CNS spectrums

Published by Cambridge University Press (CUP)
Print ISSN: 1092-8529
While both blunted and enhanced cortisol suppression following a dexamethasone suppression test (DST) are described in eating disorders, some evidence suggests that enhanced cortisol suppression might be associated with the presence of trauma history. The objective of this study is to investigate hypothalamic-pituitary-adrenal axis response to a modified DST in eating disorders and its relationship with childhood trauma. Fifty-two patients with eating disorders were studied with a 0.25 mg DST and with measures of childhood trauma. Patients with bulimia symptoms had significantly greater cortisol suppression than controls and restrictive anorexia patients (F=8.2, P<.05). Cortisol suppression was significantly correlated with intensity of childhood traumatic events (F=0.32, P<.05). Hypersensitive hypothalamic-pituitary-adrenal axis response to DST in eating disorders may be related with a history of childhood trauma and suggests some biological similarities with posttraumatic syndromes that should be further explored.
Unlabelled: The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients with schizophrenia. Objective: To clarify if selective 5HT-6 antagonist AVN-211 (CD-008-0173) adds clinical and cognitive effects to stable antipsychotic treatment. Methods: A randomized, double-blind, placebo-controlled, add-on, 4r-week trial in 47 schizophrenia patients (21 patients receiving study drug and 26 receiving placebo) who were stabilized on antipsychotic medication was performed. Seventeen patients from the study drug group and 25 patients from the placebo group completed the trial. Treatment effects were measured using clinical rating scales and attention tests. Results: With no differences at baseline, there was a significant difference between the groups in Positive and Negative Syndrome Scale (PANSS) positive subscale score (p = 0.058) in favor of patients in the treatment group at the endpoint. The PANSS positive subscore (p = 0.0068) and Clinical Global Impression-Severity (CGI-S) (p = 0.048) score significantly changed only in the treatment group. Only in the placebo group were significant changes in Calgary Depression Rating Scale (CDRS) total score registered. The indices of attention tests at endpoint did not show differences between the groups, with the exception of the scope of change in the results of the subtest VIII of the Wechsler Adult Intelligence Scale (WAIS), which showed difference between the groups (p = 0.02) and was significantly larger in the treatment group. Only inside the study drug group, significant changes in selectivity and continuous attention were observed regarding total correct responses (p = 0.0038) and reaction time (p = 0.058) in the Continuous Attention Task (CAT) test. Conclusion: Selective 5HT6 antagonist AVN-211 (CD-008-0173) added antipsychotic and some procognitive (attention) effects to antipsychotic medication.
Alcohol withdrawal continues to present significant morbidity and mortality in hospitalized medical/surgical patients. The authors present a case of a patient with delirium tremens requiring up to 1,600 mg/day of lorazepam and discuss alternative treatments for alcohol withdrawal.
There is little research on the consequences of large-scale violent disasters in a community despite their unfortunate prevalence over many decades. The primary source of epidemiological data for the greater New York community in dealing with the September 11, 2001, attacks was the Oklahoma City bombing. In the latter event, 45% of directly exposed adults met criteria for a major psychiatric disorder 6 months later, including 34% with posttraumatic stress disorder (PTSD). The first survey after the World Trade Center and Pentagon attacks, conducted within one week, revealed a remarkable degree of symptomatology across the nation in both adults and children. Forty-four percent of adults reported at least 1 of 5 PTSD screening symptoms in the 3–5 days after the attacks; 35% of parents reported children who had at least one symptom, and 47% of children worried about their own or someone else's safety. Coping behaviors were consistent with a community mental health model and included turning to open discussion (98%), religion (90%), and community activities (60%) in order to cope with their reactions. Rates of disorder were also high in a survey conducted 5–8 weeks later in Manhattan below 110th Street, with 38% saying they directly witnessed the World Trade Center attack. The current prevalence of new-onset PTSD was 7.5%, and of new-onset major depressive disorder, 9.7%. This translates into 67,000 persons with PTSD and 87,000 persons with major depression. This survey also found a significant increase in tobacco, alcohol, and marijuana use, but primarily among adults already using these substances. All surveys found strong associations between media exposure and symptomatology. The greatest need at this point in the literature is therapeutics research after such traumatic events.
The September 11, 2001, attack on New York City was the largest human-made disaster in United States history. In the first few days after the attack, it became clear that the scope of the attacks (including loss of life, property damage, and financial strain) was unprecedented and that the attacks could result in substantial psychological sequelae in the city population. Researchers at the Center for Urban Epidemiologic Studies at the New York Academy of Medicine designed and implemented an assessment of the mental health of New Yorkers 5-8 weeks after the attacks. To implement this research in the immediate postdisaster period, researchers at the center had to develop, in a compressed time interval, new academic collaborations, links with potential funders, and unique safeguards for study respondents who may have been suffering from acute psychological distress. Results of the assessment contributed to a New York state mental health needs assessment that secured Federal Emergency Management Agency funding for mental health programs in New York City. This experience suggests that mechanisms should be in place for rapid implementation of mental health assessments after disasters.
Acute administration of the partial serotonin (5-HT) agonist meta-chlorophenylpiperazine (m-CPP), that is used also as a street drug, has been reported to induce a "high" and craving response in various impulsive and substance addiction disorders. Introduction: To clarify altered 5-HT metabolism in pathological gamblers and to explore the specific role of serotonergic system in non-substance addictions, we assessed behavioral ("high" and "craving") and neuroendocrine (prolactin and cortisol) responses to an oral single dose of m-CPP and placebo in pathological gamblers and matched controls. Moreover, the relationship between neuroendocrine outcome and clinical severity has been assessed. Twenty-six pathological gamblers and 26 healthy control subjects enter a double-blind, placebo-controlled-crossed administration of orally dose m-CPP 0.5 mg/kg. Outcome measures included prolactin and cortisol levels, gambling severity, mood, craving and "high" scales. Pathological gamblers had significantly increased prolactin response compared to controls at 180 minutes and at 210 minutes post-administration. Greater pathological gamblers severity correlated with increased neuroendocrine responsiveness to m-CCP, suggesting greater 5-HT dysregulation. Pathological gambling patients had a significantly increased "high" sensation after m-CPP administration compared with control. These results provide additional evidence for 5-HT disturbance in pathological gamblers and they support the hypotheses that the role of the 5-HT dysfunction related to the experience of "high" might represent the pathway that leads to dyscontrolled behavior in pathological gamblers. Furthermore, the "high" feeling induced by m-CPP in pathological subjects may represent a marker of vulnerability to both behavioral and substance addictions.
Subdivisions of the cerebellum used to compare volumes in trichotillomania and controls. Trichotillomania has been associated with reduced cerebellum volumes, and hair-pulling severity inversely correlated with left primary sensorimotor cluster volumes 11 
Severe hair-pulling is characteristic of trichotillomania, an impulse control disorder not otherwise classified. Other pathological habits, including severe nail-biting and skin-picking, are also prevalent and are potentially diagnosable as stereotypic movement disorder. There is increasing awareness of the morbidity associated with these kind of habit disorders but, to date, relatively few randomized controlled trials of pharmacotherapy or psychotherapy have been undertaken. Advances in the understanding of the underlying cognitive-affective mechanisms driving stereotypies in animals and humans may ultimately lead to new approaches. An affect regulation, behavioral addiction, and cognitive control (A-B-C) approach is outlined to conceptualizing and managing these conditions.
fMRI activation of the right amygdala during an aversive conditioning task was increased in social anxiety disorder (middle), and decreased in psychopathy (bottom), in comparison to health controls (top) 20  
Specific phobia is the most prevalent of the anxiety disorders. Although there have been relatively few studies of its psychobiology and pharmacotherapy, there is a rich laboratory of literature on fear conditioning and extinction and a clear evolutionary perspective. Advances in the cognitive-affective neuroscience of fear processing may ultimately lead to new approaches to the clinical management of phobias.
As part of an established traumatic stress research and treatment program located in New York City, we experienced the September 11, 2001, terrorist attacks on the World Trade Center first as New Yorkers, but also as professionals with an interest in both treating the survivors and furthering scientific knowledge regarding the neurobiology and treatment of traumatic stress. This paper gives vignettes of calls to our program and the treatment of World Trade Center terrorist attack survivors.
Empirical data from research studies are vital to guiding mental health interventions following disasters. However, few data are available for this purpose. Important advances in policy and procedures for the conduct of organized research emerged from the Oklahoma City bombing, yielding cooperative working relationships among researchers and culminating in the ethical attainment of informative research data. However, the academic community was again caught off guard after the September 11, 2001, terrorist attacks. Suggestions to surmount these obstacles include incorporating research infrastructures into disaster preparedness plans in advance; organizing the community of researchers; and working closely with major funding organizations. Methodological issues pertaining to measurement of psychopathology include the importance of obtaining diagnostic data; interpreting the meaning of symptoms in the absence of a psychiatric disorder; differentiating preexisting symptoms from those that emerged after the disaster, and optimal timing of postdisaster assessment.
* Distribution of overall and local California Web site usage over 24 hours  
This article reports on the planning, development, and implementation of a large national Internet-based panel study of how Americans are coping with the terrorist attacks of September 11, 2001. The study was designed to determine predictors and correlates of risk and resilience, both cross-sectionally and longitudinally. In order to acquire timely and meaningful data, we developed/adapted an extensive set of measures, obtained human subjects approval, and posted a research Web site just 17 days after the attacks. This article describes the major hurdles we confronted and the guidelines we recommend regarding these topics, including the methodological trade-offs inherent in Internet-based research, information technology requirements and tribulations, human subjects issues, selection of measures and securing permission for their use, and the challenges of participant recruitment. We also discuss issues that we did not anticipate, including the survey intervention. We focus not on findings, but on the concrete procedural, administrative, technical, and scientific challenges we encountered and the solutions we devised under considerable time and resource pressures.
Behavioral addictions, such as pathological gambling, kleptomania, pyromania, compulsive buying, and compulsive sexual behavior, represent significant public health concerns and are associated with high rates of psychiatric comorbidity and mortality. Although research into the biology of these behaviors is still in the early stages, recent advances in the understanding of motivation, reward, and addiction have provided insight into the possible pathophysiology of these disorders. Biochemical, functional neuroimaging, genetic studies, and treatment research have suggested a strong neurobiological link between behavioral addictions and substance use disorders. Given the substantial co-occurrence of these groups of disorders, improved understanding of their relationship has important implications not only for further understanding the neurobiology of both categories of disorders but also for improving prevention and treatment strategies.
Current diagnostic algorithm for diagnosing and subtyping MCI  
Predicted outcome of MCI subtypes according to presumed etiology  
Mild cognitive impairment (MCI) refers to the transitional state between the cognitive changes of normal aging and very early dementia. MCI has generated a great deal of research from both clinical and research perspectives. Several population- and community-based studies have documented an accelerated rate of progression to dementia and Alzheimer's disease in individuals diagnosed with MCI. Clinical subtypes of MCI have been proposed to broaden the concept and include prodromal forms of a variety of dementias. An algorithm is presented to assist the clinician in identifying subjects and subclassifying them into the various types of MCI. Progression factors, including genetic, neuroimaging, biomarker, and clinical characteristics, are discussed. Neuropathological studies indicating an intermediate state between normal aging and early dementia in subjects with MCI are presented. The recently completed clinical trials as well as neuropsychological and nutritional interventions are discussed. Finally, the clinical utility of MCI, and directions for future research are proposed.
Exposure to a traumatic event is required for the diagnosis of posttraumatic stress disorder (PTSD). The symptoms of PTSD are believed to reflect stress-induced changes in neurobiological systems and/or an inadequate adaptation of neurobiological systems to exposure to severe stressors. More recently, there have been attempts to link the identified neurobiological changes to the specific features that constitute PTSD, such as altered mechanisms of learning and extinction, sensitization to stress, and arousal. Furthermore, there have been efforts to understand whether certain neurobiological changes in PTSD reflect preexisting vulnerability factors rather than consequences of trauma exposure or correlates of PTSD. Genetic variability, sex differences, and developmental exposures to stress influence neurobiological systems and moderate PTSD risk. On the basis of these findings, important hypotheses for developing novel strategies to identify subjects at risk, promote resilience, and devise targets for the prevention or treatment of PTSD can be derived.
In clinical samples, body dysmorphic disorder (BDD) is associated with substantial suffering and reduced quality of life. Limited surveys report widely varying prevalence estimates. To better establish the prevalence of BDD, we conducted a United States nationwide prevalence survey. We conducted a random sample national household telephone survey in the spring and summer of 2004 and interviewed 2,513 adults, of whom 2,048 qualified for the BDD-module administration. The computer-assisted, structured interviews, conducted by trained lay interviewers, addressed Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for BDD, along with information regarding several impulse-control disorders and the respondents' financial and demographic data. The rate of response was 56.3%, which compared favorably with rates in federal national health surveys. The cooperation rate was 97.6%. Respondents included a higher percentage of women and people >55 years of age than in the US adult population, and a lower percentage of Hispanics. The estimated point prevalence of DSM-IV BDD among respondents was 2.4% (49/2,048) (by gender: 2.5% for women, 2.2% for men), exceeding the prevalence of schizophrenia and bipolar disorder type I and about that of generalized anxiety disorder. BDD prevalence decreased after 44 years of age, and a larger proportion of BDD respondents were never married. Of those meeting DSM-IV criteria for BDD, 90% (45/49) met the DSM-IV distress criterion, and 51% (25/49) met the interference-with-functioning criterion. A study using clinically valid interviews is needed to evaluate these results. Such studies could inform treatment by documenting rates of seeking treatment from various sources, suicide attempt rates, and the prevalence of comorbid conditions.
Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-alpha treatment show that inflammation can cause depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation. Loss of astroglia, a feature of depression, upsets the balance of anti- and pro-inflammatory mediators and further impairs the removal of excitatory amino acids. Microglia activated by excess inflammation, astroglial loss, and inappropriate glutamate receptor activation ultimately disrupt the delicate balance of neuroprotective versus neurotoxic effects in the brain, potentially leading to depression.
A 14-year-old girl with anorexia nervosa (AN) was found to have an intracranial neoplasm. Atypical psychological symptoms prompted further evaluation, including electroencephalogram and neuroimaging, which revealed a sellar and suprasellar mass. This patient had an eating disorder and a brain tumor, which appear to be two unrelated conditions. However, it remains unclear how each affected the other. The diagnosis of AN, like all other psychiatric disorders, requires that possible medical etiologies and coexisting medical problems be excluded. AN and other eating disorders are particularly difficult to diagnose in children and adolescents because they often do not present in the manner typical of adults. Perceptual and cognitive disturbances associated with AN are difficult to evaluate because children and adolescents normally change over time as they progress through different stages of development. Therefore, it is particularly important to evaluate for the presence of medical conditions when a diagnosis of an eating disorder is made in a child or adolescent.
To evaluate the long-term safety and effectiveness of lisdexamfetamine dimesylate (LDX) in the treatment of adults with attention-deficit/hyperactivity disorder (ADHD). Following a 4-week, placebo-controlled, double-blind trial, 349 adults with ADHD were enrolled into an open-label, single-arm study for up to 12 months. Treatment was initiated at 30 mg/day and titrated up to 70 mg/day at subsequent visits to achieve optimal effectiveness and tolerability. Safety assessments included adverse events inquiries, vital signs, and electrocardiograms while the primary effectiveness assessment was the ADHD Rating Scale (ADHD-RS) total score. A total of 191 (54.7%) subjects completed the study. The most common treatment-emergent adverse events (TEAEs) were upper respiratory tract infection (21.8%), insomnia (19.5%), headache (17.2%), dry mouth (16.6%), decreased appetite (14.3%), and irritability (11.2%). Most TEAEs were mild to moderate in severity. At endpoint, small but statistically significant increases in pulse and blood pressure were noted. Significant improvements in mean ADHD-RS total scores were observed at week 1 and sustained throughout the study (P < .0001 at all postbaseline visits). At endpoint, the mean improvement from baseline ADHD-RS total score was 24.8 (P < .0001). LDX demonstrated a safety profile consistent with long-acting stimulant use and provided continued effectiveness in adults with ADHD for up to 12 months.
This study was conducted to show that catatonia is a predisposing factor for neuroleptic malignant syndrome (NMS) and to review the nosological relationship between catatonia and NMS. Seventeen consecutive cases of NMS were analyzed prospectively with reference to clinical and investigative findings before and after exposure to a neuroleptic. The series comprised eight males and nine females, ranging in age from 18 years to 65 years. Prior to neuroleptic exposure, all patients exhibited features compatible with criteria for catatonia (mutism/excitement) according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised, (DSM-III-R). Following neuroleptic administration (single dose in nine cases), patients deteriorated into a febrile, rigid, and obtunded state accompanied by autonomic dysfunction and raised creatine phosphokinase levels. These features were consistent with a diagnosis of NMS. Neuroleptics were discontinued and supportive medical treatment instituted. Benzodiazepines were beneficial in eight cases in relieving stupor, but bromocriptine and dantrolene were generally ineffective. In all patients diagnosed with NMS in the authors' series, catatonia was an invariable prodromal state. It appears that the administration of a neuroleptic intensified the preexisting catatonic state and precipitated a malignant variant of the disorder, which is currently recognized as NMS. The authors, therefore, challenge the separate nosological status of NMS and catatonia and suggest that these syndromes are part of a unitary pathophysiological disorder.
Brain regions showing greater glucose metabolism in the Internet game overusers than in the normal users
Brain regions showing lower glucose metabolism in the Internet game overusers than in the normal users
Introduction: Internet game overuse is an emerging disorder and features diminished impulse control and poor reward-processing. In an attempt to understand the neurobiological bases of Internet game overuse, we investigated the differences in regional cerebral glucose metabolism at resting state between young individuals with Internet game overuse and those with normal use using 18F-fluorodeoxyglucose positron emission tomography study. Methods: Twenty right-handed male participants (9 normal users: 24.7+/-2.4 years of age, 11 overusers: 23.5+/-2.9 years of age) participated. A trait measure of impulsivity was also completed after scanning. Results: Internet game overusers showed greater impulsiveness than the normal users and there was a positive correlation between the severity of Internet game overuse and impulsiveness. Imaging data showed that the overusers had increased glucose metabolism in the right middle orbitofrontal gyrus, left caudate nucleus, and right insula, and decreased metabolism in the bilateral postcentral gyrus, left precentral gyrus, and bilateral occipital regions compared to normal users. Conclusion: Internet game overuse may be associated with abnormal neurobiological mechanisms in the orbitofrontal cortex, striatum, and sensory regions, which are implicated in impulse control, reward processing, and somatic representation of previous experiences. Our results support the idea that Internet game overuse shares psychological and neural mechanisms with other types of impulse control disorders and substance/non-substance-related addiction.
Baseline metabolic differences and lateralization index  
The impact of HF-rTMS treatment on the predefined regions of interest in responders (n=9)  
High frequency repetitive transcranial magnetic stimulation (HF-rTMS) of the left dorsolateral prefrontal cortex (DLPFC) might be a promising strategy to treat depression, but not all patients show a positive outcome. In this open study, we evaluate whether a favorable HF-rTMS treatment outcome could be predicted by baseline prefrontal brain glucose metabolism (CMRglc), measured by 18fluorodeoxyglucose positron emission tomography (18FDG-PET). A sample of 21 antidepressant-free, treatment-resistant depression (TRD) patients of the melancholic subtype received 10 sessions of HF-rTMS delivered on the left DLPFC. Patients underwent a static 18FDG-PET before and after HF-rTMS treatment. Forty-three percent of the patients showed a reduction of at least 50% on their Hamilton Rating Scale for Depression scores. Higher baseline metabolic activities in the DLPFC and the anterior cingulate cortex (ACC) were associated with better clinical outcome. Successful HF-rTMS treatment was related to metabolic changes in subdivisions of the ACC (Brodmann areas 24 and 32). This biological impact of HF-rTMS on regional brain CMRglc explains to some extent how HF-rTMS may improve moods in TRD patients. Larger sham-controlled HF-rTMS treatment studies are needed to confirm these results.
How did the 1995 Oklahoma City bombing differ from prior disasters and what implications did it have for disaster mental health services and service delivery? The federal disaster mental health approach in this country developed largely out of experiences with natural disasters. The 1995 Oklahoma City bombing differed in several important ways, including the large number of human casualties, higher rates of psychopathology, and an extended period of concern due to the criminal investigation and trials, which suggested the need to consider modifications in the program. Outreach was extensive, but psychiatric morbidity of direct victims was greater than that of victims of natural disasters, emphasizing the need for attention to the triage and referral process. Other concerns that warrant consideration include practices related to record keeping and program evaluation.
Mechanism of action of the SPARI vilazodone, part 1. When the SPARI vilazodone is administered, about half of serotonin transporters (SERTs) and half of serotonin 5HT1A receptors are occupied immediately.  
Mechanism of action of the SPARI vilazodone, part 4. Once the somatodendritic receptors down-regulate, as depicted in Figure 4, there is no longer inhibition of impulse flow in the serotonin neuron. Thus, neuronal impulse flow is turned on. The consequence of this is release of serotonin in the axon terminal on the right (red circle).
Issue: Vilazodone is an antidepressant with a novel mechanism of pharmacologic action: serotonin partial agonist reuptake inhibitor (SPARI).
The Internet has positively altered many aspects of life. However, for a subset of users, the medium may have become a consuming problem that exhibits features of impulse control disorders recognized in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. This is the first large-scale epidemiological study of problematic Internet use through a random-digit-dial telephone survey of 2,513 adults in the United States. Given the lack of validated criteria, survey questions were extrapolated from established diagnostic criteria for impulse control disorders, obsessive-compulsive disorder, and substance abuse. Four possible diagnostic criteria sets were generated. The least restrictive set required the respondent to report an unsuccessful effort to reduce Internet use or a history of remaining online longer than intended, Internet use interfering with relationships, and a preoccupation with Internet use when offline. The response rate was 56.3%. Interviews averaged 11.3 minutes in duration. From 3.7% to 13% of respondents endorsed > or =1 markers consistent with problematic Internet use. The least restrictive proposed diagnostic criteria set yielded a prevalence of problematic Internet use of 0.7%. Potential markers of problematic Internet use seem present in a sizeable proportion of adults. Future studies should delineate whether problematic Internet use constitutes a pathological behavior that meets criteria for an independent disorder, or represents a symptom of other psychopathologies.
Happy New 2008: From Mild Cognitive Impairment to Pleasure Circuitry - Volume 13 Issue 1 - Eric Hollander
Prevalence (%) and 95% confidence interval (CI) of physical violence by demographic category
Length of stay (LOS), in days, by total number of violent assaults during the study period
Introduction We examined physical violence in a large, multihospital state psychiatric system during 2011-2013, and associated demographic and clinical characteristics of violent patients to better understand issues of patient and staff safety. Acts of physical violence committed by patients against other patients (n=10,958) or against staff (n=8429) during 2011-2013 were collected and analyzed for all hospitalized patients during the same time period to derive prevalence rates and associated odds ratios. Overall, 31.4% of patients committed at least 1 violent assault during their hospitalization. Differential risk factor patterns were noted across patient and staff assault. Younger age was associated with a higher prevalence of both patient and staff assault, as was nonforensic legal status. Females had a higher prevalence of staff assault than patient assault. Ethnic groups varied on rates of patient assault, but had no significant differences for staff assault. Schizoaffective disorder was associated with higher prevalence and odds of patient (OR 1.244, 95% CI 1.131 to 1.370) and staff (OR 1.346, 95% CI 1.202 to 1.507) assault when compared to patients diagnosed with schizophrenia. Most personality disorder diagnoses also had a higher prevalence and odds of physical violence. One percent of patients accounted for 28.7% of all assaults. Additionally, violent patients had a significantly longer length of hospitalization. Discussion Implications of these findings to enhance patient safety and inform future violence reduction efforts, including the need for new treatments in conjunction with the use of violence risk assessments, are discussed.
The last decade has witnessed remarkable progress in the understanding of the mammalian cannabinoid system, from the cloning of the endogenous cannabinoid receptor to the discovery of new pharmacologic compounds acting on this receptor. Current and planned studies in humans include compounds with effects ranging from direct antagonists to inhibitors of reuptake and breakdown. This progress has been accompanied by a much greater understanding of the role of the cannabinoid system in modulating the neural circuitry that mediates anxiety and fear responses. This review focuses on the neural circuitry and pharmacology of the cannabinoid system as it relates to the acquisition, expression, and extinction of conditioned fear as a model of human anxiety. Preclinical studies suggest that these may provide important emerging targets for new treatments of anxiety disorders.
Neuroanatomy for the 21st Century - Volume 12 Issue 3 - Michael Trimble
During the past 10 years, there has been a welcome influx of novel agents for the treatment of epilepsy. Many show advantages compared to older agents, including better adverse effect profiles and lack of drug-drug interactions. The sheer number of agents now available makes distinction among them confusing at times. Agents differ in spectrum of action, pharmacokinetic profile (affecting dosing schedule and drug interactions), and titration time. This review highlights the differences between the various new agents and the more traditional antiseizure drugs. Evidence for the widespread use of these compounds outside their indication, particularly for diseases other than epilepsy, is reviewed as well.
Elucidation of genetic factors in schizophrenia and bipolar disorder remains a challenging task to psychiatric researchers. As a rule, data from genetic linkage and association studies are quite controversial. In this article, we further explore the possibility that in addition to DNA sequences variation, a putative epigenetic dysregulation of brain genes plays an important role in the etiopathogenesis of major psychosis. We provide an epigenetic interpretation of unclear genetic findings specifically pertaining to chromosome 22 in schizophrenia and bipolar disorder. It is suggested that epigenetic strategies, when applied in conjunction with traditional genetic ones, may significantly expedite the uncovering of the molecular causes of major psychosis.
Monoamine oxidase inhibitors are well recognized as effective antidepressant agents but are rarely used due, in part, to the risk of hypertensive crisis following the ingestion of foods high in tyramine ("cheese reaction"). A selegiline transdermal system (STS) was developed to provide antidepressant concentrations of selegiline in the brain, while preserving the gastrointestinal monoamine oxidase A (MAO-A) barrier. The present study was conducted to determine the effect of the STS 6 mg/24 hour on cardiovascular safety following the ingestion of approximately 400 mg of tyramine consumed as a component of aged cheeses. In this open-label, single-center phase I study, cardiovascular vital signs were recorded following tyramine challenges during placebo and STS 6 mg/24 hr treatment. Subjects were observed for clinical signs and symptoms of a pressor response and/or potential hypertensive crisis during and following the challenges. Ingestion of tyramine-enriched meals following 13 consecutive days of treatment with the STS 6 mg/24 hr (pharmacokinetic steady-state) produced no clinically significant changes in cardiovascular vital signs in 12 healthy adult male subjects. No evidence of a tyramine pressor effect on systolic blood pressure or evidence of hypertensive crisis occurred during the STS treatment. These results suggest that STS 6 mg/24 hr may be administered without concern for dietary tyramine consumption.
Issue: Many individuals with total blindness can develop a circadian rhythm disorder-called non-24 sleep wake syndrome-because they cannot detect light to resynchronize their sleep-wake cycles. A new melatonin 1 and melatonin 2 agonist tasimelteon improves sleep in these patients, resetting their circadian sleep-wake clocks.
Neural mechanisms underlying the regulation of ingestive behavior and energy balance are well conserved among mammals. Many neural pathways, each reflecting the function of many genes, interact to regulate these processes. Systematic genetic perturbations are not feasible in humans--the examination of gene functions relevant to feeding regulation must be performed in other species. Many advances in this field have been made through molecular genetic studies of mice, the most genetically tractable of mammalian species. The relevance of mouse ingestive behavior to the mechanisms underlying the regulation of feeding in humans is discussed. Approaches for evaluating the contributions of genes to the regulation of energy balance and to the actions of anorectic drugs are described in the context of studies focused on a line of mice lacking the serotonin 5-HT2C receptor subtype. These animal display reduced responsiveness to serotonergic anorexic drugs and a late-onset obesity syndrome associated with features reminiscent of common forms of human obesity. Developmental studies of energy balance uncovered a novel age-dependent physiological process that may contribute generally to the predisposition of humans and other mammals to accumulate fat stores during "middle-age." These findings are presented to illustrate considerations in the use of mouse molecular genetic technologies to investigate genetic influences on ingestive behavior and energy balance.
Scientific literature has never described a poor metabolizer for both the cytochrome P450 (CYP) 2D6 and the CYP 2C19. They are expected to be rare (<1% in different ethnic groups) and prone to adverse drug reactions with many antidepressants. In an ongoing pharmacogenetic study, after genotyping 1,576 subjects in three Kentucky state hospitals we have found one poor metabolizer for both CYP 2D6 and CYP 2C19, which corresponds to a prevalence of 0.06% (95% CI 0.01 to 0.36). The naturalistic antidepressant treatment of this poor metabolizer for both enzymes is described in this article. As genotyping reaches clinical practice, it will be interesting to prospectively establish whether mirtazapine is a reasonable choice as an antidepressant for these patients, as the data and this case suggest.
Substantial evidence suggests that alterations in noradrenergic function contribute to the cognitive impairments of schizophrenia. Activation of post-junctional alpha 2a-adrenergic receptors in the prefrontal cortex by the alpha 2a-selective agonist guanfacine has demonstrated some preliminary benefit in subjects with schizophrenia treated with atypical antipsychotics. alpha 1-adrenergic receptor activity may be less important in mediating the cognitive impairments of schizophrenia. beta-adrenergic receptors may serve as another potential target for cognitive remediation in schizophrenia. However, the potential increase in memory consolidation in schizophrenia patients produced by beta-adrenergic agonists may be outweighed by the impairment in cognitive flexibility and executive functioning produced by beta-adrenergic agonists. Finally, norepinephrine reuptake inhibitors, such as atomoxetine, hold promise as potential cognitive enhancers in schizophrenia because of their ability to indirectly but selectively increase extracellular dopamine concentrations in the prefrontal cortex.
Mitochondria are intracellular organelles involved in adenosine triphosphate production. The literature has established the presence of mitochondrial dysfunction in some subjects with psychiatric disorders. Also, there are multiple reports of patients with mitochondrial dysfunction who have various psychiatric disorders. Although the literature on mitochondrial dysfunction and its relation to psychiatric disorders is growing, there remain many unanswered questions. To review subjects with mitochondrial cytopathies for prevalence of psychiatric comorbidity. For this study, 36 adults were interviewed. The Mini International Neuropsychiatric Interview and the Short-Form 36 Health Survey, version 1 were used. Lifetime diagnoses included 54% major depressive disorder, 17% bipolar disorder, and 11% panic disorder. These prevalence rates are compared with the general population and subjects with cancer and epilepsy. Subjects with a comorbid psychiatric diagnosis were older (P=.05), had more hospital admissions (P=.02), more medical conditions (P=.01), and lower quality of life (P=.01) than subjects with mitochondrial disease alone. Clinicians caring for persons with mitochondrial cytopathies should note the high prevalence of psychiatric problems. Also, this comorbidity might have etiological and therapeutic implications.
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 heterogeneous 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. 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 homogeneous group of drug-naive first-episode schizophrenic patients in a longitudinal setting. 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-naive, 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. The patients showed considerable cognitive deficits when drug-naive. 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. 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-naive schizophrenia patients after 3 months of medication, because neither could be distinguished from retest effects of the healthy control group.
Deep brain stimulation (DBS) is established as a therapy for movement disorders, and it is an investigational treatment in other neurologic conditions. DBS precisely targets neuroanatomical targets deep within the brain that are proposed to be centrally involved in the pathophysiology of some neuropsychiatric illnesses. DBS is nonablative, offering the advantages of reversibility and adjustability. This might permit therapeutic effectiveness to be enhanced or side effects to be minimized. Preclinical and clinical studies have shown effects of DBS locally, at the stimulation target, and at a distance, via actions on fibers of passage or across synapses. Although its mechanisms of action are not fully elucidated, several effects have been proposed to underlie the therapeutic effects of DBS in movement disorders, and potentially in other conditions as well. The mechanisms of action of DBS are the focus of active investigation in a number of clinical and preclinical laboratories. As in severe movement disorders, DBS may offer a degree of hope for patients with intractable neuropsychiatric illness. It is already clear that research intended to realize this potential will require a very considerable commitment of resources, energy, and time across disciplines including psychiatry, neurosurgery neurology, neuropsychology, bioengineering, and bioethics. These investigations should proceed cautiously.
Icon of vortioxetine showing its 6 pharmacologic mechanisms. Highlighted here are the 5 actions principally linked to regulation of serotonin (5HT) release, namely serotonin transporter (SERT) inhibition; 5HT1A agonism; 5HT1B partial agonism; and 5HT1D and 5HT7 antagonism. 
Vortioxetine is an antidepressant that targets multiple pharmacologic modes of action at sites-or nodes-where serotonergic neurons connect to various brain circuits. These multimodal pharmacologic actions of vortioxetine lead to enhanced release of various neurotransmitters, including serotonin, at various nodes within neuronal networks.
Array CGH image showing the breakpoint of the deletion on the short arm of chromosome 12, just proximal to gene CD9 *
Genetic factors are known to contribute to the development of schizophrenia and related psychoses. Cytogenetic abnormalities have been occasionally found in patients with psychotic disorders and, thus, have helped identify candidate gene contributors for these conditions. The individual described here first presented with mental retardation and anxiety disorder in his mid-childhood. In his early 20s, the patient started exhibiting various psychotic manifestations, including delusions and hallucinations. His psychotic symptoms were difficult to control with psychotropic medications. The family history was negative for psychiatric disorders. This patient was found to have a 6.2 megabase deletion of the terminal portion of the short arm of chromosome 12 that was characterized using fluorescence in situ hybridization and microarray comparative genomic hybridization analysis. The maternal chromosomes were normal, but the paternal chromosomes could not be tested. To-date such a chromosomal abnormality has not been described in association with schizophrenia/psychosis. This case suggests that psychosis-associated gene(s) may be located in the terminal region of the short arm of chromosome 12.
This study was conducted to describe Axis I sexual diagnoses of 60 males arrested for possession of child pornography obtained via the Internet and/or attempting to meet children via the Internet. Data was obtained from a chart review of evaluations conducted on 60 males referred for a psychosexual evaluation following an arrest for possession of child pornography and/or attempting to meet children. All crimes involved use of the Internet. Information obtained from the chart review was entered into SAS. All diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Simple descriptive statistics were computed and cross tabulations were tested for significance using chi2 or Fisher's Exact test. Of the total sample, 40% had at least one paraphilia. Thirty-one percent had a diagnosis of pedophilia and 18% of a paraphilia not otherwise specified (NOS). Thirty-three percent had a sexual disorder NOS, characterized by hypersexuality. Seventy percent of the total sample had an Axis I disorder that antedated and was judged to be contributory to the behavior leading to their arrest. This sample of men arrested for committing crimes against children and adolescents via the Internet has a high incidence of lifetime sexual and other psychopathology.
Norepinephrine and epinephrine are involved in the control of several important functions of the central nervous system (CNS), including sleep, arousal, mood, appetite, and autonomic outflow. Catecholamines control these functions through activation of a family of adrenergic receptors (ARs). The ARs are divided into three subfamilies (alpha1, alpha2, and beta) based on their pharmacologic properties, signaling mechanisms, and structure. ARs in the CNS are targets for several therapeutic agents used in the treatment of depression, obesity, hypertension, and other diseases. Not much is known, however, about the role of specific AR subtypes in the actions of these drugs. In this paper, we provide an overview of adrenergic pharmacology in the CNS, focusing on the pharmacologic properties of subtype-selective AR agonists and antagonists, the accessibility of these drugs to the CNS, and the distribution of ARs in different areas of the brain.
Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. PTSD is disabling and commonly follows a chronic course. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. A twin study of Vietnam veterans has shown significant genetic contribution to PTSD. The fact that PTSD's underlying genotypic vulnerability is only expressed following trauma exposure limits the usefulness of family-based linkage approaches. In contrast to the other major psychiatric disorders, large studies for the search of underlying genes have not been described in PTSD to date. Complementary approaches for locating involved genes include association-based studies employing case-control or parental genotypes for transmission dysequilibrium analysis and quantitative trait loci studies in animal models. Identification of susceptibility genes will increase our understanding of traumatic stress disorders and help to elucidate their molecular basis. The current review provides an up-to-date outline of progress in the field of PTSD.
Objective: We sought to determine attitudes toward patients with borderline personality disorder (BPD) among mental health clinicians at nine academic centers in the United States. Methods: A self-report questionnaire was distributed to 706 mental health clinicians, including psychiatrists, psychiatry residents, social workers, nurses, and psychologists. Results: The study showed that most clinicians consider BPD a valid diagnosis, although nearly half reported that they preferred to avoid these patients. The clinician's occupational subgroup was significantly related to attitude. Staff nurses had the lowest self-ratings on overall caring attitudes, while social workers had the highest. Social workers and psychiatrists had the highest ratings on treatment optimism. Social workers and psychologists were most optimistic about psychotherapy effectiveness, while psychiatrists were most optimistic about medication effectiveness. Staff nurses had the lowest self-ratings on empathy toward patients with BPD and treatment optimism.DiscussionNegative attitudes persist among clinicians toward BPD, but differ among occupational subgroups. Overall, caring attitudes, empathy, and treatment optimism were all higher among care providers who had cared for a greater number of BPD patients in the past 12 months. Conclusion: These findings hold important implications for clinician education and coordination of care for patients with BPD.
Top-cited authors
Dan J. Stein
  • University of Cape Town
Eric Hollander
  • Montefiore Medical Center
Stephen Stahl
  • University of California, San Diego
Donatella Marazziti
  • Università di Pisa
Marc Potenza
  • Yale University