European Neuropsychopharmacology (v.26, #10)

Contents (OBC).

Cognitive enhancement treatments for bipolar disorder: A systematic review and methodological recommendations by Kamilla W. Miskowiak; André F. Carvalho; Eduard Vieta; Lars V. Kessing (1541-1561).
Cognitive dysfunction is an emerging treatment target in bipolar disorder (BD). Several trials have assessed the efficacy of novel pharmacological and psychological treatments on cognition in BD but the findings are contradictory and unclear. A systematic search following the PRISMA guidelines was conducted on PubMed and PsychInfo. Eligible articles reported randomized, controlled or open-label trials investigating pharmacological or psychological treatments targeting cognitive dysfunction in BD. The quality of the identified randomized controlled trials (RCTs) was evaluated with the Cochrane Collaboration’s Risk of Bias tool. We identified 19 eligible studies of which 13 were RCTs and six were open-label or non-randomized studies. The findings regarding efficacy on cognition were overall disappointing or preliminary, possibly due to several methodological challenges. For the RCTs, the risk of bias was high in nine cases, unclear in one case and low in three cases. Key reasons for the high risk of bias were lack of details on the randomization process, suboptimal handling of missing data and lack of a priori priority between cognition outcomes. Other challenges were the lack of consensus on whether and how to screen for cognitive impairment and on how to assess efficacy on cognition. In conclusion, methodological problems are likely to impede the success rates of cognition trials in BD. We recommend adherence to the CONSORT guidelines for RCTs, screening for cognitive impairment before inclusion of trial participants and selection of one primary cognition outcome. Future implementation of a ‘neurocircuitry-based’ biomarker model to evaluate neural target engagement is warranted.
Keywords: Cognitive dysfunction; Bipolar disorder; Intervention; Randomized controlled trials; Cognitive enhancement; Systematic review;

Mood stabilizers and antipsychotics during breastfeeding: Focus on bipolar disorder by Isabella Pacchiarotti; Jordi León-Caballero; Andrea Murru; Norma Verdolini; Maria Antonietta Furio; Corinna Pancheri; Marc Valentí; Ludovic Samalin; Eva Solé Roigé; Ana González-Pinto; Jose Manuel Montes; Antonio Benabarre; Jose Manuel Crespo; Consuelo de Dios Perrino; Jose Manuel Goikolea; Luis Gutiérrez-Rojas; André F. Carvalho; Eduard Vieta (1562-1578).
Breast milk is considered the best source of nutrients and provides much better protection than immune modified milk. However, the postpartum period is a phase of increased risk for all women to experience psychiatric symptoms and recurrences or new episodes of bipolar disorder (BD), especially in those who have discontinued treatment. This is a systematic review of the risks and benefits of mood stabilizers and antipsychotics during breastfeeding as they relate to the health and well-being of mothers and their infants. Evidence-based treatment advice for women with BD during lactation is also provided. This systematic review has been conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. We included studies examining the exposure and the effects of antipsychotics and mood stabilizers used to treat BD on infants during breastfeeding clearly reporting the estimated amount of drug or effects on infants. The final selection included 56 studies. The available data supports the use of lithium as a possible treatment option during breastfeeding. Carbamazepine and valproic acid are also considered relatively safe. Lamotrigine can be used but at the lowest doses and considered for individual cases. Among the antipsychotics, quetiapine and olanzapine should be considered as first-line treatment options. Risperidone may be compatible with breastfeeding under medical supervision. Clozapine and amisulpiride are currently contraindicated. Long-term outcome studies evaluating the infant׳s health and psychosocial and cognitive functioning are needed.
Keywords: Lactation; Bipolar disorder; Mood stabilizers; Antipsychotics; Breastfeeding;

The cannabinoid receptor type 1 (CB1) is highly expressed in the dorsal portion of hippocampus – a brain region that has been involved in the control of conditioned emotional response (CER) in the contextual fear conditioning (CFC) model. These responses are characterized by increased freezing behavior and autonomic parameters. Moreover, CB1 receptors activation negatively modulate the release of several neurotransmitters, including glutamate and GABA, which also have been related to modulation of CER. Therefore, our aim was to investigate the involvement of CB1 receptors in the dorsal hippocampus on CER expression. Independent groups of male Wistar rats submitted to the contextual fear conditioning received bilateral intra-hippocampal injections (500 nL/side) of the following drugs or vehicle before re-exposure to the aversive context: AM251 (CB1 antagonist; 0.1, 0.3 and 1 nmol); AP7 (NMDA antagonist; 1nmol)+AM251 (0.3 nmol); NPLA (0.01 nmol; nNOS inhibitor)+AM251 (0.3 nmol); Bicuculline (1.3 pmol; GABAA antagonist)+AM251 (0.1 and 1 nmol). In the present paper, AM251 (0.3 nmol) increased CER, while this response was prevented by both AP7 and NPLA pretreatment. After pretreatment with Bicuculline, the lower and higher ineffective doses of AM251 were able to increase the CER, supporting the balance between GABAergic and glutamatergic mechanisms controlling this response. Our results suggest that increased CER evoked by CB1 blockade in the dorsal hippocampus depends on NMDA receptor activation and NO formation. Moreover, a fine-tune control promoted by GABAergic and glutamatergic mechanisms in this brain area modulate the CER after CB1 blockade.
Keywords: Endocannabinoid system; CB1 receptors; NMDA receptors; Nitric oxide; Freezing behavior; Autonomic responses;

Anandamide reverses depressive-like behavior, neurochemical abnormalities and oxidative-stress parameters in streptozotocin-diabetic rats: Role of CB1 receptors by Helen de Morais; Camila P. de Souza; Luisa M. da Silva; Daniele M. Ferreira; Cristiane Hatsuko Baggio; Ana Carolina Vanvossen; Milene Cristina de Carvalho; José Eduardo da Silva-Santos; Leandro José Bertoglio; Joice M. Cunha; Janaina M. Zanoveli (1590-1600).
The pathophysiology associated with increased prevalence of depression in diabetics is not completely understood, although studies have pointed the endocannabinoid system as a possible target. Then, we aimed to investigate the role of this system in the pathophysiology of depression associated with diabetes. For this, diabetic (DBT) male Wistar rats were intraperitoneally treated with cannabinoid CB1 (AM251, 1 mg/kg) or CB2 (AM630, 1 mg/kg) receptor antagonists followed by anandamide (AEA, 0.005 mg/kg) and then submitted to the forced swimming test (FST). Oxidative stress parameters, CB1 receptor expression and serotonin (5-HT) and noradrenaline levels in the hippocampus (HIP) and prefrontal cortex (PFC) were also performed. It was observed that DBT animals presented a more pronounced depressive-like behavior and increase of CB1 receptor expression in the HIP. AEA treatment induced a significant improvement in the depressive-like behavior, which was reversed by the CB1 antagonist AM251, without affecting the hyperglycemia or weight gain. AEA was also able to restore the elevated CB1 expression and also to elevate the reduced level of 5-HT in the HIP from DBT animals. In addition, AEA restored the elevated noradrenaline levels in the PFC and induced a neuroprotective effect by restoring the decreased reduced glutathione and increased lipid hydroperoxides levels along with the decreased superoxide dismutase activity observed in HIP or PFC. Together, our data suggest that in depression associated with diabetes, the endocannabinoid anandamide has a potential to induce neuroadaptative changes able to improve the depressive-like response by its action as a CB1 receptor agonist.
Keywords: Diabetes; Depression; Oxidative stress; CB1 receptor; Serotonin; Noradrenaline;

Evidence for an expanded time-window to mitigate a reactivated fear memory by tamoxifen by Thiago R. da Silva; Reinaldo N. Takahashi; Leandro J. Bertoglio; Roberto Andreatini; Cristina A.J. Stern (1601-1609).
The mechanisms underpinning the persistence of emotional memories are inaccurately understood. Advancing the current level of understanding with regards to this aspect is of potential translational value for the treatment of post-traumatic stress disorder (PTSD), which stems from an abnormal aversive memory formation. Tamoxifen (TMX) is a drug used in chemotherapy for breast cancer and associated with poor cognitive performances. The present study investigated whether the systemic administration of TMX (1.0–50 mg/kg) during and/or beyond the reconsolidation time-window could attenuate a reactivated contextual fear memory in laboratory animals. When administered 0, 6 or 9 h (but not 12 h) post-memory retrieval and reactivation, TMX (50 mg/kg) reduced the freezing behavior in male rats re-exposed to the paired context on day 7, but not on day 1, suggesting a specific impairing effect on memory persistence. Importantly, this effect lasts up to 21 days, but it is prevented by omitting the memory retrieval or memory reactivation. When female rats in the diestrous or proestrous phase were used, the administration of TMX 6 h after retrieving and reactivating the fear memory also impaired its persistence. Altogether, regardless of the gender, the present results indicate that the TMX is able to disrupt the persistence of reactivated fear memories in an expanded time-window, which could shed light on a new promising therapeutic strategy for PTSD.
Keywords: Memory reconsolidation; Memory persistence; Protein kinase C; Tamoxifen;

Neurocognitive profile in psychotic versus nonpsychotic individuals with 22q11.2 deletion syndrome by Ronnie Weinberger; James Yi; Monica Calkins; Yael Guri; Donna M. McDonald-McGinn; Beverly S. Emanuel; Elaine H. Zackai; Kosha Ruparel; Miri Carmel; Elena Michaelovsky; Abraham Weizman; Ruben C. Gur; Raquel E. Gur; Doron Gothelf (1610-1618).
The 22q11.2 deletion syndrome (22q11DS) is associated with increased rates of psychotic disorders and cognitive deficits, but large scale studies are needed to elucidate their interaction. The objective of this two-center study was to identify the neurocognitive phenotype of individuals with 22q11DS and psychotic disorders. We hypothesized that psychotic 22q11DS individuals compared to nonpsychotic deleted individuals would have more severe neurocognitive deficits, especially in executive function and social cognition. These deficits would be present when compared to IQ- matched individuals with Williams Syndrome (WS).Three groups were ascertained from the Tel Aviv and Philadelphia centers: 22q11DS individuals with a psychotic disorder (n=31), nonpsychotic 22q11DS (n=86) and typically-developing controls (TD, n=828). In Tel Aviv a group of individuals with WS (n=18) matched in IQ to the 22q11DS psychotic group was also included. The Penn Computerized Neurocognitive Battery (CNB) was used to assess a wide-range of cognitive functions and all patients underwent structured psychiatric evaluations. 22q11DS individuals performed poorly on all CNB domains compared to TD. Participants with 22q11DS and psychosis, compared to nonpsychotic 22q11DS, had more severe deficits in global neurocognitive performance (GNP), executive function, social cognition and episodic memory domains. The primary deficits were also significant when comparing the Tel Aviv 22q11DS psychotic group to IQ-matched individuals with WS. In conclusion, 22q11DS individuals with a psychotic disorder have specific neurocognitive deficits that are reliably identified cross nationality using the CNB. These cognitive dysfunctions should be further studied as potential endophenotypes of psychosis in 22q11DS and as targets for intervention.
Keywords: 22q11.2 deletion syndrome; Neurocognition; Schizophrenia; Psychosis; Penn computerized neurocognitive battery;

Oxytocin to modulate emotional processing in schizophrenia: A randomized, double-blind, cross-over clinical trial by Michela Brambilla; Maria Cotelli; Rosa Manenti; Jessica Dagani; Davide Sisti; Marco Rocchi; Matteo Balestrieri; Stefano Pini; Sara Raimondi; Francesco Maria Saviotti; Paolo Scocco; Giovanni de Girolamo (1619-1628).
Deficits in social cognition, including emotional processing, are hallmarks of schizophrenia and antipsychotic agents seem to be ineffectual to improve these symptoms. However, oxytocin does seem to have beneficial effects on social cognition. The aim of this study was to examine the effects of four months of treatment with intranasal oxytocin, in 31 patients with schizophrenia, on distinct aspects of social cognition. This was assessed using standardized and experimental tests in a randomized, double-blind, placebo-controlled, cross-over trial. All patients underwent clinical and experimental assessment before treatment, four months after treatment and at the end of treatment. Social cognition abilities were assessed with the Mayer–Salovey–Caruso Emotional Intelligence Test (MSCEIT) and the Reading the Mind in the Eyes task (RMET). Furthermore, an Emotional Priming Paradigm (EPP) was developed to examine the effects of oxytocin on implicit perceptual sensitivity to affective information and explicit facial affect recognition.We found that oxytocin improved performance on MSCEIT compared to placebo in Branch 3-Understanding Emotion (p-value=0.004; Cohen׳s d=1.12). In the EPP task, we observed a significant reduction of reaction times for facial affect recognition (p-value=0.021; Cohen׳s d=0.88). No effects were found for implicit priming or for theory of mind abilities. Further study is required in order to highlight the potential for possible integration of oxytocin with antipsychotic agents as well as to evaluate psycho-social treatment as a multi-dimensional approach to increase explicit emotional processing abilities and compensate social cognition deficits related to schizophrenia.
Keywords: Pharmacological treatment; Psychosis; Social cognition;

Melatonin mediated antidepressant-like effect in the hippocampus of chronic stress-induced depression rats: Regulating vesicular monoamine transporter 2 and monoamine oxidase A levels by Bojana Stefanovic; Natasa Spasojevic; Predrag Jovanovic; Nebojsa Jasnic; Jelena Djordjevic; Sladjana Dronjak (1629-1637).
The hippocampus is sensitive to stress which activates norepinephrine terminals deriving from the locus coeruleus. Melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behaviour. Thus, in the present study, an examination was made of the effect of chronic melatonin treatment on norepinephrine content, synthesis, uptake, vesicular transport and degradation in the hippocampus of rats exposed to CUMS. This entailed quantifying the norephinephrine, mRNA and protein levels of DBH, NET, VMAT 2, MAO-A and COMT. The results show that CUMS evoked prolonged immobility. Melatonin treatment decreased immobility in comparison with the placebo group, reflecting an antidepressant-like effect. Compared with the placebo group, a dramatic decrease in norepinephrine content, decreased VMAT2 mRNA and protein and increased MAO-A protein levels in the hippocampus of the CUMS rats were observed. However, no significant differences in the levels of DBH, NET, COMT mRNA and protein and MAO-A mRNA levels between the placebo and the stressed groups were found. The results showed the restorative effects of melatonin on the stress-induced decline in the norepinephrine content of the hippocampus. It was observed that melatonin treatment in the CUMS rats prevented the stress-induced decrease in VMAT2 mRNA and protein levels, whereas it reduced the increase of the mRNA of COMT and protein levels of MAO-A. Chronic treatment with melatonin failed to alter the gene expression of DBH or NET in the hippocampus of the CUMS rats. Additionally, the results show that melatonin enhances VMAT2 expression and norepinephrine storage, whilst it reduces norepinephrine degrading enzymes.
Keywords: Melatonin; Norepinephrine; Hippocampus; Depression; Enzymes; Transporters;

The impact of cognitive reserve in the outcome of first-episode psychoses: 2-year follow-up study by S. Amoretti; M. Bernardo; C.M. Bonnin; M. Bioque; B. Cabrera; G. Mezquida; B. Solé; E. Vieta; C. Torrent (1638-1648).
The concept of cognitive reserve (CR) suggests that the premorbid intelligence quotient (IQ), years of education and leisure activities provide more efficient cognitive networks and therefore allow a better management of some conditions associated to cognitive impairment.Fifty-two DSM-IV diagnosed FEP subjects were matched with 41 healthy controls by age, gender and parental socio-economic status. All subjects were assessed clinically, neuropsychologically and functionally at baseline and after a two-year follow-up. To assess CR at baseline, three proxies have been integrated: premorbid IQ, years of education-occupation and leisure activities.Higher CR was associated with better cognitive, functional and clinical outcomes at baseline. The CR proxy was able to predict working memory, attention, executive functioning, verbal memory and global composite cognitive score accounting for 48.9%, 19.1%, 16.9%, 10.8% and 14.9% respectively of the variance at two-year follow-up. CR was also significantly predictive of PANSS negative scale score (12.5%), FAST global score (13.4%) and GAF (13%) at two-year follow-up. In addition, CR behaved as a mediator of working memory (B=4.123) and executive function (B=3.298) at baseline and of working memory (B=5.034) at 2-year follow-up. An additional analysis was performed, in order to test whether this mediation could be attributed mainly to the premorbid IQ. We obtained that this measure was not enough by itself to explain this mediation.CR may contribute to neuropsychological and functional outcome. Specific programs addressed to improve cognition and functioning conducted at the early stages of the illness may be helpful in order to prevent cognitive and functional decline.
Keywords: Cognitive reserve; Neuropsychology; Cognition; Psychotic disorders; Memory short-term; Follow-up studies;

Pharmacodynamic effects of suvorexant and zolpidem on EEG during sleep in healthy subjects by Arie Struyk; Cynthia Gargano; Melissa Drexel; S. Aubrey Stoch; Vladimir Svetnik; Junshui Ma; David Mayleben (1649-1656).
The objective of this study was to evaluate sleep electrophysiology in healthy subjects after bedtime administration of therapeutic doses of two insomnia treatments - the orexin receptor antagonist suvorexant or the GABAergic agonist zolpidem. Eighteen healthy men received single bedtime doses of suvorexant 20 mg, zolpidem 10 mg, or placebo in a double-blinded, randomized, balanced 3-period crossover study. EEG power spectral densities during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep were recorded in a polysomnography (PSG) laboratory using a 19-lead EEG recording array. Spectral density was analyzed for each lead for frequencies between 1–32 Hz. During NREM and REM sleep, zolpidem treatment reduced spectral density across theta and alpha frequency bands in all leads. In contrast, suvorexant had no significant effects on spectral density in any frequency band during NREM sleep, and modestly increased spectral density in the theta frequency band during REM sleep. Although the study was not designed to detect effects on PSG sleep endpoints in healthy subjects, both suvorexant and zolpidem increased mean total sleep time and sleep efficiency. Zolpidem reduced latency to persistent sleep whereas suvorexant did not. Suvorexant decreased wake after sleep onset, whereas zolpidem did not. These findings suggest that EEG power spectral density profile after administration of suvorexant in healthy subjects more closely approximates placebo sleep physiology than after zolpidem treatment.
Keywords: Suvorexant; Zolpidem; EEG; Sleep; Healthy subjects;

Degree connectivity in body dysmorphic disorder and relationships with obsessive and compulsive symptoms by Jan C. Beucke; Jorge Sepulcre; Ulrike Buhlmann; Norbert Kathmann; Teena Moody; Jamie D. Feusner (1657-1666).
Individuals with body dysmorphic disorder (BDD) and obsessive–compulsive disorder (OCD) are categorized within the same major diagnostic group and both show regional brain hyperactivity in the orbitofrontal cortex (OFC) and the basal ganglia during symptom provocation. While recent studies revealed that degree connectivity of these areas is abnormally high in OCD and positively correlates with symptom severity, no study has investigated degree connectivity in BDD. We used functional magnetic resonance imaging (fMRI) to compare the local and distant degree of functional connectivity in all brain areas between 28 unmedicated BDD participants and 28 demographically matched healthy controls during a face-processing task. Correlational analyses tested for associations between degree connectivity and symptom severity assessed by the BDD version of the Yale-Brown obsessive–compulsive scale (BDD-Y-BOCS). Reduced local amygdalar connectivity was found in participants with BDD. No differences in distant connectivity were found. BDD-Y-BOCS scores significantly correlated with the local connectivity of the posterior-lateral OFC, and distant connectivity of the posterior-lateral and post-central OFC, respectively. These findings represent preliminary evidence that individuals with BDD exhibit brain-behavioral associations related to obsessive thoughts and compulsive behaviors that are highly similar to correlations previously found in OCD, further underscoring their related pathophysiology. This relationship could be further elucidated through investigation of resting-state functional connectivity in BDD, ideally in direct comparison with OCD and other obsessive–compulsive and related disorders.
Keywords: Body dysmorphic disorder; Obsessive–compulsive disorder; Amygdala; Orbitofrontal cortex; Connectivity;

Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [3H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries.
Keywords: Drug addiction; Drug-induced plasticity; Natural reward; Psychostimulant; Dopamine; Response contingency;

H1-histamine receptor affinity predicts weight gain with antidepressants by Virginio Salvi; Claudio Mencacci; Francesco Barone-Adesi (1673-1677).
Weight gain and metabolic abnormalities are extensively found in patients taking psychotropic medications. Although mainly antipsychotics have been implicated, also antidepressants carry the potential to induce weight gain, with tricyclics and mirtazapine being associated with the greatest weight gain. It has been suggested that this could be due to the different ability of antidepressants to block adrenergic, cholinergic, and histaminergic postsynaptic receptors. To date, however, the link between antidepressant-induced weight gain and their receptor affinity profile has not been established. We reanalysed data from a previous meta-analysis to evaluate whether weight change is associated with specific receptor affinity of antidepressants.We retrieved data from the only meta-analysis that assessed weight change with antidepressants. We searched in the Psychoactive Drug Screening Program (PDSP) Ki database data on the affinities of antidepressants to receptors hypothetically linked with weight change: H1-histamine, 5HT2c, M3-muscarinic, and α1A-adrenergic receptors. The association between weight change and receptor affinities was estimated using meta-regression.We found a significant association between the affinity of antidepressants to H1-receptor and weight gain (p value: <0.001). An association between weight gain and receptor affinity was also observed in the models for 5HT2c, M3, and α1A receptors. However, the association disappeared when H1-receptor was included in the models.This reanalysis of data demonstrates that anti-histaminergic activity is the strongest predictor of weight gain with antidepressants. These results further stress a reclassification of antidepressants according to their pharmacodynamic properties, and suggest avoiding prescribing antidepressants with an anti-histaminergic profile to patients at risk for cardio-metabolic disturbances.
Keywords: Weight gain; Antidepressants; Receptor affinity; Histamine;

Since the therapeutic treatment of depression is far from being satisfactory, new therapeutic strategies ought to be pursued. In addition, further investigation on brain areas involved in the action mechanism of antidepressants can shed light on the aetiology of depression. We have previously reported that typical and atypical antidepressants strongly stimulate catecholamine transmission in the bed nucleus of stria terminalis (BNST). In this study, we have built on that work to examine the effect of ketamine, an unusual antidepressant that can produce a fast-acting and long-lasting antidepressant effect after administration of a single sub-anaesthetic dose. Ketamine is an antagonist of the ionotropic N-methyl-D-aspartate (NMDA) receptor but can also act through its metabolite (2R-6R)-hydroxynorketamine. Using the microdialysis technique in freely moving rats, we monitored the acute effect of ketamine on catecholamine release in the BNST to gain clues to its prompt antidepressant effect. Male Sprague-Dawley rats were implanted with a microdialysis probe in the BNST and 48 h later, were injected with ketamine (10, 20, and 40 mg/kg, i.p.). Ketamine increased norepinephrine (127%, 155%, 186%) and dopamine (114%, 156%, 176%) extracellular concentration above basal in a time and dose dependent manner, without significantly modifying motility. Since the effect of ketamine, although lower, was not substantially different from that produced by classical antidepressants, we suggest that catecholamine increase in BNST is not likely to be related to a rapid ketamine antidepressant effect, though it might be related to its performance in predictive tests of antidepressant properties.
Keywords: Ketamine; Bed nucleus of stria terminalis; Dopamine; Norepinephrine; Microdialysis;

Pharmacogenetic study of the effects of raloxifene on negative symptoms of postmenopausal women with schizophrenia: A double-blind, randomized, placebo-controlled trial by Javier Labad; Lourdes Martorell; Elena Huerta-Ramos; Jesús Cobo; Elisabet Vilella; Elena Rubio-Abadal; Gemma Garcia-Pares; Marta Creus; Cristian Núñez; Laura Ortega; Eva Miquel; Judith Usall (1683-1689).
Several double-blind clinical trials have reported improvement in positive, negative and cognitive symptoms of schizophrenia with raloxifene, a selective receptor estrogen modulator. However, there are some inconsistencies in replicating findings between studies of different countries. The failure to replicate these findings may result from genetic factors that could explain some of the variability in the treatment response. However, pharmacogenetic studies exploring this topic in women with schizophrenia are lacking. We aimed to conduct an exploratory pharmacogenetic analysis of a double-blind, randomized, parallel, placebo-controlled study of 24 weeks’ duration of raloxifene aiming to improve negative symptoms in postmenopausal women with schizophrenia. Four single nucleotide polymorphisms (SNPs) were studied: rs9340799, rs2234693 and rs1801132 in the Estrogen Receptor 1 (ESR1) gene, and rs1042597 in the UDP-glucuronosyltransferase 1A8 (UGT1A8) gene. Sixty-five postmenopausal women with schizophrenia (DSM-IV) were randomized to either 60 mg/day adjunctive raloxifene (36 women) or adjunctive placebo (29 women). Psychopathological symptoms were assessed at baseline and at weeks 4, 12, and 24 with the Positive and Negative Syndrome Scale (PANSS). Of the four studied SNPs, the rs1042597 variant in the UGT1A8 gene was associated with a different treatment response in negative symptoms with raloxifene treatment, whereas the rs2234693 variant in the ESR1 gene was associated with a distinct response in general psychopathology. In conclusion, our study suggests that genetic variants in UGT1A8 and ESR1 genes modulate the treatment response to adding raloxifene to antipsychotic treatment in postmenopausal women with schizophrenia.
Keywords: Raloxifene; Negative symptoms; Schizophrenia; Genetics; Pharmacogenetics; Postmenopause;

Systematic prevention of severe constipation induced by antipsychotic agents: A quasi-experimental study by Virginie Bulot; Cédric Lemogne; Nicaise Nebot; Hugues Blondon; Paul Roux (1690-1691).

The antidepressant effect of ketamine: Mediated by AMPA receptors? by Dragos Inta; Rolf Sprengel; Stefan Borgwardt; Undine E. Lang; Peter Gass (1692-1693).