Most Cited European Neuropsychopharmacology Articles
The most cited articles published since 2011, extracted from Scopus.
The size and burden of mental disorders and other disorders of the brain in Europe 2010H. U. Wittchen | F. Jacobi | J. Rehm | A. Gustavsson | M. Svensson | B. Jönsson | J. Olesen | C. Allgulander | J. Alonso | C. Faravelli | L. Fratiglioni | P. Jennum | R. Lieb | A. Maercker | J. van Os | M. Preisig | L. Salvador-Carulla | R. Simon | H. C. Steinhausen
Volume 21, Issue 9, September 2011, Pages 655-679
Aims: To provide 12-month prevalence and disability burden estimates of a broad range of mental and neurological disorders in the European Union (EU) and to compare these findings to previous estimates. Referring to our previous 2005 review, improved up-to-date data for the enlarged EU on a broader range of disorders than previously covered are needed for basic, clinical and public health research and policy decisions and to inform about the estimated number of persons affected in the EU. Method: Stepwise multi-method approach, consisting of systematic literature reviews, reanalyses of existing data sets, national surveys and expert consultations. Studies and data from all member states of the European Union (EU-27) plus Switzerland, Iceland and Norway were included. Supplementary information about neurological disorders is provided, although methodological constraints prohibited the derivation of overall prevalence estimates for mental and neurological disorders. Disease burden was measured by disability adjusted life years (DALY). Results: Prevalence: It is estimated that each year 38.2% of the EU population suffers from a mental disorder. Adjusted for age and comorbidity, this corresponds to 164.8. million persons affected. Compared to 2005 (27.4%) this higher estimate is entirely due to the inclusion of 14 new disorders also covering childhood/adolescence as well as the elderly. The estimated higher number of persons affected (2011: 165. m vs. 2005: 82. m) is due to coverage of childhood and old age populations, new disorders and of new EU membership states. The most frequent disorders are anxiety disorders (14.0%), insomnia (7.0%), major depression (6.9%), somatoform (6.3%), alcohol and drug dependence (>4%), ADHD (5%) in the young, and dementia (1-30%, depending on age). Except for substance use disorders and mental retardation, there were no substantial cultural or country variations. Although many sources, including national health insurance programs, reveal increases in sick leave, early retirement and treatment rates due to mental disorders, rates in the community have not increased with a few exceptions (i.e. dementia). There were also no consistent indications of improvements with regard to low treatment rates, delayed treatment provision and grossly inadequate treatment.Disability: Disorders of the brain and mental disorders in particular, contribute 26.6% of the total all cause burden, thus a greater proportion as compared to other regions of the world. The rank order of the most disabling diseases differs markedly by gender and age group; overall, the four most disabling single conditions were: depression, dementias, alcohol use disorders and stroke. Conclusion: In every year over a third of the total EU population suffers from mental disorders. The true size of "disorders of the brain" including neurological disorders is even considerably larger. Disorders of the brain are the largest contributor to the all cause morbidity burden as measured by DALY in the EU. No indications for increasing overall rates of mental disorders were found nor of improved care and treatment since 2005; less than one third of all cases receive any treatment, suggesting a considerable level of unmet needs. We conclude that the true size and burden of disorders of the brain in the EU was significantly underestimated in the past. Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for disorders of the brain as the core health challenge of the 21st century. © 2011.
Cost of disorders of the brain in Europe 2010Anders 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 Vos | Weili Xu | Hans Ulrich Wittchen | Bengt Jönsson | Jes Olesen
Volume 21, Issue 10, October 2011, Pages 718-779
Background: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386. billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514. million people. Aims: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country. Methods: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27. +. Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010. Results: The total cost of disorders of the brain was estimated at €798. billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477. billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US. Discussion: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges. Recommendations: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives. © 2011.
Magnetic resonance imaging studies in unipolar depression: Systematic review and meta-regression analysesD. Arnone | A. M. McIntosh | K. P. Ebmeier | M. R. Munafò | I. M. Anderson
Volume 22, Issue 1, January 2012, Pages 1-16
Previous meta-analyses of structural MRI studies have shown diffuse cortical and sub-cortical abnormalities in unipolar depression. However, the presence of duplicate publications, recruitment of particular age groups and the selection of specific regions of interest means that there is uncertainty about the balance of current research. Moreover, the lack of systematic exploration of highly significant heterogeneity has prevented the generalisability of finding. A systematic review and random-effects meta-analysis was carried out to estimate effect sizes. Possible publication bias, and the impact of various study design characteristics on the magnitude of the observed effect size were systematically explored. The aim of this study was 1) to include structural MRI studies systematically comparing unipolar depression with bipolar disorder and healthy volunteers; 2) to consider all available structures of interest without specific age limits, avoiding data duplication, and 3) to explore the influence of factors contributing to the measured effect sizes systematically with meta-regression analyses. Unipolar depression was characterised by reduced brain volume in areas involved in emotional processing, including the frontal cortex, orbitofrontal cortex, cingulate cortex, hippocampus and striatum. There was also evidence of pituitary enlargement and an excess of white matter hyperintensity volume in unipolar depression. Factors which influenced the magnitude of the observed effect sizes were differences in methods, clinical variables, pharmacological interventions and sample age. © 2011 Elsevier B.V.
Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacyStefano Porcelli | Chiara Fabbri | Alessandro Serretti
Volume 22, Issue 4, April 2012, Pages 239-258
In the last decade the serotonin transporter gene promoter polymorphism (5-HTTLPR) was likely the most studied genetic variant as predictor of antidepressant response. Nevertheless results are not consistent across studies and previous meta-analysis, since various factors seem to modulate its effect on antidepressant response. With the aim of clarifying this issue, we systematically reviewed literature, selecting 33 studies for an exploratory analysis without any a priori hypothesis. Then we analyzed separately 19 studies performed on Caucasians and 11 on Asians. We tested two phenotypes - remission and response rates - and three genotype comparisons - ll versus ls/ss, ss versus ll/ls and ll versus ss - using the Cochrane review manager. Evaluations were performed separately for SSRIs and mixed/other drugs. Possible clinical modulators were investigated. In the exploratory analysis, we found an association between l allele and l/l genotype and remission. When the analysis was split for ethnic group, in Caucasians we found an association between l allele and both response (OR = 1.58, C.I. 1.16-2.16, p = 0.004), and remission (OR = 1.53, C.I. 1.14-2.04, p = 0.004) in the SSRI group. Only a marginal association between l allele and remission (OR = 1.41, C.I. 1.02-1.95, p = 0.04) survived pooling together mixed antidepressant treatments. In Asians, a small effect of 5-HTTLPR on remission for mixed antidepressants was detected (OR = 2.10, C.I. 1.15-3.84, p = 0.02). Gender, age and age at onset modulated the association in Caucasians. Gender, age and depression severity at baseline modulated the association in Asians. In conclusion, in Caucasians 5-HTTLPR may be a predictor of antidepressant response and remission, while in Asians it does not appear to play a major role. © 2011 Elsevier B.V. and ECNP.
A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependenceAntoni Gual | Yuan He | Lars Torup | Wim van den Brink | Karl Mann
Volume 23, Issue 11, November 2013, Pages 1432-1442
This study evaluated the efficacy of as-needed use of the opioid system modulator nalmefene in reducing alcohol consumption in patients with alcohol dependence. Seven hundred and eighteen patients (placebo=360; nalmefene=358), ≥18 years of age, with a diagnosis of alcohol dependence, ≥6 heavy drinking days and an average alcohol consumption ≥WHO medium drinking risk level in the 4 weeks preceding screening, were randomised (1:1) to 24 weeks of as-needed placebo or nalmefene 18. mg/day.The co-primary efficacy analyses showed a significantly superior effect of nalmefene compared to placebo in the change from baseline to month 6 in heavy drinking days (group difference: -1.7 days/month [95% CI -3.1; -0.4]; p=0.012) and a better but not significant effect in reducing total alcohol consumption (group difference: -5.0. g/day last month [95% CI -10.6; 0.7]; p=0.088). A subgroup analysis showed that patients who did not reduce their drinking prior to randomisation benefitted more from nalmefene. Improvements in Clinical Global Impression and reductions in liver enzymes were greater in the nalmefene group than in the placebo group. Adverse events were more common with nalmefene; the incidence of adverse events leading to dropout was similar in both groups.This study provides evidence for the efficacy of nalmefene, which constitutes a new pharmacological treatment paradigm in terms of treatment goal (reduced drinking) and dosing regimen (as-needed), in alcohol dependent patients unable to reduce alcohol consumption on their own. © 2013 Elsevier B.V. and ECNP.
Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and clinical evidenceJerome Sarris | Alexander Panossian | Isaac Schweitzer | Con Stough | Andrew Scholey
Volume 21, Issue 12, December 2011, Pages 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. © 2011 Elsevier B.V.
Efficacy and safety of second-generation antipsychotics in children and adolescents with psychotic and bipolar spectrum disorders: Comprehensive review of prospective head-to-head and placebo-controlled comparisonsDavid Fraguas | Christoph U. Correll | Jessica Merchán-Naranjo | Marta Rapado-Castro | Mara Parellada | Carmen Moreno | Celso Arango
Volume 21, Issue 8, August 2011, Pages 621-645
To review data on efficacy and safety of second-generation antipsychotics (SGAs) in children and adolescents with psychotic and bipolar spectrum disorders. Methods: Medline. /PubMed/Google Scholar search for studies comparing efficacy and/or tolerability: (i) between two or more SGAs; (ii) between SGAs and placebo; and (iii) between at least one SGA and one first-generation antipsychotic (FGA). The review focused on three major side-effect clusters: 1. body weight, body mass index, and cardiometabolic parameters, 2. prolactin levels, and 3. neuromotor side effects. Results: In total, 34 studies with 2719 children and adolescents were included. Studies lasted between 3. weeks and 12. months, with most studies (79.4%) lasting 3. months or less. Nine studies (n = 788) were conducted in patients with schizophrenia, 6 (n = 719) in subjects with bipolar disorder, and 19 (n = 1212) in a mixed population. Data on efficacy showed that, except for clozapine being superior for refractory schizophrenia, there were no significant differences between SGAs. By contrast, safety assessments showed relevant differences between SGAs. Mean weight gain ranged from 3.8. kg to 16.2. kg in patients treated with olanzapine (n = 353), from 0.9. kg to 9.5. kg in subjects receiving clozapine (n = 97), from 1.9. kg to 7.2. kg in those on risperidone (n = 571), from 2.3. kg to 6.1. kg among patients taking quetiapine (n = 133), and from 0. kg to 4.4. kg in those treated with aripiprazole (n = 451). Prolactin levels increased the most in subjects on risperidone (mean change ranging from 8.3. ng/mL to 49.6. ng/mL), followed by olanzapine (-1.5. ng/mL to +. 13.7. ng/mL). Treatment with aripiprazole was associated with decreased prolactin levels, while clozapine and quetiapine were found to be mostly neutral. With respect to neuromotor side effects, SGAs were associated with less parkinsonism and akathisia than FGAs. Most of the studies comparing neuromotor side effects between SGAs found no significant differences. Conclusions: SGAs do not behave as a homogeneous group in children and adolescents with psychotic and mood disorders. Except for clozapine, the heterogeneity within the SGA group is mainly due to differences in the rates and severity of adverse events, especially regarding weight gain as a proxy for the risk of cardiometabolic disturbances. © 2011.
High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: Interplay between clinical and animal studiesJoseph Zohar | Hila Yahalom | Nitsan Kozlovsky | Shlomit Cwikel-Hamzany | Michael A. Matar | Zeev Kaplan | Rachel Yehuda | Hagit Cohen
Volume 21, Issue 11, November 2011, Pages 796-809
High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100-140. mg) or placebo within 6. h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. In parallel, a comparative study of morphological arborization in dentate gyrus and its modulating molecules was performed in stress-exposed animals treated with high-dose hydrocortisone. Steroid-treated stressed animals displayed significantly increased dendritic growth and spine density, with increased levels of brain-derived neurotrophic factor (BDNF) and obtunded postsynaptic density-95 (PSD-95) levels. The animal study provided insights into the potential mechanism of this intervention, as it identified relevant morphological and biochemical associations to the clinical observations. Thus, evidence from clinical and animal studies suggests that there is a "window of opportunity" in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD. © 2011 Elsevier B.V. and ECNP.
Modeling the impact of alcohol dependence on mortality burden and the effect of available treatment interventions in the European UnionJ. Rehm | K. D. Shield | G. Gmel | M. X. Rehm | U. Frick
Volume 23, Issue 2, February 2013, Pages 89-97
Alcohol consumption is a major risk factor for the burden of disease, and Alcohol Dependence (AD) is the most important disorder attributable to this behavior. The objective of this study was to quantify mortality associated with AD and the potential impact of treatment. For the EU countries, for the age group 15-64 years, mortality attributable to alcohol consumption in general, to heavy drinking, and to AD were estimated based on the latest data on exposure and mortality. Potential effects of AD treatment were modeled based on Cochrane and other systematic reviews of the effectiveness of the best known and most effective interventions. In the EU 88.9% of men and 82.1% of women aged 15-64 years were current drinkers; and 15.3% of men and 3.4% of women in this age group were heavy drinkers. AD affected 5.4% of men and 1.5% of women. The net burden caused by alcohol consumption was 1 in 7 deaths in men and 1 in 13 deaths in women. The majority of this burden was due to heavy drinking (77%), and 71% of this burden was due to AD. Increasing treatment coverage for the most effective treatments to 40% of all people with AD was estimated to reduce alcohol-attributable mortality by 13% for men and 9% for women (annually 10,000 male and 1700 female deaths avoided). Increasing treatment rates for AD was identified as an important issue for future public health strategies to reduce alcohol-attributable harm and to complement the current focus of alcohol policy. © 2012 Elsevier B.V. and ECNP.
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)David S. Baldwin | Henrik Loft | Marianne Dragheim
Volume 22, Issue 7, July 2012, Pages 482-491
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 10. mg Lu AA21004, placebo, or 60. mg duloxetine. The 5. mg and 10. mg 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 5. mg, n. =. 155) and -. 1.5 points (Lu AA21004 10. mg, n. =. 151) were not statistically significant; nor were those for Lu AA21004 2.5. mg (-. 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 5. mg and 10. mg 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 (2.5. mg, 5. mg and 10. mg, 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 5. mg and 10. mg and duloxetine. Lu AA21004 (2.5, 5 and 10. mg) was well tolerated. © 2011 Elsevier B.V.
Common and distinct neural correlates of emotional processing in Bipolar Disorder and Major Depressive Disorder: A voxel-based meta-analysis of functional magnetic resonance imaging studiesGiuseppe Delvecchio | Philippe Fossati | Patrice Boyer | Paolo Brambilla | Peter Falkai | Oliver Gruber | Jarmo Hietala | Stephen M. Lawrie | Jean Luc Martinot | Andrew M. McIntosh | Eva Meisenzahl | Sophia Frangou
Volume 22, Issue 2, February 2012, Pages 100-113
Neuroimaging studies have consistently shown functional brain abnormalities in patients with Bipolar Disorder (BD) and Major Depressive Disorder (MDD). However, the extent to which these two disorders are associated with similar or distinct neural changes remains unclear. We conducted a systematic review of functional magnetic resonance imaging studies comparing BD and MDD patients to healthy participants using facial affect processing paradigms. Relevant spatial coordinates from twenty original studies were subjected to quantitative Activation Likelihood Estimation meta-analyses based on 168 BD and 189 MDD patients and 344 healthy controls. We identified common and distinct patterns of neural engagement for BD and MDD within the facial affect processing network. Both disorders were associated with increased engagement of limbic regions. Diagnosis-specific differences were observed in cortical, thalamic and striatal regions. Decreased ventrolateral prefrontal cortical engagement was associated with BD while relative hypoactivation of the sensorimotor cortices was seen in MDD. Increased responsiveness in the thalamus and basal ganglia were associated with BD. These findings were modulated by stimulus valence. These data suggest that whereas limbic overactivation is reported consistently in patients with mood disorders, future research should consider the relevance of a wider network of regions in formulating conceptual models of BD and MDD. © 2011 Elsevier B.V.
Interaction of mephedrone with dopamine and serotonin targets in ratsJosé Martínez-Clemente | Elena Escubedo | David Pubill | Jorge Camarasa
Volume 22, Issue 3, March 2012, Pages 231-236
Introduction: 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. Experimental procedures: 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. Results: In isolated synaptosomes from rat cortex or striatum, mephedrone inhibited the uptake of serotonin (5-HT) with an IC 50 value lower than that of dopamine (DA) uptake (IC 50=0.31±0.08 and 0.97±0.05μM, respectively). Moreover, mephedrone displaced competitively both [ 3H]paroxetine and [ 3H]WIN35428 binding in a concentration-dependent manner (Ki values of 17.55±0.78μM and 1.53±0.47μM, respectively), indicating a greater affinity for DA than for 5-HT membrane transporters. The affinity profile of mephedrone for the 5-HT 2 and D 2 receptors was assessed by studying [ 3H]ketanserin and [ 3H] raclopride binding in rat membranes. Mephedrone showed a greater affinity for the 5-HT 2 than for the D 2 receptors. Discussion: 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. © 2011 Elsevier B.V. and ECNP.
Genetics of circadian rhythms and mood spectrum disordersB. Etain | V. Milhiet | F. Bellivier | M. Leboyer
Volume 21, Issue SUPPL.4, September 2011, Pages S676-S682
Mood spectrum disorders (bipolar disorder, recurrent depressive disorder and seasonal affective disorder) are accompanied by circadian deregulations, which can occur during acute mood episodes as well as during euthymic periods, and are particularly common among bipolar patients in remission. This suggests that altered circadian rhythms may be biological markers of these disorders. Rhythm dysfunctions have been observed in mood disorder patients by using actigraphic measures and by assessing social metric rhythms, diurnal preferences and melatonin secretion. Since many of these markers are heritable and therefore driven by clock genes, these genes may represent susceptibility factors for mood spectrum disorders. Indeed, several genetic association studies have suggested that certain circadian gene variants play a role in susceptibility to these disorders. Such connections to circadian genes such as CLOCK, ARNTL1, NPAS2, PER3 and NR1D1 have been repeatedly demonstrated for bipolar disorders, and to a lesser extent for recurrent depressive disorders and seasonal affective disorders. The study of circadian phenotypes and circadian genes in mood spectrum disorders represents a major field of research that may yet reveal the pathophysiological determinants of these disorders. © 2011 Elsevier B.V. and ECNP.
Lu AA21004, a novel multimodal antidepressant, produces regionally selective increases of multiple neurotransmitters-A rat microdialysis and electrophysiology studyAlan L. Pehrson | Thomas Cremers | Cecile Bétry | Marieke G C van der Hart | Laerke Jørgensen | Mathias Madsen | Nasser Haddjeri | Bjarke Ebert | Connie Sanchez
Volume 23, Issue 2, February 2013, Pages 133-145
The monoaminergic network, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA) pathways, is highly interconnected and has a well-established role in mood disorders. Preclinical research suggests that 5-HT receptor subtypes, including 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors as well as the 5-HT transporter (SERT), may have important roles in treating depression. This study evaluated the neuropharmacological profile of Lu AA21004, a novel multimodal antidepressant combining 5-HT3 and 5-HT7 receptor antagonism, 5-HT1B receptor partial agonism, 5-HT1A receptor agonism, and SERT inhibition in recombinant cell lines. Extracellular 5-HT, NE and DA levels were evaluated in the ventral hippocampus (vHC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute and subchronic treatment with Lu AA21004 or escitalopram. The acute effects of LuAA21004 on NE and DA neuronal firing were also evaluated in the locus coeruleus (LC) and ventral tegmental area (VTA), respectively. Acute Lu AA21004 dose-dependently increased 5-HT in the vHC, mPFC and NAc. Maximal 5-HT levels in the vHC were higher than those in the mPFC. Furthermore, mPFC 5-HT levels were increased at low SERT occupancy levels. In the vHC and mPFC, but not the NAc, high Lu AA21004 doses increased NE and DA levels. Lu AA21004 slightly decreased LC NE neuronal firing and had no effect on VTA DA firing. Results are discussed in context of occupancy at 5-HT3, 5-HT1B and 5-HT1A receptors and SERT. In conclusion, Lu AA21004, acting via two pharmacological modalities, 5-HT receptor modulation and SERT inhibition, results in a brain region-dependent increase of multiple neurotransmitter concentrations. © 2012 Elsevier B.V. and ECNP.
ECNP Summit on the future of CNS drug research in Europe 2011: Report prepared for ECNP by David Nutt and Guy GoodwinDavid Nutt | Guy Goodwin
Volume 21, Issue 7, July 2011, Pages 495-499
Circadian rhythms and mood regulation: Insights from pre-clinical modelsColleen A. Mcclung
Volume 21, Issue SUPPL.4, September 2011, Pages S683-S693
Affective disorders such as major depression, bipolar disorder, and seasonal affective disorder are associated with major disruptions in circadian rhythms. Indeed, altered sleep/wake cycles are a critical feature for diagnosis in the DSM IV and several of the therapies used to treat these disorders have profound effects on rhythm length and stabilization in human populations. Furthermore, multiple human genetic studies have identified polymorphisms in specific circadian genes associated with these disorders. Thus, there appears to be a strong association between the circadian system and mood regulation, although the mechanisms that underlie this association are unclear. Recently, a number of studies in animal models have begun to shed light on the complex interactions between circadian genes and mood-related neurotransmitter systems, the effects of light manipulation on brain circuitry, the impact of chronic stress on rhythms, and the ways in which antidepressant and mood-stabilizing drugs alter the clock. This review will focus on the recent advances that have been gleaned from the use of pre-clinical models to further our understanding of how the circadian system regulates mood. © 2011 Elsevier B.V. and ECNP.
Second generation antipsychotics (SGAs) for non-psychotic disorders in children and adolescents: A review of the randomized controlled studiesAlessandro Zuddas | Roberta Zanni | Tatiana Usala
Volume 21, Issue 8, August 2011, Pages 600-620
In children and adolescents the Second Generation Antipsychotics (SGAs) represent the class of psychotropic drugs whose use has grown more significantly in recent years: they are primarily used for treatment of patients with disruptive behavior disorders, mood disorders and pervasive developmental disorders or mental retardation. In order to compare the efficacy and tolerability of antipsychotics against placebo or each other, a systematic Medline/PubMed search for randomized, double blind studies on SGA in patients younger than 18. years of age at enrolment, was conducted. Papers on schizophrenia, discussed in another article of this specific issue, were excluded by the efficacy analysis. A set of standard efficacy and safety indices, such as treatment effect sizes (ES), the Numbers Needed to Treat (NNT) and Numbers Needed to Harm (NNH), was used to compare medications. 32 studies analyzing efficacy and/or tolerability of SGAs in children and adolescents with bipolar, autistic or disruptive behavior disorders, and Tourette syndrome were identified. SGAs efficacy on mania, extreme mood variability, irritability, aggression and disruptive behavior appears to be greater than for psychotic symptoms in schizophrenia: average NNT was 2-5, whereas for schizophrenia it varies between 3 for risperidone and 10 for olanzapine, quetiapine, and aripiprazole.As for schizophrenia, different SGAs show a similar efficacy for specific non-psychotic disorders, but they significantly differ in their safety profile. In randomized studies, adverse effects were usually relatively minor, easily predictable and manageable, whereas long-term open-label studies have indicated that some adverse event, such as the metabolic effects, may be severe and potentially life threatening on the long-term. Taken together, these findings suggest that the choice of a specific treatment should be guided primarily by the safety profile of specific antipsychotics, considering specific risk factors (i.e. obesity and BMI, family history of diabetes or cardiovascular disorder, etc) for the single patient. © 2011 Elsevier B.V.
Polarity index of pharmacological agents used for maintenance treatment of bipolar disorderDina Popovic | Maria Reinares | Jose Manuel Goikolea | Caterina Mar Bonnin | Ana Gonzalez-Pinto | Eduard Vieta
Volume 22, Issue 5, May 2012, Pages 339-346
Over one half of bipolar patients have been reported to be more prone to either depressive or manic relapses. This study aimed to define profiles of drugs used for maintenance treatment of bipolar disorder (BD) by the means of Polarity Index.Polarity Index is a new metric indicating the relative antimanic versus antidepressive preventive efficacy of drugs. Polarity Index was retrieved by calculating Number Needed to Treat (NNT) for prevention of depression and NNT for prevention of mania ratio, as emerging from the results of randomized placebo-controlled trials. Included trials were randomized and double blind, with a minimal duration of 24. weeks, assessing effectiveness of a mood stabilizer or antipsychotic drug alone or in combination with a mood stabilizing agent versus a placebo comparator in BD maintenance treatment.Polarity Index value above 1.0 indicates a relative greater antimanic prophylactic efficacy, number below 1.0 a relative greater antidepressive efficacy. The polarity index for the drugs used in maintenance therapy for bipolar disorder was 12.09 for risperidone, 4.38 for aripiprazole, 3.91 for ziprasidone, 2.98 for olanzapine, 1.39 for lithium, 1.14 for quetiapine, and 0.40 for lamotrigine. Polarity index of valproate and oxcarbazepine may not be reliable due to the failure of their maintenance trials.The polarity index provides a measure of how much antidepressant versus antimanic a drug is in bipolar disorder prophylaxis, and may guide the choice of maintenance therapy in bipolar patients. © 2011 Elsevier B.V. and ECNP.
The hippocampal-prefrontal pathway: The weak link in psychiatric disorders?Bill P. Godsil | Janos P. Kiss | Michael Spedding | Thérèse M. Jay
Volume 23, Issue 10, October 2013, Pages 1165-1181
While the hippocampal formation and the prefrontal cortex each have a well-established role in cognitive and mnemonic processes, the extent and manner in which these structures interact to achieve these functions has not been fully delineated. Recent research in rodents compellingly supports the idea that the projection of neurons extending from the CA1 region of the hippocampus and from the subiculum to the prefrontal cortex, referred to here as the H-PFC pathway, is critically involved in aspects of cognition related to executive function and to emotional regulation. Concurrently, it is becoming evident that persons suffering from schizophrenia, depression, and post-traumatic stress disorder display structural anomalies and aberrant functional coupling within the hippocampal-prefrontal circuit. Considering that these disorders involve varying degrees of cognitive impairment and emotional dysregulation, dysfunction in the H-PFC pathway might therefore be the common element of their pathophysiology. This overlap might also be intertwined with the pathway's evident susceptibility to stress and with its relationship to the amygdala. In consequence, the H-PFC pathway is a potentially crucial element of the pathophysiology of several psychiatric diseases, and it offers a specific target for therapeutic intervention, which is consistent with the recent emphasis on reframing psychiatric diseases in terms of brain circuits. © 2012 Elsevier B.V. and ECNP.
Mechanisms of neuropathic painFlorian T. Nickel | Frank Seifert | Stefan Lanz | Christian Maihöfner
Volume 22, Issue 2, February 2012, Pages 81-91
Neuropathic pain is a disease of global burden. Its symptoms include spontaneous and stimulus-evoked painful sensations. Several maladaptive mechanisms underlying these symptoms have been elucidated in recent years: peripheral sensitization of nociception, abnormal excitability of afferent neurons, central sensitization comprising pronociceptive facilitation, disinhibition of nociception and central reorganization processes, and sympathetically maintained pain. This review aims to illustrate these pathophysiological principles, focussing on molecular and neurophysiological findings. Finally therapeutic options based on these findings are discussed. © 2011 Elsevier B.V. and ECNP.
European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorderDavid Coghill | Tobias Banaschewski | Michel Lecendreux | Cesar Soutullo | Mats Johnson | Alessandro Zuddas | Colleen Anderson | Richard Civil | Nicholas Higgins | Andrew Lyne | Liza Squires
Volume 23, Issue 10, October 2013, Pages 1208-1218
This study evaluated the efficacy and safety of lisdexamfetamine dimesylate (LDX) compared with placebo in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in Europe. Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference arm. Patients (6-17 years old) with a baseline ADHD Rating Scale version IV (ADHD-RS-IV) total score ≥28 were randomized (1:1:1) to dose-optimized LDX (30, 50, or 70. mg/day), OROS-MPH (18, 36, or 54. mg/day) or placebo for 7 weeks. Primary and key secondary efficacy measures were the investigator-rated ADHD-RS-IV and the Clinical Global Impressions-Improvement (CGI-I) rating, respectively. Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms, and vital signs. Of 336 patients randomized, 196 completed the study. The difference between LDX and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was -18.6 (95% confidence interval [CI]: -21.5 to -15.7) (p<0.001; effect size, 1.80). The difference between OROS-MPH and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was -13.0 (95% CI: -15.9 to -10.2) (p<0.001; effect size, 1.26). The proportions (95% CI) of patients showing improvement (CGI-I of 1 or 2) at endpoint were 78% (70-86), 14% (8-21), and 61% (51-70) for LDX, placebo, and OROS-MPH. The most common TEAEs for LDX were decreased appetite, headache, and insomnia. Mean changes in vital signs were modest and consistent with the known profile of LDX. LDX was effective and generally well tolerated in children and adolescents with ADHD. © 2012 Elsevier B.V. and ECNP.
Insulin receptor signaling in rat hippocampus: A study in STZ (ICV) induced memory deficit modelRahul Agrawal | Ethika Tyagi | Rakesh Shukla | Chandishwar Nath
Volume 21, Issue 3, March 2011, Pages 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. © 2010 Elsevier B.V. and ECNP.
Blood microRNA changes in depressed patients during antidepressant treatmentLuisella Bocchio-Chiavetto | Elisabetta Maffioletti | Paola Bettinsoli | Caterina Giovannini | Stefano Bignotti | Daniela Tardito | Dario Corrada | Luciano Milanesi | Massimo Gennarelli
Volume 23, Issue 7, July 2013, Pages 602-611
MicroRNAs (miRNAs) are potent modulators of protein expression that play key roles in brain pathways regulating neurogenesis and synaptic plasticity. These small RNAs may be critical for the pathophysiology of mental disorders and may influence the effectiveness of psychotropic drugs. To investigate the possible involvement of miRNAs in the mechanism of action of antidepressants (AD), we conducted a whole-miRNome quantitative analysis with qRT-PCR of the changes in the blood of 10 depressed subjects after 12 weeks of treatment with escitalopram. Thirty miRNAs were differentially expressed after the AD treatment: 28 miRNAs were up-regulated, and 2 miRNAs were strongly down-regulated. miRNA target gene prediction and functional annotation analysis showed that there was a significant enrichment in several pathways associated with neuronal brain function (such as neuroactive ligand-receptor interaction, axon guidance, long-term potentiation and depression), supporting the hypothesis that the differentially regulated miRNAs may be involved in the AD mechanism. © 2012 Elsevier B.V. and ECNP.
Reward circuit connectivity relates to delay discounting in children with attention-deficit/hyperactivity disorderTaciana G. Costa Dias | Vanessa B. Wilson | Deepti R. Bathula | Swathi P. Iyer | Kathryn L. Mills | Bria L. Thurlow | Corinne A. Stevens | Erica D. Musser | Samuel D. Carpenter | David S. Grayson | Suzanne H. Mitchell | Joel T. Nigg | Damien A. Fair
Volume 23, Issue 1, January 2013, Pages 33-45
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder that has poor long-term outcomes and remains a major public health concern. Recent theories have proposed that ADHD arises from alterations in multiple neural pathways. Alterations in reward circuits are hypothesized as one core dysfunction, leading to altered processing of anticipated rewards. The nucleus accumbens (NAcc) is particularly important for reward processes; task-based fMRI studies have found atypical activation of this region while the participants performed a reward task. Understanding how reward circuits are involved with ADHD may be further enhanced by considering how the NAcc interacts with other brain regions. Here we used the technique of resting-state functional connectivity MRI (rs-fcMRI) to examine the alterations in the NAcc interactions and how they relate to impulsive decision making in ADHD. Using rs-fcMRI, this study: examined differences in functional connectivity of the NAcc between children with ADHD and control children; correlated the functional connectivity of NAcc with impulsivity, as measured by a delay discounting task; and combined these two initial segments to identify the atypical NAcc connections that were associated with impulsive decision making in ADHD. We found that functional connectivity of NAcc was atypical in children with ADHD and the ADHD-related increased connectivity between NAcc and the prefrontal cortex was associated with greater impulsivity (steeper delayed-reward discounting). These findings are consistent with the hypothesis that atypical signaling of the NAcc to the prefrontal cortex in ADHD may lead to excessive approach and failure in estimating future consequences; thus, leading to impulsive behavior. © 2012 Elsevier B.V. and ECNP.
Stratified medicine for mental disordersGunter Schumann | Elisabeth B. Binder | Arne Holte | E. Ronald de Kloet | Ketil J. Oedegaard | Trevor W. Robbins | Tom R. Walker-Tilley | Istvan Bitter | Verity J. Brown | Jan Buitelaar | Roberto Ciccocioppo | Roshan Cools | Carles Escera | Wolfgang Fleischhacker | Herta Flor | Chris D. Frith | Andreas Heinz | Erik Johnsen | Clemens Kirschbaum | Torkel Klingberg | Klaus Peter Lesch | Shon Lewis | Wolfgang Maier | Karl Mann | Jean Luc Martinot | Andreas Meyer-Lindenberg | Christian P. Müller | Walter E. Müller | David J. Nutt | Antonio Persico | Giulio Perugi | Mathias Pessiglione | Ulrich W. Preuss | Jonathan P. Roiser | Paolo M. Rossini | Janusz K. Rybakowski | Carmen Sandi | Klaas E. Stephan | Juan Undurraga | Eduard Vieta | Nic van der Wee | Til Wykes | Josep Maria Haro | Hans Ulrich Wittchen
Volume 24, Issue 1, January 2014, Pages 5-50
There is recognition that biomedical research into the causes of mental disorders and their treatment needs to adopt new approaches to research. Novel biomedical techniques have advanced our understanding of how the brain develops and is shaped by behaviour and environment. This has led to the advent of stratified medicine, which translates advances in basic research by targeting aetiological mechanisms underlying mental disorder. The resulting increase in diagnostic precision and targeted treatments may provide a window of opportunity to address the large public health burden, and individual suffering associated with mental disorders.While mental health and mental disorders have significant representation in the "health, demographic change and wellbeing" challenge identified in Horizon 2020, the framework programme for research and innovation of the European Commission (2014-2020), and in national funding agencies, clear advice on a potential strategy for mental health research investment is needed. The development of such a strategy is supported by the EC-funded "Roadmap for Mental Health Research" (ROAMER) which will provide recommendations for a European mental health research strategy integrating the areas of biomedicine, psychology, public health well being, research integration and structuring, and stakeholder participation. Leading experts on biomedical research on mental disorders have provided an assessment of the state of the art in core psychopathological domains, including arousal and stress regulation, affect, cognition social processes, comorbidity and pharmacotherapy. They have identified major advances and promising methods and pointed out gaps to be addressed in order to achieve the promise of a stratified medicine for mental disorders. © 2013 Elsevier B.V. and ECNP.