A substantial number of patients with panic disorder and agoraphobia may remain symptomatic after standard treatment (including selective serotonin reuptake inhibitors, tricyclic antidepressants, benzodiazepines, or irreversible monamine oxidase inhibitors). In this review, recommendations for the treatment of patients with panic disorder and agoraphobia who do not respond to these drugs are provided. Nonresponse to drug treatment could be defined as a failure to achieve a 50% reduction on a standard rating scale after a minimum of 6 weeks of treatment in adequate dose. When initial treatments have failed, the medication should be changed to other standard treatments. In further attempts at treatment, drugs should be used that have shown promising results in preliminary studies, such as venlafaxine. Combination treatments may be used, such as the combination of an selective serotonin reuptake inhibitor and a benzodiazepine. Psychological treatments such as cognitive-behavioral therapy have to be considered in all patients, regardless whether they are nonresponders or not. According to existing studies, a combination of pharmacologic treatment with cognitive-behavioral therapy can be recommended.

Despite a congenital stroke, overall intelligence at school age is generally within the normal range. Language acquisition problems are more prominent when children are younger (<5 years of age) than when they are older. They are present after both right and left lesions, but appear to have different features. They are less apparent than in the child with a developmental language disorder. Acquired aphasia in childhood results in subtle and often persisting deficits. Children with congenital strokes are at risk for behavioral and psychiatric problems. Those with congenital right hemisphere strokes appear to be more difficult infants, but there is no clear side of lesion effect in older children. Children with congenital right hemisphere strokes have more prominent spatial difficulties than their left lesion counterparts. Evaluating both the process and the product highlights this. Increasing the difficulty of the task often brings out deficits in the right lesion group even when they seemingly recovered.

The past decade has witnessed a dramatic acceleration in research on the role of the neuropeptides in the regulation of eating behavior and body weight homeostasis. This expanding research focus has been driven in part by increasing public health concerns related to obesity and the eating disorders anorexia nervosa (AN) and bulimia nervosa (BN). Preclinical advances have been facilitated by the development of new molecular and behavioral research methodologies. With a focus on clinical investigations in AN and BN, this article reviews research on selected hypothalamic and gut-related peptide systems with prominent effects on eating behavior. Studies of the orexigenic peptides neuropeptide Y and the opioid peptides have shown state-related abnormalities in patients with eating disorders. With respect to gut-related peptides, there appears to be substantial evidence for blunting in the meal-related release of the satiety promoting peptide cholecystokinin in BN. Fasting plasma levels of the orexigenic peptide ghrelin have been found to be elevated in patients with AN. As discussed in this review, additional studies will be needed to assess the role of nutritional and body weight changes in neuropeptide alterations observed in symptomatic eating disorder patients, and to identify stable trait-related abnormalities in neuropeptide regulation that persist in individuals who have recovered from an eating disorder.

Objective: We describe the clinical and imaging studies of 11 full-term babies with neonatal stroke. We classify the neonatal non-hemorrhagic strokes as thrombotic, embolic, or global vascular insufficiency and determine if this classification is improved by adding magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) to conventional magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA).

Methods: Clinically, eight of the 11 babies presented with seizures, one with apnea, and two with lethargy. Conventional MRI and DWI were used to classify each infarct as being either borderzone or vascular distribution. The location of infarction revealed the presumed vascular pathophysiology.

Results: Infants were classified as having either embolic (bilateral middle cerebral artery, n=1), global ischemic (bilateral borderzone, n=2), or thrombotic infarction (unilateral middle cerebral artery, n=7; bilateral posterior cerebral arteries, n=1). DWI and MRS detected a small infarct better than conventional MRI in one patient. MRA showed abnormal intracranial arteries in three, all of who were in the thrombotic group. Even though MRS was more sensitive than conventional MRI in detecting ischemia/ infarction in one patient, in another there was no detectable lactate in the stroke region found on conventional MRI. Clinical presentation was similar in global ischemia and focal infarctions, but newborn stroke was more likely to present with lateralizing focal motor seizures. Seizures were the most common presenting sign, with a paucity of other focal neurological deficits.

Conclusion: MRI is the best approach to determine stroke pathophysiology. Brain infarction frequently presents with seizures. We speculate that the location and distribution of infarction might determine stroke timing, pathophysiology and outcome. Ongoing clinical studies will likely clarify this speculation.

Evidence from a recent randomized controlled trial of surgical versus medical therapy of temporal lobe epilepsy proves that antero'mesial resection is safe and more effective than medical therapy. The number of patients needed to treat for one patient to become free of disabling seizures is two, which is superior to most interventions in neurology. A meta-analysis of non-randomized trials gives almost identical results; about two-thirds of patients become seizure-free, compared with only 8% with medical therapy. The results are remarkably similar among studies from different parts of the world. Quality of life improves early after epilepsy surgery, the improvements are both statistically and clinically significant, and they are sustained. Surgical morbidity with clinically important permanent sequelae is 2%. Epilepsy surgery remains underutilized in developed countries and it does not exist in all but a few developing countries. Current randomized trials are underway to explore the effect of early surgery versus optimum medical therapy on the prevention of disability in patients with mesial temporal lobe epilepsy, and to examine the effectiveness of novel interventions, such as minimally invasive surgery and brain stimulation.

There are specific challenges to studying the design of pharmacologic trials in child/adolescent and adult autism, such as subject stratification and parallel versus crossover designs. This article describes how optimal study design is influenced by subject selection and outcome measures chosen. Lessons learned in study design from the Research Units on Pediatric Psychopharmacology Autism Network trial with risperidone, Seaver Center trials with fluoxetine and valproate, Dartmouth trials with amantadine, and National Institutes of Health secretin trials are highlighted. The Internet System for Assessing Autistic Children system for managing multicenter clinical trials in autism and statistical issues in autism research are also described.

This article provides an overview of the etiology, epidemiology, and first-line treatment options for obsessive-compulsive disorder (OCD). The subject of treatment-resistant and treatment-refractory OCD is the discussed, including a definition of these often-debated terms, and the latest treatment options delineated. This includes a review of the latest research concerning the pharmacological agents that have been studied as monotherapy or augmenting agents for the treatment of OCD, the use of experimental medications and procedures, treatment with reversible, minimally invasive procedure, such as vagal nerve stimulation and transcranial magnetic stimulation, invasive but the potentially reversible deep brain stimulation, and irreversible lesioning with ablative psychosurgery. A discussion of the role of psychotherapy in the treatment of OCD is also included.

The cholinergic system is a major neuromodulatory neurotransmitter system, interacting with core regions of the brain and affecting learning and memory function. Cholinergic function is severely reduced in patients with pathologic conditions, such as Alzheimer's disease. Muscarinic receptors M1–M5 are located at the postsynaptic level of the central cholinergic synapse. Blockage of certain muscarinic receptors has been shown to affect cognitive functioning. The roles of the individual receptor subtypes has implications for pharmacotherapy; eg, nonselective antimuscarinic/anticholinergic medications may block muscarinic neurotransmission, causing deficits in recall and new learning, while M1-receptor agonists and M2-receptor antagonists may not interfere with cognitive functioning. Studies investigating central nervous system (CNS) depressant effects of drugs have shown that antimuscarinic agents have the potential to cause impairment of CNS functioning. CNS dysfunction may be manifested as changes in memory, disruption of sleep, hallucinations, confusion, and delirium.

Anticholinergic load refers to the cumulative effect of taking multiple drugs with anticholinergic activity. The extent to which a particular drug affects the cholinergic system can be determined by its ability to cross the blood-brain barrier, the integrity of which decreases with age. Elderly individuals are also at high risk for increased anticholinergic load due to reductions in metabolism and elimination as well as pharmacokinetic drug interactions. In addition, elderly people are often prescribed several medications that have direct anticholinergic properties and take over-the-counter medications which may also carry substantial anticholinergic burden. The cumulative effect of these medications in vulnerable elderly patients may precipitate early cognitive declines or further exacerbate cognitive deficits in those already suffering from dementia. Risk of cognitive impairment in patients with overactive bladder can thus be reduced through use of M3-selective antagonists, such as darifenacin, and via alternatives to pharmacotherapy, such as behavioral modification, pelvic floor strengthening, and bladder-retraining exercises.

Objective: To assess the impact of childhood conduct disorder (CD) and intelligence quotient (IQ) on later substance use in adolescence.

Methods: Neuropsychological and structured diagnostic evaluations were initially administered to 32 children with disruptive behavior disorder when they were 7–11 years of age. They were then re-evaluated on average 6.7 years later using an array of interviews and rating scales with a focus on substance use.

Results: Early CD and IQ scores together accounted for a significant proportion of the variance in later substance use (R2=.248). In addition, there was a significant CD and Verbal IQ interaction (R2=.164) such that high Verbal IQ was linked to increased substance use in adolescents who had childhood CD.

Conclusion: These data indicate that the presence of conduct disorder may interact with high Verbal IQ during childhood in such a way as to predict later adolescent substance use in disruptive behavior disorder populations.

Women's mental health during pregnancy has important implications not only for the well-being of the mother, but also for the development, health, and well-being of her unborn child. A growing body of empirical evidence from population-based studies suggests that two indicators of women's mental health during pregnancy—psychosocial stress and social support—may exert a significant influence on fetal development and infant birth outcomes, such as birth weight and length of gestation, even after controlling for the effects of established sociodemographic, obstetric, and behavioral risk factors. This paper describes the role of three major biological systems involved in the physiology of pregnancy and stress physiology: neuroendocrine, immune/inflammatory, and cardiovascular systems. These systems have been hypothesized to mediate the effects of maternal mental health on fetal developmental and health outcomes, and a central role has been proposed for placental corticotropin-releasing hormone in this process. However, not all women reporting high prenatal stress and/or low social support proceed to develop adverse birth outcomes, raising the question of the determinants of susceptibility/vulnerability in the context of high stress and/or low social support. In this context, the role of race/ethnicity and genetic predisposition are. discussed as two promising avenues of further investigation.

Background: Studies on the effects of antipsychotics on cognitive deficits in schizophrenia mostly suggest a superior effect of atypical over typical compounds, although findings are inconsistent and effect sizes small. Several methodological issues, such as heterogenous patient samples, incomparable drug doses, effects of prior medication, construct validity, and retest effects on neuropsychological tasks, confound most results and the comparability between studies. Consequently, the conclusion concerning effects of antipsychotics on cognition is still equivocal.

Objective: The present randomized clinical trial examined the effects on cognition of comparatively low doses of a typical antipsychotic (zuclopenthixol) and an atypical antipsychotic (risperidone) in a homogenous group of drug-naïve first-episode schizophrenic patients in a longitudinal setting.

Methods: First-episode schizophrenic patients who had never previously been exposed to antipsychotic treatment (N-25) were randomly allocated to treatment with flexible doses of zuclopenthixol or risperidone in an open-label design. Cognitive functions were examined both when patients were drug-naïve, and after 13 weeks of treatment. A comprehensive neuropsychological battery was used in order to optimize construct validity, and principal components of cognitive functions were extrapolated in order to reduce type I errors. A healthy control group was tested at baseline and after 13 weeks, in order to examine retest effects. The cognitive domains studied were executive functions, selective attention, and reaction time.

Results: The patients showed considerable cognitive deficits when drug-naïve. There were few differential effects of risperidone and zuclopenthixol on cognitive deficits, except for a differential significance, respectively, tendency towards improved reaction and movement times in the risperidone group, and a lack of such in the zuclopenthixol group. These differences were no longer significant after covarying for extrapyramidal side effects and anticholinergic medication that were more prevalent in the zuclopenthixol group and the increases after medication were comparable with retest effects in controls.

Conclusion: The study underscores the importance of examining impact of factors, such as clinical improvement, extrapyramidal side effects, anticholinergic medication and retest effects in longitudinal efficacy studies. This study does not support efficacy of either risperidone or zuclopenthixol on cognitive functions in drug-naïve schizophrenia patients after 3 months of medication, because neither could be distinguished from retest effects of the healthy control group.

Alzheimer's disease (AD) is a complex medical condition involving abnormalities in multiple biological and environmental domains. Current knowledge suggests that simultaneous intervention in these domains may be the most effective way to help AD patients and their families. Treatments for AD are centered on the inhibition of enzymes responsible for the degradation of acetylcholine—a neurotransmitter that is reduced in AD patients. Four cholinesterase inhibitors have been approved by the United States Food and Drug Administration, three of which are routinely used for the symptomatic treatment of mild-to-moderate AD. Strategies will be reviewed with regard to cognitive, functional, and behavioral domains. Providing a different treatment option for patients with AD, memantine is a low-to-moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that has been approved for the treatment of moderate-to-severe AD. The clinical efficacy and tolerability of memantine monotherapy and combination therapy in patients with AD will be presented. Finally, the role of non-pharmacologic intervention will be discussed.

The mainstay of treatment for chronic posttraumatic stress disorder (PTSD) is a combination of psychotherapy and medication treatments. The first-line medications for PTSD are antidepressants, with two selective serotonin reuptake inhibitors (sertraline and paroxetine) currently Food and Drug Administration-indicated for PTSD. However, many patients do not have an adequate response to antidepressants, therefore, combinations with other antidepressants or with other classes of psychotropic medication are often utilized to enhance the therapeutic response. Other agents that have been used include mood stabilizers, antiadrenergics, anxiolytics, and atypical antipsychotics. The heterogeneity of symptom clusters in PTSD as well as the complex psychiatric comorbidities (eg, with depression or substance abuse) further support the notion that combinations of medications may be needed. To date, there is a paucity of data to support specific strategies for augmenting antidepressants in PTSD. This review will address representative existing studies and discuss several potential pharmacologic strategies for patients suffering from treatment refractory PTSD.

Research has shown that many of the long-term deficits that are observable in schizophrenia populations are present prior to the emergence of psychotic symptoms. Recent research suggests schizophrenia has a “prodromal” period, whereby significant changes from premorbid functioning can be observed. Accurate classification of this period could have far-reaching implications for schizophrenia prevention. This article aims to provide an indepth evaluation of the perceived benefits of vulnerability marker research in this unique phase. It is hoped that identification of such markers may improve the predictive potency of prodromal criteria, and perhaps pave the way for future screening and primary prevention strategies.