The expression of cytokines and chemokines in the blood of patients with severe weight loss from anorexia nervosa: an exploratory study.

Anorexia nervosa (AN) is a serious, potentially life-threatening disorder characterized by severe weight loss, dysregulated eating, and often excessive exercise. While psychiatric illnesses such as depression are associated with increased levels of pro-inflammatory mediators, evidence for such disturbances in patients with AN has been less clear. In an exploratory study of possible disturbances in immune responses in AN, we assayed a panel of cytokines and chemokines in the blood of patients undergoing inpatient treatment, testing the hypothesis that metabolic disturbances in this disease would lead to a pattern of immune disturbances distinct from that of other psychiatric diseases. For this purpose, we evaluated patients by the Beck Depression Inventory-II (BDI-II) and the Eating Disorders Examination-Questionnaire and assessed cytokines and chemokines by enzyme-linked immunosorbent assays. Patients reported a moderate level of depression (mean BDI-II = 22.6) but exhibited few immunologic abnormalities of the kind associated with major depressive disorder [e.g., increased interleukin (IL)-6]; RANTES showed the most frequent elevations and was increased in 4 of the patients studied. Together, these findings suggest that features of AN such as loss of adipose tissue and excessive exercise may attenuate cytokine production and thus modulate the experience of illness that impacts on core features of disease.

Remission, continuation and incidence of eating disorders during early pregnancy: a validation study in a population-based birth cohort.

BACKGROUND: We internally validated previously published rates of remission, continuation and incidence of broadly defined eating disorders during pregnancy in the Norwegian Mother and Child Cohort (MoBa) at the Norwegian Institute of Public Health. METHOD: A total of 77 267 pregnant women enrolled at 17 weeks gestation between 2001 and 2009 were split into a training sample (n = 41 243) from the version 2 dataset and a validation sample (n = 36 024) from the version 5 dataset who were not in the original study. Internal validation of original rate models involved fitting a calibration model to compare model parameters between the two samples and bootstrap estimates of bias in the entire version 5 dataset. RESULTS: Remission, continuation and incidence estimates remained stable. Pre-pregnancy prevalence estimates in the validation sample were: anorexia nervosa (AN; 0.1%), bulimia nervosa (BN; 1.0%), binge eating disorder (BED; 3.3%) and eating disorder not otherwise specified-purging disorder (EDNOS-P; 0.1%). In early pregnancy, estimates were: BN (0.2%), BED (4.8%) and EDNOS-P (<0.01%). Incident BN and EDNOS-P during pregnancy were rare. The highest rates were for full or partial remission for BN and EDNOS-P and continuation for BED. CONCLUSIONS: We validated previously estimated rates of remission, continuation and incidence of eating disorders during pregnancy. Eating disorders, especially BED, during pregnancy were relatively common, occurring in nearly one in every 20 women. Pregnancy was a window of remission from BN but a window of vulnerability for BED. Training to detect eating disorders by obstetricians/gynecologists and interventions to enhance pregnancy and neonatal outcomes warrant attention.

Patterns and prevalence of disordered eating and weight control behaviors in women ages 25-45.

OBJECTIVE: The current study describes detailed eating behaviors, dieting behaviors, and attitudes about shape and weight in 4023 women ages 25 to 45. METHOD: The survey was delivered on-line and participants were identified using a national quota-sampling procedure. RESULTS: Disordered eating behaviors, extreme weight loss measures, and negative cognitions about shape and weight were widely endorsed by women in this age group and were not limited to White participants. Thirty-one percent of women without a history of anorexia nervosa or binge eating reported having purged to control weight, and 74.5% of women reported that their concerns about shape and weight interfered with their happiness. DISCUSSION: Unhealthy approaches to weight control and negative attitudes about shape and weight are pervasive even among women without eating disorders. The development of effective approaches to address the impact of these unhealthy behaviors and attitudes on the general well-being and functioning of women is required.

Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood.

Previous studies of postnatal synaptic development in human frontal cortex have shown that synaptic density rises after birth, reaches a plateau in childhood and then decreases to adult levels by late adolescence. A similar pattern has been seen in nonhuman primate cortex. These earlier studies in human cortex are limited, however, by significant age gaps in study subjects at critical inflection points of the developmental curve. Additionally, it is unclear if synaptic development occurs in different patterns in different cortical layers in prefrontal cortex (PFC). The purpose of this study was to examine synaptic density in human PFC across development by measuring two synaptic marker proteins: synaptophysin (presynaptic), and postsynaptic density protein 95 (PSD-95; postsynaptic). Western blotting was used to assess the relative levels of synaptophysin and PSD-95 in dorsolateral PFC of 42 subjects, distributed in age from 18 weeks gestation to 25 years. In addition, synaptophysin immunoreactivity was examined in each layer of areas 9 and 46 of PFC in 24 subjects, ranging in age from 0.1-25 years. Synaptophysin levels slowly increased from birth until age 5 and then increased more rapidly to peak in late childhood around age 10. Synaptophysin subsequently decreased until the adult level was reached by mid-adolescence, around age 16. PSD-95 levels increased postnatally to reach a stable plateau by early childhood with a slight reduction in late adolescence and early adulthood. The pattern of synaptophysin immunoreactivity seen with immunohistochemistry was similar to the Western experiments but the changes across age were more subtle, with little change by layer within and across age. The developmental patterns exhibited by these synaptic marker proteins expand upon previous studies of developmental synaptic changes in human frontal cortex; synaptic density increases steadily from birth to late childhood, then decreases in early adolescence to reach adult levels by late adolescence.

Measuring brain volume by MR imaging: impact of measurement precision and natural variation on sample size requirements.

BACKGROUND AND PURPOSE: To determine the sample size needed to provide adequate statistical power in studies of brain volume by MR imaging, we examined the precision and variability of measurements in healthy controls. MATERIALS AND METHODS: A cohort of 52 people (mean age, 25.1 years) was examined at weeks 0 and 12 at 1.5 T. We used an axial multisection T1-weighted sequence and a contiguous proton-attenuation/T2-weighted sequence. Data were registered to a probabilistic brain atlas, and an automated atlas-based program was used to segment brain tissue by type and by lobe. We assumed that there were no changes in volume because there were no intervening neurologic events. Sample sizes required to yield 80% statistical power in detecting a significant difference in volume were calculated for various experimental designs, assuming a patient-control volume difference of 5% or 2%. RESULTS: The precision of most measurements was excellent, but required sample sizes were larger than anticipated. If the goal was to detect a 5% difference in whole brain volume in a 2-sample cross-sectional study, the required sample was 73 patients and 73 controls because brain volume varies between individuals in a way that is not informative about disease effects. For a similar 2-sample longitudinal study, the required sample size was just 5 patients and 5 controls. CONCLUSIONS: Our results argue strongly for longitudinal studies in preference to cross-sectional studies, especially as research budgets decline. Our findings also suggest that there may be more uncertainty than expected in published MR imaging brain volume studies.

Early postnatal development of corpus callosum and corticospinal white matter assessed with quantitative tractography.

BACKGROUND AND PURPOSE: The early postnatal period is perhaps the most dynamic phase of white matter development. We hypothesized that the early postnatal development of the corpus callosum and corticospinal tracts could be studied in unsedated healthy neonates by using novel approaches to diffusion tensor imaging (DTI) and quantitative tractography. MATERIALS AND METHODS: Isotropic 2 x 2 x 2 mm(3) DTI and structural images were acquired from 47 healthy neonates. DTI and structural images were coregistered and fractional anisotropy (FA), mean diffusivity (MD), and normalized T1-weighted (T1W) and T2-weighted (T2W) signal intensities were determined in central midline and peripheral cortical regions of the white matter tracts of the genu and splenium of the corpus callosum and the central midbrain and peripheral cortical regions of the corticospinal tracts by using quantitative tractography. RESULTS: We observed that central regions exhibited lower MD, higher FA values, higher T1W intensity, and lower T2W intensity than peripheral cortical regions. As expected, MD decreased, FA increased, and T2W signal intensity decreased with increasing age in the genu and corticospinal tract, whereas there was no significant change in T1W signal intensity. The central midline region of the splenium fiber tract has a unique pattern, with no change in MD, FA, or T2W signal intensity with age, suggesting different growth trajectory compared with the other tracts. FA seems to be more dependent on tract organization, whereas MD seems to be more sensitive to myelination. CONCLUSIONS: Our novel approach may detect small regional differences and age-related changes in the corpus callosum and corticospinal white matter tracts in unsedated healthy neonates and may be used for future studies of pediatric brain disorders that affect developing white matter.

Limited influence of olanzapine on adult forebrain neural precursors in vitro.

We evaluated the activity of the atypical antipsychotic drug olanzapine on differentiation and gene expression in adult neural precursor cells in vitro. Neural precursors obtained from forebrain subventricular zone (SVZ)-derived neurospheres express a subset (13/24) of receptors known to bind olanzapine at high to intermediate affinities; in contrast, all 24 are expressed in the SVZ. In the presence of 10 nM, 100 nM or 1 microM olanzapine, there is no significant change in the frequency of oligodendrocytes, neurons, GABAergic neurons and astrocytes generated from neurosphere precursors. In parallel, there is no apparent change in cell proliferation in response to olanzapine, based upon bromodeoxyuridine incorporation. There are no major changes in cytological differentiation in response to the drug; however, at one concentration (10 nM) there is a small but statistically significant increase in the size of glial fibrillary acidic protein-labeled astrocytes derived from neurosphere precursors. In addition, olanzapine apparently modulates expression of one serotonin receptor -- 5HT2A -- in differentiating neurosphere cultures; however, it does not modify expression of several other receptors or schizophrenia vulnerability genes. Thus, olanzapine has a limited influence on differentiation and gene expression in adult neural precursor cells in vitro.

Olanzapine and haloperidol in first episode psychosis: two-year data.

Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.

Borderline and schizotypal personality disorders treated with low-dose thiothixene vs placebo.

Fifty outpatients with borderline and/or schizotypal personality disorder were randomly allocated to thiothixene (Navane) or placebo treatment that was continued for 12 weeks. The mean daily dosage of thiothixene hydrochloride in the final week of the study was 8.7 mg, a lower dosage than is used in outpatient schizophrenics. Significant drug-placebo differences were found, regardless of diagnosis, on "illusions," "ideas of reference," "psychoticism," "obsessive-compulsive symptoms," and "phobic anxiety," but not on "depression." Thiothixene seems to have more than an antipsychotic effect. Since response to treatment studies are a means for reformulating diagnostic concepts, we suggest a subdiagnosis defined by those symptoms that are drug-responsive, some of which are not included in current diagnostic criteria. Patients with borderline and schizotypal disorder without the foregoing symptoms probably would not profit from thiothixene and might needlessly be placed at risk for adverse drug effects.

The neuroendocrine and behavioral response to dextroamphetamine in normal individuals.

Dextroamphetamine 30 mg and placebo were administered by mouth in a double-blind randomized cross-over trial to ten subjects. Behavior was assessed and blood samples analyzed for growth hormone (GH), prolactin (PRL), homovanillic acid (HVA), and amphetamine. There was a statistically significant increase in well-being following d-amphetamine as compared to baseline and placebo on both the Amphetamine Interview Rating Scale and the Hopkins Mood Scale. No subject became psychotic. There was a statistically significant increase in GH from baseline to peak following d-amphetamine ingestion. When compared to placebo, the increase in GH was invariable and statistically significant for the 90-min sampling. PRL decreased from baseline following both d-amphetamine and placebo and there was no significant drug-placebo difference. Serum HVA was measured at baseline and 120 min, for eight subjects. Six subjects had an increase in HVA following d-amphetamine but there was no significant drug effect.

Amphetamine challenge test, response to treatment, and lateral ventricle size in schizophrenia.

The hypothesis of two independent pathologies in schizophrenia proposed by Crow (1980) were tested. Two dimensions of the dopamine variable, namely, the behavioral response during the Amphetamine Challenge Test (ACT) and the response to neuroleptic treatment, were studied in a cohort of 19 subjects with a research diagnosis of schizophrenia (n = 18) or schizoaffective disorder (n = 1) in an acute inpatient setting. The size of the lateral ventricle was assessed by mesauring the ventricle-brain ratio (VBR) on the computerized tomographic brain scan. Patients who had greater symptom reduction with the neuroleptic treatment worsened more in their positive psychotic symptoms during the ACT. Those with larger VBRs showed less treatment responsiveness and no worsening during the ACT. The findings are supportive of Crow's hypothesis. The ACT has the potential to be an index of both Type I and Type II pathologies.

Effects of buspirone and alprazolam on the cognitive performance of normal elderly subjects.

OBJECTIVE: To increase understanding of the potential in elderly persons for disability related to behavioral side effects of anxiolytic medications, cognitive and psychomotor effects of clinical doses of buspirone and a popular intermediate-acting benzodiazepine, alprazolam, were examined in carefully screened, healthy elderly subjects. METHOD: Sixty subjects recruited through community organizations and newspaper advertisements and screened on the basis of history, physical examination, and laboratory studies were randomly assigned to one of three drug treatment groups. After 2 days of washout placebo, subjects were given 0.25 mg t.i.d. of alprazolam, 5 mg t.i.d. of buspirone, or placebo three times a day for a total of 14 days in a double-blind design. Behavioral assessments were completed beginning 1 hour after ingestion of medication on the second washout placebo day, day 1 of the treatment period, and day 14 of the treatment period. Tests included the continuous performance test, recall memory for word lists, digit-symbol substitution, retention of pictorial stimuli over 1 hour, the Profile of Mood States, and subjective ratings of mental status. RESULTS: Buspirone did not affect reaction time, vigilance, psychomotor speed, or memory function. Alprazolam had minimal effects on vigilance, psychomotor speed, and memory on the first treatment day and had no effects after repeated doses. CONCLUSIONS: Buspirone did not produce behavioral side effects that could lead to disability, and alprazolam had minimal side effects. Because the patients were carefully screened, it is unclear whether these medications in the doses used would have more side effects in less healthy elderly patients.

Relation of psychopathology in general medical inpatients to use and cost of services.

The authors investigated the relation between psychopathology in medically ill inpatients and use and cost of medical care services. Of 455 medical inpatients, the Medical Inpatient Screening Test identified 27.9% as very depressed, 27.5% as very anxious, 20.2% as having cognitive dysfunction, and 8.6% as having high pain levels. Overall, the test identified 51% of the patients as having high levels of psychopathology or pain. These subjects had a 40% longer median length of hospital stay and 35% greater mean hospital costs than those with low levels of psychopathology or pain. Patients with greater psychopathology also had higher hospital charges, more procedures during hospitalization, and more discharge diagnoses but did not differ from the other patients in sex, race, age, diagnosis-related group (DRG) major diagnostic category, or DRG weight.

A randomized controlled study of psychiatric consultation guided by screening in general medical inpatients.

OBJECTIVE: The purpose of the study was to test the hypothesis that psychiatric consultation would reduce health care utilization during and after medical hospitalization. METHOD: A randomized, double-controlled clinical trial of psychiatric consultation was conducted on the general medical inpatient services of a university hospital. After meeting inclusion criteria, 1,541 patients were screened for depression, anxiety, confusion, and pain over a period of 21 months. The 741 patients with high levels of psychopathology or pain were subdivided into baseline control subjects (N = 232), contemporaneous control subjects (N = 253), and an experimental consultation group (N = 256). The major outcome measures were length of hospital stay and hospital costs. Secondary outcome measures were posthospital health status, rehospitalization rates, and use of outpatient medical care. RESULTS: This study did not demonstrate an effect of experimental psychiatric consultation on hospital resource use or posthospital medical care utilization after adjustment was made for disease severity. Hospital resource use decreased in the entire sample over the 21-month duration of the study. CONCLUSIONS: The brief, efficient screen for anxiety, depression, confusion, and pain identified a group of patients who also used more hospital resources, but a single experimental psychiatric consultation did not reduce costs. The double-controlled nature of the design proved essential to avoid being misled by background changes in hospital resource use.

Ventricular enlargement in teenage patients with schizophrenia spectrum disorder.

Recent research has demonstrated statistically significant differences between the ventricular-brain ratios (VBRs) of schizophrenic patients and control subjects. In this study the VBRs of teenage schizophrenic/schizophreniform patients (N = 15) and borderline patients (N = 8) were measured and compared with those of controls of similar ages (N = 18). The schizophrenic group had significantly larger ventricles than the other two groups (p less than .0001). These findings support the hypothesis of previous investigators that ventricular enlargement is present early in the course of schizophrenia.

Borderline personality disorder: symptomatology and MMPI characteristics.

Using the Schedule for Interviewing Borderlines and the MMPI, 20 subjects diagnosed as borderline and/or schizotypal personality disorder were examined to determine 1) whether having one diagnosis affected the likelihood of having the other, 2) the amount of diagnostic overlap between the two diagnoses, and 3) whether different MMPI profiles could be found. The results indicated some overlap but also some differentiation between the borderline and schizotypal disorders. The modest overlap in diagnostic criteria was consistent with other studies and justifies the continued separation of the two diagnoses. The MMPI may be used as an initial screen to identify persons who warrant further evaluation for a borderline personality disorder but would not be appropriate as a screen for a schizotypal personality disorder.

Who benefits from tricyclic antidepressants: a survey.

To determine what patients are likely to benefit from treatment with a tricyclic antidepressant, the authors surveyed American researchers, teachers of psychiatry, general psychiatric practitioners, and foreign researchers. Areas of agreement were appreciable and can serve as an index of accepted community practice and as guidelines for teaching. Responses indicated that patients most likely to benefit from a tricyclic antidepressant are those with primary depression; early morning awakening; motor retardation; loss of appetite; weight loss; prior positive response to a tricyclic antidepressant; loss of interest in work or hobbies; sad, blue, or depressed feelings; improved mood in evening; and loss of interest in sex. Amitriptyline was preferred for agitated depressions, and imipramine was preferred for retarded depressions.

Differences in CT findings within schizophrenics may be due to varying severity of the illness.

The authors investigated the importance of severity and duration of illness in schizophrenia with regard to findings on computerised tomographic (CT) scans. Two groups are compared, one from a state hospital's chronic ward and the other group from a university hospital. They provide evidence to propose increased ventricular size is an indicator of severity of illness.

Association of a serotonin transporter gene promoter polymorphism with harm avoidance behaviour in an elderly population.

A polymorphic 44-nucleotide insertion/deletion in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to affect the level of expression of the serotonin transporter protein. An association between anxiety-related behavioural traits and the short form of the 5-HTTLPR has been reported. We determined the 5-HTTLPR genotype in genomic DNA samples from 84 subjects (47 Parkinson's disease patients and 37 controls) with a mean age of 67.4 years. The TPQ of Cloninger was used to obtain values for harm avoidance (HA), reward dependence and novelty seeking for all subjects. Analysis of variance showed a significant influence of the s-allele of the 5-HTTLPR on HA in both subject groups, with no significant interaction between diagnosis and genotype. Subjects with the l/l-genotype had significantly lower mean HA scores than the l/s subjects (P < 0.04) and s/s subjects (P < 0.003). A linear change in HA with genotype was observed, indicating a gene dose effect of the 5-HTTLPR s-allele on this personality dimension. Based on these findings it is suggested that there may be increased influence of the 5-HTTLPR short allele on anxiety-related traits during aging.

Sildenafil effects on sexual and cardiovascular responses in women with spinal cord injury.

OBJECTIVES: Sexual dysfunction is common in women with spinal cord injuries (SCIs) and other neurologic conditions. Sildenafil has previously been shown to be safe and effective in the treatment of erectile dysfunction due to SCI. This study is the first to evaluate the sexual and cardiovascular effects of sildenafil in women with SCIs in a controlled, laboratory setting. METHODS: Nineteen premenopausal women with SCIs were randomly assigned to receive either sildenafil (50 mg) or placebo in a double-blind, crossover design study. Physiologic and subjective measures of sexual response, heart rate, and blood pressure were recorded during baseline and sexual stimulation conditions. Adverse events were also recorded. RESULTS: Significant increases in subjective arousal (SA) were observed with both drug (P <0.01) and sexual stimulation conditions (P <0.001), and a borderline significant (P <0.07) effect of drug administration on vaginal pulse amplitude (VPA) was noted. Maximal responses occurred when sildenafil was combined with visual and manual sexual stimulation. Cardiovascular data showed modest increases in heart rate (+/-5 bpm) and mild decreases in blood pressure (+/-4 mm Hg) across all stimulation conditions, consistent with the peripheral vasodilatory mechanism of the drug. Sildenafil was well tolerated with no evidence of significant adverse events. CONCLUSIONS: Findings suggest that sildenafil may partially reverse the sexual dysfunction commonly associated with SCI in women. Consistent with previous findings in men, the sexual effects of the drug were most evident under conditions of optimal stimulation. Mild, clinically insignificant cardiovascular effects were also noted. Further large-scale studies of sildenafil's effects in women with neurogenic sexual dysfunction are strongly indicated.