Journal of Psychiatric Research

The I1-imidazoline receptor is a novel brainstem modulator of sympathetic outflow that is elevated on platelets and in brains of depressed patients. A positive correlation has been reported (accompanying manuscript) between plasma norepinephrine (NE) concentrations and the densities (Bmax) of platelet I1 binding sites (I1 sites). I1-candidate proteins of 33 kDa and 85 kDa are now identified on Western blots probed with anti-imidazoline receptor antiserum (IRBP antiserum), that correlate with Bmax values for I1 sites. Furthermore, a human megakaryoblastoma cell line (MEG-01) has been used to study the regulation of these proteins on megakaryocytic cells, while bovine adrenal chromaffin cells provide a standard I1 cell type for comparison. Both the 33 kDa and 85 kDa IRBP-immunoreactive bands were enriched in plasma membrane fractions. IRBP antiserum did not cross-react with I2 imidazoline binding sites located on platelet mitochondrial membranes. The 85 kDa band was enhanced under conditions lacking fetal bovine serum (FBS) from the culture medium 6 h prior to harvesting. Conversely, 33 kDa protein was enhanced on MEG-01 cells grown in the presence of 10% FBS; suggesting that a precursor (85 kDa) and product (33 kDa) relationship might be induced by serum. The 85 kDa band was robustly up-regulated in response to imidazoline receptor-sensitive ligands; moxonidine, idazoxan and agmatine (10 microM each for 6 h). NE also up-regulated the 85 kDa IRBP-immunoreactive protein on MEG-01 membranes, but to a lesser extent. Idazoxan, an imidazoline alpha 2-antagonist, off-set its induction of 85 kDa protein by reducing the 33 kDa band. Yohimbine, a non-imidazoline alpha 2-antagonist, was ineffective alone, or in combination with moxonidine (up to 40 microM), but yohimbine blocked NE's induction of the 85 kDa band. Therefore, a rise in either plasma NE and/or endogenous I-site ligands (i.e. agmatine) could explain an elevation of imidazoline receptors observed in depression.

Major depression is a common mental health problem and associated with significant morbidity and mortality, including impaired social and physical functioning and increased risk for suicide. Electroconvulsive therapy (ECT) is highly efficacious in treatment-resistant depressive disorders, but cognitive side effects are frequently associated with the treatment. Magnetic seizure therapy (MST) is a form of convulsive therapy, using magnetic fields in order to induce therapeutic seizures. First studies suggested that cognitive side effects of MST, including postictal recovery time, are more benign than those resulting from ECT treatment. In this open-label study we tested the hypothesis that MST is associated with clinically significant antidepressant effects in treatment-resistant depression (TRD) as an add-on therapy to a controlled pharmacotherapy. Twenty patients suffering from TRD were randomly assigned to receive either MST or ECT starting from July 2006 until November 2008. Primary outcome measure was antidepressant response assessed by Montgomery Åsberg Depression Scale. Secondary outcome measures included Hamilton Depression Rating Scale, Hamilton Anxiety Scale, Beck Depression Inventory and 90-Item Symptom Checklist. Antidepressant response (improvement of 50% in MADRS ratings) was statistically significant and of similar size in both treatment groups. Cognitive side effects were observed in neither group. Characteristics in MST- and ECT-induced seizures were comparable, especially regarding ictal activity and postictal suppression. Thus, MST may be a potential alternative to ECT if efficacy and safety are validated in larger clinical trials.

Current knowledge on behavioural patterns and personal characteristics of subjects who choose the railway as means of suicide is sparse. The aim of this study was to determine the frequency of three distinct behaviour patterns (jumping, lying, wandering) in railway suicides and to explore associated variables. Cases were derived from the National Central Registry of person accidents on the German railway net covering the period from 2002 to 2006. A retrospective analysis of registry protocols of all 4127 suicidal acts allowed classification of behaviour patterns in 1004 cases. Types of suicidal behaviour occurred with nearly equal frequencies; jumping in 32.2%, lying in 32.6% and wandering in 34.2% of cases. Age and sex were not associated with type of suicidal behaviour. The proportion of jumping was highest during 9:01 am to 6:00 pm while at night, lying was used most frequently. Jumping predominated in the station area, while lying and wandering on the open track. Fatality was highest in liers and lowest in jumpers. The frequency of jumping decreased during the study period by 12.6% (p < .05). These findings may help to elucidate differential risk features of this highly lethal suicide method.

Myo-inositol (mI) as a precursor in the phosphatidylinositol second messenger system has been reported to be reduced in depression. By means of proton-magnetic resonance spectroscopy (1H-MRS) the mI levels in the frontal brain were investigated in vivo in the present study. Twenty-two patients (mean age: 42.8 +/- 10.7 years) with depressive episodes according to ICD 10 (HAMD score > 17) were compared to 22 healthy subjects (28.0 +/- 5.3 years). Two voxels (30 x 20 x 20 mm3) in the frontal lobes were examined in a Siemens Magnetom SP 4000 at 1.5 T (STEAM sequence: TR = 3500 ms, TE = 55 ms). With the total creatine (Cr) as an internal standard, mI/Cr ratios were calculated to follow the mI levels. In the left frontal lobe, mI/Cr was 0.43 +/- 0.06 in depressive patients and 0.46 +/- 0.07 in healthy subjects; concerning the right frontal lobe, mI/Cr was 0.46 +/- 0.08 and 0.48 +/- 0.06, respectively. There were neither significant differences between the two groups nor between the hemispheres. Since there was a significant positive correlation (R = 0.6) between the age and the mI/Cr in the right frontal lobe of depressed patients, age matched pairs analysis was performed (n = 2 x 10, in each group: nine females, one male, < 40 years). In the right frontal lobe, the patients' mI/Cr of 0.40 +/- 0.05 was now significantly lower than the controls' mI/Cr of 0.45 +/- 0.06. However, most of the patients were on antidepressive medication. Interestingly, it was exactly this group of patients which showed significantly lower mI levels. We regard our investigation as a pilot study which suggests an influence of age and antidepressants on mI levels and should be taken into consideration in further investigations in depressive patients.

The effect of type of depressive disorder on mortality has been rarely addressed in the relevant literature. It is especially true in considering comorbid disorders and by population-based longitudinal cohort sample. The aims of this study are to compare all-cause and unnatural (suicides and accidents) mortality rates between subjects with bipolar depression (BD) and those with other types of depression (OTD). A cohort of patients diagnosed as clinically depressed between 1999 and 2004 according to the National Health Insurance Dataset (NHID) were followed until the end of 2008. The occurrence of death was identified by the National Mortality Registry (NMR) in Taiwan. Patients in this cohort were further classified into BD and OTD groups. Proportional hazards regression model were used to evaluate the different mortality risks between two groups. BD (n = 1542) was associated with a significantly greater risk in all-cause mortality (adjusted hazard ratio = 1.3, 95% CI: 1.1, 1.5) than was OTD (n = 17,480), even after controlling for demographic features and comorbid disorders. BD was associated with approximately twice the risk for suicide and accidental death compared with OTD after other variables were held constant. Bipolar depression (v.s. OTD) exerted adjusted hazard ratio 3.76 (95% CI: 2.17, 6.51) in depressed patients with CVD but only aHR 1.43 (95% CI: 0.79, 2.58) in those without CVD. Compared with OTD, BD was related to a significantly increased risk for all-cause mortality, suicide, and accidental death. Under the comorbidity with CVD, the risk of suicide was 4-fold times more likely in BD than in OTD. This magnitude of suicide risk among BD patients comorbid with CVD was also higher than those BD without CVD. Thus, patients with both BD and CVD may constitute one of groups at highest risk for suicide and accidental death.

Body image disturbance (BID) among men has only recently become a phenomenon of clinical significance with noted heterogeneity in the behavioral consequences of these disturbances. The degree of heterogeneity among appearance and performance enhancing drug (APED) users is unknown and an empirically derived framework for studying BID is necessary. APED users (N=1000) were recruited via the Internet and they completed a comprehensive online assessment APED use patterns, motivations, consequences, and BID. Data were evaluated using latent trait, latent class, and factor mixture models. Model results were validated using a range of covariates including cycle characteristics, age, APED history, and APED risk. A 1-Factor, 4-Class model provided the best fit to the data with Class 1 scoring the highest on all measures of BID and Class 4 the lowest on all measures. Class 2 differed in their preference for being lean over muscular and Class 3 preferred adding mass and size. Each class was associated with unique risks, APED history, and training identity. Not all APED users suffer from significant BID and there are unique profiles for those with elevated BID. Future research on male BID should account for this structure in order to better define relevant diagnostic categories and evaluate the clinical significance of BID.

Suicide is an act deliberately initiated and performed by a person with full knowledge that a fatal outcome is probable. The serotonin 2A (5-HT2A) receptor gene has been implicated in the pathogenesis of suicidal behaviour by a genetic association between the 5-HT2A T102C silent polymorphism and suicidality in patients with mood disorders and schizophrenia. However, a recent meta-analysis failed to confirm this association. We developed an improved quantitative assay for the measurement of allele-specific methylation of the 5-HT2A gene, and found that the methylation of the C allele in the pre-frontal cortex of heterozygous suicide victims (n=10) was not significantly different in comparison with the non-suicide group (n=10) (p=0.084). We also analyzed methylation of the C allele in white blood cell DNA from bipolar and schizophrenic attempters and found a significant difference in the schizophrenic attempters (p=0.00013) but not in the bipolar attempters (p=0.616). Because the 5-HT2A gene is subject to imprinting, the parent-of-origin may affect inheritance of suicidal behaviour. Thus, we examined the parental origin of specific alleles for genetic association in a genetic family-based sample of major psychoses in which information on suicidal behaviour was available. This result suggests that methylation of the 102C allele does not influence completed suicide.

Studies examining the relationship between maternal smoking during pregnancy and the development of Attention Deficit Hyperactivity Disorder (ADHD) among offspring have yielded mixed results, with some studies suggesting a strong association and others finding no association. These studies have varied in quality of design and measures. The purpose of this study was to evaluate the association between maternal smoking during pregnancy and offspring ADHD, using detailed prospective smoking data and subsequent follow-up data from the Collaborative Perinatal Project (CPP). Maternal smoking status was collected throughout pregnancy during the original CPP study. Offspring were followed-up in early adulthood and questioned about ADHD symptoms and diagnosis. Logistic regression was used to model the association between maternal smoking during pregnancy and ADHD. Linear and logistic regression were used to examine clinical characteristics and remission rates associated with ADHD in relation to maternal smoking. No association was found between maternal smoking during pregnancy and offspring ADHD. Further, no differences in age of onset, number of symptoms, or likelihood of remission were found among ADHD subjects with and without a history of maternal smoking during pregnancy. These findings do not support the hypothesis that maternal smoking during pregnancy is causally related to ADHD. Ongoing research should continue to strive to identify those environmental or genetic factors that may enhance the impact of maternal smoking on ADHD or that may be associated more clearly with the development and potential prevention of ADHD.

Individuals exposed to psychological stressors may experience a long-term resetting of behavioral and neuroendocrine aspects of their "stress response" so that they either hyper or hypo-respond to subsequent stressors. These effects of psychological or traumatic stressors may be mimicked in rats using the resident-intruder model of social defeat. The social defeat model has been characterized to model aspects of the physiology and behavior associated with anxiety and depression. The objective of this study was to determine if behaviors elicited following repeated social defeat can also reflect aspects of ethologically relevant stresses associated with existing post traumatic stress disorder (PTSD) models. Socially defeated rats displayed weight loss and an enhanced and prolonged response to acoustic startle which was displayed for up to 10days following repeated social defeat. These data indicate that the severe stress of social defeat can produce physiologic and behavioral outcomes which may reflect aspects of traumatic psychosocial stress.

We used a purpose-designed questionnaire to survey the prevalence of binge-eating and bulimia in a sample of 1063 Dublin third-level students aged 17-25 yr. There were 361 males and 701 females. The questionnaire was based on DSM-III, and included a written definition of a binge and cross-check questions. Although 17.7% of males and 37% of females claimed to have had an eating binge, cross-check items reduced this to 1.1% of males and 10.8% of females who met the DSM-III definition. No male and only 7.7% of females also met the behavioural criteria under item B of DSM-III, and only 5% of females reported dysphoric mood. Excluding those experiencing fewer than one episode per week gave a prevalence of 2.8% in females and 0% on males. Previously-reported prevalences using questionnaire may be inflated due to poor respondent understanding of the psychiatric terms being used.

Despite the existence of several follow-up studies of children with ADHD followed up into adulthood, there is limited information on whether patterns of persistence and remission in ADHD can be predicted over the long term. The main aim of this study was to evaluate predictors of persistence of ADHD in a large sample of boys with and without ADHD followed prospectively for 11 years into young adulthood. Subjects were Caucasian, non-Hispanic boys with (N = 110) and without (N = 105) ADHD who were 6-17 years old at the baseline assessment (mean age 11 years) and 15 to 31 years old at the follow-up assessment (mean age 22 years). Subjects were comprehensively and blindly assessed with structured diagnostic interviews and assessments of cognitive, social, school, and family functioning. At the 11-year follow-up, 78% of children with ADHD continued to have a full (35%) or a partial persistence (subsyndromal (22%), impaired functioning (15%), or remitted but treated (6%)). Predictors of persistence were severe impairment of ADHD, psychiatric comorbidity, and exposure to maternal psychopathology at baseline. These findings prospectively confirm that persistence of ADHD over the long term is predictable from psychosocial adversity and psychiatric comorbidity ascertained 11 years earlier.

Schizophrenia is likely to be a consequence of serial alterations in a number of genes that, together with environmental factors, will lead to the establishment of the illness. The dorsolateral prefrontal cortex (Brodmann's Area 46) is implicated in schizophrenia and executes high functions such as working memory, differentiation of conflicting thoughts, determination of right and wrong concepts, correct social behavior and personality expression. We performed a comparative proteome analysis using two-dimensional gel electrophoresis of pools from 9 schizophrenia and 7 healthy control patients' dorsolateral prefrontal cortex aiming to identify, by mass spectrometry, alterations in protein expression that could be related to the disease. In schizophrenia-derived samples, our analysis revealed 10 downregulated and 14 upregulated proteins. These included alterations previously implicated in schizophrenia, such as oligodendrocyte-related proteins (myelin basic protein and transferrin), as well as malate dehydrogenase, aconitase, ATP synthase subunits and cytoskeleton-related proteins. Also, six new putative disease markers were identified, including energy metabolism, cytoskeleton and cell signaling proteins. Our data not only reinforces the involvement of proteins previously implicated in schizophrenia, but also suggests new markers, providing further information to foster the comprehension of this important disease.

This study examined the association of lifetime traumatic stress with psychiatric diagnostic status and symptom severity in veterans serving in the US military after 9/11/01. Data from 356 US military veterans were analyzed. Measures included a standardized clinical interview measure of psychiatric disorders, and paper-and-pencil assessments of trauma history, demographic variables, intellectual functioning, posttraumatic stress disorder (PTSD) symptoms, depression, alcohol misuse, and global distress. Ninety-four percent of respondents reported at least one traumatic stressor meeting DSM-IV criterion A for PTSD (i.e., life threatening event to which the person responded with fear, helplessness or horror), with a mean of four criterion A traumas. Seventy-one percent reported serving in a war-zone, with 50% reporting occurrence of an event meeting criterion A. The rate of current psychiatric disorder in this sample was: 30% PTSD, 20% major depressive disorder, 6% substance abuse or dependence and 10% for the presence of other Axis I psychiatric disorders. After accounting for demographic covariates and combat exposure, childhood physical assault and accident/disasters were most consistently associated with increased likelihood of PTSD. However, PTSD with no comorbid major depressive disorder or substance use disorder was predicted only by combat exposure and adult physical assault. Medical/unexpected-death trauma and adult physical assault were most consistently associated with more severe symptomatology. Particular categories of trauma were differentially associated with the risk of psychiatric diagnosis and current symptom severity. These findings underscore the importance of conducting thorough assessment of multiple trauma exposures when evaluating recently post-deployed veterans.

In quantifying the effects of mild sedatives both physiological and subjective aspects of sleep must be taken into account. A questionnaire analysis on a mild sedative (400 mg of an aqueous extract of Valeriana officinalis L.) showed that by subjective criteria it is sedative (i.e. it significantly decreased perceived sleep latencies and night awakenings, and improved sleep quality). In an EEG study on the same preparation the pattern of results tended to confirm the subjective evaluation (i.e. shorter mean sleep latency, increased mean latency to first awakening) but the changes did not reach statistical significance. The discussion critically examines some of the approaches used to test putative mild sedatives and suggests a rational approach to analysing their effects.

Administration of the N-methyl-D-aspartate (NMDA) antagonist S-ketamine in normals produces a psychosis-like syndrome including several positive and negative symptoms of schizophrenic disorders (Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH. The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 1998;31:104-109). Given the clinical efficacy of dopamine (DA) D2 receptor antagonists in the treatment of positive symptoms, it is conceivable that S-ketamine-induced psychotic symptoms are partially due to a secondary activation of dopaminergic systems. To date, animal and human studies of the effects of NMDA antagonists on striatal DA levels have been inconsistent. The present study used positron emission tomography (PET) to determine whether a psychotomimetic dose of S-ketamine decreases the in vivo binding of [11C]raclopride to striatal DA D2 receptors in humans (n = 8). S-ketamine elicited a psychosis-like syndrome, including alterations in mood, cognitive disturbances, hallucinations and ego-disorders. S-ketamine decreased [11C]raclopride binding potential (BP) significantly in the ventral striatum (-17.5%) followed by the caudate nucleus (-14.3%) and putamen (-13.6%), indicating an increase in striatal DA concentration. The change in raclopride BP in the ventral striatum correlated with heightened mood ranging from euphoria to grandiosity. These results provide evidence that the glutamatergic NMDA receptor may contribute to psychotic symptom formation via modulation of the DA system.

The benzodiazepine antagonist Ro 15-1788 was labelled with [11C] and examined for possible use as ligand for PET scan studies on benzodiazepine receptors in the brain of cynomolgus monkeys and human subjects. [11C] Ro 15-1788 allowed the in vivo visualization of benzodiazepine receptor binding in cerebral and cerebellar cortical areas as well as in basal brain nuclei in PET scan images. [11C] Ro 15-1788 exhibited a high ratio of specific benzodiazepine receptor binding (cerebral cortex) to non-specific binding (pons) and the kinetics of binding should be satisfactory for quantitative clinical PET scan studies using [11C]. The in vivo binding of [11C] Ro 15-1788 in the cerebral cortex of cynomolgus monkeys and healthy human subjects was reduced by approximately 90% within 10 min after the intravenous injection of a high dose of unlabelled Ro 15-1788 (0.5 mg/kg i.v.). Different areas of the healthy human brain showed an approximately 10-fold variation in maximal [11C] Ro 15-1788 binding that corresponded to the previously known distribution of benzodiazepine receptors in these regions. The highest degree of binding was obtained in the medial occipital cerebral cortex followed by frontal cortex, cerebellum, thalamus, striatum and pons. Two psychiatric patients with anxiety syndromes who had been treated for a long time with high doses of benzodiazepines had roughly the same degree of maximal [11C] Ro 15-1788 binding in brain regions as the healthy subjects but the rate of decline of [11C] Ro 15-1788 in the brain was higher. This indicates that there is measurable competition between [11C] Ro 15-1788 binding and clinical benzodiazepine concentrations in the body fluids of psychiatric patients. The results demonstrate that [11C] Ro 15-1788 should be a valuable tool for quantitative analyses of benzodiazepine receptor characteristics and receptor occupancy in the brain of patients with neuropsychiatric disorders.

Previous in vivo imaging studies reported no difference in dopamine transporter (DAT) bindings in the striatum between control subjects and patients with schizophrenia. However, as the signals of radioligands with moderate affinity were insufficient for allowing the evaluation of small amounts of DAT, DAT binding in extrastriatal regions has not been determined. Positron emission tomography scanning using [(11)C]PE2I was performed on eight patients with schizophrenia and twelve normal control subjects. Binding potential (BP(ND)) for DAT in the caudate, putamen, thalamus and substantia nigra was calculated, using the cerebellum as reference region. In patients with schizophrenia, clinical symptoms were evaluated by Positive and Negative Syndrome Scale (PANSS). BP(ND) in the thalamus of patients with schizophrenia was significantly higher than in control subjects (P=0.044). In patients with schizophrenia, there were significantly positive correlations between BP(ND) in the thalamus and total (r=0.75), positive (r=0.78) and negative PANSS scores (r=0.82). Altered DAT in the thalamus might be related to the pathophysiology and clinical symptoms of schizophrenia.

Blood-injury-injection (BII) phobia presents with a unique anxiety response that often involves blood pressure drops and pronounced bradycardia, which can culminate in fainting. The current recommended treatment for BII phobia is Applied Tension (AT), a tension technique that includes in vivo exposure. However, surprisingly little empirical evidence is available on the additive efficacy of tension beyond exposure alone. Our literature search yielded five controlled treatment studies for BII phobia, all from one research group. Beyond AT, these studies also tested Exposure only (E), Tension only, Applied Relaxation (AR), or a combination of AR and AT. Based on self-reported levels of anxiety, in-session avoidance and fainting, AT was superior over other conditions; however, when considering pre- to post-treatment effect sizes on BII-related questionnaires, E outperformed all other treatments. In addition, AT did not yield better results on physiological measures, and individuals with BII fears improved similarly within studies across treatment groups, regardless of fainting status. Heterogeneity in patient populations (e.g. extent of fainting-proneness), differential targeting of BII phobia manifestations, and small sample sizes may explain some of the variability in findings. Further research is needed to determine the efficacy of treatment techniques for BII phobia patients with and without fainting history.

Though there is considerable evidence that prefrontal repetitive transcranial magnetic stimulation (rTMS) exerts antidepressant effects, the neurobiological action of rTMS in patients with depression is poorly understood. Preclinical studies in animals and humans have demonstrated that prefrontal rTMS can induce dopamine release in mesostriatal and mesolimbic regions. We therefore investigated whether rTMS also modulates striatal dopaminergic neurotransmission in depressed patients using a dynamic [123I] iodobenzamide (IBZM) single photon emission computed tomography (SPECT) approach. Five patients with a major depressive episode (DSM-IV) underwent an acute 10 Hz rTMS challenge with 3000 stimuli over the left dorsolateral prefrontal cortex during an [123I] IBZM-SPECT bolus and constant infusion protocol. In four subjects the protocol was repeated after a three week rTMS standard treatment. Striatal IBZM binding to dopamine D2 receptors was assessed with a region-of-interest (ROI) technique. The change in striatal IBZM binding after the rTMS challenge was regarded as measure of change in endogenous striatal dopamine. Data of nine SPECT investigations showed a significant reduction by 9.6+/-6.2% in IBZM binding to striatal dopamine D2 receptors after rTMS challenge compared to baseline (p=0.01, Wilcoxon test). In this preliminary study, the reduction of IBZM binding observed after rTMS challenge is suggestive of a release in endogenous dopamine induced by prefrontal rTMS. In future, this approach can be used to differentiate specific and non-specific reward-related effects of rTMS on dopaminergic neurotransmission.

Glutamate, and the NMDA glutamate receptor, may be involved in Alzheimer's Disease (AD). Reductions in NMDA receptors are found in AD, possibly contributing to memory deficits. However the NMDA receptor is involved in excitotoxicity, which may play a role in cell death and the production of neurofibrillary tangles in AD; although with lower levels of glutamate than occur in cerebral ischaemia. Therefore reductions in the NMDA receptor may worsen memory deficit in AD, but increased stimulation of the receptor may contribute to the progress of the disease. MK-801 has been used to image excessive glutamate activation following ischaemia in rats. However, it is unclear how effective MK-801 is in conditions with lower levels of glutamate release. This study attempts to gain insight into the utility of the tracer in these conditions, exploring glutamatergic mechanisms in AD. It describes the retention and elimination of 123iodo-MK-801 in five AD and five control subjects, comparing this to regional cerebral blood flow (rCBF). The initial uptake of 123I-MK-801 is dominated by delivery of the ligand. However, despite significant reductions in rCBF in the AD patients, there is no significant difference in the uptake of 123I-MK-801. This suggests increased retention of 123I-MK-801 in the AD patients. In addition the washout of 123I-MK-801 was less in the AD patients, again suggesting increased retention, although this only reached significance in one region. Theses data hint at possible increases in NMDA activation in AD but ultimately 123I-MK-801 does not provide a sufficiently accurate measurement to demonstrate this conclusively. Further NMDA ligands are now at a late stage of development and may provide more conclusive answers to the role of glutamate in AD.

Background: Caudal regions of the prefrontal cortex, including the dorsolateral (DLPFC) and ventrolateral (VLPFC) prefrontal cortex, are involved in essential cognitive functions such as working memory. In contrast, more rostral regions, such as the frontopolar cortex (FpC), have integrative functions among cognitive functions and thereby contribute crucially to real-world social activity. Previous functional magnetic resonance imaging studies have shown patients with schizophrenia had different DLPFC activity pattern in response to cognitive load changes compared to healthy controls; however, the spatial relationship between the caudal and rostral prefrontal activation has not been evaluated under less-constrained conditions. Method: Twenty-six patients with schizophrenia and 26 age-, sex-, and premorbid-intelligence-matched healthy controls participated in this study. Hemodynamic changes during n-back working memory tasks with different cognitive loads were measured using multi-channel near-infrared spectroscopy (NIRS). Results: Healthy controls showed significant task-related activity in the bilateral VLPFC and significant task-related decreased activity in the DLPFC, with greater signal changes when the task required more cognitive load. In contrast, patients with schizophrenia showed activation in the more rostral regions, including bilateral DLPFC and FpC. Neither decreased activity nor greater activation in proportion to elevated cognitive load occurred. Conclusions: This multi-channel NIRS study demonstrated that activation intensity did not increase in patients with schizophrenia associated with cognitive load changes, suggesting hypo-frontality as cognitive impairment in schizophrenia. On the other hand, patients had broader prefrontal activity in areas such as the bilateral DLPFC and FpC regions, thus suggesting a hyper-frontality compensatory response.

Studies have previously documented that microRNAs (miRNAs), with their key roles in regulating both synaptic plasticity and brain development, are candidate genetic contributors to the etiopathology of bipolar disorder (BD). Moreover, miRNA identified as targets for the actions of chronic lithium and VPA are known to play diverse and intriguing roles in brain function. In particular, the brain specific miR-134 has recently been identified as a potential regulator of dendritic spine volume and synapse formation. Recently, circulating miRNAs have been reported as promising biomarkers for various pathologic conditions. We assessed the hypothesis that miRNA-134 may be present and detectable in circulating blood, and that miRNA-134 may serve as a biomarker of mania episodes in BD. In the present study, we recruited 21 bipolar I, manic (DSM-IV) patients and controls matched by sex and age for quantification of miR-134 level in plasma using real-time RT-PCR method. We found that: Plasma miR-134 levels in drug-free, 2-week medicated, and 4-week medicated bipolar mania patients were significantly decreased when compared with controls, and the level was increased on following medication. Decreased circulating miR-134 level both in drug-free and medicated patients did presented negative correlation with the clinical scales. Overall, these results suggest that the decreased plasma miR-134 levels may be directly associated with the pathophysiology and severity of manic symptoms in BD. Plasma miRNA-134 in BD may be considered as a potential peripheral marker that can respond to acute manic episodes and associate with effective mood stabilizers treatment.

MicroRNAs (miRNAs) are small non-coding RNAs that act as potent regulators of gene expression. A recent GWAS reported the rs1625579 SNP, located downstream of miR-137, as the strongest new association with schizophrenia [Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011;43:969–76.]. Prior to this GWAS finding, a schizophrenia imaging-genetic study found miR-137 target genes significantly enriched for association with activation in the dorsolateral prefrontal cortex (DLPFC) [Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA, et al. Identifying gene regulatory networks in schizophrenia. Neuroimage 2010;53:839–47.].

THE CONCEPT of attention has had an extremely uneven importance in the history of experimental psychology. In the late 1800’s and early 1900’s, attention was regarded as one of the core problems for experimental psychology. Then, with the rise of Behaviorism and Gestalt Psychology, the concept of attention fell into disrepute. It was not until 1958, with the publication of BROADBENT’S book, Perception and Communication,’ that the seal ofrespectability was again put on experimental investigations of human attention. Since the 1950’s, experimental research on attention has been abundant, fruitful, and exciting. However, it has become increasingly clear that many different kinds of behavior are included under the concept of attention. Some of these behaviors appear to bear little relation to one another except for being similarly classified as involving attention. In fact, one is struck by the disparities among attentional tasks rather than by any feature which the tasks have in common. The hypothesis of an attentional deficit in schizophrenia has generated much research in recent years. However, as NEALE and CROMWELL~ have pointed out:

Social withdrawal is a robust childhood risk factor for later schizophrenia. The aims of this paper were to assess the evidence for childhood social withdrawal among adults with schizophrenia and, comparatively, in children aged 9-14 years who are putatively at-risk of developing schizophrenia. We conducted a meta-analysis, including cohort and case-control studies reporting social withdrawal measured by the Child Behavior Checklist (CBCL) in adults with schizophrenia vs. controls. Further, an experimental study compared CBCL withdrawal scores from typically-developing children with scores from two groups of putatively at-risk children: (i) children displaying a triad of replicated antecedents for schizophrenia, and (ii) children with at least one first- or second-degree relative with schizophrenia or schizoaffective disorder. Six studies met inclusion criteria for the meta-analysis (N = 3828), which demonstrated a large effect of increased childhood social withdrawal in adults with schizophrenia (standardized mean difference [SMD] score = 1.035, 95% CI = 0.304-1.766, p = 0.006), with no indication of publication bias, but considerable heterogeneity (I(2) = 91%). Results from the experimental study also indicated a large effect of increased social withdrawal in children displaying the antecedent triad (SMD = 0.743, p = 0.001), and a weaker effect in children with a family history of schizophrenia (SMD = 0.442, p = 0.051). Childhood social withdrawal may constitute a vulnerability marker for schizophrenia in the presence of other antecedents and/or genetic risk factors for schizophrenia.

There is some evidence that schizophrenia may be accompanied by alterations in cell-mediated immunity (CMI) and that antipsychotic agents may modulate CMI. The purpose of this study was to investigate the plasma levels of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sIL-2R, and transferrin-receptor (TfR) in schizophrenia and mania, and the effects of treatment with neuroleptics or mood stabilizers on these variables. The subjects were 14 schizophrenic patients, 10 manic patients and 21 healthy volunteers. The above immune variables were measured in baseline conditions and after treatment with neuroleptics in schizophrenic patients and valproate in manic patients. Plasma concentrations of IL-6, sIL-6R, sIL-2R and TfR were significantly higher in the combined group of psychotic patients than in healthy volunteers. Plasma IL-6 was significantly higher in schizophrenic patients, while plasma sIL-6R and sIL-2R were significantly higher in mania than in normal controls. In schizophrenic patients, plasma levels of IL-6, sIL-6R and TfR were significantly lower after treatment with neuroleptics than before treatment. No significant effects of valproate on the immune-inflammatory markers could be found in the manic patients. It is suggested that activation of CMI may occur in both schizophrenia and mania and that neuroleptics may have immunosuppressive effects through suppression of IL-6 or IL-6R-related mechanisms.

Depressed patients have been reported to have a higher than normal density of platelet binding sites for 3H-clonidine, an alpha 2-adrenoceptor agonist. Paradoxically, other studies using 3H-alpha 2, antagonists have found no differences from controls. Because 3H-clonidine interacts with platelet alpha 2-adrenoceptors to form G-protein complexes, whereas 3H-alpha 2-antagonists bind with uncoupled receptors, an elevation in G-protein coupling might explain this paradox. Another possibility is that depression might be associated with increased non-adrenergic I1-imidazoline binding sites, which are also clonidine sensitive. To distinguish these possibilities, we utilized p125I-clonidine to measure density (Bmax) and affinity (KD) of platelet G-protein coupled alpha 2-adrenoceptors as well as platelet I1 binding sites, and compared diagnostic groups of major depressive disorder (MDD), generalized anxiety disorder (GAD) and healthy subjects. Specific inhibition of binding by norepinephrine (NE = 10 microM) was used to selectively quantify alpha 2-adrenoceptors, whereas inhibition by 10 microM moxonidine (a > 100-fold selective I1 ligand) quantified I1 binding sites under a NE mask. I1 sites were found to be markedly elevated by, on average, +136% in MDD patients (p = .0007), whereas there was only a marginal increase in alpha 2-adrenoceptor Bmax values in MDD patients (p = .08; GAD and healthy subjects did not differ). Treatment of MDD patients for 6-8 weeks with desipramine downregulated I1 sites as well as alpha 2-adrenoceptors. Positive correlations were also noted for both sites: (a) between Bmax values and the severity of depression (using the Hamilton Depression Rating Scale); and (b) between end-of-treatment plasma desipramine concentrations and the extent of downregulation in Bmax values when subject groups were pooled. None of the binding parameters was associated with plasma catecholamine concentrations. The results suggest that an increased density of platelet I1 binding sites may partially explain the utility of radiolabeled clonidine as a potential biological marker for depressive illness, although an additional increase in G-protein coupling cannot be excluded.

Due to the increasing importance of the amine in psychiatric research, [14C]-tyramine was instilled intraduodenally (i.d.), into the colon or infused into the portal vein of chloralosed or spinal cats in order further to investigate its metabolism, distribution and interactions. Tyramine and p-hydroxyphenylacetic acid (pHPA) accounted for 83% of the radioactivity recovered in blood, the remainder being octopamine, tyramine sulphate, methyltyramine and tyrosol, Progressively greater portal venous (PV), cranial mesenteric arterial (CMA) and PV-CMA concentrations of tyramine and pHPA were observed with an increase in the amount of tyramine instilled i.d.; pHPA preponderated over tyramine in portal venous and arterial blood. Tyramine and pHPA also appeared in portal and arterial blood after installation of [14C]-tyramine into the colon. When histamine (5 μmol/kg) was combined with tyramine i.d., 1.7 μmol/kg, tyramine and pHPA were significantly increased in portal venous and arterial blood, in liver and in distal intestine. Arterial tyramine concentrations were increased 7- to 46-fold by the non-selective MAO inhibitors tested following tyramine, 1.7 μmol/kg i.d.; arterial pHPA was reduced despite the elevated tyramine. The proportion of octopamine, tyramine sulphate, methyltyramine and tyrosol was not increased by mebanazine over the duration of experiments. Clorgyline but not deprenyl elevated portal venous and arterial tyramine. Sympathomimetic effects were obtained with infusion for 20 min of tyramine, 340 (nmol/kg)/min, into the portal vein (arterial tyramine concentration > 2.6 nmol/ml) but not with infusion of 85 or 170 (nmol/kg)/min (arterial tyramine concentration < 1.25 nmol/ml) either in control cats or those pretreated with clorgyline but were elicited in cats treated with mebanazine when arterial tyramine concentrations reached 3 nmol/ml. Sympathomimetic effects were elicited also by tyramine 8.5 μmol/kg i.d. after clorgyline, arterial mean tyramine concentration being 2.4 nmol/ml; tyramine, 17 μmol/kg i.d., in the absence of clorgyline failed to evoke sympathomimetic phenomena despite arterial mean tyramine concentration increasing to 2.2 nmol/ml. [14C]-Tyramine and pHPA were found in the liver, lungs, distal small intestine and kidney after tyramine instilled i.d. The amount of [14C]-tyramine and pHPA in the kidney of control cats was between 7- and 32-fold than in other tissues. With tyramine, 1.7 μmol/kg i.d., tyramine content of tissues was substantially increased by the non-selective MAO inhibitors and in the liver and small intestine by clorgyline but not by deprenyl. In vitro inhibition of MAO A was 80% with the non-selective MAO inhibitors, 70% with clorgyline and 30–45% with deprenyl; except for the liver, where deprenyl and the non-selective MAO inhibitors were effective, in vitro inhibition of MAO B was less satisfactory. In vitro inhibition of tyramine oxidation was 47% or more with all the MAO inhibitors, except in the distal small intestine.

The traditional historic-prospective follow-up study of anorexia nervosa patients may be well served by recent methods of statistical analysis, the so-called models for the analysis of survival data. These models are particularly suited to the sort of incomplete observations usually produced a longitudinal studies. They include methods for estimating the probability of death and relapse as a function of time. This makes possible powerful comparisons among studies and among subsamples in single studies. In the present study, 151 patients were followed-up after 4-22 yrs. The hazard of death was on average 0.5% per year, the hazard of relapse 3% per year. With both measures, the risk declined steadily after therapeutic contact.

The dimensional structure of the 16-item Negative Symptom Assessment (NSA-16) was validated in a sample of 223 unmedicated schizophrenic inpatients and cross-validated on an independent sample of 276 patients with schizophrenia. Using a confirmatory factor analytic procedure, a five factor model was found to best characterize the structure of this rating instrument. These factors include: Communication, Emotion/Affect, Social Involvement, Motivation, and Retardation. The latent structure of the NSA-16 is similar to the larger instrument from which it was derived. The findings provide support for a multidimensional model of negative symptoms in schizophrenia and offer a useful measure for their assessment.

Increasing evidence suggests that there may be significant morphological changes in the neuropil of the dorsolateral prefrontal cortex in schizophrenia. A controversial issue surrounding these deficits in the cortical neuropil is the confounding effects of antipsychotic (neuroleptic) medication as well as the question of generality to psychiatric disorders. To begin to address these issues we examined brains from Huntington's patients matched to a cohort of schizophrenics and controls. Many Huntington's patients take neuroleptics similar to schizophrenics; therefore, by comparing the two groups to controls we can begin to determine if neuroleptics play a role in the deficits reported in schizophrenia. Using MAP2 immunohistochemistry and thionin staining eight matched triplets of Huntington, schizophrenia and control, in areas 9 and 17 layers III and V were analyzed. Our results confirmed previous published data showing a schizophrenia-associated decrease in MAP2 in area 9 with no change in area 17. Similarly the Huntington's patients showed no change in area 9 layer III and no change in area 17. There was however, a modest decrease observed in layer V area 9 of the Huntington's patients. Neuron density measurements showed no change in either layer or brain region in any of the diagnostic categories. These observations suggest that antipsychotic medication may not be responsible for some of the morphological changes observed in the neuropil of the PFC in schizophrenia.

Schizophrenia is chronic and debilitating mental disorder. In broad spectrum of possible causes or contributing factors, immune system and cytokines were investigated in the onset and development of schizophrenia. The aim of our study was to analyze the serum concentrations of type-1 cytokines: TNF-α, IFN-γ, type-2 cytokines: IL-4, IL-10, type-17 cytokine: IL-17 and regulatory cytokines: TGF-β, IL-27, IL-6, in drug-naive patients with First Episode Psychosis - FEP (n = 88) and Schizophrenia in relapse - SC in relapse patients (n = 45), comparing to healthy controls (n = 36). Also, we attempted to determine potential correlation between cytokine levels and/or cytokine ratios with clinical parameters, such as severity of illness, positive, negative and general psychopathology. Our results showed decreased levels of IL-17 (p = 0.018), demonstrating that type-17 response is blunted in psychotic episode. Increased levels of IL-4 (p = 0.033) showed that type-2 response is overweight in psychotic episode. Also, levels of IL-4 in serum of SC in relapse patients were higher than controls (p < 0.0005) and patient with FEP (p = 0.003). This alteration was accompanied with increase in production of TGF-β in psychotic patients (p = 0.009) and also in FEP (p < 0.0005) and SC in relapse (p < 0.0005). Analysis showed that TGF-β can be a valuable marker for psychosis. The presence of enhanced anti-inflammatory/immunosuppressive activity in schizophrenia may be an attempt to counteract or limit ongoing pro-inflammatory processes and downregulating chronic inflammation. Finally we have documented decreased levels of IL-17 and IL-17/TGF-β ratio in these types of psychotic patients, suggesting the new aspects of schizophrenia pathophysiology.

The urinary excretions of 17-KS and 17-OHCS of 9 schizophrenic patients were determined for 5-day averages over a drug-free observation of 7 months. In addition, urinary steroids were measured in 1-day specimens in 2 patients both during sudden exacerbations of schizophrenic symptoms as well as over randomly selected 3-week periods.It was found that the mean excretion of 17-KS of this group of schizophrenic patients was consistently higher than that of normal subjects of comparable ages. The excretion of 17-OHCS was also raised above normal, but to a lesser extent. Individual excretion rates of 17-KS as well as the means were almost unchange throughout the observation period in all but 2 patients.Two schizophrenic patients displaying a great degree of motor activity and/or anxiety without marked fluctuations of their schizophrenic symptoms were found to have generally high excretion rates of 17-KS, while a withdrawn catatonic patient with signs of intense tension and anxiety not only revealed elevated values for 17-KS but also the highest rates of all for 17-OHCS.Sudden severe exacerbations of schizophrenic symptoms in 2 patients were accompanied by rises of both 17-KS and 17-OHCS. Ratings on the severity of schizophrenic symptoms and the degree of motor activity revealed a tendency of elevated urinary steroid hormones to be related to concomitant high degrees of motor activity and anxiety. Although statistically not significant on day-to-day correlations, the more marked daily variations of motor activity and schizophrenic behavior were associated with highly variable steroid excretion.

War captivity is one of the most severe human-inflicted traumatic experiences with wide and substantial long-term negative effects. However, only one retrospective study examined suicidal ideation (SI) among ex-prisoners of war (ex-POWs). This study aimed to prospectively assess SI among ex-POWs and its associations with posttraumatic stress disorder (PTSD) symptoms over a 17-year period. Two groups of male Israeli veterans from the 1973 Yom Kippur War were examined: ex-POWs and comparable veterans who were not taken captive. Both groups were assessed via self-report measures of SI and PTSD symptoms at three time points: T1 18 (1991), T2 30 (2003), and T3 35 (2008) years after the war. Latent growth curve modeling (LGM) results showed that ex-POWs reported higher levels of SI at T2 and T3 and a pattern of increase in SI levels trajectory over time, compared to control veterans. Furthermore, among ex-POWs, PTSD symptoms at T1 contributed to the increase in rate of change in SI overtime. In addition, PTSD symptoms affected SI at the same measurement, above and beyond above the trajectories of SI. Clinical implications of these findings for the relations between captivity trauma and suicidality are discussed.

Mood-related phenotypes are commonly comorbid with, and have been implicated in the development of, neurological disorders. APOE is a major susceptibility gene for neurodegeneration. Recent evidence from case-control studies has suggested that the apoE 2 allele is associated with major depressive disorder (MDD). However, evidence from large-scale community-based studies is limited. APOE was genotyped for 17,507 men and women, aged 41-80 years, participating in the European Prospective Investigation into Cancer-Norfolk study, who had also completed a psychosocial assessment that included measures of emotional health status defined by MDD, psychological distress (as represented by the Mental Health Inventory, MHI-5), and by an assessment of neuroticism. No associations were found between APOE genotypes and measures either of past-year or lifetime MDD, or of emotional health defined according to the MHI-5 or by neuroticism. Data from this large-scale, community-based, study are not supportive of an association between either MDD or associated measures of emotional state and APOE genotype. These findings suggest that the association between APOE and MDD risk is more modest than has been previously reported.

Many of the symptoms of schizophrenia appear to involve dysfunction of the cognitive processes mediated by the neural circuitry of the cerebral cortex. The application of modern neuroscience techniques to the study of postmortem human brain specimens provides a powerful approach for exploring the manner in which cortical circuitry may be disrupted in schizophrenia. In this paper, we describe a strategy for the conduct of postmortem investigations of schizophrenia that involves (1) the use of a nonhuman primate model to guide the design and interpretation of studies in humans; (2) the detailed characterization of the normal organization of neural systems in the human cerebral cortex, and the range of inter-individual variations in that organization; and (3) the testing of specific hypotheses about the disruption of that organization in schizophrenia. The application of this strategy, and its value in overcoming some of the potential pitfalls of postmortem studies, is demonstrated in a series of investigations designed to test the hypothesis that dopamine neurotransmission is impaired in the entorhinal cortex in schizophrenia.

The effect of 17 beta-estradiol (E2) on the response of dopamine (DA) and serotonin (5-HT) to acute lithium in the brains of ovariectomized rats was investigated. An E2 injection (100 ng/s.c.) to ovariectomized rats did not change striatal DA levels, whereas the levels of its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), increased 30 min later; concentrations of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), also remained unchanged. In the frontal cortex, DA, 5-HT, HVA and 5-HIAA levels remained unchanged after the E2 injection, whereas DOPAC levels and DOPAC/DA and HVA/DA ratios increased 30 min later. Injection of LiCl (10 mEq) decreased striatal DA levels, increased DOPAC levels and slightly decreased HVA levels; by contrast, frontal cortex DA and HVA levels increased but DOPAC levels were unchanged. A biphasic response of striatal 5-HT levels occurred, increasing shortly after injection of LiCl, followed by a decrease; 5-HIAA levels, however, increased. In the frontal cortex, injection of rats with LiCl led to a gradual increase in 5-HT levels, whereas 5-HIAA concentrations decreased. In the presence of E2, LiCl effected a greater decrease in striatal DA than injection of LiCl alone, advanced the DOPAC peak by 30 min and increased HVA levels; E2 had less effect on the 5-HT response to LiCl, except the decreases in 5-HT and 5-HIAA at 60 min were greater. Furthermore, in the striatum, the increased DA turnover caused by LiCl, estimated by the DOPAC/DA and HVA/DA ratios, was advanced in rats treated with E2. In the presence of E2, LiCl slightly increased frontal cortex DA, DOPAC and HVA levels compared with treatment with LiCl alone, whereas DOPAC levels decreased in rats treated with LiCl + E2 compared with levels in E2-treated rats. Generally, higher levels of 5-HT and 5-HIAA were measured in the frontal cortices of rats treated with LiCl + Ex compared with rats injected with LiCl. These results indicate that E2 potentiates the acute effect of lithium on striatal and frontal cortex DA and 5-HT levels and metabolism, suggesting a role of the hormonal state on this drug response.

Schizophrenia is associated with various abnormalities in the immune system including elevated levels of Interleukin-18 (IL-18), a potent inflammatory cytokine in T-helper 1 (Th1) responses. The aim of this study was to assess the clinical significance of serum IL-18 levels in various stages of schizophrenia. We measured serum IL-18 levels using a sandwich enzyme-linked immunosorbent assay (ELISA) from 78 never-medicated first-episode schizophrenia, 79 medicated chronic schizophrenia and 78 healthy control subjects. The symptoms of schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS). The chronic patients had significantly greater serum IL-18 levels than both first-episode patients and controls. Serum IL-18 was also positively correlated with the PANSS general psychopathology subscore in chronic schizophrenic patients. Our results showed elevated IL-18 pathway activity may be involved in the psychopathology of schizophrenia.

Background: Early attrition can impede treatment success of depression; its contributing factors and impacts on subsequent treatment course need further clarification. Methods: All Taiwanese adult patients prescribed with antidepressants for depression (n=216,557) in 2003 were identified through a total population health insurance claims database; their initial contact patterns could be classified into three types of attrition: non-attrition, returning attrition and non-returning attrition. Demographic and clinical characteristics associated with each attrition type were described and relationships between attrition type and subsequent treatment course over an 18-month follow-up period were examined with these demographic/clinical confounders being controlled for. Results: 41.6% of Study subjects had early attrition; among them, 35.3% returned to treatment later. Type of depression, medical/psychiatric comorbidities, painful physical symptoms and past treatment history, as well as prescribing physician specialty and choice of antidepressants, were associated with early attrition. Three types of follow-up pattern over the 18-month follow-up period were identified: sustained treatment-free, continuous treatment and late re-contacts. Patients remaining engaged with treatment within the first three months had higher odds of achieving sustained treatment-free (OR=1.21; 99% CI: 1.16, 1.27) and lower odds of having late re-contacts (OR=0.20; 99% CI: 0.19, 0.21) over the 18-month period, compared to those who returned after early attrition. Conclusions: Early attrition is a significant barrier for depression treatment in daily clinical practice and has negative impacts on later treatment course and/or outcome. Early attrition needs to be minimized through shared decision-making, exchange of treatment preferences and proper patient-physician communication.

The study examined the relationship between pre-treatment nocturnal hypothalamic-pituitary-adrenal (HPA) activity, as reflected by nocturnal urinary free cortisol (NUFC) response to a single-dose of sustained-release bupropion, and the antidepressant effect of the drug. NUFC changes in response to treatment with bupropion also were assessed. NUFC was measured in 20 patients with unipolar major depressive disorder before and after initiating treatment with sustained-release bupropion. Prior to treatment, subjects were studied on two separate sessions, one week apart. On the morning of each session, the participants received bupropion (150 mg, PO) or placebo using a randomized, double-blind procedure. Following the second session, subjects then received open-label treatment with bupropion for 8 weeks. NUFC sampling was repeated at the end of treatment. There was a significant interaction between NUFC concentration in response to single-dose bupropion and its antidepressant effect. Treatment non-responders showed a significant increase in NUFC in response to a single-dose of bupropion, whereas responders showed no such change. In addition, the NUFC response to bupropion challenge correlated significantly with the change in depression ratings as a result of treatment. In contrast to many other antidepressants, treatment with bupropion for 8 weeks did not reduce HPA activity in either responders or non-responders. These findings suggest that the NUFC response to a test-dose of bupropion might be helpful in predicting its antidepressant effect. One possible mechanism for the association between the NUFC response to acute bupropion challenge and antidepressant efficacy might be linked through dopaminergic and/or noradrenergic mechanisms.

Numerous studies report dysfunctional dopaminergic and noradrenergic neurotransmission in the pathogenesis of schizophrenia. Dopamine beta-hydroxylase (DBH) is an intracellular enzyme catalyzing the conversion of dopamine to noradrenaline. Functional polymorphisms have been reported in the promoter region of DBH gene, including a 19 bp insertion/deletion polymorphism. The purpose of this study was to investigate whether there was an association between the functional polymorphism (DBH5'-Ins/Del) and schizophrenia in a Han Chinese population. This polymorphism was genotyped in 221 first-episode schizophrenics, 360 chronic schizophrenics and 318 healthy controls using a case-control design. We assessed their psychopathology using the Positive and Negative Syndrome Scale (PANSS). We showed that the DBH5'-Ins/Del deletion (Del) allelic and genotypic frequencies were significantly lower in controls than first-episode of schizophrenics (FES) (both p < 0.001), but controls were not different from chronic schizophrenics. Furthermore, the PANSS positive symptom and total scores were significantly higher in FES with the Del/Del genotype than those with Ins/Del and Ins/Ins genotypes (all p < 0.05). The DBH5'-Ins/Del polymorphism may play a role in susceptibility to the positive symptoms of FES and to these FES not progressing on to chronic schizophrenia.

Unlabelled: The objective was to determine if a cluster of chronic fatigue syndrome (CFS)-like illness had occurred among employees in two large state office buildings in northern California, and to identify risk factors for and features of fatiguing illness in this population. Design: case-control study. Population and setting: Over 3300 current employees in two state office buildings and employees in a comparable "control" building. Information was collected on demographic and occupational variables, the occurrence of fatiguing illness for at least one month in the previous year, and the presence of 36 symptoms. A total of 3312 (82%) of 4035 employees returned questionnaires. Overall, 618 (18.7%) persons reported fatigue lasting at least one month; including 382 (11.5%) with fatigue of at least six months' duration and 75 (2.3%) with symptoms compatible with a CFS-like illness. Independent risk factors for fatigue lasting one month or longer were found to be Native American ethnicity (OR 2.4, CI 1.1,5.3), Hispanic ethnicity (OR 1.7, CI 1.3,2.3), female sex (OR 1.5, CI 1.2,1.9), gross household incomes of less than $50,000 (OR 1.3, CI 1.1,1.6), and less than a college education (OR 1.3, CI 1.1,1.6). Similar risks were observed for persons who reported fatigue lasting six months or longer. Female sex (OR 3.2, CI 1.7, 6.4) was the only independent risk factor found for those persons classified as having a CFS-like illness. Case prevalence rates for all three categories of fatigue, as determined by multivariate analysis, were not significantly different among buildings. Despite finding a substantial number of employees with fatiguing illness in the two state office buildings, the prevalence was not significantly different than that for a comparable control building. Previously unidentified risk factors for fatigue of at least one month and at least six months identified in this population included Hispanic ethnicity, not having completed college, and income below $50,000.