strengthening resilience, minimizing social dysregulation stress, and fostering the development of life skills, coping resources, and social support. Anomic suicide has important psychological and societal implications, emphasizing the importance of fostering social cohesion and assisting persons experiencing purposelessness or a lack of direction in life.

Bipolar disorder (BD) is a potentially chronic mental disorder marked by recurrent depressive and manic episodes, circadian rhythm disruption, and changes in energetic metabolism. “Metabolic jet lag” refers to a state of shift in circadian patterns of energy homeostasis, affecting neuroendocrine, immune, and adipose tissue function, expressed through behavioral changes such as irregularities in sleep and appetite. Risk factors include genetic variation, mitochondrial dysfunction, lifestyle factors, poor gut microbiome health and abnormalities in hunger, satiety, and hedonistic function. Evidence suggests metabolic jet lag is a core component of BD pathophysiology, as individuals with BD frequently exhibit irregular eating rhythms and circadian desynchronization of their energetic metabolism, which is associated with unfavorable clinical outcomes. Although current diagnostic criteria lack any assessment of eating rhythms, technological advancements including mobile phone applications and ecological momentary assessment allow for the reliable tracking of biological rhythms. Overall, methodological refinement of metabolic jet lag assessment will increase knowledge in this field and stimulate the development of interventions targeting metabolic rhythms, such as time-restricted eating.