European Neuropsychopharmacology - Articles in Press

Chronic effects of corticosterone on GIRK1-3 subunits and 5-HT1A receptor expression in rat brain and their reversal by concurrent fluoxetine treatment - Corrected Proof

2012-05-17

Abstract: Dysregulation of the serotonergic system and abnormalities of the hypothalamic–pituitary–adrenal axis have been demonstrated in major depression. Animal studies indicate that 5-HT1A receptor expression may be reduced by long-term administration of corticosterone. However, similar studies on the regulation of GIRK channels, one of the most important effectors of the neuronal 5-HT1A receptor, are limited. In order to address these issues, slow-release corticosterone pellets were implanted subcutaneously to adrenal intact male rats (200mg pellets, 35 days release). Starting on day 15, animals were treated for 21 days with fluoxetine (5mg/kg/day, i.p.), or vehicle. Using in situ hybridization histochemistry and receptor autoradiography, we found that chronic corticosterone treatment was accompanied by a significant decrease on the mRNAs coding for mineralocorticoid receptors in hippocampal areas. Under these conditions, 5-HT1A receptor mRNA expression decreased in dorsal raphe nucleus and dentate gyrus. However, 5-HT1A receptor levels, as measured by [3H]-8-OH-DPAT binding, diminished significantly only in dentate gyrus. It is noteworthy that chronic treatment with fluoxetine reversed the alterations on 5-HT1A receptor mRNA levels only in dorsal raphe. Finally, chronic corticosterone treatment produced an increase on the mRNA coding for the GIRK2 subunit in several hypothalamic and thalamic areas, which was reversed by fluoxetine. Measurements of cell density and volume of the granular layer of the dentate gyrus did not reveal significant changes after corticosterone or corticosterone plus fluoxetine treatments. These data are relevant for a better understanding of the differential regulation of pre- and postsynaptic 5-HT1A receptors by corticosterone flattened rhythm.

Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis - Corrected Proof

2012-05-16

Abstract: Altered striatal dopaminergic neurotransmission is thought to be fundamental to schizophrenia. Increased presynaptic dopaminergic activity ([18F]–DOPA PET) may predate the onset of psychotic symptoms and correlates to clinical symptoms in subjects at Ultra High Risk (UHR) for developing psychosis. Postsynaptic dopaminergic neurotransmission has not been investigated yet in UHR patients. We hypothesized that synaptic dopamine concentration would be increased in UHR patients, and that synaptic dopamine concentration would be related to symptom severity. 14 UHR patients and 15 age and IQ matched controls completed an [123I]–IBZM SPECT scan at baseline and again after dopamine depletion with alpha-methyl-para-tyrosine (AMPT). We measured changes in radiotracer binding potential, compared these between UHR patients and controls, and correlated these to symptom severity. The UHR group as a whole did not differ significantly from controls. AMPT significantly reduced symptom severity in the UHR group (p=0.014). Higher synaptic dopamine concentration predicted larger reduction of positive symptoms following depletion in the UHR group (p=0.01). In UHR patients, positive symptoms responded to dopamine depletion, comparable to observations in schizophrenia, suggesting a similar mechanism. Higher synaptic dopamine concentration was associated with more severe positive symptoms and a greater reduction of these symptoms following depletion.

Operant behavior to obtain palatable food modifies ERK activity in the brain reward circuit - Corrected Proof

2012-05-14

Abstract: Food palatability produces behavioral modifications that resemble those induced by drugs of abuse. Palatability-induced behavioral changes require both, the activation of the endogenous cannabinoid system, and changes in structural plasticity in neurons of the brain reward pathway. The ERK intracellular pathway is activated by CB1 receptors (CB1-R) and plays a crucial role in neuroplasticity. We investigated the activation of the ERK signaling cascade in the mesocorticolimbic system induced by operant training to obtain highly palatable isocaloric food and the involvement of the CB1-R in these responses. Using immunofluorescence techniques, we analyzed changes in ERK intracellular pathway activation in the mesocorticolimbic system of wild-type and CB1 knockout mice (CB1−/−) trained on an operant paradigm to obtain standard, highly caloric or highly palatable isocaloric food. Operant training for highly palatable isocaloric food, but not for standard or highly caloric food, produced a robust activation of the ERK signaling cascade in the same brain areas where this training modified structural plasticity. These changes induced by the operant training were absent in CB1−/−. We can conclude that the activation of the ERK pathway is associated to the neuroplasticity induced by operant training for highly palatable isocaloric food and might be involved in CB1-R mediated alterations in behavior and structural plasticity.

Testosterone in the brain: Neuroimaging findings and the potential role for neuropsychopharmacology - Corrected Proof

Peter Höfer, Rupert Lanzenberger, Siegfried Kasper — 2012-05-14

Abstract: Testosterone plays a substantial role in a number of physiological processes in the brain. It is able to modulate the expression of certain genes by binding to androgen receptors. Acting via neurotransmitter receptors, testosterone shows the potential to mediate a non-genomic so-called “neuroactive effect”. Various neurotransmitter systems are also influenced by the aromatized form of testosterone, estradiol. The following article summarizes the findings of preclinical and clinical neuroimaging studies including structural and functional magnetic resonance imaging (MRI/fMRI), voxel based morphometry (VBM), as well as pharmacological fMRI (phfMRI) and positron emission tomography (PET) regarding the effects of testosterone on the human brain. The impact of testosterone on the pathogenesis of psychiatric disorders and on sex-related prevalence differences have been supported by a wide range of clinical studies. An antidepressant effect of testosterone can be implicitly explained by its effects on the limbic system – especially amygdala, a major target in the treatment of depression – solidly demonstrated by a large body of neuroimaging findings.

Patients' acceptance of the deltoid application of risperidone long-acting injection - Corrected Proof

2012-05-14

Abstract: Objective: Recently risperidone long-acting injection (RLAI) was approved for alternative injection into the deltoid muscle in addition to the already established injection into the gluteal muscle. For the first time two different injection locations of a long-acting antipsychotic injection can be offered to patients. Their actual acceptance is of key interest. Experimental procedures: We surveyed 60 patients stabilized on gluteal RLAI therapy in our depot outpatient clinic. Participants were offered the possibility of switching to the alternative deltoid injection in a standardized manner. Prior to switching patients scored the extent of perceived pain and experienced level of shame through the present gluteal injection therapy on a 7-point-scale. Patients choosing to switch were followed up after three months and asked to report on their individual experience. Results: Switching to the deltoid application was chosen by 34 out of 60 patients. Three months later 15 patients were still receiving deltoid injections. The main reason for their staying with the deltoid injection was improved practicability as reported by these patients and 13 out of 15 patients clearly preferred the new location over the gluteal application. The main reason for returning to the gluteal injection was the pain experienced through the injection in the deltoid. Patients' initial decision whether to switch was not correlated with either perceived pain or the experienced level of shame through the preceding gluteal injections. Conclusions: The application of RLAI in the deltoid muscle is viewed as an alternative to the injection in the gluteal muscle by a considerable number of patients. Nevertheless, some patients experience increased injection pain through this application location while others perceive the switch as beneficial in terms of practicability. Therefore offering both injection locations with their respective pros and cons should become standard in the RLAI treatment offered.

Pre-treatment waking cortisol response and vulnerability to interferon α induced depression - Corrected Proof

2012-05-09

Abstract: Depressive disorder is a common consequence of interferon α treatment. An understanding of the aetiological processes involved is evolving. HPA axis abnormalities are clearly described in community depressive disorder and represent vulnerability to depression development. We explored whether pre-treatment HPA axis abnormalities influence depression emergence during interferon α treatment. We examined waking HPA axis response via salivary cortisol sampling in 44 non-depressed, chronic hepatitis C infected patients due to commence standard interferon α treatment. Hamilton depression scales and the structured clinical interview for DSM-IV major depressive disorder status were administered monthly during treatment. Major depressive disorder developed in 26 of 44 subjects during interferon-α treatment. The pre-treatment waking cortisol response over 1h was significantly greater in the subsequent switch to depression group (F=4.23, p=0.046). The waking cortisol response pre-treatment with interferon α appears greater in those subsequently switching to depressive disorder during treatment. This waking response may join other vulnerability factors for depression emergence in this group. This model could prove a valuable tool in understanding non-iatrogenic depressive disorder in the general population and notably the role of cytokines.

Effects of novel, high affinity glycine transport inhibitors on frontostriatal dopamine release in a rodent model of schizophrenia - Corrected Proof

Andrea Balla, Samantha Schneider, Henry Sershen, Daniel C. Javitt — 2012-05-07

Abstract: Dopaminergic hyperactivity within frontostriatal brain systems is a key feature of schizophrenia, and an objective neural correlate of positive schizophrenia symptoms. N-methyl-d-aspartate (NMDA) receptors are known to play a prominent role in regulation of frontostriatal dopamine release. Furthermore, disturbances in glutamatergic function are increasingly being linked to pathophysiology of both positive and negative symptoms of schizophrenia. Prior studies have demonstrated that subchronic continuous administration of the NMDA antagonist phencyclidine (PCP) induces schizophrenia-like hyper-reactivity of frontostriatal dopamine release to amphetamine (AMPH) in rodents, and that effects were reversed by glycine and the prototypic glycine transport inhibitor (GTI) NFPS. The present study investigates effectiveness of the novel, high affinity and well tolerated GTIs, R231857, R231860 and Org29335, to reverse schizophrenia-like enhancement of AMPH-induced DA release, along with effects of the partial glycine-site agonist d-cycloserine. As previously, PCP had no significant effect on basal DA levels, but significantly enhanced AMPH-induced DA release in prefrontal cortex. All GTIs tested, as well as d-cycloserine, significantly reduced PCP-induced enhancement of DA release in prefrontal cortex. Neither PCP nor GTIs significantly affected striatal DA release. Overall, these findings suggest that treatments which target the glycine modulatory site of the NMDA receptor may significantly reverse NMDA receptor antagonist-induced dysregulation of frontal DA systems, consistent with potential beneficial effects on positive-, in addition to negative-, symptoms of schizophrenia.

Psychiatric comorbidity of patients on methadone maintenance treatment with a history of sexual abuse - Corrected Proof

Einat Peles, David Potik, Shaul Schreiber, Miki Bloch, Miriam Adelson — 2012-05-07

Abstract: The aim of this study was to assess the prevalence of a history of sexual abuse and its relation to psychiatric comorbidity among former opiate addicts currently on methadone maintenance treatment (MMT). We evaluated the history of sexual abuse and current clinical obsessive compulsive disorder (OCD), dissociative identity disorder (DID), and complex posttraumatic distress disorder (cPTSD), and administered the Life Events Inventory Questionnaire among 125 MMT patients (76 females and 49 males). Eighty (64%) patients had experienced sexual abuse, 69 (55.2%) met the criteria for clinical OCD, 20 (16.0%) for cPTSD and 13 (10.4%) for DID. More females had clinical OCD than males (63.2% vs. 42.9%, respectively, p=0.03). Sexually abused patients had higher rates of clinical OCD than their non-abused counterparts (67.5% vs. 33.3%, respectively, p<0.0005) and a higher mean number of negative life events (8.0±2.0 vs. 7.1±1.8, p=0.01). Sexually abused patients showed a trend towards a higher Dissociative Experiences Scale score (17.6±10.1 vs. 14.6±8.1, p=0.08) and rate of DID (13.8% vs. 4.4%, p=0.1), but no significant difference in the rate of cPTSD (17.5% vs. 13.3%, p=0.6) compared to non-abused subjects. The 80 sexually abused patients were mostly female (85%), and 57.5% of them were abused by a family member. In summary, more sexually abused MMT patients were diagnosed with clinical OCD and fewer with cPTSD and DID. Those with cPTSD were characterized by more negative life events, higher dissociation scores, and assaults by a family member. We conclude that sexually abused MMT patients should be screened for clinical OCD.

Burden of psychiatric disorders in the pediatric population - Corrected Proof

2012-05-07

Abstract: In order to estimate the burden of mental disorders in a representative Italian pediatric population, an epidemiological study was performed using three administrative databases: a drug prescription, a hospital discharge form, and an outpatient ambulatory visit database. The population target was 1,616,268 children and adolescents under 18 years living in the Lombardy Region, Italy. A youth was defined as a case if during 2008 he/she received at least one psychotropic drug prescription or was hospitalized for a psychiatric disorder (International Classification of Disease codes 290–319), or attended a child neuropsychiatric outpatient unit for a visit and/or a psychological intervention or rehabilitation at least once. Epileptic children were excluded.In all, 63,550 youths (39.3 per 1000; 95%CI 39.1–39.7‰) were identified as users of health care resources for a putative mental disorder. The prevalence was higher in boys than in girls (47.0‰ versus 31.3‰) and the highest value was recorded in children 8 years old (60.2‰).A total of 59,987 youths (37.1‰) attended a child and adolescent neuropsychiatry service at least once, 3605 (2.2‰) were admitted to hospital, and 2761 (1.7‰) received at least one psychotropic drug prescription, 57% of which did not attend a child neuropsychiatry service. In all, 14,741 youths (23.1% of users) had a disorder that required a high intensity of care (e.g. recurrent prescriptions for drugs and/or ambulatory care).The proportion of youths who received care for mental disorders in the Lombardy Region seems lower than in other countries. However, the fact that many children were prescribed psychotropic drugs without the supervision of a child psychiatrist is a reason for concern.

Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder - Corrected Proof

2012-05-07

Abstract: Attention deficit hyperactivity disorder (ADHD) likely involves dopaminergic dysfunction in the frontal cortex and striatum, resulting in cognitive and motor abnormalities. Since both adenosine and dopamine modulation systems are tightly intertwined, we tested if caffeine (a non-selective adenosine receptor antagonist) attenuated the behavioral and neurochemical changes in adolescent spontaneously hypertensive rats (SHR, a validated ADHD animal model) compared to their control strain (Wistar Kyoto rats, WKY). SHR were hyperactive and had poorer performance in the attentional set-shifting and Y-maze paradigms and also displayed increased dopamine transporter (DAT) density and increased dopamine uptake in frontocortical and striatal terminals compared with WKY rats. Chronic caffeine treatment was devoid of effects in WKY rats while it improved memory and attention deficits and also normalized dopaminergic function in SHR. Additionally, we provide the first direct demonstration for the presence of adenosine A2A receptors (A2AR) in frontocortical nerve terminals, whose density was increased in SHR. These findings underscore the potential for caffeine treatment to normalize frontocortical dopaminergic function and to abrogate attention and cognitive changes characteristic of ADHD.

Those famous red pills—Deliberations and hesitations. Ethics of placebo use in therapeutic and research settings - Corrected Proof

D.P. Touwen, D.P. Engberts — 2012-04-25

Abstract: Placebo fascinates and mystifies. Even with today's medical science we still do not know how and if it works. The use of placebo both in therapy and in research evokes ethical problems that are not easily resolved either. Placebo is intrinsically linked to deception, while veracity is a basic tenet in today's thinking of a doctor–patient relationship. In research ethics placebo, though considered the golden control condition, leads to the question of the therapeutic obligation. This narrative review presents an overview of these ethical questions and offers considerations that are of relevance to daily medical and research practice both in psychiatry and elsewhere.

Detection of the acute effects of hydrocortisone in the hippocampus using pharmacological fMRI - Corrected Proof

2012-04-23

Abstract: Impaired hippocampal function is believed to be important in the pathogenesis of depression. The hippocampus contains a high concentration of both mineralocorticoid (MR) and glucocorticoid receptors (GR), and the experimental administration of corticosteroids has been reported to mimic memory impairments seen in depression. Using pharmacological functional magnetic resonance imaging (phMRI) we investigated whether hippocampal function is altered after acute administration of hydrocortisone. Changes in BOLD signal following infusion of 100mg hydrocortisone given as a rapid intravenous bolus were measured in 14 healthy volunteers in a within-subject placebo-controlled crossover design. Subsequently, subjects completed an n-back task during an fMRI scan. Hydrocortisone infusion caused a significant, time-dependent increase in fMRI BOLD signal in hippocampus reaching a maximal effect at 11–19min. The n-back task increased BOLD signal in prefrontal and parietal cortical areas and decreased it in the hippocampus. After hydrocortisone the left hippocampal decrease in BOLD signal was attenuated with the magnitude of attenuation correlating with the increase seen after hydrocortisone infusion. No difference in behavioural task performance was observed. The results suggest acute hydrocortisone has rapid direct and modulatory influences on hippocampal function, probably acting through non-genomic GR or MR signalling. Hydrocortisone infusion phMRI may be a useful tool to investigate hippocampal corticosteroid receptor function in depression.

Delayed- and early-onset hypotheses of antipsychotic drug action in the negative symptoms of schizophrenia - Corrected Proof

Stephen Z. Levine, Stefan Leucht — 2012-04-16

Abstract: The competing hypotheses that the action onset to antipsychotic medication assumes a course of early- or a delayed-response have been tested in positive and not negative symptoms in schizophrenia. The current study aims to test the early- and delayed-onset hypotheses with regard to negative symptoms. Data were re-analyzed from three clinical trials that compared placebo or amisulpride for up to 60 day. Participants had predominantly negative symptoms of schizophrenia (n=487). Response was examined with the incremental percentage Scale for the Assessment of Negative Symptoms (SANS) reduction over time. Response to the treatment, visit and treatment–visit interaction was assessed with mixed-modeling. Effect size differences on response between the amisulpride and placebo groups were reported at each visit. Across trials, mixed modeling showed that the incremental SANS reductions by the treatment–visit interaction that tests the action–onset hypothesis were not statistically significantly different across periods. The effect size differences of medication less placebo in the incremental percent SANS reduction showed non-significant differences based on overlapping confidence intervals with a moderate improvement at 8–14 day (ES=.33; 95% CI: −.07,.31), the least improvement at 28–30 day (ES=.12; 95% CI: −.07,.31), and a moderate improvement at 42–60 day to (ES=.39, 95%, CI: .19,.60). Generally, early- and delayed-response differences to antipsychotic were limited.

Geographical and temporal variations in clozapine prescription for schizophrenia - Corrected Proof

Jimmi Nielsen, Rasmus Røge, Ole Schjerning, Holger J. Sørensen, David Taylor — 2012-04-16

Abstract: Despite its unsurpassed efficacy in treatment-resistant schizophrenia, clozapine remains underutilized. Trends in the prescription of clozapine in patients with ICD-10 F20.x schizophrenia were assessed using data from Danish national registers. Three substudies were carried out: (i) an assessment of differences in national prescription patterns between 1996 and 2007 using a cross-sectional design; (ii) a comparison of time from first schizophrenia diagnosis to first prescription of clozapine in a five-year cohort study, using the Cox regression model, of two patient groups who were first diagnosed in 1996 and in 2003; (iii) an assessment of differences in the general psychiatric hospitals' use of clozapine in 2009. The results are as follows: (i) The percentage of schizophrenia patients receiving clozapine rose from 9.0% in 1996 to 10.1% in 2007 (p<0.001). In the same period, the percentage of patients having clozapine treatment augmented with another antipsychotic increased from 43.1% to 64.2%, p<0.001. (ii) Time from diagnosis with schizophrenia until first clozapine prescription was longer for patients diagnosed in 2003 compared to those diagnosed in 1996 (HR: 0.28 CI: 0.16–0.49). (iii) In 2009 there was significant variation in clozapine administration from one hospital to the other, with percentages of patients receiving the drug ranging from 5.7% to 16.8%, with 10.2% as the national mean. Although, the percentage of schizophrenia patients receiving clozapine increased from 1996 to 2007, the time from diagnosis of schizophrenia until first prescription of clozapine increased.

Reduced plasma levels of asymmetric Di-Methylarginine (ADMA) in patients with alcohol dependence normalize during withdrawal - Corrected Proof

2012-04-16

Abstract: Asymmetric Di-Methylarginine, an endogenous inhibitor of nitric oxide synthase, is increasingly recognized as vascular risk factor. Elevated ADMA levels have been described not only in ‘typical’ vascular diseases like congestive heart failure, artherosclerosis and diabetes but also for major depression and Alzheimer's disease.As homocysteine increases ADMA levels and elevated homocysteine serum levels are present in patients with alcohol dependence, the aim of the present study was to examine plasma ADMA levels in patients with alcohol dependence during withdrawal.ADMA and homocysteine levels were measured in the plasma from 42 patients drawn at baseline, on day 1, day 3 and day 7–10 of inpatient detoxification treatment. Measurements were compared against 32 healthy controls. We found significantly lower levels of ADMA in patients at baseline and on day 1 and 3, while no differences were present at the end of treatment. Plasma ADMA levels significantly increased during withdrawal. We found no association between homocysteine and ADMA levels.Our finding of reduced ADMA levels in actively drinking alcohol dependent patients is in apparent contrast to other findings regarding cardiovascular risk factors in alcoholism. However an influence of alcohol on arginine metabolism may help explain the so called ‘French paradox’.

Psychiatry should not become hostage to placebo: An alternative interpretation of antidepressant–placebo differences in the treatment response in depression - Corrected Proof

Zoltan Rihmer, Peter Dome, David S. Baldwin, Xenia Gonda — 2012-04-13

Abstract: Background: It is widely believed that in randomized controlled trials of antidepressants the difference between drug and placebo response rates is rather small (around 20%), leading to a common perception that antidepressants have limited efficacy.Aim: The aim of the present paper was to present an alternative calculation and interpretation of antidepressant–placebo difference in the treatment response to antidepressant in drug trials which may shed a new light on the efficacy of antidepressants.Issues: We have previously highlighted several controversial points concerning the calculation of antidepressant and placebo response rates in randomised controlled trials, which may influence views concerning the efficacy of drugs, and demonstrated several factors which may lead to overestimation of the placebo effect and underestimation of antidepressant efficacy. The traditional interpretation of antidepressant–placebo difference in randomized controlled trials on major depression has been also challenged previously from at least five points of view but all leading to a conclusion that currently prevailing opinions concerning relative placebo and antidepressant response rates overestimate placebo response, and thereby underestimate efficacy of antidepressant drugs. In our present paper we propose another method for calculating placebo and antidepressant response rates which may shed new light on an overlooked aspect of the efficacy of these drugs.Conclusions: We contend that opinions on the effectiveness of antidepressants should be reconsidered, and comparisons with placebo should be more carefully applied. Interpretation of the placebo response is of crucial importance for establishing the efficacy of antidepressive medications, and psychiatry should not become the hostage of placebo.

A randomized, double-blind, placebo-controlled trial to assess prevention of mood episodes with risperidone long-acting injectable in patients with bipolar I disorder - Corrected Proof

2012-04-13

Abstract: The efficacy and safety of risperidone long-acting injectable (LAI) for preventing recurrence of mood episodes in patients with bipolar I disorder was evaluated in a randomized, placebo-controlled study. After a 12-week open-label period with risperidone LAI (n=560), patients who did not experience a recurrence entered an 18-month randomized, double-blind period with risperidone LAI (n=132) or placebo (n=135); a third treatment arm (n=131) was randomized to oral olanzapine (10mg/day) for reference and exploratory comparisons. The primary efficacy endpoint was time to recurrence of any mood episode for risperidone LAI versus placebo in the double-blind period (Kaplan–Meier analysis). Additional efficacy endpoints included Young Mania Rating Scale, Montgomery–Asberg Depression Rating Scale and Clinical Global Impression. During the double-blind period, dosing was fixed at patients' final open-label dose (25mg, 66% of patients; 37.5mg, 31%; 50mg, 4%). The primary outcome demonstrated a median time to mood episode recurrence of 198 day in the placebo arm, whereas the median was not reached in the risperidone LAI arm (p=0.057). Time to recurrence of any mood episode was significantly longer with risperidone LAI versus placebo (log-rank test stratified by region only, p=0.031); the difference was significant for time to recurrence of elevated mood episodes (p=0.005) but not depressive episodes (p=0.655). Significant improvement of manic symptoms and global condition versus placebo were observed for risperidone LAI, with no evidence of worsening of depression. In conclusion, risperidone LAI significantly delayed time to recurrence of elevated mood episodes, with a safety profile consistent with previous studies.

European Group for the Study of Resistant Depression (GSRD) — Where have we gone so far: Review of clinical and genetic findings - Corrected Proof

2012-04-05

Abstract: The primary objective of this review is to give an overview of the main findings of the European multicenter project “Patterns of Treatment Resistance and Switching Strategies in Affective Disorder”, performed by the Group for the Study of Resistant Depression (GSRD). The aim was to study methodological issues, operational criteria, clinical characteristics, and genetic variables associated with treatment resistant depression (TRD), that is failure to reach response after at least two consecutive adequate antidepressant trials. The primary findings of clinical variables associated with treatment resistance include comorbid anxiety disorders as well as non-response to the first antidepressant received lifetime. Although there is a plethora of hints in textbooks that switching the mechanism of action should be obtained in case of nonresponse to one medication, the results of the GSRD challenge this notion by demonstrating in retrospective and prospective evaluations that staying on the same antidepressant mechanism of action for a longer time is more beneficial than switching, however, when switching is an option there is no benefit to switch across class. The GSRD candidate gene studies found that metabolism status according to cytochrome P450 gene polymorphisms may not be helpful to predict response and remission rates to antidepressants. Significant associations with MDD and antidepressant treatment response were found for COMT SNPs. Investigating the impact of COMT on suicidal behaviour, we found a significant association with suicide risk in MDD patients not responding to antidepressant treatment, but not in responders. Further significant associations with treatment response phenotypes were found with BDNF, 5HTR2A and CREB1. Additional investigated candidate genes were DTNBP1, 5HT1A, PTGS2, GRIK4 and GNB3.

A double-blind, randomized, placebo-controlled study with JNJ-37822681, a novel, highly selective, fast dissociating D2 receptor antagonist in the treatment of acute exacerbation of schizophrenia - Corrected Proof

2012-04-02

Abstract: JNJ-37822681 is a novel, highly selective dopamine D2 receptor antagonist characterized by a rapid dissociation rate from the dopamine D2 receptor. This profile was hypothesized to confer antipsychotic efficacy and improved tolerability. In this 12-week study, the efficacy and safety of JNJ-37822681 were evaluated in patients with an acute exacerbation of schizophrenia, randomly assigned (1:1:1:1:1) to JNJ-37822681 (10-, 20- or 30-mg bid), olanzapine (15mg once-daily), or placebo (for 6weeks followed by olanzapine for 6weeks). Of 498 randomized patients, 298 (60%) completed the study. All JNJ-37822681 dose groups and the olanzapine group showed significantly greater reduction in PANSS total score from baseline to week 6 versus placebo (all p-values<0.001). Least-squares adjusted mean changes from baseline to week 6 in PANSS total score were: −6.4 (placebo); −18.4 (10mg JNJ-37822681), −17.7 (20mg JNJ-37822681), −20.0 (30mg JNJ-37822681) and −22.9 (olanzapine). All JNJ-37822681 groups showed significant improvement versus placebo from baseline to week 6 in the PANSS subscales, Marder factors, Clinical Global Impression of Severity, and in the Subjective Well-Being on Neuroleptics scale (all p-values<0.05). The most common treatment-emergent adverse events with JNJ-37822681 were insomnia (17%) and akathisia (13%). Incidences of extrapyramidal symptoms were dose-related and were comparable for JNJ-37822681 10mg bid and olanzapine groups. All JNJ-37822681 dose groups showed lesser weight gain compared with olanzapine. The efficacy and tolerability profile of the JNJ-37822681 10mg bid was consistent with the study hypothesis.

Does prior antidepressant treatment of major depression impact brain function during current treatment? - Corrected Proof

Aimee M. Hunter, Ian A. Cook, Andrew F. Leuchter — 2012-03-26

Abstract: The relationship between prior antidepressant treatment and prefrontal brain functional response to subsequent treatment with antidepressant medication or placebo is unknown. Eighty-nine adults with Major Depressive Disorder (MDD), characterized as antidepressant-experienced or antidepressant-naive, received one week of single-blind placebo treatment prior to eight weeks of randomized treatment with medication (fluoxetine or venlafaxine; n=47) or placebo (n=42) in one of three similar placebo-controlled trials. Brain function was assessed at baseline, end of placebo lead-in, and during randomized treatment using quantitative electroencephalography (qEEG). The authors assessed change in prefrontal theta-band cordance (PFC) in antidepressant-experienced vs. antidepressant-naive subjects. Treatment history groups differed significantly on PFC change during the placebo lead-in even when controlling for clinical and demographic variables (F(1,62)=4.27, p=.04). As assessed in linear mixed models that examined treatment history (antidepressant-experienced or antidepressant-naive), treatment assignment (medication or placebo), and their interaction as predictors, treatment history also predicted PFC change during the randomized phase of treatment even when controlling for pretreatment clinical and demographic and symptom improvement during treatment (F(1,5o)=5.20, p=.03). The interaction was not significant. Post hoc analyses showed that antidepressant-experienced subjects treated with placebo showed PFC changes that did not differ from PFC changes seen in the medication group. Results suggest that prefrontal brain functional changes during treatment for MDD may differ depending upon prior treatment with antidepressant medication.

DAI-10 is as good as DAI-30 in schizophrenia - Corrected Proof

René Ernst Nielsen, Eva Lindström, Jimmi Nielsen, Sten Levander — 2012-03-22

Abstract: Drug attitude inventory (DAI-30) is considered to be the best predictor of poor adherence in first-episode schizophrenia. We compared the short version (DAI-10) with DAI-30 in long-term schizophrenia, documented if DAI was associated with poor insight, PANSS and GAF and constructed DAI-10 percentiles. DAI-30 and DAI-10 were homogenous (r=0.82 and 0.72, respectively) with good test–retest reliability (0.79). The correlation between the DAI versions was high (0.94). Percentile scores of DAI-10 were computed. DAI is an easy-to-use self-report instrument seemingly assessing a unique clinical dimension relevant to non-adherence. DAI-10 might be preferred for its simplicity and good psychometric properties.

Dexamphetamine reduces auditory P3 delta power and phase-locking while increasing gamma power - Corrected Proof

2012-03-22

Abstract: Auditory P3 amplitude reduction is one of the most robust and replicated findings in schizophrenia. Recent evidence suggests that these reductions are due to reductions in both power and phase-locking at delta and theta frequencies. We have previously shown that the auditory, but not visual, P3 is reduced in healthy participants given the catecholamine releasing agent dexamphetamine. Our aim was to determine whether the auditory P3 amplitude reduction induced by dexamphetamine has similar power and phase locking characteristics to that seen in schizophrenia. Forty-four healthy participants were given 0.45mg/kg dexamphetamine and placebo, in a double-blinded, placebo-controlled, cross-over design. The task was a three-stimulus auditory odd-ball task, target stimuli were the major stimuli of interest. Individual target trials underwent wavelet analysis to give power and phase-locking of delta (3Hz), theta (4–7Hz), alpha (8–12Hz), beta (13–30Hz) and gamma (30–50Hz) frequencies for a 50ms time window centred around the peak of the target P3. Delta power around the P3 peak was significantly reduced when participants were given dexamphetamine. Delta phase-locking was also reduced but only when analysis was targeted at the location of the peak P3 amplitude. In contrast, theta power and phase-locking were not affected by dexamphetamine. These findings suggest that increased catecholamine activity may be responsible for the power and phase-locking reductions of the auditory P3 delta component in patients with schizophrenia. Interestingly, dexamphetamine significantly increased gamma power around the P3 peak. We attempt to link this finding with the gamma alterations that have been found in patients with schizophrenia.

Synergistic antidepressant-like action of gaboxadol and escitalopram - Corrected Proof

2012-03-14

Abstract: According to current theories on the etiopathogenesis and pathophysiology of depression, both GABAergic and monoaminergic transmitter systems are perturbed. Consequently, the present study addressed the putative antidepressant action of the sedative-hypnotic GABAA receptor agonist, gaboxadol, separately and in combination with the selective serotonin reuptake inhibitor (SSRI) escitalopram. The rat chronic mild stress model was used to test the chronic antidepressant properties of gaboxadol in this depression model. Sucrose intake used as a read-out on anhedonic-like behavior indicated that the drug response rate for gaboxadol (5mg/kg/day, i.p.) was similar to that measured for escitalopram (5mg/kg/day, i.p.), however, the rate increased when the two drugs were co-administered, suggesting a synergistic action. Using in vivo electrophysiological recordings in dorsal raphe nucleus (DRN) of anesthetised rats, the present results showed that one week treatment with gaboxadol (5mg/kg/day, i.p.) or with escitalopram (5mg/kg/day, i.p.), followed by a 24h washout period, did not affect DRN 5-HT neuronal firing per se, but in rats treated with both drugs for one week, the firing rate of DRN 5-HT neurons was significantly increased. Immunohistochemical estimations of cell proliferation in the hippocampal dentate gyrus did not reveal any effect of gaboxadol on chronic mild stressed rats, indicating that neurogenesis per se is not systematically associated with recovery from anhedonic-like behavior. Taken together, our data reveal for the first time an antidepressant action of gaboxadol and indicate a synergistic mechanism, regarding rapid onset of action and efficacy, when co-administered with escitalopram.

Genetic polymorphisms in the opioid receptor mu1 gene are associated with changes in libido and insomnia in methadone maintenance patients - Corrected Proof

2012-03-14

Abstract: Methadone, a synthetic racemic opioid that primarily works as a μ-opioid receptor (OPRM1) agonist, is commonly used for the treatment of heroin addiction. Genetic association studies have reported that the OPRM1 gene is involved in the physiology of heroin and alcohol addiction. Our current study is designed to test the hypothesis that genetic polymorphisms in the OPRM1 gene region are associated with methadone dosage, plasma concentrations, treatment responses, adverse reactions and withdrawal symptoms in a methadone maintenance treatment (MMT) cohort from Taiwan. Fifteen OPRM1 single nucleotide polymorphisms (SNPs) were selected and genotyped using DNA samples from 366 MMT patients. The plasma concentrations of methadone and its metabolite were measured by high performance liquid chromatography. The results obtained using dominant model analysis indicate that the OPRM1 SNPs rs1074287, rs6912029, rs12209447, rs510769, rs3798676, rs7748401, rs495491, rs10457090, rs589046, rs3778152, rs563649, and rs2075572 are significantly associated with change-in-libido side effects (adjusted p<0.042). Using recessive model analysis, these SNPs were also found to be significantly associated with insomnia side effects in this cohort (p<0.009). The significance of the insomnia findings was mainly contributed by a subgroup of patients who had a positive urine morphine test (p<0.022), and by individuals who did not use benzodiazepine hypnotics (p<0.034). Our current data thus suggest that genetic polymorphisms in OPRM1 may influence the change-in-libido and insomnia side effects sometimes found in MMT patients.

Reduced expression of haloperidol conditioned catalepsy in rats by the dopamine D3 receptor antagonists nafadotride and NGB 2904 - Corrected Proof

Tomek J. Banasikowski, Richard J. Beninger — 2012-03-14

Abstract: Haloperidol, a dopamine (DA) D2 receptor-preferring antagonist, produces catalepsy whereby animals maintain awkward posture for a period of time. Sub-threshold doses of haloperidol fail to produce catalepsy initially, however, when the drug is given repeatedly in the same test environment, gradual day-to-day increases in catalepsy are observed. More importantly, if sensitized rats are injected with saline instead of haloperidol they continue to be cataleptic in the test environment suggesting that environment-drug associations may play a role. DA D3 receptors have been implicated in a number of conditioned behaviors. We were interested if DA D3 receptors contribute to catalepsy sensitization and conditioning in rats. We tested this hypothesis using the DA D3 receptor-selective antagonist NGB 2904 (0.5, 1.8mg/kg) and the DA D3 receptor-preferring antagonist nafadotride (0.1, 0.5mg/kg). For 10 consecutive conditioning days rats were treated with one of the D3 receptor antagonists alone or in combination with haloperidol (0.25mg/kg) and tested for catalepsy, quantified by the time a rat remained with its forepaws on a horizontal bar. On test day (day 11), rats were injected with saline or the D3 receptor antagonist and tested for conditioned catalepsy in the previously drug-paired environment. Rats treated with NGB 2904 or nafadotride alone did not develop catalepsy. Rats treated with haloperidol or haloperidol plus NGB 2904 or nafadotride developed catalepsy sensitization with repeated conditioning. When injected with saline they continued to exhibit catalepsy in the test environment — now conditioned. On the other hand, NGB 2904 (1.8mg/kg) or nafadotride (0.5mg/kg) given on the test day (after sensitization to haloperidol) significantly attenuated the expression of conditioned catalepsy. Our data suggest that the D3 receptor antagonist NGB 2904 (1.8mg/kg) and nafadotride (0.5mg/kg) significantly attenuate conditioned catalepsy in rats when given in test but not when given during sensitization. Results implicate DA D3 receptors in regulating the expression of conditioned catalepsy.

Alcohol consumption and premotor corpus callosum in older adults - Corrected Proof

2012-03-09

Abstract: Heavy alcohol consumption is toxic to the brain, especially to the frontal white matter (WM), but whether lesser amounts of alcohol negatively impact the brain WM is unclear. In this study, we examined the relationship between self-reported alcohol consumption and regional WM and grey matter (GM) volume in fifty-six men and thirty-seven women (70+− 7years) cognitively intact participants of the Baltimore Longitudinal Study of Aging (BLSA) with no history of alcohol abuse. We used regional analysis of volumes examined in normalized space (RAVENS) maps methodology for WM and GM segmentation and normalization followed by voxel based morphometry (VBM) implemented in SPM8 to examine the cross-sectional association between alcohol consumption and regional WM (and, separately, GM) volume controlling for age, sex, smoking, blood pressure and dietary thiamine intake. WM VBM revealed that in men, but not in women, higher alcohol consumption was associated with lower volume in premotor frontal corpus callosum. This finding suggests that even moderate amounts of alcohol may be detrimental to corpus callosum and white matter integrity.

Equipercentile linking of the Brief Psychiatric Rating Scale and the Clinical Global Impression Scale in a catchment area - Corrected Proof

2012-03-05

Abstract: Recent analyses tried to explain the meaning of the Brief Psychiatric Rating Scale total score (BPRS) and its percentage change from baseline by equipercentile linking with the Clinical Global Impression Scale (CGI). A major limitation was that they were conducted in clinical trial populations limiting generalisability to ‘real-world’ patients. We therefore replicated the findings in a large sample covering patients admitted to a state hospital with a catchment area. BPRS and CGI ratings at admission (n=1772) and at discharge from all patients with schizophrenic disorders (ICD-10 F20.0–F20.9) admitted between 2005 and 2008 were compared using equipercentile linking. Being considered “mildly ill” according to the CGI severity score approximately corresponded to a BPRS total score of 25, “moderately ill” to a BPRS of 33–35, “markedly ill” to a BPRS of 50 and severely ill to a BPRS of 70. To be “minimally improved” according to the CGI change score was associated with a mean BPRS reduction of 13%; and “much improved” with 50% BPRS reduction. The linking functions were not identical, but overall comparable to those in previous randomised trial samples. The suggestion that a 50% BPRS reduction from baseline is a clinically meaningful definition of response in acutely ill patients was reinforced.

Clinical response to antipsychotic drug treatment: Association study of polymorphisms in six candidate genes - Corrected Proof

2012-03-05

Abstract: Pharmacogenetic studies have demonstrated significant associations between several candidate genes (DRD2, DRD3, 5HTR2A and 5HTR2C, COMT and MTHFR) and antipsychotic drug response. The present study investigates the effect of nine polymorphisms in these genes for an association with antipsychotic treatment response. 329 Caucasian patients with a non-affective psychotic disorder using antipsychotics were included. All patients participated in the longitudinal GROUP-study in The Netherlands. We genotyped 9 SNPs in 6 candidate genes (DRD2: TaqI_A, -141C; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser; COMT: Val158Met; MTHFR: 677-C/T) using standard protocols. Polymorphisms were based on previous studies showing associations with positive symptoms treatment response. The Clinical Global Impression - Improvement (CGI-I) scale was used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used for association analyses. Ninety percent of the patients used second generation antipsychotics, with olanzapine (28%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value 0.034) and 677-C/T of MTHFR (P value 0.019) were tested statistically significant. Gly-carriers and T-carriers, respectively, showed more clinical improvement on the CGI-I. The other polymorphisms did not show a statistically significant association (P values>0.10). In conclusion, we replicated two out of nine of the previously reported associations between polymorphisms and treatment response. The direction and magnitude of the associations presented here in DRD3 (Ser9Gly) and MTHFR (677-C/T) are in line with previous association studies in Caucasian patients. These polymorphisms may be of value for predicting clinical response.

Hippocampus-specific deletion of tissue plasminogen activator “tPA” in adult mice impairs depression- and anxiety-like behaviors - Corrected Proof

Amine Bahi, Jean-Luc Dreyer — 2012-02-29

Abstract: Anxiety and depression are multifactorial disorders that have become prominent health problems all over the world. Neurotrophic factors have emerged underlying pathogenesis of these diseases. Although a number of studies indicate that the hippocampus-brain-derived neurotrophic factor (BDNF) may be involved in these psychiatric illnesses, little is known about the molecular mediators of these disorders. In this study we further investigate the role of tissue plasminogen activator (tPA), a serine protease involved in pro-BDNF cleavage to BDNF, in depression and anxiety-like behaviors in adult mice. To address this issue, we investigated the effect of hippocampus tPA manipulation, using viral vectors, on anxiety- and depression-like behaviors, including the marble burying test (MBT), elevated plus maze (EPM), tail suspension test (TST), novelty suppressed feeding (NSF) and forced swim test (FST). Our results showed that tPA knock-down – using lentiviral vectors expressing specific short hairpin RNAs (LV-shRNA) – increased the number of buried marbles together with the digging time in the MBT and decreased the time spent in open the arms of an EPM. In addition, tPA-knock down in the hippocampus increased immobility in the FST and TST, and increased time to feed in the NSF test. These effects were reversed when tPA-over-expressing vectors (LV-tPA) were injected in the hippocampus. We also found that BDNF protein levels were elevated in the hippocampus of mice receiving tPA-expressing vectors. Together, our results imply that tPA manipulation may provide an effective therapeutic intervention for depression and anxiety disorders.

Polymorphisms in AKR1C4 and HSD3B2 and differences in serum DHEAS and progesterone are associated with paranoid ideation during mania or hypomania in bipolar disorder - Corrected Proof

Anette G.M. Johansson, Pernilla Nikamo, Martin Schalling, Mikael Landén — 2012-02-23

Abstract: Paranoia is commonly a mood-incongruent psychotic symptom of mania which may be related to dopamine dysregulation. Progesterone and its metabolite allopregnanolone (ALLO) have been found in animals to antagonize the effects of dopamine. We therefore examined serum progesterone, its endogenous antagonist DHEAS and polymorphisms of the genes coding for certain steroidogenetic enzymes (AKR1C4, HSD3B2, and SRD5A1) in 64 males and 96 females with bipolar 1 or 2 disorder with or without paranoid ideation during mood elevation. Euthymic morning serum progesterone, DHEAS and cortisol concentrations were measured in males and in premenopausal women who were in follicular phase and not taking oral contraceptives. In women only, SNPs in AKR1C4 reduced the likelihood of having exhibited paranoid ideation by circa 60%. The haplotype of all 4 SNPs in the AKR1C4 gene reduced the risk of exhibiting paranoia by 80% (OR 0.19, 95% CI 0.06–0.61, p=0.05). A history of paranoid ideation was not, however, related to progesterone or DHEAS concentration. Serum DHEAS and progesterone concentrations were lower in men who had shown paranoid ideation during mania/hypomania compared with those who had not (F=7.30, p=0.006) however this was not coupled to polymorphisms in the selected genes. The ancestral G in rs4659174 in HSD3B2 was in men associated with a lower risk of paranoid ideation (likelihood ratio χ2 3.97, p=0.046, OR 0.31 (95% CI 0.10–0.96)) but did not correlate with hormone concentrations. Hence, gene variants in the steroidogenetic pathway and steroids concentration differences may be involved in the susceptibility to paranoia during mood elevation.

Association between the dexamethasone suppression test and serotonin transporter availability in healthy volunteers — A SPECT with [123I] ADAM study - Corrected Proof

2012-02-22

Abstract: Most common psychiatric diseases have been found to be associated with disturbance of both the hypothalamic–pituitary–adrenal (HPA) axis and the brain serotonergic system. The aim of this study was to explore the neuroendocrine relationships between the dexamethasone suppression test (DST) and serotonin transporter (SERT) availability in healthy volunteers. Sixty-six participants (30 males and 36 females) were recruited from the community. The DST suppression rate (D%) is the reduction in cortisol level from Day 1 (D1) to Day 2 (D2) in proportion to the Day 1 cortisol level (D%=(D1−D2)/D1×100%). SPECT with [123I] ADAM was used to measure SERT availability. A significant correlation between D% and SERT availability was noted in all subjects (Spearman's ρ=0.26, p=0.03) and in the male subjects (Spearman's ρ=0.41, p=0.02). SERT availability may be sensitive to changes in DST, especially in males.

Neuropathology markers and pathways associated with molecular targets for antipsychotic drugs in postmortem brain tissues: Exploration of drug targets through the Stanley Neuropathology Integrative Database - Corrected Proof

Sanghyeon Kim, Katerina Zavitsanou, George Gurguis, Maree J. Webster — 2012-02-22

Abstract: The atypical antipsychotics bind multiple receptor targets, including dopamine D2 receptors (DRD2), 5-HT2 receptors (HTR2A), α-2 adrenergic receptors (ADRA2A), and muscarinic receptors (CHRM1/4). Deficits in antipsychotic targets, their associated pathways, and the causal relationships between the various targets were explored using the Stanley Neuropathology Consortium Integrative Database (SNCID; http://sncid.stanleyresearch.org) and the Network Edge Orienting (NEO) software. There were brain region-specific deficits in the level of the antipsychotic targets, and the level of each target correlated with the mRNA level of the neurotrophic factor BDNF. While myelination was a common process correlated with both DRD2 mRNA levels and ADRA2A activity in the frontal cortex, metabolic processes were specifically correlated with DRD2 mRNA. Immune and inflammatory responses and apoptosis pathways were correlated with group II metabotropic glutamate receptors (GRM2), which are a target for the development of the next-generation antipsychotics. The NEO analysis revealed that HTR2A and GRM2 are likely to regulate BDNF levels in the hippocampus and frontal cortex, respectively, whereas DRD2 and ADRA2A activity are likely to be regulated by BDNF in the frontal cortex. BDNF may play an important role in mechanisms of action of the current antipsychotics and the next-generation antipsychotics that target GRM2. However, this data-mining approach indicates that the next-generation antipsychotics are likely to work through pathways that are distinct from those through which the current antipsychotics work. Exploratory analyses such as these may initiate future hypothesis-driven studies to reveal the mechanisms of action underlying the efficacy and side-effects of the antipsychotics.

The Schizophrenia and Bipolar Disorder associated BRD1 gene is regulated upon chronic restraint stress - Corrected Proof

2012-02-20

Abstract: Recent genetic evidence has implicated the bromodomain containing 1 gene (BRD1) with brain development and susceptibility to Schizophrenia and Bipolar Disorder. The BRD1 protein, which is essential for acetylation of histone H3K14, is a putative regulator of transcription during brain development and in the mature CNS. However, several issues remain to be clarified for example regarding the regulation of the BRD1 gene upon environmental interventions. Chronic restraint stress (CRS) in rats represents an environmental method for induction of morphological and functional changes in the hippocampus and the prefrontal cortex. In order to investigate whether the expression of the rat Brd1 gene may be regulated during such conditions, Brd1 mRNA and protein levels in hippocampus and prefrontal cortex extracts from rats subjected to either 1/2 or 6h of CRS per day for 21days were measured. We found a significant 2-fold up-regulation of long exon 7 splice variants of the Brd1 gene (Brd1-L) in hippocampus in both groups of CRS rats compared to controls. Concomitantly, we found a similar up-regulation of the BRD1 protein. In prefrontal cortex, we found no significant differences in Brd1 mRNA or protein levels. As selective histone deacetylase (HDAC) inhibitors not only preserve stress-induced hyperacetylation of histone H3K14 but also have hippocampal-dependent antidepressant-like activity, we propose that BRD1 by its intrinsic acetylation activity towards histone H3K14 is a player in the regulatory processes underlying adaptation to stress in the mature CNS.

The association between availability of serotonin transporters and time to relapse in heroin users — A two-isotope SPECT small sample pilot study - Corrected Proof

2012-02-15

Abstract: Neuroimaging evidence supporting an association between either dopamine or serotonin and time to relapse of heroin users is limited. In this two-isotope SPECT small sample (N=9) pilot study, the relationship between the availability of serotonin transporter (SERT) and dopamine transporter (DAT) and the relapse of heroin users was investigated. A significant negative association between SERT availability and time to relapse among those who relapsed (N=7) was found.

Marked inbred mouse strain difference in the expression of quinpirole induced compulsive like behavior based on behavioral pattern analysis - Corrected Proof

2012-02-13

Abstract: Obsessive–compulsive disorder (OCD) is a chronic and complex psychiatric disorder with a lifetime prevalence of 2–3%. Recent work has shown that OCD rituals were not only characterized by a high rate of repetition but also by an increased behavioral repertoire due to additional non-functional unique acts. These two behavioral characteristics may provide an ethological basis for studying compulsive behavior in an animal model of OCD. Here, quinpirole induced behavior (so far only investigated in rats) has been studied in A/J and C57BL/6J mice by using behavioral pattern analysis. The aim of this study is to investigate whether genetic background is mediating this behavior. Results showed that open field motor activity levels of saline treated C57BL/6J mice was significantly higher compared to A/J treated saline mice. Long-term quinpirole treatment increased open field motor activity levels in A/J, but not in C57BL/6J. Quinpirole treatment induced a strain dependent difference in behavioral repertoire. There was a dose dependent increase in the number of different behavioral patterns in A/J, whereas, in C57BL/6J there was a dose dependent decrease. This data suggest that genetic background is important in expressing quinpirole induced compulsive like behavior. Following quinpirole treatment, A/J mice express a greater behavioral repertoire with a high rate of repetition. This phenotype resembles that of OCD rituals in patients and indicates that this strain is very interesting to further validate for studying neurobiological mechanisms of compulsive behavior.

Prefrontal cortical anandamide signaling coordinates coping responses to stress through a serotonergic pathway - Corrected Proof

2012-02-13

Abstract: The endocannabinoid system has recently emerged as a vital component of the stress response and is an appealing target for the treatment of mood and anxiety disorders. Additionally, corticolimbic endocannabinoid signaling is important for stress-induced regulation of emotional behavior. However, the mechanism by which this occurs remains elusive. Combining biochemical and behavioral analyses within the forced swim test, we examined whether stress-induced regulation of endocannabinoid signaling in the medial prefrontal cortex contributes to behavioral responses to stress, and whether these responses are dependent on serotonergic neurotransmission. Forced swim stress produced a rapid and pronounced reduction in medial prefrontal anandamide content, but had no effect on 2-arachidonoylglycerol content within this region. Local administration of the anandamide hydrolysis inhibitor URB597 (0.01μg) into the ventromedial region of the prefrontal cortex decreased passive coping responses and increased active behavioral strategies, a phenomenon which was blocked by local antagonism of the CB1 receptor. Furthermore, local inhibition of anandamide hydrolysis within the medial PFC increased the firing rate of serotonergic neurons within the dorsal raphe, suggesting that prefrontal cortical endocannabinoid signaling may modulate stress coping behaviors through a regulation of serotonergic neurotransmission. Accordingly, serotonin depletion prevented the ability of inhibition of anandamide hydrolysis within the medial PFC to promote active stress coping responses. Collectively, these data argue that stress-induced changes in endocannabinoid signaling within the medial PFC modulate stress-coping behaviors through a regulation of serotonergic neurotransmission and provide a neuroanatomical framework by which we may understand the mechanisms subserving the antidepressant potential of the endocannabinoid system.

Changes in trend of antipsychotics prescription in patients treated with cholinesterase inhibitors after warnings from Italian Medicines Agency. Results from the EPIFARM-Elderly Project - Corrected Proof

2012-02-02

Abstract: The objective of the study was to assess the trend of antipsychotic prescription in elderly patients taking cholinesterase inhibitors (ChEIs) from 2002 to 2008 and the changes subsequent to two main official warnings issued by the Italian Medicines Agency to restrict their use. Elderly patients aged 65–94years who received at least one prescription of ChEIs between 1 January 2002 and 31 December 2008 were selected. We used data on prescriptions from the Lombardy Region Drug Administrative Database (Italy). The first prescription of one ChEI was used as the index day to calculate the prescription of an antipsychotic. The prescription of atypical antipsychotics in patients exposed to ChEIs declined from 21.0% in 2002 to 14.6% in 2008 (OR 0.92; 95%CI:0.90, 0.94; p<0.001), while the prescribing prevalence of typicals slightly increased (OR 1.08; 95%CI:1.03, 1.13; p=0.001). In relation to the two warnings, the prevalence of patients who received a prescription of antipsychotics was significantly lower in 2005 than 2004 (23.1% vs. 28.0%; OR 0.79; 95%CI:0.73–0.86; p<0.001) and in 2007 than 2006 (19.4% vs. 23.0%; OR 0.79; 95%CI:0.73–0.86; p<0.001). After the first safety warning the prevalence of prescriptions for risperidone and olanzapine dropped significantly, and there was a significant increase for quetiapine. Haloperidol prescriptions increased, especially after the second warning. Despite regulatory warnings issued to discourage the use of antipsychotics, they are still frequently prescribed to patients taking ChEIs. Awaiting further studies to clarify their therapeutic role, physicians should prescribe antipsychotics very cautiously and only after careful risk–benefit assessment.

A link between oxytocin and serotonin in humans: Supporting evidence from peripheral markers - Corrected Proof

2012-02-02

Abstract: Pharmacological studies indicate a functional interaction between the serotonergic and oxytocinergic systems. In particular, some selective serotonin (5-HT) reuptake inhibitors, such as citalopram and fluvoxamine, seem to exert part of their antidepressant effects through oxytocin (OT) release. Further, the administration of fenfluramine, a serotonergic agonist, to healthy subjects increases plasma OT levels. Interestingly, immunocytochemical and double-immunofluorescent techniques revealed a high degree of overlap between 5-HT transporter (SERT)-labeled fibers and OT-containing cells in the paraventricular and supraoptic nuclei of primate hypothalamus. These findings suggest that the influence of 5-HT on OT system might be mediated by SERT. In this study, we explored the possible existence of a link between OT and SERT in human subjects, by means of two peripheral markers, the platelet SERT, as measured by [3H]-paroxetine ([3H]-Par) binding, and plasma OT levels. As far as [3H]-Par binding parameters are concerned, the Bmax (mean±SD, fmol/mg protein) was 1155+130 and the Kd (mean±SD, nM) was 1.31±0.61. The OT plasma levels (mean±SD, pg/ml) were 1.14±1.07. A significant and positive correlation was found between plasma OT levels and Kd values (correlation coefficient: r: 0.466, p=.038). This result represents the first evidence of an interaction between OT and SERT, as measured by [3H]-Par binding, at peripheral levels in humans. Given the several activities mediated by both OT and 5-HT, such a relationship might provide new perspectives and insights into psychiatric disorders and/or social relationship disturbances, as well as novel treatment strategies overcoming and/or integrating the serotonergic paradigm.

Characterization of the neuropsychological phenotype of glycine N-methyltransferase−/− mice and evaluation of its responses to clozapine and sarcosine treatments - Corrected Proof

2012-01-24

Abstract: Glycine N-methyltransferase (GNMT) affects cellular methylation capacity through regulating the ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The product of its enzymatic reaction—sarcosine has antipsychotic effect in patients with schizophrenia. In this study, through RT-PCR and immunohistochemical staining, we demonstrated that GNMT expressed in various neurons located in the cerebral cortex, hippocampus, substantia nigra and cerebellum. Compared to the wild-type mice, Gnmt−/− mice had significantly lower level of sarcosine in the cerebral cortex. Real-time PCR identified genes involved in the methionine metabolism (Dnmt1 and Dnmt3a), ErbB (Nrg1 and ErbB4) and mTOR (Akt2, S6, S6k1 and S6k2) signaling pathways were dysregulated significantly in the cortex of Gnmt−/− mice. Acoustic startle reflex test demonstrated that Gnmt−/− mice had significantly lower level of prepulse inhibition and the deficit was ameliorated through clozapine or sarcosine treatment. Furthermore, liver-specific-human-GNMT transgenic with Gnmt−/− (Tg-GNMT/Gnmt−/−) mice were used to rule out that the phenotype was due to abnormal liver function. In summary, the neuropsychological abnormalities found in Gnmt−/− mice may represent an endophenotype of schizophrenia. GNMT plays an important role in maintaining normal physiological function of brain and Tg-GNMT/Gnmt−/− mice are useful models for development of therapeutics for patients with schizophrenia.

Chronic treatment with lithium or valproate modulates the expression of Homer1b/c and its related genes Shank and Inositol 1,4,5-trisphosphate receptor - Corrected Proof

2012-01-16

Abstract: Homer proteins are associated with both dopaminergic and glutamatergic function. In addition, these proteins are implicated in many signal transduction pathways that are also putative targets of the mood stabilizers lithium and valproate (VPA). This study investigated the effect of in vivo chronic administration of therapeutically-relevant doses of lithium and VPA on the expression of the inducible (Homer1a and ania-3) and constitutive (Homer1b/c) isoforms of the Homer1 gene in rat brain, and of two other Homer-related genes: Inositol 1,4,5 trisphosphate receptor (IP3R) and Shank. Homer1b/c was significantly decreased in cortex by VPA, and in striatal and accumbal subregions by both lithium and VPA. Both mood stabilizers reduced Homer1b/c expression in the dorsolateral caudate-putamen, while only VPA decreased gene expression in all other striatal subregions. Shank and IP3R were downregulated by both mood stabilizers in the cortex. Neither chronic lithium nor VPA affected Homer immediate-early genes. These results suggest that lithium and VPA similarly modulate the expression of structural postsynaptic genes with topographic specificity in cortical and subcortical regions. Thus, Homer may represent an additional molecular substrate for mood stabilizers, and a potential link with dopaminergic function.

Differential effects of ADORA2A gene variations in pre-attentive visual sensory memory subprocesses - Corrected Proof

Christian Beste, Ann-Kathrin Stock, Vanessa Ness, Jörg T. Epplen, Larissa Arning — 2012-01-13

Abstract: The ADORA2A gene encodes the adenosine A2A receptor that is highly expressed in the striatum where it plays a role in modulating glutamatergic and dopaminergic transmission. Glutamatergic signaling has been suggested to play a pivotal role in cognitive functions related to the pre-attentive processing of external stimuli. Yet, the precise molecular mechanism of these processes is poorly understood. Therefore, we aimed to investigate whether ADORA2A gene variation has modulating effects on visual pre-attentive sensory memory processing. Studying two polymorphisms, rs5751876 and rs2298383, in 199 healthy control subjects who performed a partial-report paradigm, we find that ADORA2A variation is associated with differences in the efficiency of pre-attentive sensory memory sub-processes. We show that especially the initial visual availability of stimulus information is rendered more efficiently in the homozygous rare genotype groups. Processes related to the transfer of information into working memory and the duration of visual sensory (iconic) memory are compromised in the homozygous rare genotype groups. Our results show a differential genotype-dependent modulation of pre-attentive sensory memory sub-processes. Hence, we assume that this modulation may be due to differential effects of increased adenosine A2A receptor signaling on glutamatergic transmission and striatal medium spiny neuron (MSN) interaction.

Age, sex and NK1 receptors in the human brain — A positron emission tomography study with [11C]GR205171 - Corrected Proof

2012-01-06

Abstract: The substance P/neurokinin 1 (SP/NK1) system has been implicated in the processing of negative affect. Its role seems complex and findings from animal studies have not been easily translated to humans. Brain imaging studies on NK1 receptor distribution in humans have revealed an abundance of receptors in cortical, striatal and subcortical areas, including the amygdala. A reduction in NK1 receptors with increasing age has been reported in frontal, temporal, and parietal cortices, as well as in hippocampal areas. Also, a previous study suggests sex differences in cortical and subcortical areas, with women displaying fewer NK1 receptors. The present PET study explored NK1 receptor availability in men (n=9) and women (n=9) matched for age varying between 20 and 50years using the highly specific NK1 receptor antagonist [11C]GR205171 and a reference tissue model with cerebellum as the reference region. Age by sex interactions in the amygdala and the temporal cortex reflected a lower NK1 receptor availability with increasing age in men, but not in women. A general age-related decline in NK1 receptor availability was evident in the frontal, temporal, and occipital cortices, as well as in the brainstem, caudate nucleus, and thalamus. Women had lower NK1 receptor availability in the thalamus. The observed pattern of NK1 receptor distribution in the brain might have functional significance for brain-related disorders showing age- and sex-related differences in prevalence.

A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD) - Corrected Proof

David S. Baldwin, Henrik Loft, Marianne Dragheim — 2012-01-03

Abstract: The efficacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with DSM-IV-TR diagnosed major depressive disorder (MDD) were evaluated in this 8-week, multi-site study. Patients (n=766) had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥26 and were randomly assigned (1:1:1:1:1) to 2.5, 5 or 10mg Lu AA21004, placebo, or 60mg duloxetine. The 5mg and 10mg doses of Lu AA21004 were tested separately versus placebo at p≤0.025 in a pre-specified order. In the pre-defined primary efficacy analysis [mean change from baseline in MADRS total score at Week 8, full analysis set, ANCOVA, last observation carried forward (LOCF)], the differences to placebo (n=145) of −1.7 (Lu AA21004 5mg, n=155) and −1.5 points (Lu AA21004 10mg, n=151) were not statistically significant; nor were those for Lu AA21004 2.5mg (−1.4 points, n=155) or duloxetine (−2.0 points, n=149). Using mixed model, repeated measures (MMRM) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Treatment-emergent adverse events led to the withdrawal of 72 patients: 8% (placebo), 12% (duloxetine), and 6%, 11% and 9% in the Lu AA21004 groups (2.5mg, 5mg and 10mg, respectively). The most common adverse events were nausea, headache, dizziness, and dry mouth. No clinically relevant changes were seen in vital signs, weight, ECG, or laboratory results. In summary, none of the active treatment groups, including duloxetine, separated from placebo in the primary analysis in this 'failed' study. Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Lu AA21004 (2.5, 5 and 10mg) was well tolerated.

The acute effects of d-amphetamine and d-methamphetamine on ERP components in humans - Corrected Proof

B. Silber, R. Croft, D.A. Camfield, L.A. Downey, K. Papafotiou, C. Stough — 2012-01-03

Abstract: While a number of behavioural studies have been conducted to investigate the acute effects of amphetamines on tasks of attention and information processing, there is currently a scarcity of research concerning their electrophysiological effects in healthy adults. It is also unclear as to whether amphetamines exert effects on stimulus evaluation or response selection. In two studies, independent groups of twenty healthy illicit stimulant users aged between 21 and 32years were administered 0.42mg/kg d-amphetamine versus placebo, and 0.42mg/kg d-methamphetamine versus placebo respectively, and completed an auditory oddball task on two separate testing days. A 62-channel EEG was recorded during the completion of the task, and the effects of amphetamines on N200 and P300 ERP components were analysed. d-amphetamine significantly decreased reaction time, improved accuracy, and reduced the latency of the P300 component relative to placebo, while having no effect on the N200 component. d-methamphetamine had no effect on reaction time, accuracy or the P300 component, but reduced the amplitude of the N200 component, relative to placebo. It was concluded that there is tentative support to suggest that d-amphetamine at a dose of 0.42mg/kg may enhance speed of information processing while d-methamphetamine at a dose of 0.42mg/kg may reflect changes to stimulus evaluation.

Acutely applied MDMA enhances long-term potentiation in rat hippocampus involving D1/D5 and 5-HT2 receptors through a polysynaptic mechanism - Corrected Proof

2012-01-03

Abstract: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a drug of abuse that induces learning and memory deficit. However, there are no experimental data that correlate the behavioral evidence with models of synaptic plasticity such as long-term potentiation (LTP) or long-term depression (LTD). Using field potential recordings in rat hippocampal slices of young rats, we found that acute application of MDMA enhances LTP in CA3–CA1 synapses without affecting LTD. Using specific antagonists and paired-pulse facilitation protocols we observed that the MDMA-dependent increase of LTP involves presynaptic 5-HT2 serotonin receptors and postsynaptic D1/D5 dopamine receptors. In addition, the inhibition of PKA suppresses the MDMA-dependent increase in LTP, suggesting that dopamine receptor agonism activates cAMP-dependent intracellular pathways. We propose that MDMA exerts its LTP-altering effect involving a polysynaptic interaction between serotonergic and dopaminergic systems in hippocampal synapses. Our results are compatible with the view that the alterations in hippocampal LTP could be responsible for MDMA-dependent cognitive deficits observed in humans and animals.

The melanin-concentrating hormone (MCH) system in an animal model of depression-like behavior - Corrected Proof

M.J. García-Fuster, G.S. Parks, S.M. Clinton, S.J. Watson, H. Akil, O. Civelli — 2012-01-03

Abstract: Selective breeding for divergence in locomotion in a novel environment (bHR, bred High-Responder; bLR, bred Low-Responder) correlates with stress-reactivity, spontaneous anxiety-like behaviors and predicts vulnerability in a rodent model of depression. Identifying genetic factors that may account for such vulnerability are key determinants not only for the illness outcome but also for the development of better-tailored treatment options. Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits some of the hallmarks of a regulator of affective states. The aim of this study was to ascertain the role of the MCH system in depression-like behaviors in bHR vs. bLR rats. bLR rats showed a 44% increase in hypothalamic pMCH mRNA and a 14% decrease in hippocampal CA1 MCH1R mRNA when compared to bHR rats. Interestingly, the amount of time that rats spent immobile in the FST (depressive-like behavior) correlated positively with the amount of hypothalamic pMCH mRNA and negatively with that of hippocampal CA1 MCH1R. The results indicate that the bLR–bHR is a useful rat model to investigate individual basal genetic differences that participate in the monitoring of emotional responsiveness (i.e., depression- and anxiety-like behaviors). They also point to the MCH system (i.e., chronically higher pMCH expression and consequently receptor down-regulation) as a candidate biomarker for the severity of depressive-like behavior. The data indicate that MCH1R participates in the modulation of depression-like behavior through a process that involves the CA1 region of the hippocampus, supporting the possible use of MCH1R antagonists in the treatment of depression.

Mapping serotonergic dysfunction in MDMA (ecstasy) users using pharmacological MRI - Corrected Proof

2012-01-03

Abstract: 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to induce loss of brain serotonin (5-HT) neurons. The purpose of this study was to determine the usefulness of pharmacological magnetic resonance imaging (phMRI) in assessing 5-HT dysfunction by examining the hemodynamic response evoked by infusion with the selective 5-HT reuptake inhibitor citalopram. We studied the effects of MDMA on brain hemodynamics using arterial spin labeling (ASL) based phMRI following a citalopram challenge (7.5mg/kg, i.v.), combined with [123I]β-CIT SPECT imaging in ten male MDMA users and seven healthy non-users. Single photon emission computed tomography (SPECT) imaging was used to assess the availability of 5-HT transporters (SERT). Imaging results were compared with the results of behavioral measures and mood changes following drug administration, in both groups (using the Beck Depression Inventory, Barratt Impulsiveness Scale and a visual analog scale). Reductions in SERT binding were observed in the occipital cortex of MDMA users. In line with this, citalopram induced decreases in cerebral blood flow (CBF) in the occipital cortex of MDMA users. ASL based phMRI also detected a CBF decrease in the thalamus of MDMA users. In concordance with imaging findings, behavioral measures differed significantly between MDMA users and controls. MDMA users had higher impulsivity scores and felt more uncomfortable after citalopram infusion, compared with control subjects. Our findings indicate that phMRI is very well suited for in-vivo assessment of 5-HT dysfunction.

Physiological and affective reactivity to a 35% CO2 inhalation challenge in individuals differing in the 5-HTTLPR genotype and trait neuroticism - Corrected Proof

Ellen Verschoor, C. Rob Markus — 2012-01-03

Abstract: The inhalation of 35% carbon dioxide (CO2) results in an acute stress response in healthy individuals and may accordingly provide a good paradigm to examine potential vulnerability factors for stress reactivity and stress-related psychopathology. It has been proposed that CO2 reactivity is moderated by genetic (5-HTTLPR) and personality (neuroticism) factors, yet no experimental study has investigated their effects on CO2 reactivity simultaneously. The current study examined the singular and interactive effects of the 5-HTTLPR genotype and neuroticism in predicting the affective and physiological response to a 35% CO2 challenge in a healthy sample of male and female students. From a large group of 771 students, 48 carriers of the low/low expressing allele (S/S, S/Lg, Lg/Lg) and 48 carriers of the high/high expressing allele (La/La) with the lowest and the highest neuroticism scores (77 females, 19 males; mean age±SD: 20.6±2years) were selected and underwent a 35% CO2 inhalation. Visual analogue scales for anxiety and discomfort and the Panic Symptom List were used to assess affective symptomatology, while salivary samples and heart rate were assessed to establish the physiological response. A typical pattern of responses to CO2 was observed, characterised by increases in anxiogenic symptoms and physical panic symptomatology and a reduction in heart rate; however, no effect on salivary cortisol concentration was observed. Additionally, the CO2 reactivity did not differ between groups divided by the 5-HTTLPR genotype or neuroticism. Findings of the current study do not support a role for singular or interactive effects of the 5-HTTLPR genotype and trait neuroticism on affective and physiological reactivity to a 35% CO2 inhalation procedure.

Head to head comparisons as an alternative to placebo-controlled trials - Corrected Proof

Eduard Vieta, Nuria Cruz — 2011-12-28

Abstract: Head to head trials have been proposed as an alternative to the ethical and methodological concerns related to placebo-controlled trials. While those studies may be particularly informative from the clinical and cost-effectiveness point-of-view, avoiding placebo poses several regulatory concerns: for superiority designs, the choice of the trial population, outcomes, dose and escalation of the comparator, as well as the comparator itself may be an issue; for non-inferiority studies, issues related to uncertain assay sensitivity and exposure of large samples to potentially ineffective or unsafe drugs make them inappropriate, in the absence of a previous positive superiority trial, for regulatory purposes. The inclusion of active comparators in regulatory trials should not be seen as an alternative, but as a useful complement to the information that can be obtained from placebo-controlled studies.

Early gene mapping after deep brain stimulation in a rat model of tardive dyskinesia: Comparison with transient local inactivation - Corrected Proof

Meaghan C. Creed, Clement Hamani, José N. Nobrega — 2011-12-12

Abstract: Deep brain stimulation (DBS) has been extensively used in Parkinson's disease and is also currently being investigated in tardive dyskinesia (TD), a movement disorder induced by chronic treatment with antipsychotic drugs such as haloperidol (HAL). In rodents, vacuous chewing movements (VCMs) following chronic HAL administration are suggested to model orofacial dyskinesias in TD. We show that 60min of DBS (100μA, 90μs, 130Hz) applied to the entopeduncular (EPN) or subthalamic (STN) nuclei significantly decreases HAL-induced VCMs. Using zif268 as a neural activity marker, we found that in HAL-treated animals EPN stimulation increased zif268 mRNA levels in the globus pallidus (+65%) and substantia nigra compacta (+62%) and reticulata (+76%), while decreasing levels in the motor cortex and throughout the thalamus. In contrast, after STN DBS zif268 levels in HAL-treated animals decreased in all basal ganglia structures, thalamus and motor cortex (range: 29% in the ventrolateral caudate-putamen to 100% in the EPN). Local tissue inactivation by muscimol injections into the STN or EPN also reduced VCMs, but to a lesser degree than DBS. When applied to the EPN muscimol decreased zif268 levels in substantia nigra (−29%), whereas STN infusions did not result in significant zif268 changes in any brain area. These results confirm the effectiveness of DBS in reducing VCMs and suggest that tissue inactivation does not fully account for DBS effects in this preparation. The divergent effects of STN vs. EPN manipulations on HAL-induced zif268 changes suggest that similar behavioral outcomes of DBS in these two areas may involve different neuroanatomical mechanisms.