Stroke is an important and common complication of sickle cell disease (SCD), affecting children as well as adults. Clinically evident stroke, usually brain infarction, is usually associated with stenosis or occlusion of the intracranial arteries of the Circle of Willis, sometimes with formation of moyamoya (a Japanese word for “hazy” or “like a puff of smoke” that describes the appearance of a abnormal microvasculature on angiography believed secondary to internal carotid artery stenosis or occlusion and the resultant extensive collateralization). Several types of intracranial hemorrhage are observed but usually in older children and adults. Cerebrovascular diseases restricted to small vessels may go unrecognized but is associated with cognitive and learning problems. Prevention of recurrent stroke has been accomplished with chronic blood transfusion. A primary prevention strategy for clinical stroke, based on the Stroke Prevention in Sickle Cell Anemia Trial, has been tested in a randomized clinical trial. Over 2,000 young children with SCD were screened with transcranial Doppler ultrasound (TCD) to detect elevated blood flow velocity indicative of vessel disease and high risk of future stroke. Those randomized to standard care (no transfusion) had a 10%/year risk of stroke, which was reduced >90% with chronic transfusion. This approach is the only primary stroke prevention strategy so far tested in SCD in a randomized controlled trial. Silent lesions on magnetic resonance imaging are associated with an ∼1.5%/year risk of clinical stroke and a trial is now starting in children with these lesions who do not meet Stroke Prevention in Sickle Cell Anemia Trial criteria for transfusion based on TCD. A controlled trial, based on intervention for nocturnal hypoxemia, is also underway. Hydroxyurea, bone marrow transplantation, antiplatelet, and antithrombotic agents may work but have not been tested in primary prevention in a systematic way. If early and repeated, TCD screening of children, as recommended by National Heart Lung and Blood Institute and the American Stroke Association, were implemented broadly the incidence of new strokes could be greatly reduced in these children.

Biomedical measures are critical in the initial patient-screening and -selection phases of a clinical trial in autism and related disorders. These measures can also play an important role in the assessment and characterization of response and can provide an opportunity to study underlying etiologic and pathophysiologic processes. Thus, biomedical measures, including clinical laboratory analyses, metabolic screening, and chromosomal analysis, are used to screen for potential safety-related problems, to decrease biological and genetic heterogeneity, and to define subgroups. Neurobiological measures can be examined as possible predictors, modifiers or surrogates of therapeutic response, and adverse effects. Neurobiological research measures can also be used to study mechanisms and extent of drug action and to perform baseline and longitudinal investigations of possible pathophysiologic alterations. The potential utility and desirability of specific measures are considered and the general approach to choosing measures for incorporation is discussed.

Intractable temporal lobe epilepsy that is surgically treated in adulthood is a disorder whose onset frequently occurs during childhood and early adolescence. The average duration of epilepsy prior to surgery is on the order of 20 years. The long delay between onset and surgery has at least two components: time from onset to intractability and time from evidence of intractability to surgery. The first interval is prolonged >10 years especially if the onset is during childhood. This suggests a complex natural history that we have not fully appreciated as well as a potential window of opportunity for early secondary intervention. The second interval is also prolonged, especially if onset was during childhood. Reasons for this are not fully clear but may include a reluctance to consider surgery and perhaps difficulty deciding whether seizures are sufficiently intractable to warrant surgery especially after what may have been a relatively benign initial course. Factors involved in the second delay need to be better understood so that surgical interventions can be appropriately targeted early rather than late, thereby reducing serious social, psychological, and educational consequences associated with uncontrolled seizures.

Leptin is an adipocyte-derived hormone, which is involved predominantly in the long-term regulation of body weight and energy balance by acting as a hunger suppressant signal to the brain. Leptin is also involved in the modulation of reproduction, immune function, physical activity, and some endogenous endocrine axes. Since anorexia nervosa (AN) and bulimia nervosa (BN) are characterized by abnormal eating behaviors, dysregulation of endogenous endocrine axes, alterations of reproductive and immune functions, and increased physical activity, extensive research has been carried out in the last decade in order to ascertain a role of this hormone in the pathophysiology of these syndromes. In this article, we review the available data on leptin physiology in patients with eating disorders. These data support the idea that leptin is not directly involved in the etiology of AN or BN. However, malnutrition-induced alterations in its physiology may contribute to the genesis and/or the maintenance of some clinical manifestations of AN and BN and may have an impact on the prognosis of AN.

Pregnancy has frequently been described as a time of affective well-being. However, a growing literature suggests that women are neither “protected” against new-onset or recurrence of depression during this time. Diagnosis and effective treatment of depression during pregnancy requires a careful weighing of risk of treatment which may include psychotropic medications against the risks associated with failure to adequately manage affective distress and its potential impact of maternal and fetal well-being. Treatment options during pregnancy are reviewed in the context of developing the most appropriate risk/benefit decision for individual patients with past or current depression who either anticipate pregnancy or who become pregnant.

This article examines the issue of atypical antipsychotics, glucose/insulin, and other metabolic derangements (ie, metabolic syndrome), including a general introduction to the health, concerns of our patients, a review of the literature, possible mechanisms of antipsychotic induced glucose dysregulation, monitoring approaches, and management and prevention of metabolic syndrome. Literature review leads to mechanism hypotheses and risk estimations, leading to guidelines for monitoring and treatment. The patient population suffers from a higher degree of baseline metabolic dysregulation resulting in cardiovascular disease through components of the metabolic syndrome, and this risk increases with administration of atypical antipsychotic medication at different rates, depending on both drug and patient risk factors. The growing knowledge of mechanisms behind drug induced glucose/insulin and other metabolic dysregulation, as well as advances in pharmacogenomics, will help refine drug selection and monitoring for adverse, life-threatening metabolic effects.

Objective: This study examines the impact of comorbidity of attention-deficit/hyperactivity disorder (ADHD) with disruptive and anxiety disorders in childhood on clinical course and outcome. We consider the relative contribution of each comorbid symptom constellation, and also their interaction, to assess the following questions: (1) Does early comorbidity with conduct disorder (CD) and anxiety disorders define specific developmental trajectories?; (2) Is comorbid anxiety disorders in childhood continuous with anxiety disorders in adolescence?; (3) Does comorbid anxiety disorders mitigate the negative behavioral outcome of youth with ADHD?; and (4) Is there an interaction between comorbid CD and anxiety disorders, when they occur simultaneously, that predicts a different outcome than either comorbid condition alone?

Method: Thirty-two 15- to 18-year-old adolescent males, diagnosed with ADHD between 7 and 11 years of age, were re-evaluated for assessment of adolescent outcome 4.3–9.2 years later. Hierarchical regression analyses were run with each of the eight Child Behavior Checklist and Youth Self-Report problem scales, and the four anxiety symptom subscales of the Multidimensional Anxiety Scale for Children serving as outcome variables.

Results: Findings indicate that comorbid CD at baseline predicteds parent reports of behavior problems in adolescence, while comorbid anxiety disorders in childhood predicted youth reports of anxiety and social problems. Anxiety disorders without CD did not predict poor behavioral outcome. Children with both comorbid CD and anxiety disorder had the highest levels of parent-rated symptoms on follow up. In particular, adolescent social problems were best predicted by the combination of comorbid CD and anxiety disorder in childhood.

Conclusion: These data provide evidence that children with ADHD plus anxiety disorder do in fact have anxiety disorders, and that the combination of anxiety disorder and CD predicts a more rather than less severe course.

Over the last 25 years, there has been a rapid expansion of our knowledge base of social phobia (SP). Although there are a number of well-validated treatment modalities, including pharmacotherapy and cognitive-behavioral therapy, significant gaps remain in our ability to achieve full remission in most patients. Despite advances in the neurobiology of SP, the etiology has yet to be determined. Investigations examining potential predictors of response have provided little guidance in selecting an appropriate treatment modality. These gaps in our knowledge have pushed us to examine issues related to treatment resistance. This paper presents a review of the current literature and issues related to treatment-resistant SP, including a discussion of the functional impairment associated with SP, definitions of treatment response and remission, as well as outcome measures that have been used in clinical investigations of SP. In addition, criteria for a standard treatment trial, predictors of treatment response, a review of treatment resistance studies, and potential directions for future research are examined. The most promising strategies to attain remission, will likely involve augmenting selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors with agents such as anticonvulsants, benzodiazepines, and antipsychotics as well as combining pharmacotherapy with cognitive-behavioral therapy. Our current treatment target of simply attaining a response needs to be refocused, so that an asymptomatic state and high end state functioning become the final goal of treatment.

Background: Clinical trials of aripiprazole, a recentl Food and Drug Administration-approved atypical antipsychotic, included elderly patients, but more data are needed on the effects of aripiprazole in this population, especially those with comorbid medical illnesses.

Objective: To assess the response and safety of aripiprazole treatment in elderly patients with phrenia or schizoaffective disorder.

Method: Data was obtained by retrospective review of medical records. Aripiprazole was used to treat 10 elderly hospitalized patients between 62 and 85 years of age who manifested signs of psychosis related to schizophrenia or schizoaffective disorder. All patients had been treated previously with atypical and classic antipsychotics. Response was assessed by clinical observation of patients' behavior and Clinical Global Impression Scale assigned retrospectively.

Results: Seven patients responded to treatment, two did not respond, and one had a partial response. The mean Clinical Global Impression Scale scores improved from 6 (severely ill) at baseline to 2.3 (much improved) at discharge. Treatment was discontinued in the two patients who did not respond. Of the seven patients who responded, four presented with positive symptoms and showed significant improvement while three presented with positive and negative symptoms and both symptoms improved significantly. Four patients had preexisting extrapyramidal symptoms (EPS) and these symptoms decreased in three patients. In addition, two patients were able to discontinue antiparkinson medications. One patient who had severe tardive dyskinesia showed significant improvement in the dyskinetic symptoms. Four patients showed postural hypotension (without clinical symptoms) which resolved over time without treatment. Six patients showed a mean weight loss of 5.2 lbs. No adverse consequences occurred when divalproex sodium, carbamazepine, clonazepam or citalopram were given concurrently.

Conclusion: The reduction of both positive and negative symptoms of schizophrenia and the lack of significant EPS, tardive dyskinesia, sedation, weight gain, anticholinergic effects, and QTc prolongation gives preliminary indication that aripiprazole may be a safe and effective medication for elderly patients with schizophrenia or schizoaffective disorder.

There is increasing recognition that coronory artery bypass grafting (CABG) may be a risk factor for subtle cognitive decline although the presence and pattern of such decline has varied across studies. Cognitive deficits may present as short-term memory loss, executive dysfunction and psychomotor slowing. Although they are usually are not severe enough to meet criteria for mild cognitive impairment or vascular dementia, they lower quality of life and add to hospitalization and out-of-hospital costs. Proposed mechanisms include surgical-related trauma, genetic susceptibility (eg, apolipoprotein E4 allele), microembolization, other vascular or ischemic changes, and temperature during surgery. Depression and anxiety levels predict subjective perception of these deficits more than objective cognitive performance. Both nonpharmacologic (eg, emboli reduction, temperature, or glucose management) and pharmacologic (eg, dexanabinol, glypromate, nootropics) strategies to prevent post-CABG cognitive deficits are under investigation. Given the large numbers of subjects who may already have CABG associated cognitive deficits, clinical trials of agents being tested for Alzheimer's disease (eg, donepezil, rivastigmine, memantine, neramexane, ginkgo) may also be informative. The results of multicenter long-term outcome studies (with matched control groups) as well as ongoing treatment trials will more conclusively address some of these issues. These data emphasize the need for clinicians to monitor cognitive function before and after coronary bypass surgery, and to educate patients.