European Neuropsychopharmacology (v.21, #3)

Contents (OBC).

A selective neurokinin-1 receptor antagonist in chronic PTSD: A randomized, double-blind, placebo-controlled, proof-of-concept trial by Sanjay J. Mathew; Meena Vythilingam; James W. Murrough; Carlos A. Zarate; Adriana Feder; David A. Luckenbaugh; Becky Kinkead; Michael K. Parides; David G. Trist; Massimo S. Bani; Paolo U. Bettica; Emiliangelo M. Ratti; Dennis S. Charney (221-229).
The substance P-neurokinin-1 receptor (SP-NK1R) system has been extensively studied in experimental models of stress, fear, and reward. Elevated cerebrospinal fluid (CSF) SP levels were reported previously in combat-related PTSD. No medication specifically targeting this system has been tested in PTSD. This proof-of-concept randomized, double-blind, placebo-controlled trial evaluated the selective NK1R antagonist GR205171 in predominately civilian PTSD. Following a 2-week placebo lead-in, 39 outpatients with chronic PTSD and a Clinician-Administered PTSD Scale (CAPS) score ≥ 50 were randomized to a fixed dose of GR205171 (N  = 20) or placebo (N  = 19) for 8 weeks. The primary endpoint was mean change from baseline to endpoint in the total CAPS score. Response rate (≥ 50% reduction in baseline CAPS) and safety/tolerability were secondary endpoints. CSF SP concentrations were measured in a subgroup of patients prior to randomization. There was significant improvement in the mean CAPS total score across all patients over time, but no significant difference was found between GR205171 and placebo. Likewise, there was no significant effect of drug on the proportion of responders [40% GR205171 versus 21% placebo (p  = 0.30)]. An exploratory analysis showed that GR205171 treatment was associated with significant improvement compared to placebo on the CAPS hyperarousal symptom cluster. GR205171 was well-tolerated, with no discontinuations due to adverse events. CSF SP concentrations were positively correlated with baseline CAPS severity. The selective NK1R antagonist GR205171 had fewer adverse effects but was not significantly superior to placebo in the short-term treatment of chronic PTSD. (ClinicalTrials.gov Identifier: NCT 00211861, NCT 00383786)
Keywords: NK1; Substance P; PTSD; Clinical trial; Randomized;

Early post-stressor intervention with propranolol is ineffective in preventing posttraumatic stress responses in an animal model for PTSD by Hagit Cohen; Zeev Kaplan; Ori Koresh; Michael A. Matar; Amir B. Geva; Joseph Zohar (230-240).
The therapeutic value of β-adrenoceptor blockage, using propranolol, in the aftermath of traumatic experience is uncertain. A prospective, controlled animal model of posttraumatic stress disorder (PTSD) was employed to assess the effects of propranolol on long-term behavioral responses to stress. Animals exposed to predator scent stress received a single bolus of propranolol (10 or 15 mg/kg) or vehicle 1 h post-exposure. Outcomes were assessed using the elevated plus-maze (EPM) and acoustic startle response (ASR) at 30 days and freezing response to a trauma reminder (unsoiled litter) on Day 31. Individual animals were classified as having “extreme”, “partial” and “minimal” behavioral responses, according to pre-set cut-off criteria for EPM and ASR response patterns. The physiological efficacy of the doses of propranolol was verified by collecting cardiovascular data telemetrically (from exposed or unexposed individuals given propranolol or vehicle). The effect of propranolol on long-term memory was verified using a non-spatial memory task. Both doses of propranolol effectively reduced mean heart rate and impaired the object–recognition task, as expected. No significant effect on prevalence rates of PTSD-like behavioral responses or on trauma reminder response was observed for either dose of propranolol as compared to vehicle. Despite adequate efficacy in terms of heart rate and disruption of memory, single-dose, post-stress β-blockage with propranolol was ineffective in reducing onset of PTSD-like behavioral disruption and trauma cue responses in the long term. Traumatic stress-related processes appear to be affected differently than the others.
Keywords: Post-traumatic stress disorder; Animal model; β-adrenoceptor antagonists; Propranolol; Nadolol; Memory consolidation; Secondary prevention; Heart rate;

Early improvement in positive rather than negative emotion predicts remission from depression after pharmacotherapy by Nicole Geschwind; Nancy A. Nicolson; Frenk Peeters; Jim van Os; Daniela Barge-Schaapveld; Marieke Wichers (241-247).
Knowledge on mechanisms involved in early prediction of response to antidepressant medication may help optimize clinical decision making. Recent studies regarding response to pharmacotherapy implicate resilience-like mechanisms and involvement of positive, rather than negative emotions. The aim of the current study is to examine the contribution of early change in positive affect to the prediction of response to pharmacotherapy. Positive and negative emotions were measured at baseline and during the first week of pharmacotherapy, using experience sampling techniques. The association between early change in positive and negative emotions and severity of depressive symptoms at week six was examined in a sample of 49 depressed patients. The added benefits of measuring early change in positive emotions compared to early Hamilton Depression Rating Scale (HDRS) change alone were evaluated through model comparisons. Early improvement in positive affect during the first week of treatment predicted the continuous HDRS score (β  = −0.64, p  < 0.001), response (50% reduction; OR  = 4.32, p  < 0.01), and remission (HDRS ≤ 7; OR  = 9.29, p  < 0.001) at week six with moderate to large effect sizes. Effects of early change in negative emotions were only half as large and disappeared when evaluated simultaneously with early change in positive emotions. When early change in positive emotions was added to the models including early HDRS change only, all three models improved significantly. In conclusion, early change in positive rather than negative emotions best predicted response to treatment, supporting the notion that antidepressants activate resilience-like mechanisms. Moreover, monitoring of positive emotions in early stages of treatment may improve clinical decision making.
Keywords: Affect; Depression; Treatment response; Experience sampling method; Early improvement; Prognosis;

Prefrontal NMDA receptor antagonism reduces impairments in pre-attentive information processing by Daniel Klamer; Lennart Svensson; Kim Fejgin; Erik Pålsson (248-253).
A well established theory proposes that glutamate signalling via the NMDA receptor is compromised in patients with schizophrenia. Deficits related to NMDA receptor signalling can be observed in several brain regions including the prefrontal cortex (PFC), an area extensively linked to the cognitive dysfunction in this disease and notably affected by NMDA receptor antagonists such as phencyclidine (PCP). In addition, a number of studies suggest that normalizing of PFC function could constitute a treatment rationale for schizophrenia. To further study the role of PFC function we investigated the effect of local PFC NMDA receptor blockade on impaired prepulse inhibition (PPI) induced by systemic administration of PCP. Mice received prefrontal injections of PCP (0.01, 0.1 or 1 mM) before PCP treatment (5 mg/kg) and were thereafter tested for PPI. PCP induced deficits in PPI were ameliorated by prefrontal PCP (0.1 mM) treatment whereas PPI was not affected by prefrontal cortex PCP administration per se at any of the doses tested. Taken together, inhibition of NMDA receptors in the PFC does not seem to be enough to impair PPI per se but NMDA receptor mediated signalling in the PFC may be a key factor for the PPI-disruptive effects of global NMDA receptor inhibition. This indicates that targeting PFC NMDA receptor signalling may have potential as a treatment target for schizophrenia although further studies are needed to understand pharmacology and pathophysiological role of PFC NMDA receptors.
Keywords: Prepulse inhibition; Schizophrenia; Phencyclidine; Prefrontal cortex; Mouse;

Abnormalities in the tricarboxylic acid (TCA) cycle in the brains of schizophrenia patients by P. Bubber; V. Hartounian; G.E. Gibson; J.P. Blass (254-260).
Images of brain metabolism and measurements of activities of components of the electron transport chain support earlier studies that suggest that brain glucose oxidation is inherently abnormal in a significant proportion of persons with schizophrenia. Therefore, we measured the activities of enzymes of the tricarboxylic (TCA) cycle in dorsolateral–prefrontal–cortex from schizophrenia patients (N = 13) and non-psychiatric disease controls (N = 13): the pyruvate dehydrogenase complex (PDHC), citrate synthase (CS), aconitase, isocitrate dehydrogenase (ICDH), the alpha-ketoglutarate dehydrogenase complex (KGDHC), succinate thiokinase (STH), succinate dehydrogenase (SDH), fumarase and malate dehydrogenase (MDH). Activities of aconitase (18.4%, p < 0.05), KGDHC (26%) and STH (28.2%, p < 0.05), enzymes in the first half of the TCA cycle, were lower, but SDH (18.3%, p < 0.05) and MDH (34%, p < 0.005), enzymes in the second half, were higher than controls. PDHC, CS, ICDH and fumarase activities were unchanged. There were no significant correlations between enzymes of TCA cycle and cognitive function, age or choline acetyl transferase activity, except for aconitase activity which decreased slightly with age (r = 0.55, p = 003). The increased activities of dehydrogenases in the second half of the TCA cycle may reflect a compensatory response to reduced activities of enzymes in the first half. Such alterations in the components of TCA cycle are adequate to alter the rate of brain metabolism. These results are consistent with the imaging studies of hypometabolism in schizophrenia. They suggest that deficiencies in mitochondrial enzymes can be associated with mental disease that takes the form of schizophrenia.
Keywords: Mitochondria; Tricarboxylic acid cycle; Energy metabolism; Postmortem interval; Schizophrenia;

Insulin receptor signaling in rat hippocampus: A study in STZ (ICV) induced memory deficit model by Rahul Agrawal; Ethika Tyagi; Rakesh Shukla; Chandishwar Nath (261-273).
Brain insulin receptors (IRs) have been suggested as an important regulatory factor for cognitive functions but the involvement of IR signaling in memory deficit associated with neurodegenerative conditions is not yet explored. In the present study, IR gene expression was studied by RT-PCR and signaling pathways by immunoblotting in CA1, DG and CA3 subregions of hippocampus in intracerebroventricular (ICV) administered streptozotocin (STZ, 3 mg/kg twice) induced memory deficit model in rat. The effect of pre- and post-treatment of donepezil (5 mg/kg po) and melatonin (20 mg/kg po) on signaling pathways were studied. Effect of LY294002 (ICV), a PI3 Kinase inhibitor, was also investigated on memory functions and Akt phosphorylation. An increased IR expression (both gene and protein), phosphorylation of Shc, Erk1/2, IRS-1 and Akt in CA1 and CA3 region of P2M fraction was observed after training as compared to control. STZ treated rats showed memory deficit and significant decrease in IR expression, phosphorylation of IRS-1 and Akt only in CA3 region as compared to trained group which were reversed by pre and post-treatment of melatonin but donepezil was effective only against memory deficit. LY294002 (3 mM) treatment showed delayed learning and decrease in Akt phosphorylation. This study suggests that IR expression and its signaling pathways in hippocampal CA1 and CA3 regions are involved in memory functions and STZ (ICV) induced memory deficit. Hippocampal IR system might be playing an important role in regulation of memory functions, however only IR/IRS-1/Akt pathway in CA3 region is associated with STZ induced memory deficit.
Keywords: Donepezil;; Hippocampus;; Insulin receptor signaling;; Melatonin;; Memory;; Streptozotocin;

Leptin reduces hyperactivity in an animal model for anorexia nervosa via the ventral tegmental area by Linda A.W. Verhagen; Mieneke C.M. Luijendijk; Roger A.H. Adan (274-281).
Hyperactivity in anorexia nervosa (AN) is associated with low plasma leptin levels and negatively impacts on disease outcome. Using an animal model that mimics features of AN including food-restriction induced hyperlocomotion, we demonstrate that central leptin injections in the lateral ventricle and local injections of leptin into the ventral tegmental area (VTA) suppress running wheel activity. The results support that falling levels of leptin, that accompany caloric restriction, result in increased activity levels because of decreased leptin signaling in the VTA, part of the mesolimbic reward system.
Keywords: Leptin; Hyperactivity; Ventral tegmental area; Activity-based anorexia; Running wheel activity; Anorexia nervosa;

Amisulpride vs. fluoxetine treatment of Chronic Fatigue Syndrome: A pilot study by Matteo Pardini; Silvia Guida; Alberto Primavera; Frank Krueger; Leonardo Cocito; Leonardo Emberti Gialloreti (282-286).
Different pharmacologic agents have been evaluated in the treatment of Chronic Fatigue Syndrome (CFS), albeit with moderate efficacy. Among the compounds thought to present with potential to be efficacious in CFS patients stands out low-dose amisulpride, a substituted benzamide that has been shown to be an useful treatment for conditions which exhibit some overlap with CFS such as dysthymia and somatoform disorders. We thus recruited forty non-depressed CFS patients that were randomized to receive either amisulpride 25 mg bid, or fluoxetine 20 mg uid; all subjects were un-blinded to the treatment regimen. At the time of enrollment in the study and after twelve weeks of treatment, enrolled subjects completed the Krupp Fatigue Severity Scale, the Hospital Anxiety and Depression Scale and a visual analog scale focused on pain and bodily discomfort. Moreover, all subjects were evaluated by a clinician, blinded to the treatment regimen, using the Clinical Global Impression Severity Scale. Our data revealed a significant improvement both in self-report, and observer-based measures for the amisulpride-treated, but not for the fluoxetine-treated patients. Amisulpride-treated subjects also presented with a significant reduction of somatic complaints, while the amisulpride effect on anxiety and mood levels was not significant. Both drugs were equally well tolerated. Summing up, we showed a positive symptomatic effect of amisulpride, compared to SSRI treatment, in a group of non-depressed CSF patients on self-report and on observer-based measures of fatigue and somatic complaints. If confirmed by larger, blinded studies, amisulpride thus could represent an effective approach to this difficult-to-treat condition.
Keywords: Fatigue; Antipsychotic agents;