Kluver-Bucy syndrome (KBS) is a rare neuropsychiatric disorder that may be characterized by visual agnosia, placidity, altered sexual activity, hypermetamorphosis, and hyperorality. Patients with KBS present with a complex behavioral syndrome. KBS is usually associated with lesions of the amygdala or amygdaloid pathways. However, partial KBS may occur in the absence of the classic bilateral temporal lesions. Pharmacologic treatment options have been developed from the results of case reports, which suggest that carbamazepine and antipsychotics may be helpful. We present the cases of two patients with partial KBS who responded favorably to antipsychotic medication.

How can clinicians diagnosis generalized anxiety disorder (GAD) earlier and treat it more effectively? The most successful treatment is often determined through the remission of psychic and somatic symptoms, an increase in functional capacity at work and in relationships, and how the patient handles their daily responsibilities. This monograph attempts to:

—Define GAD

—Explore psychotherapeutic and pharmacologic treatment modalities

—Identify comorbidities associated with GAD

—Understand the importance of dual uptake mechanisms in gaining remission

Premenstrual dysphoria (PMD) is a severe form of premenstrual syndrome, causing a marked reduction in the quality of life for about 5% of all women of fertile age. The cardinal symptoms are irritability and anger, which surface regularly between ovulation and menstruation and disappear completely within a few days after the onset of menstruation. Other frequent symptoms are depressed mood, affect lability, tension, and carbohydrate craving. In placebo-controlled trials, the serotonin reuptake inhibitors (SRIs) clomipramine, fluoxetine, sertraline, paroxetine, and citalopram have proven very effective for PMD, with a response rate of 60% or higher; in contrast, nonserotonergic antidepressants are not effective. The onset of action of SRIs is rapid, allowing for intermittent administration during luteal phases only. The impressive effect of SRIs for PMD is probably not equivalent to the antidepressant effect of these drugs, but is more likely to be a manifestation of the well-established influence of serotonin on aggression and irritability. It strongly reinforces the assumption that a major function of serotonergic neurons in the brain is to modulate sex-steroid—driven behavior.

Lennox-Gastaut syndrome (LGS) is a severe form of childhood epilepsy that is usually refractory to medical management. When medications fail, alternative therapies are considered. Among these are two surgical options: corpus callosotomy and vagus nerve stimulation (VNS). Safety and efficacy are two important factors to consider when selecting an appropriate treatment. VNS is safer than callosotomy, but its efficacy is more difficult to assess. Available studies evaluate its effectiveness using a mixed population of patients (some with prior epilepsy surgery), a multitude of VNS settings, and variable endpoints. To estimate the efficacy of VNS in patients with LGS, a review of the medical literature and the VNS Patient Registry was performed. Within the limits of this type of study, the results showed that VNS appears equally as effective as callosotomy. Because VNS has a lower potential for adverse events, these results suggest that VNS should be considered first in appropriately selected patient.

A bidirectional regulatory interaction between the central nervous system and the immune system is largely provided by cytokines and their specific receptors, which are expressed by cells of both systems. Transforming growth factor-β1 (TGF-β1), produced by glial cells and lymphocytes and regulated by steroid hormones, is one such cytokine. In the current study, we examined the relationship between TGF-β1 and peer affiliation in bonnet macaques (Macaca radiata) either reared normally or exposed as infants to conditions in which their mothers faced fluctuating requirements for food procurement (variable foraging demand [VFD]). Rearing under VFD conditions has been previously shown to produce dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in these animals. Serum levels of TGF-β1 after exposure to a moderate stressor had no correlation with peer affiliation under baseline conditions (r=.07), but were highly correlated with affiliation after subsequent challenge with a fear stimulus (r=.62). Affiliation after the fear stimulus also was inversely correlated with baseline levels of affiliation (r=−.71). These data suggest that changes in peripheral TGF-β1 may be reflective of latent behavioral and biochemical propensities possibly related to affect. Further examination of the effects of early adversity will improve our understanding of the relationship between the HPA axis and immune function.

The concatenation of convergent lines of evidence from basic to clinical research continues to reveal that norepinephrine (NE) is a crucial regulator of a myriad of behaviors ranging from stress response to memory formation. Furthermore, many neuropsychiatric disorders involve neurocircuitry that is directly modulated by NE. This report summarizes the physiological roles of NE, as well as the main findings implicating a role for NE system dysfunction in mood and anxiety disorders, posttraumatic stress disorder, attention-deficit/hyperactivity disorder, and Alzheimer's disease. In each of these disorders, there appears to be a complex dysregulation of NE function, with changes in locus ceruleus firing, NE availability, and both pre- and postsynaptic receptor regulation. Many symptoms of these disorders are attributable to abnormalities within distributed neural circuits regulated by NE. Appreciation of NE's role in modulating the neural circuitry mediating cognition and affect should help elucidate the pathophysiology of a variety of neuropsychiatric disorders and the development of novel treatments.

The medical records of 110 patients receiving conventional antipsychotics at two geographically distinct Veterans Administration hospitals (Syracuse, New York and Omaha, Nebraska) were reviewed. The most common reasons for continuation of conventional antipsychotics were good response and patient or physician choice. Frequently, physicians did not discuss the reasons for continuing conventional antipsychotics or the availability of alternative therapies with their patients. Geographic differences in physicians' prescribing practices of conventional antipsychotics were apparent.

Recent literature regarding drug-drug, herb-drug, and food-drug interactions must not be ignored; nor can they always be taken at face value. Studies have shown that St. John's wort (SJW) (Hypericum perforatum) can reduce plasma levels of indinavir, cyclosporin, digoxin, and possibly other drugs as well. Current knowledge regarding the metabolism of these medications suggests that the cytochrome P450 (CYP) drug metabolizing enzyme systems cannot account for all these effects. It has been reported that the P-glycoprotein (Pgp) transmembrane pump is also induced by SJW. Medications that are substrates of both CYP 3A4 a Pgp are of particular concern and may pose special interaction risks when combined with certain foods or botanical products such as SJW.

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.

Various aspects of personality or dispositional style predict risk for psychiatric disorders among adults. In particular, signs of neuroticism, emotional reactivity, or sensitivity to stress are strong predictors of later mood or anxiety disorders. The current report extends this literature to adolescents. An epidemiologic sample of 776 young people living in upstate New York received psychiatric assessments based on the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised, (DSM-III-R) and a self-report assessment of personality style in 1983 and 1985. Psychopathology was again assessed in 1992. The current study first examined demographic correlates of emotional reactivity. The study then considered the predictive relationship between emotionally reactive personality style at one study wave and psychopathology at later waves. In middle but not early adolescence, girls showed higher levels of emotional reactivity than boys. In turn, high levels of emotional reactivity predicted a range of psychiatric disorders at follow-up. The most consistent associations emerged for major depression and fearful spells, a term the authors use to describe a subclinical form of panic attacks. As in adults, midadolescent girls rate themselves as more emotionally reactive than midadolescent boys. Moreover, adolescents who rate themselves as emotionally reactive face a high risk for mood and anxiety disorders. High levels of emotional reactivity may represent a manifestation of underlying neurobiologic risk for mood and anxiety disorders.

This article discusses conceptual issues relevant to the prospective diagnosis of the schizophrenic prodrome. Recent efforts to diagnose these patients with operational criteria based on current symptoms are reviewed. Symptomatic patients so identified appear to be treatment-seeking and to have mild cognitive impairments. In addition to being currently symptomatic, these patients are imminently at risk for progression of illness and development of schizophrenia. Data from three international centers suggest that this risk is approximately 40% over the next year of follow-up if untreated. The implications of the reviewed data for the appropriateness of the term “prodromal” and for treatment/prevention research for these patients are discussed.

Circadian (24-hour) rhythms are important to the practice of medicine. The phasing and amplitude of key physiologic and biochemical circadian rhythms contribute to predict in-time patterns in the manifestation and exacerbation of most medical conditions. Moreover, body rhythms can significantly affect responses of patients to diagnostic tests and medications. Rhythmicity in the pathophysiology of medical conditions is the rationale for chronotherapeutics—the purposeful variance of the concentration of medicines in synchrony with biological rhythm-determinants of disease activity—to optimize treatment outcomes. This article discusses the concept of biological time structure and its relevance to the practice of medicine, with a focus on neurologic issues.

A subgroup of patients with childhood-onset obsessive-compulsive disorder (OCD) has been identified who share a common clinical course characterized by dramatic symptom exacerbations following Group A beta-hemolytic streptococcal (GABHS) infections. The term PANDAS has been applied to the subgroup, to indicate the postulated etiology of their symptoms: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections. Five clinical characteristics define the PANDAS subgroup: presence of OCD and/or tic disorder, prepubertal symptom onset, sudden onset or abrupt exacerbations (sawtooth course), association with neurological abnormalities (presence of adventitious movements or motoric hyperactivity during exacerbations), and temporal association between symptom exacerbations and GABHS infections. Post-streptococcal symptom exacerbations are typically quite dramatic, with patients reporting that their symptoms “…came on overnight” or “…appeared all of a sudden a few days after I had a sore throat.” The post-streptococcal inflammatory nature of the neuropsychiatric symptoms provides novel opportunities for treatment and prevention, including immunomodulatory therapies such as therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG). A recently completed placebo-controlled trial revealed that both IVIG and TPE were effective in reducing neuropsychiatric symptom severity (40% to 55% reductions, respectively) for a group of severely ill children with OCD and/or tic disorders. Further research is required to determine why the treatments are helpful, as well as to ascertain whether or not antibiotic prophylaxis can help prevent post-streptococcal symptom exacerbations.

Seasonal affective disorder (SAD) is a form of depression that starts in the fall and ends in the spring. This article reviews existing theories about the relationship between circadian rhythms and the disorder. Recent research indicates that as with pharmacologic antidepressants, at least 2–4 weeks are needed to demonstrate the effectiveness of bright-light therapy compared to placebo. The response to such treatment is strongest with precisely timed light exposure: treatment is optimal during the morning hours when the circadian systemt is susceptible to phase advance. Such clinical improvement is correlated with the magnitude of the phase shift induced. These observations suggest a model of circadian function in SAD and provide important guidelines for its treatment.

Individuals with schizophrenia are known to demonstrate cognitive and behavioral difficulties, particularly alterations in executive functions, including working memory. It is unclear whether these deficits reflect trait-related vulnerability to schizophrenia indicators and can be assessed by studying nonpsychotic relatives of patients with schizophrenia. In this study, we used an oculomotor delayed response (ODR) paradigm to examine spatial working memory in 37 “high-risk” child and adolescent offspring and siblings (age range=6–25 years) of patients with schizophrenia or schizoaffective disorder. Compared with 37 age- and sex-matched healthy controls (age range=6–23 years), high-risk subjects showed nonsignificantly greater errors in the ODR task at longer delay intervals. Statistical analyses suggested that performance improved with age in healthy control subjects, whereas it worsened with age in high-risk subjects. In both groups, the ODR errors were generally associated with poorer sustained attention (Continuous Performance Test: visuospatial d prime), some-what poorer executive function (Wisconsin Card Sorting Test), and elevated Heinrichs-Buchanan neurological soft signs scores. These findings indicate the presence of spatial working memory abnormalities in individuals at risk for schizophrenia. Furthermore, these abnormalities may be progressive in nature. The ODR task is a valuable indicator of prefrontal cortical function and spatial working memory and may be a potentially valuable marker for familial risk of schizophrenia.

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 critically examines the literature on face recognition in autism, including a discussion of the neural correlates of this ability. The authors begin by selectively reviewing the behavioral and cognitive neuroscience research on whether faces are represented by a “special” behavioral and neural system—one distinct from object processing. The authors then offer a neuroconstructivist model that attempts to account for the robust finding that certain regions in the inferior temporal cortex are recruited in the service of face recognition. This is followed by a review of the evidence supporting the view that face recognition is atypical in individuals with autism. This face-recognition deficit may indicate a continued risk for the further development of social impairments. The authors conclude by speculating on the role of experience in contributing to this atypical developmental pattern and its implications for normal development of face processing.

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.

Depression and anxiety are among the top 10 health problems for which complementary and alternative therapies (CATs) are most frequently used, and medicinal herbs are among the most popular of these treatments. St. Johns wort(Hypericum perforaturn) is a perennial herb that has become a widely used depression therapy. Extracts of hypericum have shown affinity for receptors within multiple neurochemical systems. The primary active substance responsible for the antidepressant effect is not well defined, but most work has concentrated specifically on the hypericin and hyperforin components. Although hypericum has demonstrated significant antidepressant and antianxiety effects in multiple studies, there are several recent studies that do not support the previous evidence. In all reported studies, hypericum extracts have been well tolerated. In addition, new psychiatric uses for hypericum in obsessive-compulsive disorder, generalized anxiety disorder, menopausal symptoms, and alcohol dependence have been reported. Because patients are choosing to pursue CAT as a first-line therapy, psychiatrists will need to have a better understanding of phytomedicines used for treating depression and anxiety, and thus be better prepared to serve as effective allies of their patients.

Obesity has negative health consequences related to fat distribution, particularly the central or visceral accumulation of fat. The major complications associated with visceral obesity, termed the “Metabolic Syndrome of Obesity,” or “Syndrome X,” are type II diabetes, hypertension, and dyslipidemia. As with certain mood disorders, the syndrome may be a consequence of neuroendocrine perturbations typically associated with chronic stress. Our work with bonnet macaque monkeys provides an animal model for the relationship between early stress, behavioral and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and Syndrome X. During their infant's first half-year, mothers face a variable foraging demand (VFD), in which ample food varies unpredictably in the difficulty of its acquisition, and the offspring show persistent abnormalities in systems known to modulate stress and affective regulation. Early work on the bonnet macaque noted the emergence of a sample of spontaneously obese subjects as they matured. Using the VFD model, the current study showed that there was a clear relationship between early cerebrospinal fluid corticotropin-releasing factor levels and subsequently measured body mass index, supporting the hypotheses regarding the interactive roles of early experience and HPA axis dysregulation in the ontogeny of both metabolic and mood disorders.