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  • 1. Adem, Abdu
    et al.
    Madjid, Nather
    Stiedl, Oliver
    Bonito-Oliva, Alessandra
    Konradsson-Geuken, Åsa
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Jämförande fysiologi.
    Holst, Sarah
    Fisone, Gilberto
    Ögren, Sven Ove
    Atypical but not typical antipsychotic drugs ameliorate phencyclidine-induced emotional memory impairments in mice2019Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, nr 5, s. 616-628, artikkel-id S0924-977X(19)30195-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR) transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA) task in mice and the ability of typical and atypical antipsychotic drugs (APDs) to rectify the PCP-mediated impairment. Pre-training administration of PCP (0.5, 1, 2 or 3 mg/kg) dose-dependently interfered with memory consolidation in the PA task. In contrast, PCP was ineffective when administered after training, and immediately before the retention test indicating that NMDAR blockade interferes with memory encoding mechanisms. The typical APD haloperidol and the dopamine D2/3 receptor antagonist raclopride failed to block the PCP-induced PA impairment suggesting a negligible role of D2 receptors in the PCP impairment. In contrast, the memory impairment was blocked by the atypical APDs clozapine and olanzapine in a dose-dependent manner while risperidone was effective only at the highest dose tested (1 mg/kg). The PCP-induced impairment involves 5-HT1A receptor mechanisms since the antagonist NAD-299 blocked the memory impairment caused by PCP and the ability of clozapine to attenuate the impairment by PCP. These results indicate that atypical but not typical APDs can ameliorate NMDAR-mediated memory impairments and support the view that atypical APDs such as clozapine can modulate glutamatergic memory dysfunctions through 5-HT1A receptor mechanisms. These findings suggest that atypical APDs may improve cognitive impairments related to glutamatergic dysfunction relevant for emotional memories in schizophrenia.

  • 2. Andreou, Dimitrios
    et al.
    Saetre, Peter
    Kähler, Anna K.
    Werge, Thomas
    Andreassen, Ole A.
    Agartz, Ingrid
    Sedvall, Göran C.
    Hall, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Terenius, Lars
    Jönsson, Erik G.
    Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers2011Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 21, nr 9, s. 700-704Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The dystrobrevin binding protein-1 (DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects (n=132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.

  • 3.
    Appel, Lieuwe
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Bergström, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lassen, Jorgen Buus
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: Dopamine transporter occupancy as measured by PET2014Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, nr 2, s. 251-261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tesofensine (TE) is a novel triple monoannine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [C-11]beta CIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A signnoid E-max model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.

  • 4.
    Appel, Lieuwe
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Geffen, Yona
    Heurling, Kerstin
    Eriksson, Catarina
    Antoni, Gunnar
    Kapur, Shitij
    BL-1020, a novel antipsychotic candidate with GABA-enhancing effects: D2 receptor occupancy study in humans2009Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 19, nr 12, s. 841-850Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenazine linked by an ester bound to gamma-aminobutyric acid (GABA), intending a simultaneous dopamine-2 (D(2)) receptor blockade and GABA facilitation in the brain. This positron emission tomography (PET) study, using [(11)C]raclopride, assessed the extent and duration of D(2) receptor occupancy (D(2) RO) and safety for single doses of BL-1020 in healthy male subjects. Overall, this study did not raise any safety concern. Single doses of 16-32 mg BL-1020 caused a dose dependent striatal D(2) RO. The 32 mg dose of BL-1020 resulted in an average D(2) RO of 44% at 4-6 h post dosing (pd), which declined to 33% at 24 h pd. Equimolar doses of BL-1020 and perphenazine resulted in similar D(2) RO at 24 h pd. Pharmacokinetic-pharmacodynamic analysis predicted that oral once daily administration of 32 mg BL-1020 would result in D(2) ROs ranging from 52 to 66% at a steady state.

  • 5. Bahmanyar, Shahram
    et al.
    Sundstrom, Anders
    Kaijser, Magnus
    von Knorring, Anne-Liis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Barn- och ungdomspsykiatri.
    Kieler, Hale
    Pharmacological treatment and demographic characteristics of pediatric patients with Attention Deficit Hyperactivity Disorder, Sweden2013Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, nr 12, s. 1732-1738Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to describe the pediatric population with ADHD and their pharmacological treatment. Using the Swedish National Patient Register and the Prescribed Drug Register we identified individuals below 19 years of age who were diagnosed or medically treated for ADHD for the first time 2006-2007. The unique patient identifiers were used to link information from the two registers to describe demographic characteristics, hospital care and drug treatments. Logistic regression model estimated the association between age, sex, frequency of hospitalization, diagnosis or treatment for other mental disorders and risk of gap in the treatment. Totally the study included 7931 patients of whom 74% were males. The mean age at first diagnosis was 12 years. Some 84% were medically treated for ADHD and approximately 90% received methylphenidate as the first substance. Combination therapy was rare and the most common combination was methylphenidate and atomoxetine. More than 55% of the patients, which could be followed up for two years after start of treatment, had at least one treatment gap of six months. Older age at diagnosis, lower number of hospitalizations and comorbidity with other mental disorders increased risks of gaps in medication. Approximately one fifth of the patients recorded in the National Patient Register as diagnosed with ADHD did not receive pharmacological treatment. Medication adherence seems to be low, when measured as gaps in treatment.

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  • 6.
    Bakalkin, Georgy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Yakovleva, Tatiana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The dynorphin/kappa-opioid receptor system: molecular and epigenetic adaptations in emotional circuitry of alcoholics2016Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, s. S152-S152Artikkel i tidsskrift (Annet vitenskapelig)
  • 7. Baldwin, David S
    et al.
    Allgulander, Christer
    Altamura, Alfredo Carlo
    Angst, Jules
    Bandelow, Borwin
    den Boer, Johan
    Boyer, Patrice
    Davies, Simon
    Dell'osso, Bernardo
    Eriksson, Elias
    Fineberg, Naomi
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Herran, Andres
    Maron, Eduard
    Metspalu, Andres
    Nutt, David
    van der Wee, Nic
    Vázquez-Barquero, Jose Luis
    Zohar, Joseph
    Manifesto for a European anxiety disorders research network2010Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 20, nr 6, s. 426-32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite the size, burden and costs of anxiety disorders, many patients remain unrecognised, and the effectiveness of evidence-based interventions in routine clinical practice can be disappointing. The European College of Neuropsychopharmacology (ECNP) has established the ECNP Network Initiative (ECNP-NI) to help meet the goal of extending current understanding of the causes of central nervous system disorders, thereby contributing to improvements in clinical outcomes and reducing the associated societal burden. The Anxiety Disorders Research Network (ADRN) has been adopted within the ECNP-NI: this consensus statement summarises its overall aims and objectives.

  • 8.
    Barde, Swapnali
    et al.
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.;Karolinska Inst, Dept Neurosci, Biomedicum, S-17177 Stockholm, Sweden..
    Aguila, Julio
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Zhong, Wen
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Solarz, Anna
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Mei, Irene
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    Prud'homme, Josee
    Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Verdun, PQ, Canada.;McGill Univ, Dept Psychiat, Montreal, PQ, Canada..
    Palkovits, Miklos
    Hungarian Acad Sci, Budapest, Hungary.;Semmelwe Univ, Human Brain Tissue Bank & Lab, H-1085 Budapest, Hungary..
    Turecki, Gustavo
    Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Verdun, PQ, Canada.;McGill Univ, Dept Psychiat, Montreal, PQ, Canada..
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Uhlen, Mathias
    Nagy, Corina
    Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Verdun, PQ, Canada.;McGill Univ, Dept Psychiat, Montreal, PQ, Canada..
    Mechawar, Naguib
    Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Verdun, PQ, Canada.;McGill Univ, Dept Psychiat, Montreal, PQ, Canada..
    Hedlund, Eva
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Hokfelt, Tomas
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons2024Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 78, s. 54-63Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.

  • 9. Barde, Swapnali
    et al.
    Aguila, Julio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Zhong, Wen
    Solarz, Anna
    Mei, Irene
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Prud'homme, Josee
    Palkovits, Miklos
    Turecki, Gustavo
    Mulder, Jan
    Uhlén, Mathias
    Nagy, Corina
    Mechawar, Naguib
    Hedlund, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Hökfelt, Tomas
    Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons2024Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 78, s. 54-63Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of ‘normal’ postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on ‘normal’ noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.

  • 10. Björkholm, Carl
    et al.
    Marcus, Monica M
    Konradsson-Geuken, Åsa
    Jardemark, Kent
    Svensson, Torgny H
    The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism.2017Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, s. 411-417, artikkel-id S0924-977X(17)30047-0Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Brexpiprazole (Rexulti(®)), a novel D2/3 receptor (R) partial agonist, was recently approved as monotherapy for schizophrenia, demonstrating effectiveness against both positive and negative symptoms, and also approved as add-on treatment to antidepressant drugs, inducing a potent antidepressant effect with a faster onset compared to an antidepressant given alone. Moreover, brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. To explore whether the observed effects may be mediated via modulation of prefrontal glutamatergic transmission, we investigated the effect of brexpiprazole, alone and in combination with the SSRI escitalopram, on prefrontal glutamatergic transmission using in vitro electrophysiological intracellular recordings of deep layer pyramidal cells of the rat medial prefrontal cortex (mPFC). Nanomolar concentrations of brexpiprazole potentiated NMDAR-induced currents and electrically evoked EPSPs via activation of dopamine D1Rs, in similarity with the effect of the atypical antipsychotic drug clozapine. The effect of an ineffective concentration of brexpiprazole was significantly potentiated by the addition of escitalopram. When combined with escitalopram, brexpiprazole also potentiated AMPAR-mediated transmission, in similarity with the clinically rapid acting antidepressant drug ketamine. The effect on the AMPAR-mediated currents was also D1R dependent. In conclusion, our data propose that brexpiprazole exerts a clozapine-like potentiation of NMDAR-mediated currents in the mPFC, which can explain its efficacy on negative symptoms of schizophrenia and the pro-cognitive effects observed preclinically. Moreover, add-on brexpiprazole to escitalopram also potentiated AMPAR-mediated transmission, which may provide a neurobiological explanation to the faster antidepressant effect of add-on brexpiprazole in major depression.

  • 11.
    Bolstad, Ingeborg
    et al.
    Norge.
    Andreassen, Ole A
    Norge.
    Groote, Inge
    Norge.
    Server, Andres
    Norge.
    Sjaastad, Ivar
    Norge.
    Kapur, Shitij
    Storbritannien.
    Jensen, Jimmy
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Humanvetenskap.
    Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: a pharmacological fMRI study2015Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 25, nr 12, s. 2252-2261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans.

  • 12. Brain, Cecilia
    et al.
    Allerby, Katarina
    Sameby, Birgitta
    Quinlan, Patrick
    Joas, Erik
    Karilampi, Ulla
    Lindström, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Eberhard, Jonas
    Burns, Tom
    Waern, Margda
    Drug attitude and other predictors of medication adherence in schizophrenia: 12 months of electronic monitoring (MEMS (R)) in the Swedish COAST-study2013Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, nr 12, s. 1754-1762Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim was to investigate clinical predictors of adherence to antipsychotics. Medication use was electronically monitored with a Medication Event Monitoring System (MEMS (R)) for 12 months in 112 outpatients with schizophrenia and schizophrenia-like psychosis according to DSM-IV. Symptom burden, insight, psychosocial function (PSP) and side effects were rated at baseline. A comprehensive neuropsychological test battery was administered and a global composite score was calculated. The Drug Attitude Inventory (DAI-10) was filled in. A slightly modified DAI-10 version for informants was distributed as a postal questionnaire. Nonadherence (MEMS (R) adherence <= 0.80) was observed in 27%. In univariate regression models low scores on DAI-10 and DAI-10 informant, higher positive symptom burden, poor function, psychiatric side effects and lack of insight predicted non-adherence. No association was observed with global cognitive function. In multivariate regression models, low patient-rated DAI-10 and PSP scores emerged as predictors of non-adherence. A ROC analysis showed that DAI-10 had a moderate ability to correctly identify non-adherent patients (AUC=0.73, p<0.001). At the most "optimal" cut-off of 4, one-third of the adherent would falsely be. identified as non-adherent. A somewhat larger AUC (0.78, p<0.001) was observed when the ROC procedure was applied to the final regression model including DAI-10 and PSP. For the subgroup with informant data, the AUC for the DAI-10 informant version was 0.68 (p=0.021). Non-adherence cannot be properly predicted in the clinical setting on the basis of these instruments alone. The DAI-10 informant questionnaire needs further testing.

  • 13. Brain, Cecilia
    et al.
    Sameby, Birgitta
    Allerby, Katarina
    Lindström, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Eberhard, Jonas
    Burns, Tom
    Waern, Margda
    Twelve months of electronic monitoring (MEMS (R)) in the Swedish COAST-study: A comparison of methods for the measurement of adherence in schizophrenia2014Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, nr 2, s. 215-222Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The primary aim was to compare objective and subjective measures of adherence in a naturalistic cohort of schizophrenia outpatients over 12 months between October 2008 and June 2011. Antipsychotic medication adherence was monitored in 117 outpatients diagnosed with schizophrenia or schizophrenia-like psychosis according to DSM-IV criteria in a naturalistic prospective study. Adherence was determined by the Medication Event Monitoring System (MEMS (R)), pill count, plasma levels and patient, staff, psychiatrist and close informant ratings. The plasma level adherence measure reflects adherence to medication and to lab visits. Relationships between MEMS (R) adherence and other measures were expressed as a concordance index and kappa (K). Non-adherence (MEMS (R) <= 0.80) was observed in 27% of the patients. MEMS (R) adherence was highly correlated with pill count (concordance= 89% and K=0.72, p < 0.001). Concordance and K were lower for all other adherence measures and very low for the relationship between MEMS (R) adherence and plasma levels (concordance=56% and K=0.05, p=0.217). Adherence measures were also entered into a principal component analysis that yielded three components. MEMS (R) recordings, pill count and informant ratings had their highest loadings in the first component, plasma levels alone in the second and patient, psychiatrist and staff ratings in the third. The strong agreement between MEMS (R) and pill count suggests that structured pill count might be a useful tool to follow adherence in clinical practice. The large discrepancy between MEMS (R) and the adherence measure based on plasma levels needs further study in clinical settings.

  • 14.
    Brikell, I.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ghirardi, L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chang, Z.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, B. M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    ADHD medications and the risk of epileptic seizures: a pharmacoepidemiological study using nationwide register data2017Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, nr Suppl. 4, s. S1113-S1114Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background: Attention-deficit/hyperactivity disorder (ADHD) affects 10–30% of children with epilepsy, making it one of the most common comorbidities in epilepsy. Stimulant medications are first line pharmacological treatment of ADHD, yet there areconcerns regarding the safety of stimulant treatment in patients with comorbid ADHD and epilepsy. This is due to the long held view that stimulants may lower the seizure threshold and increase seizure frequency [1]. Evidence for such an effect are however inconsistent and largely based on studies with small sample sizes, highly selected patient populations and observational studies that have not sufficiently addressed issues of confounding [2]. The aim of this pharmacoepidemiological register based study wastherefore to estimate the risk of seizures in relation to ADHD medication use in a population based cohort of individuals with a history of seizures.

    Methods: Using Swedish national registers, we identified a cohort of 62,361 individuals (48% female) born in Sweden between 1960 and 2004, with at least one seizure episode according to ICD codes. Each individual was followed from January 1st 2006, their first seizure or age five, up until December 31st 2013 or death, whichever came first. We identified periods of ADHD medication use (methylphenidate, amphetamine, dexamphetamine, lisdexamfetamine, and atomoxetine) from the Swedish National Prescribed Drug Register. A period was defined as on-medication when two consecutive prescriptions where no more than 183 days apart, and off-medication if more than 183 daysapart. We obtained information on medical visit for unplanned seizures events from the Swedish National Patient register using ICD codes. We estimated the population level association between ADHD medications and the rate of seizures during medicated and non-medication periods using a cox proportional hazards regression model. To adjust for individual-specific confounding that may influence both seizure risk and the likelihood of receiving ADHD medication, we used a stratified Cox regression model to estimate the rate of seizures during medicated and non-medicated periods, within the same individual.

    Preliminary Result: A total of 59,749 seizure events occurred during 361,501 person years of follow-up. ADHD medications were not associated with the rate of seizures at the population level (HR = 1.06, 95%CI 0.91–1.23). In the within-individual analysis, ADHD medication periods were associated with a reduced rate of seizures (HR = 0.70, 95%CI 0.62–0.79), compared to non-medicated periods. Estimates did not differ across sex, nor in age restricted analyses including only ages 5 and 20 years. All analyses were adjusted for age as a time-varying covariate. Population level analyses were additionally adjusted for sex.

    Conclusions: Our findings suggest that ADHD medications are not associated with an increased risk of seizures. Rather, results from the within-individual analysis, which adjusts for factors that are constant within the individual, such as genetic factors and underlying disorder severity, suggest a protective effect of ADHD medication treatment on seizure rates. Next, we will study the effect of concurrent antiepileptic medication use and whether the observed effect differs by stimulant and non-stimulant ADHD medications. We will also further investigate possible mechanisms contributing to the observed protective effect of ADHD medications on seizure rates.

    References

    [1] Williams, A.E., Giust, J.M., Kronenberger, W.G., Dunn, D.W., 2016. Epilepsy and attention-deficit hyperactivity disorder: links, risks, and challenges. Neuropsychiatr Dis Treat 12, 287–296.

    [2] Ravi, M., Ickowicz, A., 2016. Epilepsy, Attention-Deficit/Hyperactivity Disorder and Methylphenidate: Critical Examination of Guiding Evidence. Journal of the Canadian Academy of Child and Adolescent Psychiatry 25 (1), 50.

  • 15.
    Brikell, Isabell
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper. Karolinska Institutet, Stockholm, Sweden.
    Yi, Lu
    Karolinska Institutet, Stockholm, Sweden.
    Petterson, Erik
    Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Robert
    Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Martin, Joanna
    Karolinska Institutet, Stockholm, Sweden; Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, Wales.
    COMMON GENETIC RISK VARIANTS FOR ADHD CONTRIBUTE TO CHILDHOOD NEURODEVELOPMENTAL AND EXTERNALIZING TRAITS IN THE POPULATION2019Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, nr Suppl. 3, s. S811-S811Artikkel i tidsskrift (Annet vitenskapelig)
  • 16.
    Bulik, Cynthia M.
    et al.
    Karolinska Institutet, Solna, Sweden; University of North Carolina, Chapel Hill NC, USA.
    Clinton, David
    Karolinska Institutet, Solna, Sweden.
    Birgegård, Andreas
    Karolinska Institutet, Solna, Sweden.
    Lindstedt, Katarina
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län.
    Monell, Elin
    Karolinska Institutet, Solna, Sweden.
    Termorshuizen, Jet
    Karolinska Institutet, Solna, Sweden.
    SUBJECTIVE EXPERIENCES OF ANOREXIA NERVOSA IN PATIENTS WITH HIGH VS LOW ANOREXIA NERVOSA POLYGENIC RISK2023Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 75, nr Suppl. 1, s. S14-S14Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Recent genome-wide association studies (GWAS) suggest that genetic factors play a key role in its development and expression and that anorexia nervosa (AN) might have both psychiatric and metabolic underpinnings. One hypothesis is that those with high genetic vulnerability to AN may experience negative energy balance (NEB) (i.e., expending more energy than you consume) in a positive manner, rendering self-starvation and excessive exercise exceptionally reinforcing. This “paradoxical” response to NEB may also complicate recovery. In the Polygenic risk of Anorexia nervosa and its Clinical Expression (PACE) study, we explored differences in clinical and phenomenological/experiential phenotypes (i.e., how patients reported their experience of illness) in 10 individuals with AN who were in the top decile of AN polygenic risk (PRS) and 10 individuals with AN who were in the lowest decile in the Swedish subsample of the Anorexia Nervosa Genetics Initiative (ANGI) study. We interviewed the participants in a double-blind study design using a structured interview guide focusing on the experience of AN, including experiences of NEB (e.g., hunger, satiety, dietary restriction), the development of symptoms, as well as the reactions of others including family members and treatment providers to patients’ experiences of NEB. All interviews have been coded and the blind will be broken in May 2023 at which point group comparisons will be analyzed. This is the first study, to our knowledge, to explore experiential impact of genetic risk. Findings may aid in understanding risk, clinical course, and individual experience of AN and contribute suggestions for tailoring interventions with input from genetic risk profiles.

  • 17.
    Chatzittofis, A.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Boström, A.
    Öberg, K.
    Flanagan, J.
    Schioth, H.
    Arver, S.
    Jokinen, J.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Testosterone, luteinizing hormone levels and methylation status in men with hypersexual disorders2019Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, s. S135-S135Artikkel i tidsskrift (Annet vitenskapelig)
  • 18.
    Chatzittofis, A.
    et al.
    Univ Umea, Dept Clin Sci Psychiat, Umea, Sweden.
    Boström, Adrian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Öberg, K.
    Karoliska Inst, Dept Med, Stockholm, Sweden.
    Flanagan, J.
    Karoliska Inst, Dept Med, Stockholm, Sweden.
    Schiöth, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Arver, S.
    Karoliska Inst, Dept Med, Stockholm, Sweden.
    Jokinen, J.
    Umea Univ, Dept Clin Sci, Umea, Sweden.
    Testosterone, luteinizing hormone levels and methylation status in men with hypersexual disorders2019Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, s. S135-S135Artikkel i tidsskrift (Annet vitenskapelig)
  • 19.
    Chatzittofis, Andreas
    et al.
    Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden.
    Nordström, Peter
    Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden.
    Hellström, Christer
    Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden.
    Arver, Stefan
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Sweden.
    Åsberg, Marie
    Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden.
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden.
    CSF 5-HIAA, cortisol and DHEAS levels in suicide attempters2013Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, nr 10, s. 1280-7Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The serotonin system and the hypothalamic-pituitary-adrenal (HPA) axis are involved in the biological vulnerability to suicidal behaviour. Altered levels of dehydroepiandrosterone (DHEA) and its sulphate ester DHEAS have been reported in neuropsychiatric conditions. The aim of this study was to investigate CSF levels of 5-Hydroxyindoleacetic acid (5-HIAA) and CSF and plasma levels of cortisol and DHEAS in 28 medication free suicide attempters and 19 healthy volunteers. Another aim was to investigate the relationship between neuroendocrine measures and childhood trauma in suicide attempters. As the study design includes a longitudinal part, we investigated whether CSF cortisol, 5-HIAA or DHEAS would predict subsequent suicide. We hypothesized higher cortisol levels in suicide attempters and lower CSF 5-HIAA levels and higher cortisol levels in suicide victims. Suicide attempters had higher CSF and plasma cortisol levels compared to healthy volunteers. Male suicide attempters had higher CSF DHEAS levels and female suicide attempters had lower CSF 5-HIAA levels compared to male and female healthy volunteers respectively. Exposure to interpersonal violence as a child showed a negative correlation with CSF cortisol/DHEAS ratio adjusted for age, gender and depression severity in a regression analysis. Suicide victims tended to have low CSF 5-HIAA and high CSF cortisol. Abused suicide victims had higher CSF cortisol compared to suicide victims with low exposure to interpersonal violence as a child. The results underlie the important role of the serotonergic system and HPA axis in suicidal behaviour and suggest that CSF DHEAS may be elevated in male suicide attempters.

  • 20.
    Checknita, Dave
    et al.
    Uppsala Univ, Uppsala, Sweden..
    Bendre, Megha
    Uppsala Univ, Uppsala, Sweden..
    Ekstrom, Tomas
    Karolinska Inst, Stockholm, Sweden..
    Comasco, Erika
    Uppsala Univ, Uppsala, Sweden..
    Tiihonen, Jari
    Karolinska Inst, Stockholm, Sweden..
    Nilsson, Kent W.
    Mälardalens högskola, Akademin för hälsa, vård och välfärd, Hälsa och välfärd. Uppsala Univ, Uppsala, Sweden..
    Hodgins, Sheilagh
    Karolinska Inst, Stockholm, Sweden..
    MONOAMINE OXIDASE A (MAOA) GENOTYPE AND METHYLATION MODERATES ASSOCIATIONS OF MALTREATMENT AND AGGRESSION IN WOMEN AND MEN2019Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, s. S850-S850Artikkel i tidsskrift (Annet vitenskapelig)
  • 21.
    Comasco, Erika
    et al.
    Uppsala Univ, Dept Neurosci, Pharmacol Unit, BMC, S-75124 Uppsala, Sweden..
    Aslund, Cecilia
    Uppsala Univ, Cty Hosp, Clin Res Ctr, S-72189 Vasteras, Sweden..
    Oreland, Lars
    Uppsala Univ, Dept Neurosci, Pharmacol Unit, BMC, S-75124 Uppsala, Sweden..
    Nilsson, Kent W.
    Uppsala Univ, Cty Hosp, Clin Res Ctr, S-72189 Vasteras, Sweden..
    Three-way interaction effect of 5-HTTLPR, BDNF Val66Met, and childhood adversity on depression: A replication study2013Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, nr 10, s. 1300-1306Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Both the serotonin transporter linked promoter region (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms have been shown to interact with unfavourable environment in relation to depression symptoms and to depression diagnosis. Several attempts have been made to study a three-way interaction effect of these factors on depression, however with contradictory results. We aimed to test the hypothesis of a three-way interaction effect and to attempt at replication in an independent population-based sample. Family maltreatment, sexual abuse and depression were self-reported by an adolescent population-based cohort (N=1393) from the county of Vastmanland, Sweden. DNA was isolated from saliva, and used for genotyping of the 5-HTTLPR and BDNF Val66Met polymorphisms. Neither 5-HTTLPR or BDNF genotypes separately, nor in interaction with each other had any relation to depression, however in an environment adjusted model a two-way interaction and a three-way interaction effect was found. Both 5-HTTLPR and BDNF Val66Met interacted with unfavourable environment in relation to depressive symptoms (Adj R-2=0.19). Depressive symptoms and depression were more common among carriers of either the ss/sl+Val/Val or the ll+Met genotypes in the presence of early-life adversities. This three-way effect was more pronounced among girls. The current study, with a virtually similar set-up compared to previous studies, can partially confirm previous findings and their generalizability. The study also shows the importance of genetic plasticity in individuals with different environmental exposure, for different phenotypic expression. 

  • 22.
    Comasco, Erika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Gulinello, Maria
    Albert Einstein Coll Med, Dept Neurosci, Behav Core Facil, Bronx, NY USA..
    Hellgren, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Skalkidou, Alkistis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Sylven, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Sundström-Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Sleep duration, depression, and oxytocinergic genotype influence prepulse inhibition of the startle reflex in postpartum women2016Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, nr 4, s. 767-776Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The postpartum period is characterized by a post-withdrawal hormonal status, sleep deprivation, and susceptibility to affective disorders. Postpartum mothering involves automatic and attentional processes to screen out new external as well as internal stimuli. The present study investigated sensorimotor gating in relation to sleep duration, depression, as well as catecholaminergic and oxytocinergic genotypes in postpartum women. Prepulse inhibition (PPI) of the startle reflex and startle reactivity were assessed two months postpartum in 141 healthy and 29 depressed women. The catechol-O-methyltransferase (COMT) Val158Met, and oxytocin receptor (OXTR) rs237885 and rs53576 polymorphisms were genotyped, and data on sleep duration were collected. Short sleep duration (less than four hours in the preceding night) and postpartum depression were independently associated with lower PPI. Also, women with postpartum depression had higher startle reactivity in comparison with controls. The OXTR rs237885 genotype was related to PPI in an allele dose-dependent mode, with T/T healthy postpartum women carriers displaying the lowest PPI. Reduced sensorimotor gating was associated with sleep deprivation and depressive symptoms during the postpartum period. Individual neurophysiological vulnerability might be mediated by oxytocinergic genotype which relates to bonding and stress response. These findings implicate the putative relevance of lower PPI of the startle response as an objective physiological correlate of liability to postpartum depression.

  • 23.
    Comasco, Erika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Hellgren, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Sundström Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Influence of catechol-O-methyltransferase Val158Met polymorphism on startle response in the presence of high estradiol levels2013Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, nr 7, s. 629-635Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: both human and animal studies have shown a somewhat complex COMT-by-sex interaction effect on brain function and dysfunction. A functional variation in the gene coding for the catechol-O-methyltransferase (COMT) enzyme, which metabolizes dopamine and noradrenaline, has been related to executive and emotional functions, and to sex dimorphism. Aim: to investigate if COMT Val158Met genotype influences startle response in pregnant women, given their physiologically elevated estradiol levels. Methods: seventy-three pregnant women were assessed in gestational week 38 for acoustic startle response, measured by electromyography of the blink reflex, during control condition, positive and negative anticipation stimuli, and pleasant and unpleasant image stimuli. A blood sample was taken for measurement of estradiol levels and genetic analysis. Results: the results indicated a COMT Val158Met effect on startle response across all conditions (main effect of genotype, F(2,70=3.58), p=0.033), where Val/Val women displayed higher startle magnitudes than Val/Met carriers (Cohen's d=0.71). No significant difference by genotype was found in affective modulation. The findings also suggested an estrogen dose-dependent effect of COMT Val158Met on startle reflex. Among women with higher pregnancy-induced estradiol levels, Val/Val carriers had markedly higher startle response across conditions than heterozygotes (Cohen's d=1.36; F(4,21=11.07); p=0.003), while this effect was not present in women with estradiol levels under the median concentration. Conclusions: the observed effect of COMT Val158Met by estradiol on overall startle response is likely to be due to a variable noradrenergic transmission depending on COMT activity in a possible interaction with estradiol. 

  • 24.
    Comasco, Erika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Hellgren, Chorlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Poromaa, Inger Sundström
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Pregnancy, anxiety symptoms and catecholaminergic genotype are associated with prepulse inhibition of the startle response in women2015Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 25, s. S216-S216Artikkel i tidsskrift (Annet vitenskapelig)
  • 25.
    Comasco, Erika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Oreland, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Hallman, Jarmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Wallen-Mackenzie, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Haplotype tag single-nucleotide polymorphism analysis of the vesicular glutamate transporter 2 gene in severe alcoholism among women2012Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, nr S2, s. S397-S397Artikkel i tidsskrift (Annet vitenskapelig)
  • 26.
    Comasco, Erika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Todkar, Aniruddha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Granholm, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gene-set-based expression and DNA methylation in hypothalamus and pituitary of rats exposed to early life stress and ethanol drinking2014Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, nr Suppl. 2, s. S663-Artikkel i tidsskrift (Annet vitenskapelig)
  • 27.
    Comasco, Erika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Åslund, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Oreland, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Nilsson, Kent W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Three-way interaction effect of 5-HTTLPR, BDNF Val66Met, and childhood adversity on depression: A replication study2013Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, nr 10, s. 1300-1306Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Both the serotonin transporter linked promoter region (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms have been shown to interact with unfavourable environment in relation to depression symptoms and to depression diagnosis. Several attempts have been made to study a three-way interaction effect of these factors on depression, however with contradictory results. We aimed to test the hypothesis of a three-way interaction effect and to attempt at replication in an independent population-based sample. Family maltreatment, sexual abuse and depression were self-reported by an adolescent population-based cohort (N=1393) from the county of Västmanland, Sweden. DNA was isolated from saliva, and used for genotyping of the 5-HTTLPR and BDNF Val66Met polymorphisms. Neither 5-HTTLPR or BDNF genotypes separately, nor in interaction with each other had any relation to depression, however in an environment adjusted model a two-way interaction and a three-way interaction effect was found. Both 5-HTTLPR and BDNF Val66Met interacted with unfavourable environment in relation to depressive symptoms (Adj R2=0.19). Depressive symptoms and depression were more common among carriers of either the ss/sl+Val/Val or the ll+Met genotypes in the presence of early-life adversities. This three-way effect was more pronounced among girls. The current study, with a virtually similar set-up compared to previous studies, can partially confirm previous findings and their generalizability. The study also shows the importance of genetic plasticity in individuals with different environmental exposure, for different phenotypic expression.

  • 28. Crowley, James
    et al.
    Mudgal, Poorva
    Nordin Adolfsson, Annelie
    Umeå universitet.
    Åberg, Karolina
    Alaerts, Maaike
    Genovese, Giulio
    McCarroll, Steven
    Del-Favero, Jurgen
    Adolfsson, Rolf
    Umeå universitet.
    Sullivan, Patrick
    The genomics of bipolar and schizophrenic disorders in a large pedigree from a northern Swedish isolate2019Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, s. S902-S903Artikkel i tidsskrift (Annet vitenskapelig)
  • 29.
    Daoura, Loudin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Haaker, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Adolescent and adult male Wistar rats exposed to postnatal maternal separation differ in voluntary ethanol intake2010Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 20, nr Suppl. 1, s. S36-Artikkel i tidsskrift (Annet vitenskapelig)
  • 30.
    Engel, Jorgen A.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Pharmacol, SE-40530 Gothenburg, Sweden..
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jerlhag, Elisabet
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Pharmacol, SE-40530 Gothenburg, Sweden..
    A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice2015Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 25, nr 12, s. 2364-2371Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Metenkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leuenkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959's ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GIS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction.

  • 31.
    Engman, Jonas
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Center for Cognitive Neuroscience, Duke University, Durham, NC, USA.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Linnman, Clas
    P.A.I.N. group, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
    Pissiota, Anna
    Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden.
    Appel, Lieuwe
    PET Centre, Department of Medical Imaging, Uppsala University Hospital, Sweden; Section of Nuclear Medicine and PET, Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Sweden.
    Frans, Örjan
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Långström, Bengt
    Department of Chemistry, Uppsala University, Uppsala, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Age, sex and NK1 receptors in the human brain -- a positron emission tomography study with [¹¹C]GR2051712012Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, nr 8, s. 562-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The substance P/neurokinin 1 (SP/NK1) system has been implicated in the processing of negative affect. Its role seems complex and findings from animal studies have not been easily translated to humans. Brain imaging studies on NK1 receptor distribution in humans have revealed an abundance of receptors in cortical, striatal and subcortical areas, including the amygdala. A reduction in NK1 receptors with increasing age has been reported in frontal, temporal, and parietal cortices, as well as in hippocampal areas. Also, a previous study suggests sex differences in cortical and subcortical areas, with women displaying fewer NK1 receptors. The present PET study explored NK1 receptor availability in men (n=9) and women (n=9) matched for age varying between 20 and 50years using the highly specific NK1 receptor antagonist [¹¹C]GR205171 and a reference tissue model with cerebellum as the reference region. Age by sex interactions in the amygdala and the temporal cortex reflected a lower NK1 receptor availability with increasing age in men, but not in women. A general age-related decline in NK1 receptor availability was evident in the frontal, temporal, and occipital cortices, as well as in the brainstem, caudate nucleus, and thalamus. Women had lower NK1 receptor availability in the thalamus. The observed pattern of NK1 receptor distribution in the brain might have functional significance for brain-related disorders showing age- and sex-related differences in prevalence.

  • 32.
    Engman, Jonas
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Åhs, Fredrik
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Linnman, Clas
    Pissiota, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Frans, Örjan
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Age, sex and NK1 receptors in the human brain: A positron emission tomography study with [C-11]GR2051712012Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, nr 8, s. 562-568Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The substance P/neurokinin 1 (SP/NK1) system has been implicated in the processing of negative affect. Its role seems complex and findings from animal studies have not been easily translated to humans. Brain imaging studies on NK1 receptor distribution in humans have revealed an abundance of receptors in cortical, striatal and subcortical areas, including the amygdala. A reduction in NK1 receptors with increasing age has been reported in frontal, temporal, and parietal cortices, as well as in hippocampal areas. Also, a previous study suggests sex differences in cortical and subcortical areas, with women displaying fewer NK1 receptors. The present PET study explored NK1 receptor availability in men (n = 9) and women (n = 9) matched for age varying between 20 and 50 years using the highly specific NK1 receptor antagonist [11C]GR205171 and a reference tissue model with cerebellum as the reference region. Age by sex interactions in the amygdala and the temporal cortex reflected a lower NK1 receptor availability with increasing age in men, but not in women. A general age-related decline in NK1 receptor availability was evident in the frontal, temporal, and occipital cortices, as well as in the brainstem, caudate nucleus, and thalamus. Women had lower NK1 receptor availability in the thalamus. The observed pattern of NK1 receptor distribution in the brain might have functional significance for brain-related disorders showing age- and sex-related differences in prevalence.

  • 33.
    Evers, Kathinka
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Philosophical challenges for neuroethics2008Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 18, nr Suppl. 4, s. S202-S202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroethics is an area concerned with the possible benefitsand dangers of modern research on the brain. Researchers inneuroethics have focused mainly on applied neuroethics, suchas ethical issues involved in neuroimaging techniques, cognitiveenhancement, or neuropharmacology (Illes 2006). Another important,less prevalent, scientific approach is fundamental neuroethics:how knowledge of the brain’s functional architecture and itsevolution can deepen our understanding of identity, consciousnessand intentionality, including the development of moral thoughtand judgment (Evers 2008). The relevance of neuroscience tounderstanding moral judgment depends on the theoretical viewthat is taken on the brain. A modern, dynamic view of thebrain may provide a fruitful theoretical framework for neuroethicsthrough its high explanatory value in regard to the evolution andnature of moral judgment under the aspects of subjective evaluation,free will and personal or public responsibility (Evers 2007).Informed materialism is a model based on the notion that all theelementary cellular processes of brain networks are grounded onphysico-chemical mechanisms and adopts an evolutionary viewof consciousness as a biological function of neuronal activities,but describes the brain as an autonomously active, projective andvariable system in which emotions and values are incorporated asnecessary constraints. Dynamic processes of evaluation and theemotional systems involved in their genesis are basic properties ofour brains: we are neurobiologically predisposed to develop thesecomplex and diverse systems of moral and other values enablingus to establish appropriate relationships in our social, cultural andphysical environments.

  • 34.
    Faria, Vanda
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Imaging the placebo response: a neurofunctional review2008Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 18, nr 7, s. 473-485Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    An emerging literature has started to document the neuronal changes associated with the placebo phenomenon. This has altered placebo from being considered a nuisance factor in clinical research to a target of scientific investigation per se. This paper reviews the neuroimaging literature on the placebo effect, and illustrates how imaging tools can improve current understanding of brain mechanisms underlying the placebo response. Imaging studies provide evidence of specific, predictable and replicable patterns of neural changes associated with placebo administration. In general, placebo responses seem mediated by "top-down" processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. Dopaminergic reward pathways may underlie these expectancies. Placebo-induced clinical benefits also involve disorder-specific neuronal responses, yielding neurofunctional or neurochemical alterations similar to those produced by pharmacological treatments.

  • 35.
    Faria, Vanda
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Tech Univ Dresden, Dept Otorhinolaryngol, Smell & Taste Clin, Fetscherstr 74, D-01307 Dresden, Germany;Harvard Med Sch, Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Ctr Pain & Brain, Boston, MA 02115 USA.
    Han, Pengfei
    Tech Univ Dresden, Dept Otorhinolaryngol, Smell & Taste Clin, Fetscherstr 74, D-01307 Dresden, Germany;Southwest Univ, Minist Educ, Key Lab Cognit & Personal, Chongqing, Peoples R China;Southwest Univ, Fac Psychol, Chongqing, Peoples R China.
    Joshi, Akshita
    Tech Univ Dresden, Dept Otorhinolaryngol, Smell & Taste Clin, Fetscherstr 74, D-01307 Dresden, Germany.
    Enck, Paul
    Dept Internal Med VI Psychosomat Med & Psychother, Tubingen, Germany.
    Hummel, Thomas
    Tech Univ Dresden, Dept Otorhinolaryngol, Smell & Taste Clin, Fetscherstr 74, D-01307 Dresden, Germany.
    Verbal suggestions of nicotine content modulate ventral tegmental neural activity during the presentation of a nicotine-free odor in cigarette smokers2020Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 31, s. 100-108Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Expectancies of nicotine content have been shown to impact smokers' subjective responses and smoking behaviors. However, little is known about the neural substrates modulated by verbally induced expectancies in smokers. In this study we used functional magnetic resonance imaging (fMRI) to investigate how verbally induced expectations, regarding the presence or absence of nicotine, modulated smokers' neural response to a nicotine-free odor. While laying in the scanner, all participants (N = 24) were given a nicotine-free odor, but whereas one group was correctly informed about the absence of nicotine (control group n = 12), the other group was led to believe that the presented odor contained nicotine (expectancy group n = 12). Smokers in the expectancy group had significantly increased blood-oxygen-level-dependent (BOLD) responses during the presentation of the nicotine-free odor in the left ventral tegmental area (VTA), and in the right insula, as compared to smokers in the control group (Regions of interest analysis with pFWE-corrected p <= 0.05). At a more liberal uncorrected statistical level (p-unc <= 0.001), increased bilateral reactivity in the dorsolateral prefrontal cortex (dlPFC) was also observed in the expectancy group as compared with the control group. Our findings suggest that nicotine-expectancies induced through verbal instructions can modulate nicotine relevant brain regions, without nicotine administration, and provide further neural support for the key role that cognitive expectancies play in the cause and treatment of nicotine dependence.

  • 36.
    Fernandez-Quintana, A.
    et al.
    Uppsala Univ, Vastmanlands Country Hosp, Ctr Clin Res, Vasteras, Sweden..
    Olofsdotter, S.
    Uppsala Univ, Vastmanlands Country Hosp, Ctr Clin Res, Vasteras, Sweden..
    Vadlin, S.
    Uppsala Univ, Vastmanlands Country Hosp, Ctr Clin Res, Vasteras, Sweden..
    Nilsson, Kent W.
    Mälardalens högskola, Akademin för hälsa, vård och välfärd, Hälsa och välfärd. Uppsala Univ, Vastmanlands Country Hosp, Ctr Clin Res, Vasteras, Sweden..
    Sonnby, K.
    Uppsala Univ, Vastmanlands Country Hosp, Ctr Clin Res, Vasteras, Sweden..
    Clinical utility of two sensitivity/specificity-maximized cut-off scores of The World Health Organization ADHD Self-Report Scale for Adolescents (ASRS-A)2019Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, s. S176-S177Artikkel i tidsskrift (Annet vitenskapelig)
  • 37.
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs-A practical view2015Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 25, nr 6, s. 749-762Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover. Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling. In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view. It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone. Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of "cannabis-like" behaviours.

  • 38. Franke, Andreas G.
    et al.
    Gränsmark, Patrik
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutet för social forskning (SOFI).
    Agricola, Alexandra
    Schühle, Kai
    Ronnmel, Thilo
    Sebastian, Alexandra
    Balló, Harald E.
    Gorbulev, Stanislav
    Gerdes, Christer
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutet för social forskning (SOFI).
    Frank, Björn
    Ruckes, Christian
    Tüscher, Oliver
    Lieb, Klaus
    Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial2017Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, nr 3, s. 248-260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stimulants and caffeine have been proposed for cognitive enhancement by healthy subjects. This study investigated whether performance in chess - a competitive mind game requiring highly complex cognitive skills - can be enhanced by methylphenidate, modafinil or caffeine. In a phase IV, randomized, double-blind, placebo-controlled trial, 39 male chess players received 2 x 200 mg modafinil, 2 x 20 mg methylphenidate, and 2 x 200 mg caffeine or placebo in a 4 x 4 crossover design. They played twenty 15-minute games during two sessions against a chess program (Fritz 12; adapted to players' strength) and completed several neuropsychological tests. Marked substance effects were observed since all three substances significantly increased average reflection time per game compared to placebo resulting in a significantly increased number of games lost on time with all three treatments. Treatment effects on chess performance were not seen if all games (n=3059) were analysed. Only when controlling for game duration as well as when excluding those games lost on time, both modafinil and methylphenidate enhanced chess performance as demonstrated by significantly higher scores in the remaining 2876 games compared to placebo. In conjunction with results from neuropsychological testing we conclude that modifying effects of stimulants on complex cognitive tasks may in particular result from more reflective decision making processes. When not under time pressure, such effects may result in enhanced performance. Yet, under time constraints more reflective decision making may not improve or even have detrimental effects on complex task performance.

  • 39.
    Franke, Barbara
    et al.
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
    Michelini, Giorgia
    King's College London, Institute of Psychiatry, Psychology & Neuroscience, Social, Genetic & Developmental Psychiatry Centre, London, UK.
    Asherson, Philip
    King's College London, Institute of Psychiatry, Psychology & Neuroscience, Social, Genetic & Developmental Psychiatry Centre, London, UK.
    Banaschewski, Tobias
    Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
    Bilbow, Andrea
    Attention Deficit Disorder Information and Support Service (ADDISS), Edgware, UK; ADHD-Europe, Brussels, Belgium.
    Buitelaar, Jan K.
    Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands.
    Cormand, Bru
    Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain.
    Faraone, Stephen V.
    Departments of Psychiatry and of Neuroscience and Physiology, State University of New York Upstate Medical University, New York, USA; K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
    Ginsberg, Ylva
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Haavik, Jan
    K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
    Kuntsi, Jonna
    King's College London, Institute of Psychiatry, Psychology & Neuroscience, Social, Genetic & Developmental Psychiatry Centre, London, UK.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Lesch, Klaus-Peter
    Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Department of Translational Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands.
    Ramos-Quiroga, J. Antoni
    Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain; Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Catalonia, Spain; Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
    Réthelyi, János M.
    Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary; MTA-SE NAP-B Molecular Psychiatry Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
    Ribases, Marta
    Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain; Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Catalonia, Spain.
    Reif, Andreas
    Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
    Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan2018Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 28, nr 10, s. 1059-1088, artikkel-id S0924-977X(18)30303-1Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.

  • 40.
    Frick, Andreas
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Appel, Lieuwe
    Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Jonasson, My
    Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Wahlstedt, Kurt
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Bani, Massimo
    GlaxoSmithKline, Verona, Italy.
    Merlo Pich, Emilio
    GlaxoSmithKline, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Verona, Italy.
    Långström, Bengt
    Department of Chemistry, Uppsala University, Uppsala, Sweden.
    Lubberink, Mark
    Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder2016Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, nr 11, s. 1775-1783, artikkel-id S0924-977X(16)30182-1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40mg), the NK1R antagonist GR205171 (n=6; 5mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.

  • 41.
    Frick, Andreas
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Åhs, Fredrik
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Jonasson, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wahlstedt, Kurt
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Bani, Massimo
    GlaxoSmithKline, Verona, Italy.
    Pich, Emilio Merlo
    GlaxoSmithKline, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Verona, Italy.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Fredriksson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder2016Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, nr 11, s. 1775-1783Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Abstract Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40 mg), the NK1R antagonist GR205171 (n=6; 5 mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.

  • 42.
    Gingnell, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi. Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Bannbers, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Sundström Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Premenstrual dysphoric disorder and prefrontal reactivity during anticipation of emotional stimuli2013Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, nr 11, s. 1474-1483Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Premenstrual disorder (PMDD) affects around 5% of women in childbearing ages. An increased sensitivity in emotion processing areas of the brain to variations in ovarian steroid levels has been suggested as part of the pathophysiology in PMDD, but prior neuroimaging studies of emotion processing are yet inconclusive. Previous behavioral studies of women with PMDD have, however, reported enhanced luteal phase startle responsivity during emotional anticipation. Here we used functional magnetic resonance imaging (fMRI) to investigate central neural circuitry activity during anticipation of, and exposure to, emotional stimuli across the menstrual cycle in women with and without PMDD. As compared to healthy controls, women with PMDD displayed significantly enhanced reactivity in the prefrontal cortex during anticipation of, but not exposure to, negative emotional stimuli during the luteal phase. In PMDD patients, BOLD reactivity during anticipation or viewing of negative emotional stimuli was not dependent on absolute levels of estradiol or progesterone. However, progesterone levels were positively correlated with emotion-induced reactivity in the dorsolateral prefrontal cortex to positive emotional stimuli. These findings suggest that cortical emotional circuitry reactivity during anticipation is altered in PMDD during the luteal phase, which might be part of the pathophysiology behind the emotional symptoms or lack of emotional control reported by women with PMDD.

  • 43. Goodwin, Guy M.
    et al.
    Holmes, Emily A.
    Andersson, Erik
    Browning, Michael
    Jones, Andrew
    Lass-Hennemann, Johanna
    Månsson, Kristoffer N. T.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Klinisk psykologi. Karolinska Institutet, Sweden; Uppsala University, Sweden.
    Moessnang, Carolin
    Salemink, Elske
    Sanchez, Alvaro
    van Zutphen, Linda
    Visser, Renée M.
    From neuroscience to evidence based psychological treatments - The promise and the challenge, ECNP March 2016, Nice, France2018Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 28, nr 2, s. 317-333Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This ECNP meeting was designed to build bridges between different constituencies of mental illness treatment researchers from a range of backgrounds with a specific focus on enhancing the development of novel, evidence based, psychological treatments. In particular we wished to explore the potential for basic neuroscience to support the development of more effective psychological treatments, just as this approach is starting to illuminate the actions of drugs. To fulfil this aim, a selection of clinical psychologists, psychiatrists and neuroscientists were invited to sit at the same table. The starting point of the meeting was the proposition that we know certain psychological treatments work, but we have only an approximate understanding of why they work. The first task in developing a coherent mental health science would therefore be to uncover the mechanisms (at all levels of analysis) of effective psychological treatments. Delineating these mechanisms, a task that will require input from both the clinic and the laboratory, will provide a key foundation for the rational optimisation of psychological treatments. As reviewed in this paper, the speakers at the meeting reviewed recent advances in the understanding of clinical and cognitive psychology, neuroscience, experimental psychopathology, and treatment delivery technology focussed primarily on anxiety disorders and depression. We started by asking three rhetorical questions: What has psychology done for treatment? What has technology done for psychology? What has neuroscience done for psychology? We then addressed how research in five broad research areas could inform the future development of better treatments: Attention, Conditioning, Compulsions and addiction, Emotional Memory, and Reward and emotional bias. Research in all these areas (and more) can be harnessed to neuroscience since psychological therapies are a learning process with a biological basis in the brain. Because current treatment approaches are not fully satisfactory, there is an imperative to understand why not. And when psychological therapies do work we need to understand why this is the case, and how we can improve them. We may be able to improve accessibility to treatment without understanding mechanisms. But for treatment innovation and improvement, mechanistic insights may actually help. Applying neuroscience in this way will become an additional mission for ECNP. (C) 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

  • 44.
    Goodwin, Guy M.
    et al.
    Univ Oxford, Univ Dept Psychiat, Oxford OX3 7JX, England.;Warneford Hosp, Oxford Hlth NHS Trust, Oxford OX3 7JX, England..
    Holmes, Emily A.
    Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden..
    Andersson, Erik
    Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden..
    Browning, Michael
    Univ Oxford, Univ Dept Psychiat, Oxford OX3 7JX, England.;Warneford Hosp, Oxford Hlth NHS Trust, Oxford OX3 7JX, England..
    Jones, Andrew
    Univ Liverpool, Psychol Sci, Bedford St South, Liverpool L697ZA, Merseyside, England..
    Lass-Hennemann, Johanna
    Saarbrucken Univ, Dept Psychol, Div Clin Psychol & Psychotherapy, D-66123 Saarbrucken, Germany..
    Månsson, Kristoffer N.T.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden.;Stockholm Univ, Dept Psychol, SE-10691 Stockholm, Sweden..
    Moessnang, Carolin
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, J5, D-68159 Mannheim, Germany..
    Salemink, Elske
    Univ Amsterdam, Dept Psychol, Nieuwe Achtergracht 129B, Amsterdam, Netherlands..
    Sanchez, Alvaro
    Univ Ghent, Dept Expt Clin & Hlth Psychol, Henri Dunantlaan 2, B-9000 Ghent, Belgium..
    van Zutphen, Linda
    Maastricht Univ, Dept Clin Psychol Sci, Fac Psychol & Neurosci, Univ Singel 40, NL-6229 ER Maastricht, Netherlands..
    Visser, Renee M.
    Univ Cambridge, MRC, Cognit & Brain Sci Unit, 15 Chaucer Rd, Cambridge CB2 7EF, England..
    From neuroscience to evidence based psychological treatments - The promise and the challenge, ECNP March 2016, Nice, France2018Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 28, nr 2, s. 317-333Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This ECNP meeting was designed to build bridges between different constituencies of mental illness treatment researchers from a range of backgrounds with a specific focus on enhancing the development of novel, evidence based, psychological treatments. In particular we wished to explore the potential for basic neuroscience to support the development of more effective psychological treatments, just as this approach is starting to illuminate the actions of drugs. To fulfil this aim, a selection of clinical psychologists, psychiatrists and neuroscientists were invited to sit at the same table. The starting point of the meeting was the proposition that we know certain psychological treatments work, but we have only an approximate understanding of why they work. The first task in developing a coherent mental health science would therefore be to uncover the mechanisms (at all levels of analysis) of effective psychological treatments. Delineating these mechanisms, a task that will require input from both the clinic and the laboratory, will provide a key foundation for the rational optimisation of psychological treatments. As reviewed in this paper, the speakers at the meeting reviewed recent advances in the understanding of clinical and cognitive psychology, neuroscience, experimental psychopathology, and treatment delivery technology focussed primarily on anxiety disorders and depression. We started by asking three rhetorical questions: What has psychology done for treatment? What has technology done for psychology? What has neuroscience done for psychology? We then addressed how research in five broad research areas could inform the future development of better treatments: Attention, Conditioning, Compulsions and addiction, Emotional Memory, and Reward and emotional bias. Research in all these areas (and more) can be harnessed to neuroscience since psychological therapies are a learning process with a biological basis in the brain. Because current treatment approaches are not fully satisfactory, there is an imperative to understand why not. And when psychological therapies do work we need to understand why this is the case, and how we can improve them. We may be able to improve accessibility to treatment without understanding mechanisms. But for treatment innovation and improvement, mechanistic insights may actually help. Applying neuroscience in this way will become an additional mission for ECNP.

    Fulltekst (pdf)
    fulltext
  • 45.
    Grimes, Poppy
    et al.
    University of Edinburgh, Edinburgh Midlothian, Scotland.
    Adams, Mark
    University of Edinburgh, Edinburgh Midlothian, Scotland.
    Edmonson-Stait, Amelia
    University of Edinburgh, Edinburgh Midlothian, Scotland.
    Thng, Gladi
    University of Edinburgh, Edinburgh Midlothian, Scotland.
    Yi, Lu
    Karolinska Institutet, Solna, Sweden.
    Cullen, Breda
    University of Glasgow, Glasgow Lanark, Scotland.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Whalley, Heather
    University of Edinburgh, Edinburgh Midlothian, Scotland.
    Kwong, Alex S. F.
    University of Edinburgh, Edinburgh Midlothian, Scotland.
    UNVEILING GENETIC ARCHITECTURES FOR STRATIFYING TRAJECTORIES OF ADOLESCENT DEPRESSION2023Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 75, nr Suppl. 1, s. S127-S127, artikkel-id W44Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background: Adolescent-onset depression is characterised by high levels of inter-individual variability and genetic heritability. Investigating the genetic factors that underlie trajectories of depression is crucial to enhancing mechanistic understanding of the onset, persistence and severity of adolescent depression. However, predicting trajectories from complex and heterogeneous genetic architectures in psychopathology poses challenges due to the high genetic correlation among traits. It remains unclear whether multi-trait models provide a superior prediction of depression trajectories compared to univariate models focused solely on depression. Addressing this question is important for effective stratification and targeted treatments.

    Methods: To validate depression trajectories during adolescence, we conducted growth mixture modelling in two longitudinal cohorts (ABCD and ALSPAC; total N=20,509). We then computed polygenic risk scores for seven traits: major depressive disorder (MDD), anxiety, neuroticism, schizophrenia, bipolar disorder, attention-deficit-hyperactivity disorder (ADHD), and autism for participants with European ancestry. We also generated MDD scores for individuals of African, East Asian, and Hispanic ancestries in ABCD. Using genomic structural equation modelling, we compared three multi-trait factor models (common, correlated, hierarchical) to assess the relationships among the seven traits. To generate multi-trait risk scores from these models in our target cohorts, we conducted multivariate genome-wide association analysis to determine the effects of single nucleotide polymorphisms on genetic latent p-factors. Finally, we examined the association between all polygenic risk scores for univariate traits and multi-trait models with depression trajectories.

    Results: Four distinct trajectories were replicated across two cohorts with partial age-range overlap encompassing adolescents from two generations. Trajectories included stable low, adolescent acute, increasing and decreasing. The hierarchical factor model was the best fit for multi-trait genetic information and was most predictive of adolescent acute trajectories (odds ratio [OR], 1.46; 95% CI, 1.27-1.68), with increasing and decreasing showing comparable risk (OR, 1.32; 95% CI, 1.16-1.50). Multi-trait models showed a similar genetic risk for depression trajectory as MDD-only risk across trajectories. Anxiety was associated with the adolescent acute trajectories (OR, 1.27; 95% CI, 1.10-1.45). Psychotic conditions were associated with later-onset depression patterns and ADHD with earlier-onset, aligning with the developmental timelines of these respective conditions.

    Discussion: The investigated genetic traits collectively contribute to diverse longitudinal patterns of depression, varying in severity, onset, and duration. A hierarchical factor model of multivariate genetic psychopathology demonstrated a comparable prediction of genetic risk to univariate depression scores for stratifying longitudinal depression in adolescence. It is important to acknowledge the genetic influence of multiple conditions on depression outcomes, particularly at different stages of vulnerability. Taking into account detailed and integrated genetic information will be valuable in effectively stratifying trajectories across adolescence and mental health conditions.

  • 46. Gustavsson, Anders
    et al.
    Svensson, Mikael
    Örebro universitet, Handelshögskolan vid Örebro universitet.
    Jacobi, Frank
    Allgulander, Christer
    Alonso, Jordi
    Beghi, Ettore
    Dodel, Richard
    Ekman, Mattias
    Faravelli, Carlo
    Fratiglioni, Laura
    Gannon, Brenda
    Jones, David Hilton
    Jennum, Poul
    Jordanova, Albena
    Jonsson, Linus
    Karampampa, Korinna
    Knapp, Martin
    Kobelt, Gisela
    Kurth, Tobias
    Lieb, Roselind
    Linde, Mattias
    Ljungcrantz, Christina
    Maercker, Andreas
    Melin, Beatrice
    Moscarelli, Massimo
    Musayev, Amir
    Norwood, Fiona
    Preisig, Martin
    Pugliatti, Maura
    Rehm, Juergen
    Salvador-Carulla, Luis
    Schlehofer, Brigitte
    Simon, Roland
    Steinhausen, Hans-Christoph
    Stovner, Lars Jacob
    Vallat, Jean-Michel
    Van den Bergh, Peter
    van Os, Jim
    Vos, Pieter
    Xu, Weili
    Wittchen, Hans-Ulrich
    Jonsson, Bengt
    Olesen, Jes
    Cost of disorders of the brain in Europe 20102011Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 21, nr 10, s. 718-779Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    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 (sic)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 (sic)285 for headache and (sic)30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was (sic)1550 on average but varied by country. The cost (in billion (sic)PPP 2010) of the disorders of the brain included in this study was as folows: addiction: (sic)65.7; anxiety disorders: (sic)74.4; brain tumor: (sic)5.2; child/adolescent disorders: (sic)21.3; dementia: (sic)105.2; eating disorders: (sic)0.8; epilepsy: (sic)13.8; headache: (sic)43.5; mental retardation: (sic)43.3; mood disorders: (sic)113.4; multiple sclerosis: (sic)14.6; neuromuscular disorders: (sic)7.7; Parkinson's disease: (sic)13.9; personality disorders: (sic)27.3; psychotic disorders: (sic)93.9; sleep disorders: (sic)35.4; somatoform disorder: (sic)21.2; stroke: (sic)64.1; traumatic brain injury: (sic)33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted (sic)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.

  • 47. Gustavsson, Anders
    et al.
    Svensson, Mikael
    Jacobi, Frank
    Allgulander, Christer
    Alonso, Jordi
    Beghi, Ettore
    Dodel, Richard
    Ekman, Mattias
    Faravelli, Carlo
    Fratiglioni, Laura
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Gannon, Brenda
    Jones, David Hilton
    Jennum, Poul
    Jordanova, Albena
    Jönsson, Linus
    Karampampa, Korinna
    Knapp, Martin
    Kobelt, Gisela
    Kurth, Tobias
    Lieb, Roselind
    Linde, Mattias
    Ljungcrantz, Christina
    Maercker, Andreas
    Melin, Beatrice
    Moscarelli, Massimo
    Musayev, Amir
    Norwood, Fiona
    Preisig, Martin
    Pugliatti, Maura
    Rehm, Juergen
    Salvador-Carulla, Luis
    Schlehofer, Brigitte
    Simon, Roland
    Steinhausen, Hans-Christoph
    Stovner, Lars Jacob
    Vallat, Jean-Michel
    Van den Bergh, Peter
    den Bergh, Peter Van
    van Os, Jim
    Vos, Pieter
    Xu, Weili
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Wittchen, Hans-Ulrich
    Jönsson, Bengt
    Olesen, Jes
    Cost of disorders of the brain in Europe 20102011Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 21, nr 10, s. 718-779Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

  • 48.
    Gustavsson, Anders
    et al.
    I3 Innovus, Stockholm.
    Svensson, Mikael
    Karlstads universitet, Fakulteten för ekonomi, kommunikation och IT, Avdelningen för nationalekonomi och statistik.
    Jacobi, Frank
    Allgulander, Christer
    Alonso, Jordi
    Beghi, Ettore
    Dodel, Richard
    Ekman, Mattias
    Faravelli, Carlo
    Fratiglioni, Laura
    Gannon, Brenda
    Jones, David Hilton
    Jennum, Poul
    Jordanova, Albena
    Jönsson, Linus
    Karampampa, Korinna
    Knapp, Martin
    Kobelt, Gisela
    Kurth, Tobias
    Lieb, Roselind
    Linde, Mattias
    Ljungcrantz, Christina
    Maercker, Andreas
    Melin, Beatrice
    Moscarelli, Massimo
    Musayev, Amir
    Norwood, Fiona
    Preisig, Martin
    Pugliatti, Maura
    Rehm, Juergen
    Salvador-Carulla, Luis
    Schlehofer, Brigitte
    Simon, Roland
    Steinhausen, Hans-Christoph
    Stovner, Lars Jacob
    Vallat, Jean-Michel
    Van den Bergh, Peter
    den Bergh, Peter Van
    van Os, Jim
    Vos, Pieter
    Xu, Weili
    Wittchen, Hans-Ulrich
    Jönsson, Bengt
    Olesen, Jes
    Cost of disorders of the brain in Europe 2010.2011Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 21, nr 10, s. 718-79Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

  • 49. Gustavsson, Anders
    et al.
    Svensson, Mikael
    Jacobi, Frank
    Allgulander, Christer
    Alonso, Jordi
    Beghi, Ettore
    Dodel, Richard
    Ekman, Mattias
    Faravelli, Carlo
    Fratiglioni, Laura
    Gannon, Brenda
    Jones, David Hilton
    Jennum, Poul
    Jordanova, Albena
    Jönsson, Linus
    Karampampa, Korinna
    Knapp, Martin
    Kobelt, Gisela
    Kurth, Tobias
    Lieb, Roselind
    Linde, Mattias
    Ljungcrantz, Christina
    Maercker, Andreas
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Moscarelli, Massimo
    Musayev, Amir
    Norwood, Fiona
    Preisig, Martin
    Pugliatti, Maura
    Rehm, Juergen
    Salvador-Carulla, Luis
    Schlehofer, Brigitte
    Simon, Roland
    Steinhausen, Hans-Christoph
    Stovner, Lars Jacob
    Vallat, Jean-Michel
    Van den Bergh, Peter
    van Os, Jim
    Vos, Pieter
    Xu, Weili
    Wittchen, Hans-Ulrich
    Jönsson, Bengt
    Olesen, Jes
    Cost of disorders of the brain in Europe 20102011Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 21, nr 10, s. 718-779Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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, ofan 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.

  • 50.
    Gustavsson, Anders
    et al.
    Optumlnsight, Stockholm, Sweden.
    Svensson, Mikael
    Karlstads universitet, Fakulteten för ekonomi, kommunikation och IT, Avdelningen för nationalekonomi och statistik.
    Jacobi, Frank
    Germany.
    Allgulander, Christer
    Karolinska University Hospital.
    Alonso, Jordi
    Spain.
    Beghi, Ettore
    Ist Mario Negri, Lab Malottie Neurol, Milan, Italy..
    Dodel, Richard
    Univ Marburg, Dept Neurol Marburg, D-35032 Marburg, Germany..
    Ekman, Mattias
    Optumlnsight, Stockholm, Sweden.
    Faravelli, Carlo
    Italy.
    Fratiglioni, Laura
    Karolinska Institute.
    Gannon, Brenda
    England.
    Jones, David Hilton
    England.
    Jennum, Pout
    Denmark.
    Jordanova, Albena
    Belgium.;Bulgaria.
    Jonsson, Linus
    Optumlnsight, Stockholm, Sweden.
    Karampampa, Korinna
    Optumlnsight, Stockholm, Sweden.
    Knapp, Martin
    Belgium.
    Kobelt, Gisela
    Lund Univ, S-22100 Lund, Sweden.;European Hlth Econ, Mulhouse, France..
    Kurth, Tobias
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA..
    Lieb, Roselind
    Univ Basel, Dept Psychol, CH-4003 Basel, Switzerland..
    Linde, Mattias
    Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway.;St Olavs Hosp, Div Neurol & Neurophysiol, Trondheim, Norway..
    Ljungcrantz, Christina
    Optumlnsight, Stockholm, Sweden..
    Maercker, Andreas
    Univ Zurich, Dept Psychol, CH-8006 Zurich, Switzerland..
    Melin, Beatrice
    Umea Univ, Dept Oncol, Umea, Sweden..
    Moscarelli, Massimo
    USA.
    Musayev, Amir
    Optumlnsight, Stockholm, Sweden..
    Norwood, Fiona
    England.
    Preisig, Martin
    Switzerland.
    Pugliatti, Maura
    Italy.
    Rehm, Juergen
    Canada.
    Salvador-Carulla, Luis
    Spain.
    Schlehofer, Brigitte
    Germany.
    Simon, Roland
    Portugal.
    Steinhausen, Hans-Christoph
    Denmark, Switzerland.
    Stovner, Lars Jacob
    Norway.
    Vallat, Jean-Michel
    France.
    Van den Bergh, Peter
    Belgium.
    van Os, Jim
    England.
    Vos, Pieter E.
    Netherlands.
    Xu, Weili
    Karolinska Institute.
    Wittchen, Hans-Ulrich
    Germany.
    Jonsson, Bengt
    Stockholm School of Economics.
    Olesen, Jes
    Denmark.
    Corrigendum to “Cost of disorders of the brain in Europe 2010” [Eur. Neuropsychopharmacol. 21 (2011) 718–779]2012Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, nr 3, s. 237-238Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

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