Over the last half of the 20th century, there have been a series of psychopharmacologic strategies for treatment of depression. As we approach the next century, new therapies in varying stages of American release are being developed. This review will focus on information available for the following proposed antidepressants: 1) reboxetine, a norepinephrine selective reuptake inhibitor; 2) milnacipran, a combined serotonin/norepinephrine reuptake inhibitor; 3) a new enantiomer of fluoxetine, a selective serotonin reuptake inhibitor; 4) duloxetine, another combined serotonin/norepinephrine reuptake inhibitor; 5) sunepitron, a combined 5-HT1A agonist and α2 antagonist; and, 6) MK-869, a substance P inhibitor. Finally, other possible developing directions will be reviewed, including corticotropin-releasing factor.

Debate continues regarding the relationship between shyness and social phobia. Some have proposed that this relationship is best understood by adopting a spectrum approach where increasing levels of shyness eventually merge into the clinical disorder of social phobia. This paper begins to explore the validity of this spectrum by reviewing similarities and differences between shyness and social phobia and investigating how shyness relates to social phobia subtypes. This paper will also explore precursors to social phobia, namely childhood behavioral inhibition.

Seventeen years after professional baseball player Jim Eisenreich first developed symptoms of Tourette syndrome (TS), the correct diagnosis was finally made.

At age 6, his rapid eye blinking led to a diagnosis of hyperactivity. “I was told I would grow out of it,” says the 39-year-old Eisenreich, who may have played his last game as a Los Angeles Dodger. “I knew I was different even then.”

In the early 1980s, Eisenreich's condition first became public. Since then, his achievements as a professional athlete have made him a role model for other TS patients.

Sports were always a haven for him as he grew up. “I found peace, comfort, and security in sports. Whatever the season, I played the sport—football, baseball, hockey,” says Eisenreich. “Socially, I didn't go to the movies or go out much with girls.”

After 2 years in the minor leagues, he was called up by the Minnesota Twins in 1982 as an outfielder. During the season, a TS specialist recognized his grunting and sniffling as signs of the disease. “I had no idea what the specialist was talking about, and the Twins doctors dismissed it because I didn't have copralalia,” he says. The Twins team physician (an internist) prescribed a sedative. Then Eisenreich tried Inderal, which caused hyperventilation, and Catapres, which caused depression.

The growing number of reports on candidate genes an genomic regions of interest in bipolar disorder reveals a tremendously active field of study. As with other complex psychiatric syndromes, these early findings will require a great deal of effort to replicate and clarify. This review serves both as an update and an introduction to some of the issues confronting investigators. Potential strategies in study design, population selection, and molecular methods are explored as well.

The end of the millennium provides an opportunity to review some of the common practices that were present in psychopharmacology during the 20th century. The author focuses on two approaches that have dominated research and guided the clinical application of psychopharmacologic therapeutics: the unitary clinically-based and single-lesion perspectives. The author expands upon these older formulations of neuropsychiatric disease pathogenesis and describes how the approach to psychopharmacologic research and therapeutics has changed in light of advances in the basic neurosciences. Relevant recent advances in the basic neurosciences that shed light on the pathophysiology of neuropsychiatric disease states and that guide psychopharmacologic practices are described. The use of atypical antipsychotic agents to treat schizophrenia is given as one example of the clinical applications of the approach to psychopharmacology in the next century.

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.

Many psychiatric disorders are influenced by genetic factors, but the genetic components of complex diseases may not follow clear inheritance patterns. Although the patients may share a common clinical phenotype, the cause of the syndrome may consist of a heterogeneous collection of both genetic and/or environmental components. One method to minimize genetic heterogeneity in studies of complex disorders is to select a very homogenous study population. The average number of families with the same last name, when corrected for population size, is an excellent marker for the degree of homogeneity. We used surname analysis to evaluate the homogeneity of the Portuguese population of Madeira, comparing it with previous data on the homogeneity of populations of mainland Portugal, the Azores, and both rural and urban US populations. The average number of families with the same last name corrected for population size was 33.84 in Madeira, 30.88 in the Azores, and 21.42 in Coimbra (mainland Portugal) compared with 1.13 in rural and 0.38 in urban United States. This surname analysis supports the premise that the Portuguese population is a highly homogenous population, with the highest homogeneity in Madeira and the Azores, making it a good study population for molecular genetic analyses.

It is just 3 or 4 weeks after my diagnosis of Tourette syndrome (TS). I have been slowly and conscientiously titrating upward the dose of medication prescribed by my neurologist, waiting skeptically, but not without hope, for some amelioration of my tics. A typical scientist/patient, I have downloaded all available information about this drug from the Internet and have been recalculating the increasing dose in mg/kg body weight every few days. Today I have ducked out of my lab and am doing a very hard training run along the Muddy River in Boston, gearing up for my 21st year of spring and summer races, when I am caught unprepared by a flash of insight. I am speeding along the path with a smoothness and crispness of rhythm that I have seldom felt—maybe just one of those rare great days?—when it occurs to me that I am taking a good deep breath every four strides, in-and-out without fail, every four strides. And only at that moment do I realize that I have always suffered from “skipping” breaths, even on the hardest runs, and have always taken it for granted. Indeed, I have always assumed that all other runners' breathing is as ragged as my own. But now—how remarkable!—I am not missing a single precious breath. This, I realize, is because my phonic tic is gone. So my teammates and competitors must have never missed those breaths, not a single one, because they don't have TS!

There is clear overlap in the clinical symptoms of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). As a result, OCD (with or without tics) and TS (with or without obsessive-compulsive symptoms [OCS]) have been conceptualized to form a disorder spectrum—an overlapping set of phenotypes reflecting presumed commonality at the level of the underlying genetics and neuropathology. We identified the characteristics of a research sample of patients with OCD or TS, based on information obtained in semistructured clinical interviews, to examine the similarities and differences in the clinical symptoms across this spectrum. This sample conformed to known age-of-onset and sex distribution patterns for OCD and TS. Previously reported patterns of predominant aggressive and sexual obsessions and touching compulsions were observed in subjects with tic-related OCD, compared with non—tic-related OCD (ie, OCD alone). The majority of patients with tic-related OCD experienced horrifically violent obsessions that were less common in OCD alone and much less common in TS. Nonetheless, symptomatic and functional impairment in TS subjects was clearly related to the intensity of their OCS. The specific obsessions and compulsions associated with clinical impairment in TS differed from those associated with impairment in OCD. These results suggest that, despite the many overlapping dimensions of these disorders, the symptoms and associated impairment in “pure” OCD, tic-related OCD, and TS do not form a simple continuous spectrum.

This article discusses the neurocircuitry and the neurochemical systems, as well as the molecular elements within these systems, that are believed to be important in the etiology of alcoholism. Alcoholism is a complex behavioral disorder characterized by excessive consumption of alcohol; a narrowing of the behavioral repertoire toward excessive consumption; the development of tolerance and dependence; and impairment in social and occupational functioning. Animal models of the complete syndrome of alcoholism are difficult if not impossible to achieve, but validated animal models exist for many of the different components of the syndrome.

Recent work has begun to define the neurocircuits responsible for the major sources of positive and negative reinforcement that are key to animal models of excessive alcohol intake. Alcohol appears to interact with alcohol-sensitive elements within neuronal membranes that convey the specificity of neurochemical actions. Positive reinforcement appears to be mediated by an activation γ-aminobutyric acid A receptors, release of opioid peptides and dopamine, inhibition of glutamate receptors, and interaction with serotonin systems. These neurocircuits may be altered by chronic alcohol administration. This is reflected by their exhibiting opposite effects during acute alcohol withdrawal, and by the recruitment of other neurotransmitter systems, such as the stress neuropeptide corticotropin-releasing factor. These neuropharmacologic actions are believed to produce allostatic changes in set-point, which set up the vulnerability to relapse that is so characteristic of alcoholism. Future challenges include a focus on understanding exactly how these neuroadaptive changes convey vulnerability to relapse in animals with a history of alcohol dependence.

There are few clinical or biologic predictors of response to treatments for depression. This article reviews growing evidence that electrophysiologic and neurocognitive measures of brain function may be of value as predictors of therapeutic response to antidepressants. Initial studies using dichotic listening, quantitative electroencephalography, or event-related brain potential measures have found differences between treatment responsive and nonresponsive subgroups of depressed patients. The neurophysiologic basis for these differences and the potential clinical utility of electrophysiologic and dichotic predictors of treatment out come remain to be determined in future studies.

Irritable bowel syndrome (IBS), a condition common in the health-care setting, can be especially challenging to manage for both the referring physician and the psychiatrist. Much of this difficulty arises from the understanding and treatment of the disorder from a disease-based biomedical approach rather than a biopsychosocial model. The latter model offers a more effective method to understand the development and clinical expression of IBS, and as a result, directly informs subsequent management. This article defines and describes the epidemiology of IBS, reviews its pathophysiology, identifies the role of psychosocial factors using a biopsychosocial model of IBS, and clarifies the role of the mental health professional in its management. IBS management involves identifying psychiatric comorbidities, assessing the patient's perspective of the role of psychosocial factors, offering psychotherapy directed toward adaptive coping mechanisms, providing psychotropic medication consultation, and engaging in ongoing collaboration with the referring physician.

Chronic benign pain (CBP) can be defined as a type of unpleasant sensory experience that arises from inflammation, visceral stress or damage, or other such pathophysiologic process(es), and that is not associated with a metastatic process. A patient's complaint of pain should be taken seriously by the practitioner, both in terms of the discomfort evoked and the likelihood that the potential cause of the pain requires diagnostic evaluation. This article reviews the diagnosis and treatment of the following common conditions associated with CBP syndromes: fibromyalgia, lower back pain syndrome, sickle-cell disease, reflex sympathetic dystrophy syndrome, and peripheral neuropathies.

New cognitive models of social phobia have been developed based, in part, on a growing number of studies suggesting that people with social phobia process information related to social threat differently than people who are not socially anxious and, in some cases, differently than individuals with other anxiety disorders. In addition to providing an overview of recent models of social phobia, this paper reviews the research literature to date on the following aspects of cognition in social phobia: attention, memory, attributions and appraisals, imagery and perspective, and perfectionism.

This paper reviews the literature on gender differences in major depressive disorder (MDD) and bipolar disorder (BPD). Beginning in adolescence, women are at a higher risk than men of becoming depressed. Avenues of investigation that might ultimately help to explain this phenomenon include studies of gender differences in the processing of emotional stimuli, the psychotropic effects of gonadal steroids, and environment/gene interactions in men and women. With the exception of the elevated suicide rate among men, consistent gender differences in the course and symptoms of MDD have not been found. In BPD, women are more likely than men to develop a rapid-cycling course. Gender differences in treatment response, particularly in regard to mood stabilizing medications, warrant further study.

Clozapine is a prototype atypical antipsychotic drug and displays efficacy in 30% to 60% of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70% to 80% of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patieents There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the free plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, investigated the (G)n mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.

The objective of this study was to compare efficacy of two meditation protocols for treating patients with obsessive-compulsive disorder (OCD). Patients were randomized to two groups—matched for sex, age, and medication status—and blinded to the comparison protocol. They were told the trial would last for 12 months, unless one protocol proved to be more efficacious. If so, groups would merge, and the group that received the less efficacious treatment would also be afforded 12 months of the more effective one. The study was conducted at Children's Hospital, San Diego, Calif. Patients were selected according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R) criteria and recruited by advertisements and referral. At baseline, Group 1 included 11 adults and 1 adolescent, and Group 2 included 10 adults. Group 1 employed a kundalini yoga meditation protocol and Group 2 employed the Relaxation Response plus Mindfulness Meditation technique. Baseline and 3-month interval testing was conducted using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Symptoms Checklist-90-Revised Obsessive Compulsive (SCL-90-R OC) and Global Severity Index (SCL-90-R GSI) scales, Profile of Moods scale (POMS), Perceived Stress Scale (PSS), and Purpose in Life (PIL) test. Seven adults in each group completed 3 months of therapy. At 3 months, Group 1 demonstrated greater improvements (Student's independent groups t-test) on the Y-BOCS, SCL-90-R OC and GSI scales, and POMS, and greater but nonsignificant improvements on the PSS and PIL test. An intent-to-treat analysis (Y-BOCS) for the baseline and 3-month tests showed that only Group 1 improved. Within-group statistics (Students paired t-tests) showed that Group 1 significantly improved on all six scales, but Group 2 had no improvements. Groups were merged for an additional year using Group 1 techniques. At 15 months, the final group (N=11) improved 71%, 62%, 66%, 74%, 39%, and 23%, respectively, on the Y-BOCS, SCL-90-R OC SCL-90-R GSI, POMS, PSS, and PIL; P<0.003 (analysis of variance). This study demonstrates that kundalini yoga techniques are effective in the treatment of OCD.