European Neuropsychopharmacology (v.21, #12)

Contents (OBC).

Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and clinical evidence by Jerome Sarris; Alexander Panossian; Isaac Schweitzer; Con Stough; Andrew Scholey (841-860).
Research in the area of herbal psychopharmacology has increased markedly over the past decades. To date however, a comprehensive review of herbal antidepressant, anxiolytic and hypnotic psychopharmacology and applications in depression, anxiety and insomnia has been absent. A search of MEDLINE (PubMed), CINAHL, PsycINFO, and the Cochrane Library databases was conducted (up to February 21st 2011) on commonly used psychotropic herbal medicines. A review of the literature was conducted to ascertain mechanisms of action of these botanicals, in addition to a systematic review of controlled clinical trials for treatment of mood, anxiety and sleep disorders, which are common comorbid psychiatric disorders. Specific emphasis was given to emerging phytomedicines. Analysis of evidence levels was conducted, as were effect sizes (Cohen's d) where data were available. Results provided evidence of a range of neurochemical, endocrinological, and epigenetic effects for 21 individual phytomedicines, which are detailed in this paper. Sixty six controlled studies were located involving eleven phytomedicines. Several of these provide a high level of evidence, such as Hypericum perforatum for major depression, and Piper methysticum for anxiety disorders. Several human clinical trials provide preliminary positive evidence of antidepressant effects (Echium amoenum, Crocus sativus, and Rhodiola rosea) and anxiolytic activity (Matricaria recutita, Ginkgo biloba, Passiflora incanata, E. amoenum, and Scutellaria lateriflora). Caution should however be taken when interpreting the results as many studies have not been replicated. Several herbal medicines with in vitro and in vivo evidence are currently unexplored in human studies, and along with use of emerging genetic technologies “herbomics”, are areas of potential future research.
Keywords: Herbal medicine; Antidepressant; Depression; Anxiolytic; Anxiety; Insomnia; Psychopharmacology; Herbomics; St John's wort; Kava;

Density of striatal D2 receptors in untreated first-episode psychosis: An I123-IBZM SPECT study by Iluminada Corripio; María J. Escartí; Maria J. Portella; Víctor Pérez; Eva Grasa; Rosa B. Sauras; Anna Alonso; Gemma Safont; M. Valle Camacho; Rosa Dueñas; Belén Arranz; Luis San; Ana M. Catafau; Ignasi Carrió; Enric Álvarez (861-866).
There is as yet no definite prognostic marker to determine whether a first-episode psychosis will become schizophrenia or not. The aim of the present study is to address whether the mechanism of sensitization of the subcortical dopaminergic pathway – yielding to an increase of the postsynaptic D2 receptors – may serve as a prognostic marker of clinical outcome in drug naïve patients with a first-episode psychosis, by means of a prospective and multicentric study with untreated first-episode psychosis patients (n = 37). 123I-IBZM SPECT was performed at the time of the inclusion in the study, before antipsychotic medication was initiated. One year later, patients were assessed again so as to determine their diagnosis. There was a significant group effect at baseline in D2 Striatal/Frontal (S/F) ratios (F = 10.2, p < 0.001). Bonferroni posthoc comparisons attested significant differences between diagnosis (p = 0.006), and between schizophrenia and control groups (p < 0.001) but no differences between non-schizophrenia and control groups (p = 0.9). The logistic regression model showed that D2R binding (p = 0.02) and PAS (Premorbid Adjustment Scale) adulthood score (p = 0.03) were predictive of the final diagnosis (schizophrenia/non-schizophrenia; Nagelkerke R2  = 0.59; X 2  = 11.08, p = 0.001). These findings replicate previous results on the usefulness of D2R binding as an objective prognostic parameter, together with the evaluation of premorbid adjustment, of the evolution of first-episode psychosis. In this regard, the results may provide a new view in the approach of early and personalized treatment in the debut of a psychosis.
Keywords: Schizophrenia; First psychotic episode; Outcome; I123-IBZM SPECT; Striatal dopaminergic receptors;

The objective of this study was to compare coronary heart disease (CHD) risk and metabolic syndrome (MS) prevalence in patients with deficit (DS) and non-deficit schizophrenia treated with antipsychotics. A total of 1452 antipsychotic-treated outpatients meeting criteria for schizophrenia, schizophreniform or schizoaffective disorder were included in this cross-sectional multicentre study. CHD risk was assessed by SCORE (10-year cardiovascular death) risk score, and metabolic syndrome was assessed according to NCEP-ATP III criteria. A total of 1452 patients (863 men, 60.9%), 40.7 ± 12.2 years (mean ± SD) were included. DS was found in 404 patients (35.1%). Patients with DS were older, more frequently male and obese, more likely to be receiving sickness benefits, and had longer illness duration and fewer previous hospitalisations. Furthermore, DS patients had higher negative PANSS scores (56.3% vs. 40.6% of patients with PANSS-N > 21). High/very high risk of fatal CHD according to SCORE function (≥ 3%) was significantly higher in DS [11.8% (95% CI: 8.8–15.5) vs. 6.0% (95% CI: 4.4–8.1), (p < 0.05)]. Schizophrenia spectrum patients with DS were more obese and had a higher CHD risk than non-deficit patients.
Keywords: Deficit schizophrenia; Schizophrenia; Outpatients; Negative symptoms; Antipsychotic treatment; Cardiovascular disease;

Posttraumatic obsessions have been reported in a few studies and case series. However, the magnitude of this phenomenon is still unknown. In the current study we systematically evaluated the prevalence of OCD in a sample of combat and terror related PTSD patients. Out of 44 referrals, 43% of the participants had PTSD with no OCD and 41% were diagnosed also with OCD. Six percent had sub-threshold OC symptoms. No difference was found between PTSD and PTSD–OCD participants' characteristics (including demographics, trauma-related factors, and other psychiatric co-morbidity). The surprisingly high number of OCD found in the current study suggests that PTSD–OCD might be underdiagnosed, signifies the importance of direct assessment of OCD in patients with PTSD, and raise questions regarding the underlying mechanism of post-traumatic OCD.
Keywords: Posttraumatic obsessions;; Posttraumatic stress disorder;; Obsessive–compulsive disorder;; Comorbidity;; Prevalence;

Neural hyperactivation in carriers of the Alzheimer's risk variant on the clusterin gene by Thomas M. Lancaster; Alison Baird; Claudia Wolf; Margaret C. Jackson; Stephen J. Johnston; Rossen Donev; Johannes Thome; David E.J. Linden (880-884).
Recent GWAS identified a risk variant for Alzheimer's disease (AD) at a locus (rs11136000) of the clusterin gene (CLU). Here we use functional magnetic resonance imaging (fMRI) during working memory to probe the effect of the risk variant on brain activation in healthy individuals. Participants with the CLU risk genotype had higher activity than participants with the protective allele in frontal and posterior cingulate cortex and the hippocampus, particularly during high memory demand. These results inform pathophysiological models of the preclinical progression of AD.
Keywords: Dementia; Genetic imaging; Working memory; Clusterin; Hippocampus; Prefrontal cortex;

Effects of age on dopamine D2 receptor availability in striatal subdivisions: A high-resolution positron emission tomography study by Jong-Hoon Kim; Young-Don Son; Hang-Keun Kim; Sang-Yoon Lee; Seo-Eun Cho; Young-Bo Kim; Zang-Hee Cho (885-891).
The purpose of the present study was to examine the relationship between age and dopamine D2 receptor availability in striatal subdivisions of young and middle-aged healthy subjects using high-resolution positron emission tomography (PET) with [11C]raclopride to better characterize the nature of age-related decrements in striatal D2 receptor availability. Twenty-four healthy volunteers completed 3-Tesla magnetic resonance imaging and high-resolution [11C]raclopride PET scans. The analyses using linear and exponential models revealed that age had a significant negative correlation with D2 receptor availability in the post-commissural putamen (postPU) and that D2 receptor binding in the postPU decreased significantly more with age than in the ventral striatum, suggesting subregional differences in age-related changes in D2 receptor binding. The postPU, which belongs to the sensorimotor striatum, may be particularly vulnerable to the effects of age in young and middle-aged subjects.
Keywords: Age; Dopamine; D2 receptor; Striatal subdivisions; Positron emission tomography; Raclopride;

Erk activation in the amygdala and hippocampus induced by fear conditioning in ethanol withdrawn rats: Modulation by mk-801 by María Eugenia Bertotto; Noelia Martina Maldonado; Elena Anahi Bignante; Silvana Vanesa Gorosito; María Julia Cambiasso; Víctor Alejandro Molina; Irene Delia Martijena (892-904).
The extracellular signal-regulated kinase (ERK) pathway, which can be activated by NMDA receptor stimulation, is involved in fear conditioning and drug addiction. We have previously shown that withdrawal from chronic ethanol administration facilitated the formation of contextual fear memory. In order to explore the neural substrates and the potential mechanism involved in this effect, we examined: 1) the ERK1/2 activation in the central (CeA) and basolateral (BLA) nuclei of the amygdala and in the dorsal hippocampus (dHip), 2) the effect of the NMDA receptor antagonist MK-801 on fear conditioning and ERK activation and 3) the effect of the infusion of U0126, a MEK inhibitor, into the BLA on fear memory formation in ethanol withdrawn rats.Rats made dependent via an ethanol-containing liquid diet were subjected to contextual fear conditioning on day 3 of ethanol withdrawal. High basal levels of p-ERK were found in CeA and dHip from ethanol withdrawn rats. ERK activation was significantly increased both in control (60 min) and ethanol withdrawn rats (30 and 60 min) in BLA after fear conditioning. Pre-training administration of MK-801, at a dose that had no effect on control rats, prevented the increase in ERK phosphorylation in BLA and attenuated the freezing response 24 h later in ethanol withdrawn rats. Furthermore, the infusion of U0126 into the BLA, but not the CeA, before fear conditioning disrupted fear memory formation. These results suggest that the increased fear memory can be linked to changes in ERK phosphorylation, probably due to NMDA receptor activation in BLA in ethanol withdrawn rats.
Keywords: Ethanol dependence; Fear learning; ERK activation; NMDA receptor; Amygdala; Hippocampus;

The anxiolytic- and antidepressant-like effects of the neurokinin (NK) receptor antagonists have been shown in behavioral studies. According to the involvement of neurotrophin signaling in the mechanisms of action of psychotropic agents, we aimed to investigate whether the selective NK1, NK2, or NK3 receptor antagonists (GR-205171, SR48968, and SR142801, respectively) affect nerve growth factor (NGF) contents in the brain regions involved in the modulation of emotions. To gain a mechanistical insight into the process by which the NK antagonists regulate brain NGF levels, we evaluated the role of the cannabinoid system which is linked to depression and/or antidepressant effects and appears to interact with neurotrophin signaling. According to the results, single injection of the NK receptor antagonists (3, 5, and 10 mg/kg, i.p.) into gerbils did not alter NGF or endocannabinoid (eCB) levels quantified by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. Three-week administration of 10 mg/kg NK antagonists significantly elevated both NGF and eCB levels in brain-region specific fashion. Pre-application of the CB1 receptor neutral antagonist AM4113 (5.6 mg/kg) prevented the elevation of NGF or eCB induced by the NK antagonists. AM4113 showed no effect by itself. We conclude that the cannabinoid system is implicated in the mechanisms of action of NK receptor antagonists including the upregulation of brain NGF levels.
Keywords: Neurokinin receptor antagonists; Nerve growth factor; Cannabinoid system; Brain; Gerbil;

Effects of olanzapine on extracellular concentrations and tissue content of neurotensin in rat brain regions by Susanne H.M. Gruber; Francesco Angelucci; George G. Nomikos; Aleksander A. Mathé (918-927).
We have previously shown that both the psychostimulant d -amphetamine and the antipsychotics haloperidol and risperidone affect extracellular concentrations and tissue content of neurotensin (NT) in distinct brain regions. This study investigated the effects of acute olanzapine (1, 5 mg/kg, s.c.) on extracellular NT-like immunoreactivity (− LI) concentrations in the ventral striatum (vSTR) and the medial prefrontal cortex (mPFC), and the effects of acute d -amphetamine (1.5 mg/kg, s.c.) on extracellular NT-LI in these brain regions after a 30-day olanzapine (15 mg/kg, p.o.) administration in rats. The effects of a 30-day olanzapine (3, 15 mg/kg, p.o.) administration and d -amphetamine (1.5 mg/kg, s.c.) coadministration during either the last day (acute) or the last 8 days (chronic) on NT-LI tissue content in distinct rat brain regions were also studied. Acute olanzapine increased extracellular NT-LI, in both the vSTR and the mPFC. Chronic olanzapine increased and decreased basal extracellular NT-LI in the vSTR and the mPFC, respectively, and abolished the stimulatory effects of acute d -amphetamine on extracellular NT-LI in these brain regions. Chronic olanzapine as well as acute and chronic d -amphetamine affected NT-LI tissue content in a brain region-dependent manner. Chronic olanzapine prevented the effects of acute and chronic d -amphetamine on NT-LI tissue content in certain brain regions. The fact that olanzapine and d -amphetamine affected extracellular NT-LI in the vSTR and mPFC as well as NT-LI tissue content in distinct brain regions further supports the notion that NT plays a role in the therapeutic actions of antipsychotic drugs and possibly also in the pathophysiology of schizophrenia.
Keywords: Neurotensin; Olanzapine; d -amphetamine; Schizophrenia; Striatum; Cortex; Microdialysis;