Publications by authors named "Andrea Murru"

70 Publications

Genetic Variations Associated with Long-Term Treatment Response in Bipolar Depression.

Genes (Basel) 2021 Aug 18;12(8). Epub 2021 Aug 18.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036 Barcelona, Catalonia, Spain.

Several pharmacogenetic-based decision support tools for psychoactive medication selection are available. However, the scientific evidence of the gene-drug pairs analyzed is mainly based on pharmacogenetic studies in patients with major depression or schizophrenia, and their clinical utility is mostly assessed in major depression. This study aimed at evaluating the impact of individual genes, with pharmacogenetic relevance in other psychiatric conditions, in the response to treatment in bipolar depression. Seventy-six patients diagnosed with bipolar disorder and an index major depressive episode were included in an observational retrospective study. Sociodemographic and clinical data were collected, and all patients were genotyped using a commercial multigene pharmacogenomic-based tool (Neuropharmagen, AB-Biotics S.A., Barcelona, Spain). Multiple linear regression was used to identify pharmacogenetic and clinical predictors of efficacy and tolerability of medications. The pharmacogenetic variables response to serotonin-norepinephrine reuptake inhibitors (SNRIs) () and reduced metabolism of quetiapine () predicted patient response to these medications, respectively. was also linked to the tolerability of SNRIs. An mTOR-related multigenic predictor was also associated with a lower number of adverse effects when including switch and autolytical ideation. Our results suggest that the predictors identified could be useful to guide the pharmacological treatment in bipolar disorder. Additional clinical studies are necessary to confirm these findings.
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http://dx.doi.org/10.3390/genes12081259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391230PMC
August 2021

Duration of untreated illness and bipolar disorder: time for a new definition? Results from a cross-sectional study.

J Affect Disord 2021 Nov 22;294:513-520. Epub 2021 Jul 22.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036, Barcelona, Catalonia, Spain.

Background: We primarily aimed to explore the associations between duration of untreated illness (DUI), treatment response, and functioning in a cohort of patients with bipolar disorder (BD).

Methods: 261 participants with BD were recruited. DUI was defined as months from the first affective episode to the start of a mood-stabilizer. The functioning assessment short test (FAST) scores and treatment response scores for lithium, valproate, or lamotrigine according to the Alda Scale Total Score (TS) were compared between patients with short (<24 months) or long DUI. Differences in FAST scores among good (GR; TS≥7), poor (PR; TS=2-6), or non-responders (NR; TS<2) to each mood-stabilizer were analyzed. Linear regression was computed using the FAST global score as the dependent variable.

Results: DUI and FAST scores showed no statistically significant correlation. Patients with a longer DUI showed poorer response to lithium (Z=-3.196; p<0.001), but not to valproate or lamotrigine. Response to lithium (β=-1.814; p<0.001), number of hospitalizations (β=0.237; p<0.001), and illness duration (β=0.160; p=0.028) were associated with FAST total scores. GR to lithium was associated with better global functioning compared to PR or NR [H=27.631; p<0.001].

Limitations: The retrospective design could expose our data to a recall bias. Also, only few patients were on valproate or lamotrigine treatment.

Conclusions: Poor functioning in BD could be the result of multiple affective relapses, rather than a direct effect of DUI. A timely diagnosis with subsequent effective prophylactic treatment, such as lithium, may prevent poor functional outcomes in real-world patients with BD.
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http://dx.doi.org/10.1016/j.jad.2021.07.062DOI Listing
November 2021

Bipolar disorder and Susac syndrome: a case report.

Int Clin Psychopharmacol 2021 Jul 15. Epub 2021 Jul 15.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM Autoimmune Diseases Department, Institut d'Investigacions August Pi i Sunyer, Universitat de Barcelona, Hospital Clinic, Barcelona, Catalonia, Spain.

Susac-syndrome is a rare autoimmune disease that manifests with mood alterations in up to 15% of cases and is usually treated with corticosteroids. We present the case of a 41-year-old woman with a first manic episode and history of Susac-syndrome, secondary Cushing's syndrome after receiving high doses of corticosteroids and a previous depressive episode. Differentiating between primary and secondary mania is difficult, as people with bipolar disorder are prone to multiple psychiatric and nonpsychiatric comorbidities, in this case, the differential diagnosis included secondary mania, corticoid-induced manic episode and primary bipolar disorder. Upon admission, corticosteroid treatment was suspended, and the patient was started on lithium and risperidone. Secondary causes of mania were discarded and, assessing temporal and dosage criteria, it was deemed unlikely that the present episode was corticosteroid-induced. One-year outpatient follow-up pointed towards a primary bipolar type I disorder, as a separate entity from her Susac-syndrome. Corticosteroid use or abrupt withdrawal pose an underestimated risk of inducing depressive or manic symptoms, which may unmask affective disorders in susceptible individuals. Many medical conditions share CNS involvement and/or high-dose/prolonged corticosteroid treatment. In such cases, psychiatric manifestations such as mania or depression should be regarded as secondary and studied to determine the existence of medical complications before considering primary psychiatric conditions.
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http://dx.doi.org/10.1097/YIC.0000000000000375DOI Listing
July 2021

Lithium therapy and weight change in people with bipolar disorder: A systematic review and meta-analysis.

Neurosci Biobehav Rev 2021 Jul 13. Epub 2021 Jul 13.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel St, 12-0, 08036, Barcelona, Spain.

Lithium remains the gold standard maintenance treatment for Bipolar Disorder (BD). However, weight gain is a side effect of increasing relevance due to its metabolic implications. We conducted a systematic review and meta-analysis aimed at summarizing evidence on the use of lithium and weight change in BD. We followed the PRISMA methodology, searching Pubmed, Scopus and Web of Science. From 1003 screened references, 20 studies were included in the systematic review and 9 included in the meta-analysis. In line with the studies included in the systematic review, the meta-analysis revealed that weight gain with lithium was not significant, noting a weight increase of 0.462 Kg (p = 0158). A shorter duration of treatment was significantly associated with more weight gain. Compared to placebo, there were no significant differences in weight gain. Weight gain was significantly lower with lithium than with active comparators. This work reveals a low impact of lithium on weight change, especially compared to some of the most widely used active comparators. Our results could impact clinical decisions.
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http://dx.doi.org/10.1016/j.neubiorev.2021.07.011DOI Listing
July 2021

The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release.

Front Immunol 2021 21;12:650808. Epub 2021 Jun 21.

Division of Infectious Diseases and Immunology, Laval University, Centres Hospitaliers Universitaires (CHU) de Québec Research Center, Québec, QC, Canada.

The myeloid inhibitory C-type lectin receptor CLEC12A limits neutrophil activation, pro-inflammatory pathways and disease in mouse models of inflammatory arthritis by a molecular mechanism that remains poorly understood. We addressed how CLEC12A-mediated inhibitory signaling counteracts activating signaling by cross-linking CLEC12A in human neutrophils. CLEC12A cross-linking induced its translocation to flotillin-rich membrane domains where its ITIM was phosphorylated in a Src-dependent manner. Phosphoproteomic analysis identified candidate signaling molecules regulated by CLEC12A that include MAPKs, phosphoinositol kinases and members of the JAK-STAT pathway. Stimulating neutrophils with uric acid crystals, the etiological agent of gout, drove the hyperphosphorylation of p38 and Akt. Ultimately, one of the pathways through which CLEC12A regulates uric acid crystal-stimulated release of IL-8 by neutrophils is through a p38/PI3K-Akt signaling pathway. In summary this work defines early molecular events that underpin CLEC12A signaling in human neutrophils to modulate cytokine synthesis. Targeting this pathway could be useful therapeutically to dampen inflammation.
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http://dx.doi.org/10.3389/fimmu.2021.650808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256872PMC
June 2021

Patients' adherence to smartphone apps in the management of bipolar disorder: a systematic review.

Int J Bipolar Disord 2021 Jun 3;9(1):19. Epub 2021 Jun 3.

Department of Psychiatry, CHU Clermont-Ferrand, University of Clermont Auvergne, CNRS, Clermont Auvergne INP, Institut Pascal, Clermont-Ferrand, France.

Background: Despite an increasing number of available mental health apps in the bipolar disorder field, these tools remain scarcely implemented in everyday practice and are quickly discontinued by patients after downloading. The aim of this study is to explore adherence characteristics of bipolar disorder patients to dedicated smartphone interventions in research studies.

Methods: A systematic review following PRISMA guidelines was conducted. Three databases (EMBASE, PsychInfo and MEDLINE) were searched using the following keywords: "bipolar disorder" or "mood disorder" or "bipolar" combined with "digital" or "mobile" or "phone" or "smartphone" or "mHealth" or "ehealth" or "mobile health" or "app" or "mobile-health".

Results: Thirteen articles remained in the review after exclusion criteria were applied. Of the 118 eligible studies, 39 did not provide adherence characteristics. Among the selected papers, study length, sample size and definition of measures of adherence were strongly heterogeneous. Activity rates ranged from 58 to 91.6%.

Conclusion: The adherence of bipolar patients to apps is understudied. Standardised measures of adherence should be defined and systematically evaluated in future studies dedicated to these tools.
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http://dx.doi.org/10.1186/s40345-021-00224-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175501PMC
June 2021

PRimary carE digital Support ToOl in mental health (PRESTO): Design, development and study protocols.

Rev Psiquiatr Salud Ment 2021 Apr 29. Epub 2021 Apr 29.

Department of Psychiatry and Psychology, Institute of Neuroscience, Hospital Clínic de Barcelona, 170 Villarroel st, 12-0, 08036 Barcelona, Catalonia, Spain; Digital Innovation Group, Bipolar and Depressive Disorders Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain; University of Barcelona, Barcelona, Catalonia, Spain; Mental Health Research Networking Center (CIBERSAM), Madrid, Spain; Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. Electronic address:

Background: About 30-50% of Primary Care (PC) users in Spain suffer mental health problems, mostly mild to moderate anxious and depressive symptoms, which account for 2% of Spain's total Gross domestic product and 50% of the costs associated to all mental disorders. Mobile health tools have demonstrated to cost-effectively reduce anxious and depressive symptoms while machine learning (ML) techniques have shown to accurately detect severe cases. The main aim of this project is to develop a comprehensive ML digital support platform (PRESTO) to cost-effectively screen, assess, triage, and provide personalized treatments for anxious and depressive symptoms in PC.

Methods: The project will be carried out in 3 complementary phases: First, a ML predictive severity model will be built based on all the cases referred to the PC mental health support programme during the last 5 years in Catalonia. Simultaneously, a smartphone app to monitor and deliver psychological interventions for anxiety and depressive symptoms will be developed and tested in a clinical trial. Finally, the ML models and the app will be integrated in a comprehensive decision-support platform (PRESTO) which will triage and assign to each patient a specific intervention based on individual personal and clinical characteristics. The effectiveness of PRESTO to reduce waiting times in receiving mental healthcare will be tested in a stepped-wedge cluster randomized controlled trial in 5 PC centres.

Discussion: PRESTO will offer timely and personalized cost-effective mental health treatment to people with mild to moderate anxious and depressive symptoms. This will result in a reduction of the burden of mental health problems in PC and on society as a whole.

Trial Registration: The project and their clinical trials were registered in Clinical Trials.gov: NCT04559360 (September 2020).
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http://dx.doi.org/10.1016/j.rpsm.2021.04.003DOI Listing
April 2021

Risk of cancer in bipolar disorder and the potential role of lithium: International collaborative systematic review and meta-analyses.

Neurosci Biobehav Rev 2021 07 5;126:529-541. Epub 2021 Apr 5.

Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, and the Department of Psychiatry, The University of Melbourne, Parkville, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia. Electronic address:

We examined bipolar disorder (BD) as a risk factor for developing cancer and the role of lithium on cancer incidence. We conducted two systematic review and meta-analyses of population-based studies providing data on these associations. We screened articles indexed in MEDLINE, Scopus, Embase, and PsycINFO up to August 2020. The first random-effects meta-analysis, based on 4,910,661 individuals from nine studies estimated an increased risk of cancer of any kind [RR = 1.24 (1.05-1.46); p < 0.01], especially breast cancer [RR = 1.33 (1.15-1.55); p < 0.01] in BD. The second random-effects meta-analysis, based on 2,606,187 individuals from five studies did not show increased risk of cancer in people with BD using lithium, and even suggested a small protective effect both in overall [RR = 0.94 (0.72-1.22); p = 0.66] and urinary cancer [RR = 0.93 (0.75-1.14); p = 0.48] although these findings did not reach statistical significance. The current evidence highlights that cancer risk is increased in individuals with BD, particularly breast cancer in women. Lithium may have a potential protective effect on cancer, including urinary cancer. The role of lithium as a mainstay of treatment for BD is reinforced by this study.
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http://dx.doi.org/10.1016/j.neubiorev.2021.03.034DOI Listing
July 2021

Patient and physician perspectives of a smartphone application for depression: a qualitative study.

BMC Psychiatry 2021 01 29;21(1):65. Epub 2021 Jan 29.

Department of Psychiatry, CHU Clermont-Ferrand, University of Clermont Auvergne, EA 7280, Clermont-Ferrand, France.

Background: Despite an increasing number of smartphone apps, such therapeutic tools have not yet consistently demonstrated their efficacy and many suffer from low retention rates. To ensure the development of efficient apps associated with high adherence, we aimed to identify, through a user-centred design approach, patient and physician expectations of a hypothetical app dedicated to depression.

Methods: We conducted semi-structured interviews with physicians (psychiatrists and general practitioners) and patients who had experienced a major depressive episode during the last 12 months using the focus group method. The interviews were audio recorded, transcribed and analysed using qualitative content analysis to define codes, categories and emergent themes.

Results: A total of 26 physicians and 24 patients were included in the study. The focus groups showed balanced sex and age distributions. Most participants owned a smartphone (83.3% of patients, 96.1% of physicians) and were app users (79.2% of patients and 96.1% of physicians). The qualitative content analysis revealed 3 main themes: content, operating characteristics and barriers to the use of the app. Expected content included the data collected by the app, aiming to provide information about the patient, data provided by the app, gathering psychoeducation elements, therapeutic tools and functionalities to help with the management of daily life and features expected for this tool. The "operating characteristics" theme gathered aims considered for the app, its potential target users, considered modalities of use and considerations around its accessibility and security of use. Finally, barriers to the use of the app included concerns about potential app users, its accessibility, safety, side-effects, utility and functioning. All themes and categories were the same for patients and physicians.

Conclusions: Physician and patient expectations of a hypothetical smartphone app dedicated to depression are high and confirmed the important role it could play in depression care. The key points expected by the users for such a tool are an easy and intuitive use and a personalised content. They are also waiting for an app that gives information about depression, offers a self-monitoring functionality and helps them in case of emergency.
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http://dx.doi.org/10.1186/s12888-021-03064-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847000PMC
January 2021

Changing trends in psychiatric emergency service admissions during the COVID-19 outbreak: Report from a worldwide epicentre.

J Affect Disord 2021 03 27;282:26-32. Epub 2020 Dec 27.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036 Barcelona, Catalonia, Spain. Electronic address:

Background: During the COVID-19 pandemic, a structural reorganization was imposed on public health systems. Psychiatry services were also affected with the imposed reduction of non-urgent consultations. We aim to explore the effect of these changes on a Psychiatry Emergency Service during COVID-19 lockdown in Spain.

Methods: A retrospective analysis was performed on all patients admitted to our Psychiatric Emergency Service 90 days before and after March 14, 2020, the first day of lockdown in Spain. Extracted data were compared between the two periods. Poisson regression analysis was performed to analyze changes in admission rates.

Results: 1,958 psychiatric emergency admissions were analyzed. Although the number of admissions decreased by 37.9%, we observed a significant increase in the percentage of acute psychiatric hospitalization during the lockdown. Anxiety spectrum disorders accumulated the greatest significant decrease in admission rates during the lockdown. On the other hand, a significant increase in admissions rates was found in patients with dementia, autism spectrum disorders, and substance use disorders during the lockdown.

Limitations: This study was conducted in a single psychiatric emergency service, preventing a generalization of our results. The comparison time period might have biased our results due to the influence of external factors.

Conclusion: Mental health consequences of COVID-19 are becoming apparent. A reduction of admission rates for anxiety disorders might be related telepsychiatry implementation during the lockdown. Other conditions particularly vulnerable to the routine changes and lack of social support have suffered the most, and efforts should be placed to treat these situations.
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http://dx.doi.org/10.1016/j.jad.2020.12.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765763PMC
March 2021

Long-term treatment of bipolar disorder type I: A systematic and critical review of clinical guidelines with derived practice algorithms.

Bipolar Disord 2021 06 7;23(4):324-340. Epub 2021 Jan 7.

Bipolar and Depressive Disorders Unit, Hospital Clinic, University of Barcelona, Institute of Neuroscience, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.

Objectives: This systematic review aimed at providing a critical, comprehensive synthesis of international guidelines' recommendations on the long-term treatment of bipolar disorder type I (BD-I).

Methods: MEDLINE/PubMed and EMBASE databases were searched from inception to January 15th, 2019 following PRISMA and PICAR rules. International guidelines providing recommendations for the long-term treatment of BD-I were included. A methodological quality assessment was conducted with the Appraisal of Guidelines for Research and Evaluation-AGREE II.

Results: The final selection yielded five international guidelines, with overall good quality. The evaluation of applicability was the weakest aspect across the guidelines. Differences in their updating strategies and the rating of the evidence, particularly for meta-analyses, randomized clinical trials (RCTs) and observational studies, could be responsible of some level of heterogeneity among recommendations. Nonetheless, the guidelines recommended lithium as the 'gold standard' in the long-term treatment of BD-I. Quetiapine was another possible first-line option as well as aripiprazole (for the prevention of mania). Long-term treatment should contemplate monotherapy, at least initially. Clinicians should check regularly for efficacy and side effects and if necessary, switch to first-line alternatives (i.e. Valproate), combine first-line compounds with different mechanisms of action or switch to second-line options or combinations.

Conclusions: The possibility to monitor improvements in long-term outcomes, namely relapse prevention and inter-episode subthreshold depressive symptoms, based on the application of their recommendations is an unmet need of clinical guidelines. In terms of evidence of clinical guidelines, there is a need for more efficacious treatment strategies for the prevention of bipolar depression.
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http://dx.doi.org/10.1111/bdi.13040DOI Listing
June 2021

Clinical correlates of seasonality in bipolar disorder: A specifier that needs specification?

Acta Psychiatr Scand 2021 02 25;143(2):162-171. Epub 2020 Dec 25.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain.

Objective: Seasonal pattern (SP) is a bipolar disorder (BD) specifier that indicates a tendency towards affective relapses during specific moments of the year. SP affects 15%-25% of BD patients. In the past, SP was applied only to depressive relapses while, in DSM-5, SP may be applied to both depressive and (hypo)manic episodes. We examined the association between different clinical correlates of BD and SP according to its current definition in a cohort of patients with BD type I (BDI) and II (BDII).

Methods: Patients were recruited from a specialized unit and assessed according to the season of relapse and type of episode per season. SP and non-SP patients were compared looking into sociodemographic and clinical correlates. Significant variables at univariate comparisons were included in multivariate logistic regression with SP as the dependent variable.

Results: 708 patients were enrolled (503 BDI, 205 BDII), and 117 (16.5%) fulfilled DSM-5 criteria for SP. The mean age was 45.3 years (SD = 14.18), and 389 were female (54.9%). The logistic regression model included a significant contribution of BDII (OR = 2.23, CI 1.4-3.55), family history of mood disorder (OR = 1.97, CI 1.29-3.01), undetermined predominant polarity (OR = 0.44, CI 0.28-0.70), and aggressive behavior (OR = 0.42, CI 0.23-0.75).

Conclusion: Our results outline a novel positive association of SP with undetermined predominant polarity, BDII, family history of mood disorder, and with fewer aggressiveness-related symptoms. Seasonality is associated with a biphasic pattern with similar dominance of (hypo)mania and depression and is more frequent in BDII as compared to BDI. Seasonal episodes may be easier to predict, but difficult to prevent.
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http://dx.doi.org/10.1111/acps.13251DOI Listing
February 2021

The biology of aggressive behavior in bipolar disorder: A systematic review.

Neurosci Biobehav Rev 2020 12 24;119:9-20. Epub 2020 Sep 24.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel St, 12-0, 08036, Barcelona, Catalonia, Spain.

Aggressive behavior (AB) represents a public health concern often associated with severe psychiatric disorders. Although most psychiatric patients are not aggressive, untreated psychiatric illness, including bipolar disorder (BD), may associate with an increased risk of AB. Accurate predictive models of AB are still lacking and it is crucial to delineate AB biomarkers state of the art in BD. We performed a systematic review according to PRISMA guidelines to identify biological correlates of AB in BD. Final results included 20 studies: 10 involving genetic and 10 other biological AB biomarkers (total sample size N = 5,181). Our results pointed to a serotoninergic hypoactivation in violent suicidal BD patients. Similarly, BD violent suicide attempters had a blunted hypothalamic-pituitary-adrenal (HPA) activity. Violent behavior in BD was associated with a chronic inflammatory state. While the role of lipids as biomarkers for AB remains equivocal, uric acid appears as a potential biomarker for hetero-AB in BD. Available data can be useful in the fulfill of specific biomarkers of AB in BD, ultimately leading to the development of accurate predictive models.
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http://dx.doi.org/10.1016/j.neubiorev.2020.09.015DOI Listing
December 2020

Deconstructing major depressive episodes across unipolar and bipolar depression by severity and duration: a cross-diagnostic cluster analysis on a large, international, observational study.

Transl Psychiatry 2020 07 19;10(1):241. Epub 2020 Jul 19.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.

A cross-diagnostic, post-hoc analysis of the BRIDGE-II-MIX study was performed to investigate how unipolar and bipolar patients suffering from an acute major depressive episode (MDE) cluster according to severity and duration. Duration of index episode, Clinical Global Impression-Bipolar Version-Depression (CGI-BP-D) and Global Assessment of Functioning (GAF) were used as clustering variables. MANOVA and post-hoc ANOVAs examined between-group differences in clustering variables. A stepwise backward regression model explored the relationship with the 56 clinical-demographic variables available. Agglomerative hierarchical clustering with two clusters was shown as the best fit and separated the study population (n = 2314) into 65.73% (Cluster 1 (C1)) and 34.26% (Cluster 2 (C2)). MANOVA showed a significant main effect for cluster group (p < 0.001) but ANOVA revealed that significant between-group differences were restricted to CGI-BP-D (p < 0.001) and GAF (p < 0.001), showing greater severity in C2. Psychotic features and a minimum of three DSM-5 criteria for mixed features (DSM-5-3C) had the strongest association with C2, that with greater disease burden, while non-mixed depression in bipolar disorder (BD) type II had negative association. Mixed affect defined as DSM-5-3C associates with greater acute severity and overall impairment, independently of the diagnosis of bipolar or unipolar depression. In this study a pure, non-mixed depression in BD type II significantly associates with lesser burden of clinical and functional severity. The lack of association for less restrictive, researched-based definitions of mixed features underlines DSM-5-3C specificity. If confirmed in further prospective studies, these findings would warrant major revisions of treatment algorithms for both unipolar and bipolar depression.
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http://dx.doi.org/10.1038/s41398-020-00922-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370235PMC
July 2020

Lithium's antiviral effects: a potential drug for CoViD-19 disease?

Int J Bipolar Disord 2020 May 20;8(1):21. Epub 2020 May 20.

Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.

Background: Since its introduction in modern medicine, naturalistic observations emerged about possible uses of lithium treatment for conditions different from recurring affective disorders, for which it is still a first-line treatment option. Some evidence about the antiviral properties of lithium began in the early 1970s, when some reports found a reduction of labial-herpetic recurrences. The present review aims to present most of the pre-clinical and clinical evidence about lithium's ability to inhibit DNA and RNA viruses, including Coronaviridae, as well as the possible pathways and mechanisms involved in such antiviral activity.

Main Body: Despite a broad number of in vitro studies, the rationale for the antiviral activity of lithium failed to translate into methodologically sound clinical studies demonstrating its antiviral efficacy. In addition, the tolerability of lithium as an antiviral agent should be addressed. In fact, treatment with lithium requires continuous monitoring of its serum levels in order to prevent acute toxicity and long-term side effects, most notably affecting the kidney and thyroid. Yet lithium reaches heterogeneous but bioequivalent concentrations in different tissues, and the anatomical compartment of the viral infection might underpin a different, lower need for tolerability concerns which need to be addressed.

Conclusions: Lithium presents a clear antiviral activity demonstrated at preclinical level, but that remains to be confirmed in clinical settings. In addition, the pleiotropic mechanisms of action of lithium may provide an insight for its possible use as antiviral agent targeting specific pathways.
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http://dx.doi.org/10.1186/s40345-020-00191-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239605PMC
May 2020

Symptom networks in acute depression across bipolar and major depressive disorders: A network analysis on a large, international, observational study.

Eur Neuropsychopharmacol 2020 06 12;35:49-60. Epub 2020 May 12.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036 Barcelona, Catalonia, Spain.

Major Depressive Episode (MDE) is a transdiagnostic nosographic construct straddling Major Depressive (MDD) and Bipolar Disorder (BD). Prognostic and treatment implications warrant a differentiation between these two disorders. Network analysis is a novel approach that outlines symptoms interactions in psychopathological networks. We investigated the interplay among depressive and mixed symptoms in acutely depressed MDD/BD patients, using a data-driven approach. We analyzed 7 DSM-IV-TR criteria for MDE and 14 researched-based criteria for mixed features (RBDC) in 2758 acutely depressed MDD/BD patients from the BRIDGE-II-Mix study. The global network was described in terms of symptom thresholds and symptom centrality. Symptom endorsement rates were compared across diagnostic subgroups. Subsequently, MDD/BD differences in symptom-network structure were examined using permutation-based network comparison test. Mixed symptoms were the most central and highly interconnected nodes in the network, particularly agitation followed by irritability. Despite mixed symptoms, appetite gain and hypersomnia were significantly more endorsed in BD patients, associations between symptoms were highly correlated across MDD/BD (Spearman's r = 0.96, p<0.001). Network comparison tests showed no significant differences among MDD/BD in network strength, structure, or specific edges, with strong edges correlations (0.66-0.78). Upstream differences in MDD/BD may produce similar symptoms networks downstream during acute depression. Yet, mixed symptoms, appetite gain and hypersomnia are associated to BD rather than MDD. Symptoms during mixed-MDE might aggregate according to 2 different clusters, suggesting a possible stratification within mixed states. Future symptom-based studies should implement clinical, longitudinal, and biological factors, in order to establish tailored therapeutic strategies for acute depression.
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http://dx.doi.org/10.1016/j.euroneuro.2020.03.017DOI Listing
June 2020

Mixed Features in Depression: The Unmet Needs of Diagnostic and Statistical Manual of Mental Disorders Fifth Edition.

Psychiatr Clin North Am 2020 03 28;43(1):59-68. Epub 2019 Nov 28.

Barcelona Bipolar and Depressive Disorders Program, Hospital Clinic, University of Barcelona, Institute of Neuroscience, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, Barcelona, Catalonia 08036, Spain.

The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition introduced the specifier "with mixed features" including 3 or more nonoverlapping typical manic symptoms during a major depressive episode in bipolar disorder type I or II or unipolar major depressive disorder. Excluding overlapping excitatory symptoms, which are frequently observed in mixed depression, leaves many patients with mixed depression undiagnosed. As a consequence, alternative diagnostic criteria have been proposed, claiming for the inclusion in the rubric of mixed features the following symptoms: psychomotor agitation, mood lability, and aggressiveness. A deeper diagnostic reconsideration of mixed features in depression should be provided by the new nosologic classification systems.
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http://dx.doi.org/10.1016/j.psc.2019.10.006DOI Listing
March 2020

Corrigendum to ``Violent criminal behavior in the context of bipolar disorder: Systematic review and meta-analysis'' [Journal of Affective Disorders (2018) 239:161-170].

J Affect Disord 2020 Feb 25;263:735-738. Epub 2019 Oct 25.

Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036, Barcelona, Catalonia, Spain; CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Barcelona, Spain.

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http://dx.doi.org/10.1016/j.jad.2019.10.022DOI Listing
February 2020

Lithium Exposure During Pregnancy and the Postpartum Period: A Systematic Review and Meta-Analysis of Safety and Efficacy Outcomes.

Am J Psychiatry 2020 01 18;177(1):76-92. Epub 2019 Oct 18.

Departments of Neuroscience, Reproductive Science, and Dental Science and Section of Psychiatry, University School of Medicine "Federico II," Naples (Fornaro); Department of Neurosciences, University of Padua, Padua, Italy (Maritan, Miola, Solmi); Department of Mental Health, Local Health Unit 6 "Euganea," Padua (Ferranti, Zaninotto); National Social Security Institute, Latina, Italy (Anastasia); Department of Psychiatry and Psychology, Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain (Murru, Solé, Vieta); Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London (Stubbs); Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, and South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, U.K. (Stubbs, Young); Centre for Addiction and Mental Health, Toronto (Carvalho); Department of Psychiatry, University of Bologna, Bologna, Italy (Serretti); Early Psychosis: Interventions and Clinical Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Fusar-Poli, McGuire, Dazzan, Solmi); OASIS service, South London and Maudsley NHS Foundation Trust, London (Fusar-Poli); Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy (Fusar-Poli); Women's College Research Institute and Department of Psychiatry, Women's College Hospital, Toronto, and Department of Psychiatry, Faculty of Medicine and Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto (Vigod); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y. (Correll); Department of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, N.Y. (Correll); Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll); Padova Neuroscience Center, University of Padua, Padua (Solmi).

Objective: Uncertainty surrounds the risks of lithium use during pregnancy in women with bipolar disorder. The authors sought to provide a critical appraisal of the evidence related to the efficacy and safety of lithium treatment during the peripartum period, focusing on women with bipolar disorder and their offspring.

Methods: The authors conducted a systematic review and random-effects meta-analysis assessing case-control, cohort, and interventional studies reporting on the safety (primary outcome, any congenital anomaly) or efficacy (primary outcome, mood relapse prevention) of lithium treatment during pregnancy and the postpartum period. The Newcastle-Ottawa Scale and the Cochrane risk of bias tools were used to assess the quality of available PubMed and Scopus records through October 2018.

Results: Twenty-nine studies were included in the analyses (20 studies were of good quality, and six were of poor quality; one study had an unclear risk of bias, and two had a high risk of bias). Thirteen of the 29 studies could be included in the quantitative analysis. Lithium prescribed during pregnancy was associated with higher odds of any congenital anomaly (N=23,300, k=11; prevalence=4.1%, k=11; odds ratio=1.81, 95% CI=1.35-2.41; number needed to harm (NNH)=33, 95% CI=22-77) and of cardiac anomalies (N=1,348,475, k=12; prevalence=1.2%, k=9; odds ratio=1.86, 95% CI=1.16-2.96; NNH=71, 95% CI=48-167). Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion (N=1,289, k=3, prevalence=8.1%; odds ratio=3.77, 95% CI=1.15-12.39; NNH=15, 95% CI=8-111). Comparing lithium-exposed with unexposed pregnancies, significance remained for any malformation (exposure during any pregnancy period or the first trimester) and cardiac malformations (exposure during the first trimester), but not for spontaneous abortion (exposure during the first trimester) and cardiac malformations (exposure during any pregnancy period). Lithium was more effective than no lithium in preventing postpartum relapse (N=48, k=2; odds ratio=0.16, 95% CI=0.03-0.89; number needed to treat=3, 95% CI=1-12). The qualitative synthesis showed that mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations.

Conclusions: The risk associated with lithium exposure at any time during pregnancy is low, and the risk is higher for first-trimester or higher-dosage exposure. Ideally, pregnancy should be planned during remission from bipolar disorder and lithium prescribed within the lowest therapeutic range throughout pregnancy, particularly during the first trimester and the days immediately preceding delivery, balancing the safety and efficacy profile for the individual patient.
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http://dx.doi.org/10.1176/appi.ajp.2019.19030228DOI Listing
January 2020

"Do depressive and manic symptoms differentially impact on functioning in acute depression? Results from a large, cross-sectional study".

J Affect Disord 2020 01 1;261:30-39. Epub 2019 Oct 1.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036, Barcelona, Catalonia, Spain.

Background: Diagnostic criteria for a major depressive episode capture heterogeneous presentations across unipolar (UD) and bipolar (BD) and first-onset (FDE) depression. We evaluated the contribution of each depressive and (hypo)manic symptom to worse functioning in UD/BD/FDE subgroups.

Methods: A post-hoc analysis of the BRIDGE-II-Mix study. Acutely depressed patients were stratified into UD, BD and FDE. Each (hypo)manic or depressive symptom was included in a diagnosis-specific logistic regression model with functioning as dependent variable. Better/worse functioning was set with median diagnosis-specific GAF scores cutoffs. All p values were two-tailed. Statistical significance was set at p < 0.05.

Results: A total of 2768/2811 depressed individuals were enrolled. In BD (N = 716), "recurrent thoughts of death" (OR 2.48, p < 0.0001) and "feelings of worthlessness" (OR 2.28, p < 0.0001) among depressive symptoms, "aggressiveness" (OR 1.67, p = 0.022) as the unique (hypo)manic symptom, significantly contributed to worse functioning. In UD (N = 1357), "depressed mood" (OR 5.6, p = 0.031) and "diminished interest or pleasure" (OR 4.77, p < 0.0001) among depressive, "grandiosity" (OR 3.5, p = 0.014) among (hypo)manic symptoms, most significantly contributed to worse functioning. In FDE (N = 677) "recurrent thoughts of death" (OR 1.99, p < 0.0001) and "insomnia/hypersomnia" (OR 1.88, p = 0.039) among depressive, "grandiosity" (OR 5.98, p = 0.038) as (hypo)manic symptoms significantly contributed to worse functioning.

Limitations: The post-hoc and cross-sectional design do not allow for prognostic or causal inferences.

Conclusions: Key depressive and (hypo)manic symptoms distinctively associate with worse functional outcome in acute depression, with differential diagnostic-specific magnitude of effect. Core depressive symptoms are associated with worse functioning in unipolar depression, but not in bipolar or first-episode depression.
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http://dx.doi.org/10.1016/j.jad.2019.09.070DOI Listing
January 2020

Adverse outcomes during pregnancy and major congenital malformations in infants of patients with bipolar and schizoaffective disorders treated with antiepileptic drugs: A systematic review.

Psychiatr Pol 2019 Apr 30;53(2):223-244. Epub 2019 Apr 30.

Barcelona Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalunya, Spain.

Objectives: Antiepileptic drugs (AEDs), which are commonly used as a treatment for acute phases and prevention of relapses in bipolar disorder (BD) and schizoaffective disorder (SAD), have been often associated to adverse outcomes in pregnancy and major congenital malformations (MCM). We aimed to summarize available evidence assessing these outcomes when AEDs are used in pregnant women with BD and/or SAD.

Methods: We searched four databases from inception to 18 January, 2019. We included peer-reviewed observational studies on the use of AEDs in pregnant women with BD or SAD. We excluded studies not reporting data on BD or SAD, not specifying the AED or not assessing pregnancy outcomes or MCM.

Results: The pooled records amounted to 2,861. After duplicate removal and inclusion/exclusion criteria application, we included 9 observational studies assessing patients with BD and SAD. The AEDs evaluated were lamotrigine (LTG), valproate (VPA), carbamazepine (CBZ), oxcarbazepine (OXC), topiramate (TPR) and gabapentin (GBP). VPA and CBZ were the AED most commonly associated to MCM. LTG showed the best safety profile. Higher rates of complications during pregnancy were observed in treated and untreated women with BD compared to healthy controls.

Conclusions: AEDs may produce adverse outcomes in pregnancy and MCM in children of pregnant women with BD or SAD, showing higher risks at higher doses. LTG could be considered in this type of patients, given the low rate of adverse events. VPA and CBZ use should be avoided during pregnancy.
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http://dx.doi.org/10.12740/PP/105906DOI Listing
April 2019

A 12-month prospective study on the time to hospitalization and clinical management of a cohort of bipolar type I and schizoaffective bipolar patients.

Eur Psychiatry 2019 09 28;61:1-8. Epub 2019 Jun 28.

Bipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain. Electronic address:

Background: Schizoaffective disorder, bipolar type (SAD) and bipolar disorder I (BD) present a large clinical overlap. In a 1-year follow-up, we aimed to evaluate days to hospitalization (DTH) and predictors of relapse in a SAD-BD cohort of patients.

Methods: A 1-year, prospective, naturalistic cohort study considering DTH as primary outcome and incidence of direct and indirect measures of psychopathological compensation as secondary outcomes. Kaplan-Meyer survival analysis with Log-rank Mantel-Cox test compared BD/SAD subgroups as to DTH. After bivariate analyses, Cox regression was performed to assess covariates possibly associated with DTH in diagnostic subgroups.

Results: Of 836 screened patients, 437 were finally included (SAD = 105; BD = 332). Relapse rates in the SAD sample was n = 26 (24.8%) vs. n = 41 (12.3%) in the BD sample (p = 0.002). Mean ± SD DTH were 312.16 ± 10.6 (SAD) vs. 337.62 ± 4.4 (BD) days (p = 0.002). Patients with relapses showed more frequent suicide acts, violent behaviors, and changes in pharmacological treatments (all p < 0.0005) in comparison to patients without relapse. Patients without relapses had significantly higher mean number of treatments at T0 (p = 0.010). Cox regression model relating the association between diagnosis and DTH revealed that BD had higher rates of suicide attempts (HR = 13.0, 95%CI = 4.0-42.0, p < 0.0005), whereas SAD had higher rates of violent behavior during psychotic episodes (HR = 12.0, 95%CI = .3.3-43.5, p > 0.0005).

Conclusions: SAD patients relapse earlier with higher hospitalization rates and violent behavior during psychotic episodes whereas bipolar patients have more suicide attempts. Psychiatric/psychological follow-up visits may delay hospitalizations by closely monitoring symptoms of self- and hetero-aggression.
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http://dx.doi.org/10.1016/j.eurpsy.2019.06.001DOI Listing
September 2019

Pharmacotherapy for the peripartum management of bipolar disorder.

Expert Opin Pharmacother 2019 Oct 10;20(14):1731-1741. Epub 2019 Jun 10.

Fondation FondaMental , Créteil , France.

: The peripartum period in bipolar disorder (BD) patients is associated with high risk of relapse. Relapse during this period may affect fetal and child development. The consequences of psychotropic medication during pregnancy are also a major concern. The extent to which mood stabilizers may potentially affect the embryogenesis or the child development varies from high (e.g. valproate) to less clear and more debated (e.g. lithium). : This review describes the current state of evidence with respect to the impact of recommended pharmacological interventions for BD during the peripartum period. It compares recent international treatment guidelines for the management of BD during the peripartum period. Last, this review presents a summary of key recommendations for BD women of childbearing age, for BD women during pregnancy and postpartum period from the international guidelines. : Management of the pharmacological treatment for BD patients during the perinatal period is challenging. Although treatment guidelines may be of significant help, high heterogeneity exists across them. Shared decision-making represents a useful patient-centered approach during the perinatal period. Large cohort studies are needed to better identify risk associated to treatment discontinuation or treatment exposure.
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http://dx.doi.org/10.1080/14656566.2019.1626826DOI Listing
October 2019

Lithium and bipolar depression.

Bipolar Disord 2019 08 9;21(5):458-459. Epub 2019 May 9.

Lucio Bini Mood Disorder Centers, Cagliari and Rome, Italy.

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http://dx.doi.org/10.1111/bdi.12781DOI Listing
August 2019

Sultans of Swing: A Reappraisal of the Intertwined Association Between Affective Lability and Mood Reactivity in a Post Hoc Analysis of the BRIDGE-II-MIX Study.

J Clin Psychiatry 2019 02 19;80(2). Epub 2019 Feb 19.

Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.

Objective: This post hoc analysis of the BRIDGE-II-MIX study is aimed at evaluating affective lability (AL) as a possible clinical feature of mixed depression and assessing the relationship with atypical depressive features, particularly mood reactivity (MR).

Methods: In the BRIDGE-II-MIX multicenter, cross-sectional study, 2,811 individuals suffering from a major depressive episode (MDE; DSM-IV-TR criteria), in the context of bipolar I or II disorder (BD-I, BD-II, respectively) or major depressive disorder, were enrolled between June 2009 and July 2010. Patients with (MDE-AL, n = 694) and without (MDE-noAL, n = 1,883) AL and with (MDE-MR, n = 1,035) or without (MDE-noMR, n = 1,542) MR were compared through χ² test or Student t test. Stepwise backward logistic regression models, respectively testing AL and MR as the dependent variable, were performed to differentiate the 2 clinical constructs.

Results: AL was positively associated with BD-I (P < .001) and BD-II (P < .001), with DSM-5 mixed (DSM-5-MXS) (P < .001) and atypical (DSM-5-AD) features (P < .001) and negatively associated with MDD (P < .001). In the logistic regression models, MR was the variable most significantly associated with AL and vice versa (P < .001 for both). AL was positively associated with severity of mania and DSM-5-MXS and negatively correlated with severity of depression, while MR was better predicted by atypical symptoms such as hyperphagia, hypersomnia, and leaden paralysis and correlated with both comorbid anxiety disorders and DSM-5-MXS.

Conclusions: Mixed and atypical depression may lie on the same continuum. MR and AL could represent the underlying matrix, bridging the gap between mixed and atypical depression.
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http://dx.doi.org/10.4088/JCP.17m12082DOI Listing
February 2019

Long-acting injectable antipsychotics (LAIs) for maintenance treatment of bipolar and schizoaffective disorders: A systematic review.

Eur Neuropsychopharmacol 2019 04 12;29(4):457-470. Epub 2019 Feb 12.

Barcelona Bipolar Disorders Program, Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st., Barcelona, Catalunya, Spain. Electronic address:

Long-Acting Injectable Antipsychotics (LAIs) are used to overcome non-compliance in psychoses, mainly schizophrenia spectrum disorders. We aimed to summarize available evidence of studies comparing the efficacy of LAIs to placebo or oral medications for Bipolar Disorder (BD) and/or Schizoaffective Disorder (SAD). We searched six databases from inception to 28-March-2018, using the strategy: long-acting antipsychotics AND (bipolar disorder OR schizoaffective disorder OR mania OR manic OR bipolar depression). We included peer-reviewed double-blind comparisons of LAIs for any clinical outcome occurrence in BD, or open mirror studies with same prospective as retrospective assessment periods. We excluded studies reporting on mixed schizophrenia/SAD populations without reporting results separately. The pooled records amounted to 642. After duplicate removal and inclusion/exclusion criteria application, we included 15 studies, 6 double-blind and 9 open, 13 assessing BD and 2 SAD. Depot neuroleptics prevented manic, but not depressive recurrences and may worsen depressive symptoms. Risperidone long-acting injectable was found to be effective in protecting from any mood/manic symptom compared to placebo, but not from depressive recurrences. Add-on or monotherapy paliperidone palmitate in SAD patients protected from psychotic, depressive, and manic symptoms. In patients with BD-I with a manic episode at study enrolment, aripiprazole monohydrate significantly delayed time to recurrence of manic episodes without inducing depressive episodes. LAIs are effective and well-tolerated maintenance treatments for BD and SAD. They showed better efficacy in preventing mania than depression. LAIs may be first-line for BD-I and SAD patients with a manic predominant polarity and with non-adherence problems.
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http://dx.doi.org/10.1016/j.euroneuro.2019.02.003DOI Listing
April 2019

Cognitive Remediation Interventions in Schizoaffective Disorder: A Systematic Review.

Front Psychiatry 2018 4;9:470. Epub 2018 Oct 4.

Barcelona Bipolar Disorders Program, Institute of Neurosciences, IDIBAPS, CIBERSAM, Hospital Clinic, University of Barcelona, Barcelona, Spain.

Patients with schizoaffective disorder (SAD) suffer from cognitive impairment, which negatively influences their functionality. Cognitive remediation (CR) interventions have been shown to be effective in patients with schizophrenia (SZ) and bipolar disorder (BD), but evidence in SAD is limited so far. The aim of this study is to systematically review the published data on CR interventions, either in neurocognition or social cognition, in patients with SAD. We conducted a comprehensive, computerized literature search using terms related to CR interventions in psychotic and affective disorders, and particularly in SAD. Pubmed, Embase, and Web of Knowledge databases were used up to February 28th, 2018 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The search returned 2672 articles of which four were finally selected meeting the inclusion criteria. Cognitive Enhancement Therapy, computerized Cognitive Remediation Therapy and Cognitive Training showed positive results in subsamples of patients with SAD regarding neurocognition and functioning in comparable terms to patients with schizophrenia as well as in a greater extent in quality of life. Benefits in social cognition were also described when Social Cognition Interaction Training was considered in patients with SAD. CR interventions seem to improve neurocognition and social cognition in patients with SAD as well as functioning and quality of life. However, further randomized controlled trials on CR interventions with an optimized design focusing on selected sample of patients with SAD are imperative.
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http://dx.doi.org/10.3389/fpsyt.2018.00470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180287PMC
October 2018

Depressive mood and circadian rhythms disturbances as outcomes of seasonal affective disorder treatment: A systematic review.

J Affect Disord 2018 12 15;241:608-626. Epub 2018 Aug 15.

Division of Psychiatry, Department of Medicine, University of Perugia, Italy.

Background: The present systematic review was aimed at critically summarizing the evidence about interventions focused on circadian rhythms and mood symptoms in seasonal affective disorder (SAD).

Methods: A systematic search of the electronic databases PUBMED, PsycINFO and Web of Science was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Original papers reporting data about the effects of treatments on both mood and circadian rhythms disturbances in SAD patients were considered for inclusion. The quality of the evidence provided by the eligible studies was assessed using the Revised Cochrane Risk of Bias Tool (RoB 2.0) and the Cochrane Risk of Bias in Non-Randomized Studies of Interventions Tool (ROBINS-I).

Results: Forty papers were deemed eligible for the systematic review. The evidence of treatment outcomes referring to circadian disturbances was not robust. Despite this, bright light therapy (BLT) demonstrates to phase-advance delayed rhythms and to improve sleep-wake disorders. As for mood symptoms, both BLT and selective serotonin reuptake inhibitors (SSRIs) show evidence of efficacy. The possible connection between improvements of mood symptoms and changes in circadian outcomes seems controversial.

Limitations: The included studies presented considerable methodological heterogeneity, small sample sizes and non-optimal sample selection.

Conclusions: The effectiveness of BLT in depressive symptoms and circadian disturbances of SAD was outlined by the present systematic review. The evidence about other biological and pharmacological treatments, although promising, should be replicated. A multifactorial etiopathogenesis could explain the heterogeneous clinical presentations of SAD and the complex link between mood and circadian symptoms.
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http://dx.doi.org/10.1016/j.jad.2018.08.071DOI Listing
December 2018

Clinical characterization of rapid cycling bipolar disorder: Association with attention deficit hyperactivity disorder.

J Affect Disord 2018 11 23;240:187-192. Epub 2018 Jul 23.

Department of Neurology and Psychiatry, Faculty of Medicine, Clinica Alemana Universidad del Desarrollo, Santiago, Chile; Early Intervention Program, J Horwitz Psychiatric Institute, Santiago, Chile. Electronic address:

Background: Rapid cycling (RC) bipolar disorder (BD) is associated with more disability and worse global functioning than non-rapid cycling BD (NRC) and is understudied. This study aims to investigate clinical characteristics associated to RC in a Latin-American sample and secondarily, to generate a clinical model to test the likelihood of RC in BD.

Methods: 250 BD patients were enrolled between 2007 and 2015. All patients met DSM-IV criteria for BD type I, II or NOS. The sample was dichotomized into RC and NRC subgroups, and compared in terms of sociodemographic and clinical variables by bivariate analyses. A binary logistic regression was performed to generate a model and explain variance associated with the likelihood of presenting RC.

Results: Final sample included 235 patients, of which forty-four (18.7%) met RC criteria. When compared to NRC, a significantly higher proportion of RC patients were female (81.4% vs. 58.9% p = 0.006), BD type II (58.1% vs. 29.7% p = 0.002), presented more manic/hypomanic episodes (43.6 ± 35.8 vs. 12.8 ± 58.9, p = 0.001), and had less psychotic symptoms (20.9% vs. 42.2%, p = 0.010). Attention deficit hyperactivity disorder (ADHD) was a significant comorbidity in RC (23.7% vs. 8.3%, p = 0.007). No differences were found in suicidality, mixed symptoms, and seasonal pattern. After logistic regression, variables significantly associated with RC were presence of ADHD (OR 4.6 [95% CI 1.54-13.93] p = 0.006) and female gender (OR 3.55 [95% CI, 1.32-9.56] p = 0.012).

Limitations: It is a cross-sectional study.

Conclusions: Findings suggest that ADHD comorbidity, and female gender are risk factors for RC in BD.
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http://dx.doi.org/10.1016/j.jad.2018.07.051DOI Listing
November 2018

Violent criminal behavior in the context of bipolar disorder: Systematic review and meta-analysis.

J Affect Disord 2018 10 5;239:161-170. Epub 2018 Jul 5.

Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036, Barcelona, Catalonia, Spain; CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Barcelona, Spain.

Background: Despite the potential importance of understanding violent criminal behavior (VCB) in individuals suffering from bipolar disorder (BD), previous findings are conflicting. The aims of the present study are to clarify the association of VCB and BD in comparison to general population and other psychiatric conditions.

Methods: A systematic review of literature from January 1st, 1980 through January 16th, 2017 from 3 electronic databases (MEDLINE/PubMed, EMBASE and PsycInfo), following the PRISMA and the MOOSE statements. Original peer-reviewed studies reporting data on VCB in BD were included. A random-effects meta-analysis was performed. Potential sources of heterogeneity were examined through subgroup and meta-regression analyses. The protocol was registered in PROSPERO, CRD42017054070.

Results: Twelve studies providing data from 58,475 BD participants. The prevalence of VCB in BD was 7.1% (95%CI = 3.0‒16.5%; k = 4). The association of BD and VCB compared to general population was not significant (OR = 2.784; 95% CI, 0.687‒11.287, P = .152). The association was significant only in cross-sectional studies, in studies in which VCB was assessed through self-reported measures, and in studies conducted in the USA. BD was more likely to be associated with VCB when BD patients were compared to controls with depressive disorders, whilst it was found to be less associated with VCB when BD was compared to psychotic disorders.

Limitations: 1. the methodological heterogeneity across the included studies. 2. causal inferences were precluded by the inclusion of cross-sectional studies.

Conclusions: These findings might provide a more balance portrait of the association between BD and VCB to clinicians, law enforcement and general public.
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http://dx.doi.org/10.1016/j.jad.2018.06.050DOI Listing
October 2018
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