The end of 2001 is unlike any year's end in most of our memories. On September 10, my most serious worry was the chances for my beloved New York Yankees to win their fourth consecutive pennant. The next day, and ever since, that has hardly been a blip on the radar screen of concern. For those of us interested in studying the nervous system, we must remember that the most enduring fallout of the September 11 tragedy is emotional—our population is now a frightened one. Never before has the study of the neuro-science of emotion seemed more important. In subsequent issues, we will have much more to say on this topic.

For physicians and neuroscientists alike, we must also focus on the clinical and research issues that existed before September 11 and will continue to be our responsibility. This issue of CNS Spectrums offers articles on a diversity of topics: epilepsy, genetics, and the treatment of schizophrenia.

Freud writes in his startlingly innovative book, Wit and Its Relation to the Unconscious, that “…our philosophical inquiries have not awarded to wit the important role that it plays in our mental life.” He pointed out the difficulties of studying the phenomenon scientifically, and went on to analyze the meanings of jokes and why we laugh. He emphasized the “pleasure in economy” that the central nervous system derives from the pithy nature of the witty synthesis. Since then, several authors have brought forward their own theories, Arthur Koestler among them. However, neuroscientists have shown little interest in the subject.

This needs urgent attention. It is therefore welcome that at least one group of scientists is taking jokes seriously. They set up a “Laugh Lab” Web site to investigate humor, and respondents from all over the world were asked to vote for the “best” of several jokes displayed on the site. Their responses will be analyzed and hypotheses tested.

Since before the time of Charcot, nonepileptic seizures (NES) have intrigued and perplexed physicians. With the advent of the electroencephalogram, particularly with the addition of continuous video monitoring, the diagnosis of NES has received increasing evaluation. Characteristic historical features and clinical signs of NES, coupled with new diagnostic techniques, have progressively refined our understanding of the disorder. The treatment of patients who have NES has received much less attention and the prognosis of these patients illustrates the need for a more comprehensive, systematic, and validated intervention. These issues are discussed with an emphasis on the need for future research.

The inconsistency in linkage results that has bedeviled psychiatric genetics has been observed to occur regularly in common diseases with complex inheritance. Nonetheless, in two such instances—noninsulin-dependent diabetes mellitus (NIDDM) and inflammatory bowel disease (IBD)—susceptibility genes have been discovered based on the follow-ups of linkage findings. In bipolar illness disorder (BPD) and schizophrenia (SZ), there are some linkage reports with replication of other studies similar to the situation in NIDDM and IBD before the successful positional cloning efforts. Two of the regions with linkage reports, BPD and SZ, on the long arms of chromosomes 13 and 22, show linkage to the same markers in both diseases. This lends some plausibility to the hypothesis of some shared genetic predispositions for both disorders. Cytogenetic evidence offers another positional approach to susceptibility genes. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BPD and SZ. Endophenotypes ofSZ, previously demonstrated to be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to 6p, and an abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to the psychiatric illnesses. These genetic findings may contribute to etiologic subcategorization of BPD and SZ, and the development of new treatment approaches. A table of genetic terms is included for review.

Obsessive-compulsive disorder (OCD) could be considered a neurodevelopmental disorder, from several lines of evidence. One of the most widely studied genes in these disorders is the apolipoprotein E gene, particularly allele 4. We analyzed for association among patients with OCD versus normal controls and cognitively impaired patients. There were no significant differences between OCD probands compared with population controls. However, the cognitively impaired group showed a higher frequency of allele apolipoprotein E gene compared with normal controls and patients with OCD.

The advent of the newer “atypical” antipsychotics has revolutionized pharmacologic treatment of schizophrenia (SZ) and other psychotic disorders. In contrast to the first-generation conventional neuroleptics, these second-generation antipsychotic agents possess a broader spectrum of efficacy and cause fewer motor side effects such as extrapyramidal symptoms and tardive dyskinesia. Despite their substantial advantages, however, these second-generation agents also have significant limitations in terms of both efficacy and adverse effects. Several strategies to address these shortcomings are currently under study and some of these are likely to become part of our therapeutic armamentarium in the future. Current shortcomings in the pharmacologic treatment of SZ and strategies under investigation to address each of these deficiencies are reviewed. New formulations of existing medications and new antipsychotics under development are discussed. Developing adjunctive treatment strategies to address each of the major psychopathologic domains in SZ are summarized. The potential application of genetic information to treatment-matching in SZ is reviewed and likely refinements in the practice of evidence-based medicine in the pharmacotherapy of SZ are considered.

This paper focuses on treatments for schizophrenia (SZ)—treatments we have now and those we hope to have in the future. The treatments we have are based on serendipity, but are effective nonetheless. Pharmacologic characteristics of the most-prescribed drugs are reviewed. It is apparent that a spectrum of effective drugs exist to support individualized therapy. With a view to future discovery, a strategy is proposed for rational antipsychotic drug development. A few concrete examples from the author's own laboratory illustrate an application of the proposal. These data would support the existence of a drugtarget in the anterior cingulate and/or hippocampal cortex. The studies suggest a focus on the limbic cortex for SZ pathophysiology. It would depend on future discovery to test whether this proposal will be productive. For sure, the rapid advance of basic neuroscience provides untold promise for the future.