Search

Andrea Fagiolini,1 Ana González Pinto,2,3 Kamilla Woznica Miskowiak,4– 6 Pedro Morgado,7– 9 Allan H Young,10,11 Eduard Vieta12 1Department of Molecular and Developmental Medicine, Division of Psychiatry, University of Siena School of Medicine, Siena, 53100, Italy; 2Bioaraba Research Institute, Department of Psychiatry, Araba University Hospital, Vitoria, 01004, Spain; 3CIBERSAM, University of the Basque Country, Vitoria, Spain; 4Copenhagen Affective Disorder research Centre (CADIC), Psychiatric Centre, Copenhagen, Denmark; 5Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark; 6Department of Psychology, University of Copenhagen, Copenhagen, Denmark; 7Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, 4710-057, Portugal; 8ICVS/3B’s, PT Government Associate Laboratory, Braga/Guimarães, 4710-057, Portugal; 9Clinical Academic Center-Braga (2CA), Braga, 4710-243, Portugal; 10Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK; 11South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Kent, UK; 12Bipolar and Depressive Disorders Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, SpainCorrespondence: Andrea Fagiolini, Department of Molecular and Developmental Medicine, Division of Psychiatry, University of Siena School of Medicine, Viale Bracci 12, Siena, 53100, Italy, Tel +39- 0577-586275, Email andreafagiolini@gmail.com; andrea.fagiolini@unisi.itObjective: Major depressive disorder (MDD) often co-occurs with dementia and other neurological disorders, and treatment with antidepressants can improve symptoms, quality of life, and survival in these patients. This narrative review provides an expert opinion about the role and effectiveness of trazodone in the treatment of older adults with MDD and cognitive impairment due to physical illnesses, such as dementia.Results: Because of its mechanism of action, trazodone can treat several depression symptoms often seen in people with dementia, including insomnia, agitation, anxiety, cognitive impairment, and irritability.Conclusion: Trazodone may be beneficial for patients with dementia or other neurological disorders comorbid with MDD, especially when the clinical picture of depression includes or is comorbid to symptoms of insomnia, irritability, inner tension, anxiety, or psychomotor agitation.Keywords: major depressive disorder, depression, dementia, cognitive impairment, trazodone

Larry Culpepper,1 Eduard Vieta,2 Deanna L Kelly,3 Mehul D Patel,4 Balázs Szatmári,5 Arlene Hankinson,4 Willie R Earley4 1Boston University School of Medicine, Boston, MA, USA; 2Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain; 3Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA; 4AbbVie, Madison, NJ, USA; 5Gedeon Richter Plc., Budapest, HungaryCorrespondence: Larry Culpepper, Boston University School of Medicine, 90 Sylvia Lane, Westport, MA, 02790-1406, USA, Tel +1 617 414-6225, Email laculpep@bu.eduBackground: Many medications used to treat schizophrenia and bipolar I disorder are linked to hyperprolactinemia. The effects of cariprazine, a dopamine D3/D2 receptor partial agonist, on prolactin levels in patients with schizophrenia or bipolar I disorder were evaluated.Methods: Effects on prolactin were evaluated using pooled data from randomized, double-blind, placebo-controlled studies in patients with schizophrenia (4 studies; 6-week duration; cariprazine 1.5– 3 mg/d, 4.5– 6 mg/d, and 9– 12 mg/d), bipolar mania (3 studies; 3-week duration; cariprazine 3– 6 and 9– 12 mg/d), and bipolar depression (3 studies; 6- to 8-week duration; cariprazine 1.5 and 3 mg/d). Long-term effects were analyzed using open-label studies in patients with schizophrenia (2 studies; 48-week duration) and patients with bipolar mania (1 study; 16-week duration). Change in prolactin levels (ng/mL) from baseline to study endpoint was evaluated in subsets of sex and prior medication use.Results: In patients with schizophrenia (male, n = 1377; female, n = 558), median prolactin changes were − 1.2 for males and − 7.4 for females on placebo, and ranged from − 4.2 to − 3.6 for males and − 12.4 to +0.2 for females in the cariprazine-treatment groups. In patients with bipolar mania (male, n = 570; female, n = 395), median prolactin changes were − 0.2 for males and − 1.1 for females on placebo and ranged from − 2.1 to − 3.0 for males and 0 to +1.8 for females in the cariprazine-treatment groups. Median decreases were also seen in the long-term studies of schizophrenia (range, − 14.6 to − 2.0) and bipolar mania (range, − 0.8 to +1.9). In patients with bipolar depression (male, n = 485; female, n = 780), median prolactin changes were +0.3 for males and +0.7 for females on placebo and ranged from +0.4 to +0.5 for males and +3.0 to +3.1 for females in the cariprazine-treatment groups.Conclusion: Treatment with cariprazine for schizophrenia or bipolar I disorder was associated with minimal effects on prolactin levels.Keywords: dopamine, serotonin, mania, depression, prolactin

Islam Shahin,1 Caterina Del Mar Bonnin,2 Elsayed Saleh,3 Khaled Helmy,4,5 Usama M Youssef,6 Eduard Vieta2 1Cairo Mood Center, Cairo, Egypt; 2Barcelona Bipolar Disorders and Depressive Unit, Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain; 3Department of Psychiatry, Mansoura University, Mansoura, Egypt; 4Training and Research Unit, New Nozha Hospital, Alexandria, Egypt; 5Ciconia Recovery London (CRL), London, UK; 6Department of Psychiatry, Zagazig University, Zagazig, EgyptCorrespondence: Islam Shahin Tel +201150759876Email ishahin10@yahoo.comBackground: The DSM5-defined mixed features in depression do not include psychomotor agitation, irritability or distractibility because they are considered overlapping symptoms. A growing number of modern psychiatrists have expressed dissatisfaction with this and proposed alternative sets of mixed symptoms that are much more common and clinically relevant. Among such alternative criteria were those proposed by Koukopoulos. He utilized the research diagnostic criteria of agitated depression (RDC-A) as a mixed depression subtype, and validated another form of mixed depression, the Koukopoulos criteria for mixed depression (K-DMX).Purpose: This study provides psychometric validation for the first self-rated scale designed to measure the most common mixed symptoms in depression as proposed by Koukopoulos.Patients and Methods: We conducted a multicenter cross-sectional study of 170 patients with unipolar depression. They completed the Shahin Mixed Depression Scale (SMDS) and underwent expert interviews as a gold standard reference. SMDS’ psychometric properties were assessed, including Cronbach’s alpha, factor analysis, sensitivity, specificity, predictive value and accuracy.Results: We found significant association and agreement between mixity according to SMDS and the gold standard (K-DMX and RDC-A according to expert interview) with good internal consistency (Cronbach’s alpha=0.87), high sensitivity (=91.4%), specificity (=98.0%), positive predictive value (=96.9%), negative predictive value (= 94.2%) and accuracy (=95.2%). Factor analysis identified one factor for psychomotor agitation and another for mixity without psychomotor agitation.Conclusion: SMDS was a reliable and valid instrument for assessing the frequently encountered and clinically relevant mixed features in depression.Keywords: mixed depression, mixed depression scale, major depressive disorder, psychomotor agitation, agitated depression, unipolar depression

Sabrina Castellano,1 Carla Torrent,2 Maria Cristina Petralia,3 Justyna Godos,4 Rita Anna Cantarella,5 Andrea Ventimiglia,6 Simona De Vivo,6 Silvia Platania,1 Maria Guarnera,7 Concetta Pirrone,1 Filippo Drago,4 Eduard Vieta,2 Santo Di Nuovo,1 Dina Popovic,2,8,* Filippo Caraci4,9,* 1Department of Educational Sciences, University of Catania, Catania, Italy; 2Barcelona Bipolar Disorders Program, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain; 3IRCCS Centro Neurolesi Bonino Pulejo, Messina, Italy; 4Oasi Research Institute-IRCCS, Troina 94018, Italy; 5Department of Mental Health, ASP3 Catania, Catania, Italy; 6Villa dei Gerani Clinic ASP3 Catania, Catania, Italy; 7Faculty of Human and Social Sciences, University of Enna “KORE”, Enna, Italy; 8Bipolar Disorders Program, Sheba Medical Center, Ramat Gan, Israel; 9Department of Drug Sciences, University of Catania, Catania, Italy*These authors contributed equally to this workCorrespondence: Sabrina CastellanoDepartment of Educational Sciences, University of Catania, Via Ofelia 1, Catania 95124, ItalyTel +39 0952508060Fax +39 0952508070Email sabrina.castellano@unict.itBackground: Cognitive dysfunction represents a distinct biological and clinical dimension in major depression disorders (MDD) and cognitive performance strongly affects psychosocial functioning in patients diagnosed with MDD.Objective: To assess which neurocognitive variables at baseline predict the functional outcome of MDD patients in a 1-year follow-up study as assessed by Functioning Assessment Short Test (FAST) and whether the improvement observed on affective and cognitive symptoms in our 12 week-prospective observational study after treatment with selective serotonin reuptake inhibitors (SSRIs) and selective noradrenalin reuptake inhibitors (SNRIs) can affect the following long-term psychosocial functional outcome at 1 year in the same MDD patients.Methods: We recruited a total of 31 patients (8 males; 23 females) with MDD who had previously completed a pharmacological treatment with SSRIs (n = 22) or SNRIs (n = 9) for 12 weeks, and then continued the same pharmacological treatment for 1 year. After an average 1-year follow-up, they were interviewed with the FAST to assess functional outcome. Multivariate analyses were applied to identify clinical and neurocognitive predictors of functional outcome.Results: Total Montreal Cognitive Assessment (MoCA), Digit Span forward (Span F) and backward (Span B), and 15 Rey words immediate recall (Rey I) scores significantly correlated with FAST. However, after performing regression models only Rey immediate recall score was useful to predict long-term functional outcome (Pearson correlation coefficient R= − 0.68, p

Marco Solmi,1,2 Andrea Murru,3 Isabella Pacchiarotti,3 Juan Undurraga,4,5 Nicola Veronese,2,6 Michele Fornaro,7,8 Brendon Stubbs,2,9–11 Francesco Monaco,2 Eduard Vieta,3 Mary V Seeman,12 Christoph U Correll,13,14 André F Carvalho2,15 1Neuroscience Department, University of Padua, 2Institute for Clinical Research and Education in Medicine, Padua, Italy; 3Bipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain; 4Department of Psychiatry, Faculty of Medicine, Clínica Alemana Universidad del Desarrollo, 5Early Intervention Program, J. Horwitz Psychiatric Institute, Santiago, Chile; 6National Research Council, Ageing Section, Padua, 7Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University “Federico II”, Naples, Italy; 8New York State Psychiatric Institute, Columbia University, New York, NY, USA; 9Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 10Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, 11Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK; 12Institute of Medical Science, Toronto, ON, Canada; 13Department of Psychiatry Research, Zucker Hillside Hospital, Northwell Health, Glen Oaks, 14Department of Psychiatry and Molecular Medicine Hempstead, Hofstra Northwell School of Medicine, Hempstead, NY, USA; 15Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil Abstract: Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. Keywords: antipsychotics, side effects, tolerability, safety, psychosis, psychiatry

Beatrice Bortolato,1 Kamilla W Miskowiak,2 Cristiano A Köhler,3 Eduard Vieta,4 André F Carvalho3 1Department of Mental Health, ULSS 10 “Veneto Orientale”, Venice, Italy; 2Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 3Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; 4Bipolar Disorders Program, Institute of Neuroscience, Hospital Clínic Barcelona, IDIBAPS, CIBERSAM, University of Barcelona, Catalonia, Spain Abstract: Cognitive impairment is a core feature of schizophrenia (SZ) and bipolar disorder (BD). A neurocognitive profile characterized by widespread cognitive deficits across multiple domains in the context of substantial intellectual impairment, which appears to antedate illness onset, is a replicated finding in SZ. There is no specific neuropsychological signature that can facilitate the diagnostic differentiation of SZ and BD, notwithstanding, neuropsychological deficits appear more severe in SZ. The literature in this field has provided contradictory results due to methodological differences across studies. Meta-analytic techniques may offer an opportunity to synthesize findings and to control for potential sources of heterogeneity. Here, we performed a systematic review of meta-analyses of neuropsychological findings in SZ and BD. While there is no conclusive evidence for progressive cognitive deterioration in either SZ or BD, some findings point to more severe cognitive deficits in patients with early illness onset across both disorders. A compromised pattern of cognitive functioning in individuals at familiar and/or clinical risk to psychosis as well as in first-degree relatives of BD patients suggests that early neurodevelopmental factors may play a role in the emergence of cognitive deficits in both disorders. Premorbid intellectual impairment in SZ and at least in a subgroup of patients with BD may be related to a shared genetically determined influence on neurodevelopment. Keywords: schizophrenia, bipolar disorder, psychosis, neuropsychological tests, cognition, meta-analysis, psychiatry

Christina M van der Feltz-Cornelis,1–3 Jim van Os,4,6 Susanne Knappe,5 Gunter Schumann,6 Eduard Vieta,7 Hans-Ulrich Wittchen,5 Shôn W Lewis,8 Iman Elfeddali,2,9 Kristian Wahlbeck,10,11 Donald Linszen,4 Carla Obradors-Tarragó,12,13 Josep Maria Haro12–141Trimbos Instituut, Utrecht, 2Tilburg University, Tranzo Department, Tilburg, 3GGz Breburg, Tilburg, 4Department of Psychiatry and Psychology, South Limburg Mental Health Research and Teaching Network, Euron, Maastricht University Medical Center, Maastricht, the Netherlands; 5Institute of Clinical Psychology and Psychotherapy and Center for Epidemiology and Longitudinal Studies, Technische Universität Dresden, Dresden, Germany; 6Institute of Psychiatry, King’s College London, London, UK; 7Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain; 8School of Community-Based Medicine, University of Manchester, Manchester, UK; 9Department of Health Promotion/School of Public Health and Primary Care, Maastricht University, Maastricht, the Netherlands; 10The Nordic School of Public Health, Gothenburg, Sweden; 11National Institute for Health and Welfare, Helsinki, Finland; 12Centro de Investigación Biomédica en Red de Salud Mental, Madrid, 13Research and Development Unit, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Sant Boi de Llobregat, 14Universitat de Barcelona, Barcelona, SpainBackground: The size and increasing burden of disease due to mental disorders in Europe poses substantial challenges to its population and to the health policy of the European Union. This warrants a specific research agenda concerning clinical mental health research as one of the cornerstones of sustainable mental health research and health policy in Europe. The aim of this research was to identify the top priorities needed to address the main challenges in clinical research for mental disorders.Methods: The research was conducted as an expert survey and expert panel discussion during a scientific workshop.Results: Eighty-nine experts in clinical research and representing most European countries participated in this survey. Identified top priorities were the need for new intervention studies, understanding the diagnostic and therapeutic implications of mechanisms of disease, and research in the field of somatic-psychiatric comorbidity. The “subjectivity gap” between basic neuroscience research and clinical reality for patients with mental disorders is considered the main challenge in psychiatric research, suggesting that a shift in research paradigms is required.Conclusion: Innovations in clinical mental health research should bridge the gap between mechanisms underlying novel therapeutic interventions and the patient experience of mental disorder and, if present, somatic comorbidity. Clinical mental health research is relatively underfunded and should receive specific attention in Horizon 2020 funding programs.Keywords: clinical research, mental health, randomized clinical trials, Horizon 2020, expert survey, challenge, research agenda, Europe

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.