European Neuropsychopharmacology (v.22, #3)

Contents (OBC).

Clozapine resistance: Augmentation strategies by Stefano Porcelli; Beatrice Balzarro; Alessandro Serretti (165-182).
Background: Clozapine (CLZ) is not effective in more than 50% of treatment-resistant schizophrenic patients. In these cases, several pharmacological strategies are used in clinical practice, with different levels of evidence for both safety and efficacy. Objectives: In the present paper we critically reviewed literature data regarding the efficacy and safety of adjunctive agents in CLZ-resistant schizophrenics. The following classes of agents were considered: 1) antipsychotics, 2) antidepressants, 3) mood stabilizers, 4) other agents (e.g. fatty acid supplement and glutamatergic agents), 5) electroconvulsive therapy (ECT). For lamotrigine and risperidone sufficient data were available to perform a meta-analysis. Methods: A Medline literature search covering a 20-year period was performed. For the meta-analysis, data were entered and analyzed with the Cochrane Collaboration Review Manager Software (RevMan version 5). Results: 62 pertinent studies were identified, including 1556 schizophrenic or schizoaffective patients. Among treatments investigated, there is evidence for CLZ augmentation with 1) amisulpride and aripiprazole, 2) mirtazapine and 3) ethyl eicosapentaenoic acid (E-EPA). Although promising, ECT augmentation needs further validation. The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct. Conclusion: Overall, there is scarce evidence of efficacy and safety as regards adjunctive strategies for CLZ-resistant patients. However, several limitations do not allow to draw any definitive conclusion; among these we underline the small sample size of clinical trials, the variable definitions of CLZ resistance, the heterogeneity of outcome measures and methodological designs.
Keywords: Ultra-resistant schizophrenia; Clozapine augmentation; Super Refractory Schizophrenia; Clozapine; Risperidone; Lamotrigine;

Baseline depression severity as a predictor of single and combination antidepressant treatment outcome: Results from the CO-MED trial by Edward S. Friedman; Lori L. Davis; Sidney Zisook; Stephen R. Wisniewski; Madhukar H. Trivedi; Maurizio Fava; A. John Rush (183-199).
The objective of this manuscript is to report associations between baseline depressive severity and (1) baseline sociodemographic and clinical characteristics, (2) treatment outcomes, and (3) differential outcomes for three treatment groups. Six hundred and sixty-five outpatients with nonpsychotic, major depressive disorder were prospectively randomized to treatment with either a selective serotonin reuptake inhibitor (SSRI) monotherapy (escitalopram plus placebo) or one of two antidepressant medication combinations (bupropion-sustained release plus escitalopram, or venlafaxine-extended release plus mirtazapine). For purposes of these analyses, participants were divided into four groups based on baseline severity by the 16-item Quick Inventory of Depressive Symptomatology — Self-Report (QIDS-SR16) total score: mild (0–10) [N = 81], moderate (11–15) [N = 238], severe (16–20) [N = 260] and very severe (21–27) [N = 67]. Treatment outcomes at 12 and 28 weeks were compared among the four severity groups. A history of childhood neglect and/or abuse was strongly associated with the severity of adult depression (1/2 of participants in the very severe group versus 1/5–1/4 of those in the mild group reported abuse and/or neglect). The degree of suicidality (e.g., 15/.4% of the very severe group ever attempted suicide versus none in the mild group), the number of suicide attempts (e.g., mean of .41 ± 1.99 suicide attempts in the severe group versus 0.0 ± 0.0 in the mild group) and severity of suicidality (e.g., 9.2% of participants in very severe group had a plan or made a gesture versus 5.6% in moderate group and none in the mild group) were increased in more severe groups. Participants with a greater baseline depressive severity reported significantly more psychiatric comorbidities (e.g. [at p < .05] increased rates of agoraphobia, bulimia, generalized anxiety, hypocondriasis, panic disorder, post-traumatic stress disorder, social phobia and somatoform disorder, with 23.9% of participants in the very severe group having reported four or more psychiatric disorders versus 1.2% of the mild group). Combination medication treatments were no more effective in treating severe depressions than was SSRI monotherapy. Remission (61.7% of participants in the mild group achieved remission versus 28.4% in the very severe group) is more difficult to achieve in more severe groups than is response (48.8% of participants in the mild group achieved response versus 58.2% in the very severe group) (p < .03). These data may help us to understand the impact of baseline features on antidepressant medication effectiveness and to inform the personalization of depression treatment across the spectrum of depressive severity.
Keywords: Depression; Abuse; Suicide; Combination treatment severity; Response; Remission;

The vasodilator niacin may provoke greater facial flushing and other symptoms of anxiety in patients with social anxiety disorder than in non-anxious controls. To determine whether this also applies in non-clinical samples, niacin (100 mg) or placebo was administered double-blind to 33 young adults and flushing was investigated in relation to fear of negative evaluation (a cardinal feature of social anxiety). Increases in facial blood flow were greater in people with high than low fear of negative evaluation in the niacin condition, but were similar in both groups in the placebo condition. However, changes in pulse rate and ratings of embarrassment, anxiety, blushing and facial heat were similar in both groups in both drug conditions. These findings suggest that the facial vessels of people with a heightened fear of negative evaluation are particularly responsive to niacin under conditions of low anxiety and embarrassment.
Keywords: Facial blood flow; Vasodilatation; Niacin; Fear of negative evaluation; Social anxiety;

In mammals, the circadian and stress systems are involved in adaptation to predictable and unpredictable stimuli, respectively. A series of experiments examined the relationship between stress-induced posttraumatic stress (PTSD)-like behavioral response patterns in rats and brain levels of genes related to circadian rhythms. The effects of agomelatine, administered immediately after exposure, on stress-related behavior and on local expression of Per1 and Per2 were assessed. Animals were exposed to predator scent stress. The outcome measures included behavior in an elevated plus-maze (EPM) and acoustic startle response (ASR) 7 days after the exposure. Pre-set cut-off behavioral criteria classified exposed animals according to behavioral responses in EPM and ASR paradigms as those with ‘extreme behavioral response’ (EBR), ‘minimal behavioral response (MBR),’ or ‘partial behavioral response’ (PBR). Per1 and Per2 expression in hippocampal subregions, frontal cortex and suprachiasmatic nucleus (SCN) 8 days after exposure were evaluated using immunohistochemical and RT-PCR techniques at zeitgeber-times 19 and 13. The effects of agomelatine, on behavioral tests were evaluated on Day 8. Local brain expression of Per1 and Per2 mRNA was subsequently assessed. Data were analyzed in relation to individual behavior patterns. Animals with extreme behavioral response (EBR) displayed a distinct pattern of Per1 and Per2 expression in the SCN, which was the opposite of that observed in the control and MBR animals. In the DG, no variation in Per2 expression was observed in the EBR and PBR animals. Immediate post-exposure treatment with agomelatine significantly reduced percentage of extreme-responders and normalized the expression of Per1 and Per2 as compared to controls. Stress-induced alterations in Per genes in the EBR animals may represent an imbalance between normally precisely orchestrated physiological and behavioral processes and psychopathological processes. These findings indicate that these circadian-related genes play a role in the neurobiological response to predator scent stress and provide supportive evidence that the use of agomelatine immediately after traumatic experience may be protective against the subsequent development of PTSD.
Keywords: Animal model; Post traumatic stress disorder; Circadian rhythms; Circadian-related genes; Period 1; Period 2; Agomelatine;

fMRI fingerprint of unconditioned fear-like behavior in rats exposed to trimethylthiazoline by Melanie S. Keßler; Sébastien Debilly; Stephanie Schöppenthau; Thomas Bielser; Andreas Bruns; Basil Künnecke; Markus von Kienlin; Joseph G. Wettstein; Jean-Luc Moreau; Céline Risterucci (222-230).
Unconditioned fear plays an important yet poorly understood role in anxiety disorders, and only few neuroimaging studies have focused on evaluating the underlying neuronal mechanisms. In rodents the predator odor trimethylthiazoline (TMT), a synthetic component of fox feces, is commonly used to induce states of unconditioned fear. In this study, arterial spin labeling-based functional magnetic resonance imaging (fMRI) was applied to detect TMT-induced regional modulations of neuronal activity in Wistar rats. During TMT exposure the rats displayed increased freezing behavior and reduced exploration in the odor-associated area. Neuronal activity was selectively increased in the dorsal periaqueductal gray, superior colliculus and medial thalamus and reduced in the median raphe, locus coeruleus, nucleus accumbens shell, ventral tegmental area, ventral pallidum and entorhinal piriform cortex. This fMRI fingerprint involving distinct neuronal pathways was used to describe a schematic model of fear processing. Key brain areas known to underlie fear and anxiety-related autonomic and behavioral responses as well as centers of motivational processing were identified as being part of this functional circuitry of innate fear. Thus, preclinical fMRI studies based on unconditioned fear methods may provide a valuable translational approach to better characterize etiological and pathological processes underlying anxiety disorders.
Keywords: TMT; Predator odor; Anxiety; Neuronal network; Imaging; Fear;

Interaction of mephedrone with dopamine and serotonin targets in rats by José Martínez-Clemente; Elena Escubedo; David Pubill; Jorge Camarasa (231-236).
We described a first approach to the pharmacological targets of mephedrone (4-methyl-methcathinone) in rats to establish the basis of the mechanism of action of this drug of abuse.We performed in vitro experiments in isolated synaptosomes or tissue membrane preparations from rat cortex or striatum, studying the effect of mephedrone on monoamine uptake and the displacement of several specific radioligands by this drug.In isolated synaptosomes from rat cortex or striatum, mephedrone inhibited the uptake of serotonin (5-HT) with an IC50 value lower than that of dopamine (DA) uptake (IC50  = 0.31 ± 0.08 and 0.97 ± 0.05 μM, respectively). Moreover, mephedrone displaced competitively both [3H]paroxetine and [3H]WIN35428 binding in a concentration-dependent manner (Ki values of 17.55 ± 0.78 μM and 1.53 ± 0.47 μM, respectively), indicating a greater affinity for DA than for 5-HT membrane transporters. The affinity profile of mephedrone for the 5-HT2 and D2 receptors was assessed by studying [3H]ketanserin and [3H] raclopride binding in rat membranes. Mephedrone showed a greater affinity for the 5-HT2 than for the D2 receptors.These results provide evidence that mephedrone, interacting with 5-HT and DA transporters and receptors must display a similar pattern of other psychoactive drugs such as amphetamine-like compounds.
Keywords: Mephedrone; Dopamine; Serotonin;

Corrigendum to “Cost of disorders of the brain in Europe 2010” [Eur. Neuropsychopharmacol. 21 (2011) 718–779] by Anders Gustavsson; Mikael Svensson; Frank Jacobi; Christer Allgulander; Jordi Alonso; Ettore Beghi; Richard Dodel; Mattias Ekman; Carlo Faravelli; Laura Fratiglioni; Brenda Gannon; David Hilton Jones; Poul Jennum; Albena Jordanova; Linus Jönsson; Korinna Karampampa; Martin Knapp; Gisela Kobelt; Tobias Kurth; Roselind Lieb; Mattias Linde; Christina Ljungcrantz; Andreas Maercker; Beatrice Melin; Massimo Moscarelli; Amir Musayev; Fiona Norwood; Martin Preisig; Maura Pugliatti; Juergen Rehm; Luis Salvador-Carulla; Brigitte Schlehofer; Roland Simon; Hans-Christoph Steinhausen; Lars Jacob Stovner; Jean-Michel Vallat; Peter Van den Bergh; Jim van Os; Pieter E. Vos; Weili Xu; Hans-Ulrich Wittchen; Bengt Jönsson; Jes Olesen (237-238).