Publications by authors named "Juan Undurraga"

43 Publications

Pharmacogenetics in Psychiatry: Perceived Value and Opinions in a Chilean Sample of Practitioners.

Front Pharmacol 2021 15;12:657985. Epub 2021 Apr 15.

Center for Genetics and Genomics, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana Universidad Del Desarrollo, Santiago, Chile.

Use of pharmacogenetics (PGx) testing to guide clinical decisions is growing in developed countries. Published guidelines for gene-drug pair analysis are available for prescriptions in psychiatry, but information on their utilization, barriers, and health outcomes in Latin America is limited. As a result, this work aimed at exploring current use, opinions, and perceived obstacles on PGx testing among psychiatrists in Chile, via an online, anonymous survey. Among 123 respondents (5.9% of registered psychiatrists in the country), 16.3% reported ever requesting a PGx test. The vast majority (95%) of tests were ordered by clinicians practicing in the Metropolitan Region of Santiago. Having more than 20 years in practice was positively associated with prior use of PGx (p 0.02, OR 3.74 (1.19-11.80)), while working in the public health system was negatively associated (OR 0.30 (0.10-0.83)). Perceived barriers to local implementation included insufficient evidence of clinical utility, limited clinicians' knowledge on PGx and on test availability, and health systems' issues, such as costs and reimbursement. Despite the recognition of these barriers, 80% of respondents asserted that it is likely that they will incorporate PGx tests in their practice in the next five years. Given these results, we propose next steps to facilitate implementation such as further research in health outcomes and clinical utility of known and novel clinically actionable variants, growth in local sequencing capabilities, education of clinicians, incorporation of clinical decision support tools, and economic evaluations, all in local context.
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http://dx.doi.org/10.3389/fphar.2021.657985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082421PMC
April 2021

[Cannabis use among hospitalized young people experiencing a first episode of psychosis: a case control study].

Rev Med Chil 2020 Nov;148(11):1606-1613

Departamento de Psiquiatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

Background: Cannabis use among young people in Chile has increased significantly in the last years. There is a consistent link between cannabis and psychosis.

Aim: To compare cannabis use in patients with a first episode of psychosis and healthy controls.

Material And Methods: We included 74 patients aged 20 ± 3 years (78% males) admitted to hospital with a first episode of psychosis and a group of 60 healthy controls aged 23 ± 4 years (63% males). Cannabis consumption was assessed, including age of first time use and length of regular use.

Results: Patients with psychosis reported a non-significantly higher frequency of life-time cannabis use. Patients had longer periods of regular cannabis use compared with healthy subjects (Odds ratio [OR] 2.4; 95% confi-dence intervals [CI] 1.14-5.05). Patients also used cannabis for the first time at an earlier age (16 compared with 17 years, p < 0.0). The population attributable fraction for regular cannabis use associated with hospital admissions due to psychosis was 17.7% (95% CI 1.2-45.5%).

Conclusions: Cannabis use is related to psychosis in this Chilean group of patients. This relationship is stronger in patients with early exposure to the drug and longer the regular use. One of every five admissions due to psychosis is associated with cannabis consumption. These data should influence cannabis legisla-tion and the public policies currently being discussed in Chile.
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http://dx.doi.org/10.4067/S0034-98872020001101606DOI Listing
November 2020

Antidepressant responses in direct comparisons of melancholic and non-melancholic depression.

J Psychopharmacol 2020 12 9;34(12):1335-1341. Epub 2020 Sep 9.

International Consortium for Mood and Psychotic Disorders Research, Mailman Research Center, McLean Hospital, Belmont, USA.

Background: Efforts to develop less heterogeneous, more clinically useful diagnostic categories for depressive disorders include renewed interest in the concept of melancholia (Mel). However, clinical or biological differentiation of Mel from other (nonMel) episodes of depression has been questioned, and it remains unclear whether pharmacological responses proposed to be characteristic of Mel are supported by available research.

Methods: We carried out a systematic review seeking treatment trials reports comparing Mel and nonMel depressed subjects for meta-analyses of their differences in responses (a) to antidepressants overall, (b) to tricyclic (TCAs) or serotonin-enhancing agents (serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors) and (c) with placebo treatment.

Results: We identified 25 trials in 16 reports comparing 2597 Mel with 5016 nonMel subjects. Overall, responses to antidepressant treatment did not differ between Mel (39.4%) and nonMel (42.2%) subjects. However, all subjects responded better to TCAs (50.6%) than SRIs (30.0%; <0.0001). Mel subjects also responded less well with placebo, but also were significantly more severely depressed at intake.

Conclusions: Antidepressant responses were similar in Mel and nonMel depressed patients. Mel subjects responded 25% less with placebo but were more severely depressed initially, and there was preferential response to TCAs in both Mel and nonMel subjects. The findings provide little support for proposed differences in responses to particular treatments among Mel versus nonMel depressed patients, and underscore the need to match for illness severity in making such comparisons.
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http://dx.doi.org/10.1177/0269881120953983DOI Listing
December 2020

Structural brain abnormalities in schizophrenia in adverse environments: examining the effect of poverty and violence in six Latin American cities.

Br J Psychiatry 2021 02;218(2):112-118

LiNC, Department of Psychiatry, Universidade Federal de São Paulo, Brazil.

Background: Social and environmental factors such as poverty or violence modulate the risk and course of schizophrenia. However, how they affect the brain in patients with psychosis remains unclear.

Aims: We studied how environmental factors are related to brain structure in patients with schizophrenia and controls in Latin America, where these factors are large and unequally distributed.

Method: This is a multicentre study of magnetic resonance imaging in patients with schizophrenia and controls from six Latin American cities. Total and voxel-level grey matter volumes, and their relationship with neighbourhood characteristics such as average income and homicide rates, were analysed with a general linear model.

Results: A total of 334 patients with schizophrenia and 262 controls were included. Income was differentially related to total grey matter volume in both groups (P = 0.006). Controls showed a positive correlation between total grey matter volume and income (R = 0.14, P = 0.02). Surprisingly, this relationship was not present in patients with schizophrenia (R = -0.076, P = 0.17). Voxel-level analysis confirmed that this interaction was widespread across the cortex. After adjusting for global brain changes, income was positively related to prefrontal cortex volumes only in controls. Conversely, the hippocampus in patients with schizophrenia, but not in controls, was relatively larger in affluent environments. There was no significant correlation between environmental violence and brain structure.

Conclusions: Our results highlight the interplay between environment, particularly poverty, and individual characteristics in psychosis. This is particularly important for harsh environments such as low- and middle-income countries, where potentially less brain vulnerability (less grey matter loss) is sufficient to become unwell in adverse (poor) environments.
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http://dx.doi.org/10.1192/bjp.2020.143DOI Listing
February 2021

The incidence of non-affective psychotic disorders in Chile between 2005 and 2018: results from a national register of over 30 000 cases.

Psychol Med 2020 Aug 6:1-10. Epub 2020 Aug 6.

Psylife Group, Division of Psychiatry, University College London, London, UK.

Background: Evidence suggests the incidence of non-affective psychotic disorders (NAPDs) varies across persons and places, but data from the Global South is scarce. We aimed to estimate the treated incidence of NAPD in Chile, and variance by person, place and time.

Methods: We used national register data from Chile including all people, 10-65 years, with the first episode of NAPD (International Classification of Diseases, Tenth Revision: F20-F29) between 1 January 2005 and 29 August 2018. Denominators were estimated from Chilean National Census data. Our main outcome was treated incidence of NAPD and age group, sex, calendar year and regional-level population density, multidimensional poverty and latitude were exposures of interest.

Results: We identified 32 358 NAPD cases [12 136 (39.5%) women; median age-at-first-contact: 24 years (interquartile range 18-39 years)] during 171.1 million person-years [crude incidence: 18.9 per 100 000 person-years; 95% confidence interval (CI) 18.7-19.1]. Multilevel Poisson regression identified a strong age-sex interaction in incidence, with rates peaking in men (57.6 per 100 000 person-years; 95% CI 56.0-59.2) and women (29.5 per 100 000 person-years; 95% CI 28.4-30.7) between 15 and 19 years old. Rates also decreased (non-linearly) over time for women, but not men. We observed a non-linear association with multidimensional poverty and latitude, with the highest rates in the poorest regions and those immediately south of Santiago; no association with regional population density was observed.

Conclusion: Our findings inform the aetiology of NAPDs, replicating typical associations with age, sex and multidimensional poverty in a Global South context. The absence of association with population density suggests this risk may be context-dependent.
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http://dx.doi.org/10.1017/S0033291720002664DOI Listing
August 2020

Melancholia: does this ancient concept have contemporary utility?

Int Rev Psychiatry 2020 Aug - Sep;32(5-6):466-470. Epub 2020 Mar 16.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA.

Many efforts have been made to develop coherent and clinically useful categories of depressive illness, especially to facilitate prediction of morbidity and guide treatment-response. They include proposals to resurrect the ancient concept of , as a form of severe depression with particular symptomatic and proposed psychobiological characteristics. However, modern research is inconsistent in supporting differences between melancholic and nonmelancholic depression. In our recent study of over 3200 patient-subjects with DSM-5 major depressive episodes with/without melancholic characteristics, and matched for illness severity, prevalence of melancholic features was 35.2% with remarkably few clinical and demographic differences between melancholic and nonmelancholic subjects. Also, our systematic review of trials comparing melancholic and nonmelancholic subjects found little difference in responses to antidepressant treatments. These findings indicate that the concept of melancholia may have limited value for clinical prediction and treatment-selection. Overlap of symptoms in melancholic and nonmelancholic depression, based on DSM criteria, may limit distinction of melancholia; alternative definitions can be sought, and psychomotor retardation is a particularly strong differentiating feature. For now, however, melancholia seems best considered a state-dependent depression-type strongly associated with greater symptomatic severity, rather than a distinct syndrome. Its DSM-5 current status as a depression-type specifier seems appropriate, and it may be a logical target for genetic and other biomedical studies.
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http://dx.doi.org/10.1080/09540261.2019.1708708DOI Listing
March 2020

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

Lithium treatment for unipolar major depressive disorder: Systematic review.

J Psychopharmacol 2019 02 30;33(2):167-176. Epub 2019 Jan 30.

1 International Consortium for Mood and Psychotic Disorder Research, McLean Hospital, Belmont, MA, USA.

Background: The potential value of lithium treatment in particular aspects of unipolar major depressive disorder remains uncertain.

Methods: With reports of controlled trials identified by systematic searching of Medline, Cochrane Library, and PsycINFO literature databases, we summarized responses with lithium and controls followed by selective random-effects meta-analyses.

Results: We identified 36 reports with 39 randomized controlled trials: six for monotherapy and 12 for adding lithium to antidepressants for acute major depression, and 21 for long-term treatment. Data for monotherapy of acute depression were few and inconclusive. As an adjunct to antidepressants, lithium was much more effective than placebo ( p<0.0001). For long-term maintenance treatment, lithium was more effective than placebo in monotherapy ( p=0.011) and to supplement antidepressants ( p=0.038), and indistinguishable from antidepressant monotherapy.

Conclusions: The findings indicate efficacy of lithium as a treatment for some aspects of major depressive disorder, especially as an add-on to antidepressants and for long-term prophylaxis. It remains uncertain whether some benefits of lithium treatment occur with many major depressive disorder patients, or if efficacy is particular to a subgroup with bipolar disorder-like characteristics or mixed-features.
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http://dx.doi.org/10.1177/0269881118822161DOI Listing
February 2019

High prevalence of metabolic alterations in Latin American patients at initial stages of psychosis.

Early Interv Psychiatry 2019 12 15;13(6):1382-1388. Epub 2019 Jan 15.

Early Intervention Program, J. Horwitz Psychiatric Institute, Santiago, Chile.

Aim: Studies conducted in the United States have highlighted a higher prevalence of metabolic alterations (MA) in Latino population and Latino psychotic patients. Metabolic risk in psychosis is known to be present from initial stages of the disease. To better characterize this population, we explored the prevalence of MA and metabolic syndrome (MS) in early psychosis patients in a Latin American country.

Methods: Transversal, observational study comparing the prevalence of MA and MS in patients with early psychosis from an outpatient program in Chile (n = 148) with a community representative sample from the 2009-2010 National Health Survey (n = 568). ANOVA and regression analysis were performed obtaining odds ratio for MA and MS.

Results: The prevalence of MS was 44.7% in patients compared to 11.4% in the community sample (odds ratio [OR] 5.28, confidence interval [CI] 95% 3.07-9.08; P-value <0.001). There was no effect of gender. Subgroup analyses showed no significant association of MS with clozapine/olanzapine use, treatment duration or tobacco use. There was an association between treatment duration and hypertriglyceridemia (P = 0.024; OR 1.02, CI 95% 1.00-1.04) and obesity (P = 0.007; OR 5.93, CI 95% 1.82-20.22). Clozapine/olanzapine use was associated with hyperglycaemia (P = 0.007; OR 6.04, CI 95% 1.63-22.38) and high low density lipoprotein (P = 0.033 ANOVA; OR 5.28, CI 95% 1.14-24.37).

Conclusion: Latino psychotic patients have a high risk of MA and MS at initial stages of the disease which is not entirely explained by the higher risk in the whole Latino population, is irrespective of gender, and does not seem to be entirely a response to atypical antipsychotic use.
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http://dx.doi.org/10.1111/eip.12777DOI Listing
December 2019

Depressive symptoms are associated with higher morning plasma cortisol in primary care subjects.

Neuro Endocrinol Lett 2018 Oct;39(4):288-293

Endocrinology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile.

Background: Cortisol dysregulation has a potential role in depression.

Aim And Methods: We evaluated depressive symptoms using the Hamilton Rating Scale for Depression in 48 primary care subjects without history of previous or current depression and its association with cortisol dysregulation (morning plasma cortisol, 24-hour urinary free cortisol and cortisol metabolites). Presence of metabolic syndrome and inflammatory parameters were also assessed.

Results: Hamilton Rating Scale for Depression correlated significantly with morning cortisol, but not with urinary free cortisol or metabolites. A significant increase in morning cortisol by Hamilton groups (asymptomatic ≤8; mild to moderate: 9-18; moderate to severe: ≥19) was observed even when adjusted by age/gender. We observed no association of depressive symptoms with metabolic or inflammatory parameters.

Conclusion: Depressive symptoms in primary care subjects not consulting for their mood are associated with higher morning plasma cortisol, but not urinary cortisol or its metabolites. These observations suggest that systemic hypercortisolism and related metabolic disorders are not observed in mild/initial states of depressive disorders.
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October 2018

Imaging Social and Environmental Factors as Modulators of Brain Dysfunction: Time to Focus on Developing Non-Western Societies.

Biol Psychiatry Cogn Neurosci Neuroimaging 2019 01 25;4(1):8-15. Epub 2018 Sep 25.

Laboratory of Interdisciplinary Clinical Neuroscience, Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil.

Social and environmental factors are known risk factors and modulators of mental health disorders. We here conducted a nonsystematic review of the neuroimaging literature studying the effects of poverty, urbanicity, and community violence, highlighting the opportunities of studying non-Western developing societies such as those in Latin America. Social and environmental factors in these communities are widespread and have a large magnitude, as well as an unequal distribution, providing a good opportunity for their characterization. Studying the effect of poverty in these settings could help to explore the brain effect of economic improvements, disentangle the effect of absolute and relative poverty, and characterize the modulating impact of poverty on the underlying biology of mental health disorders. Exploring urbanicity effects in highly unequal cities could help identify the specific factors that modulate this effect as well as examine a possible dose-response effect by studying megacities. Studying brain changes in those living among violence, which is particularly high in places such as Latin America, could help to characterize the interplay between brain predisposition and exposure to violence. Furthermore, exploring the brain in an adverse environment should shed light on the mechanisms underlying resilience. We finally provide examples of two methodological approaches that could contribute to this field, namely a big cohort study in the developing world and a consortium-based meta-analytic approach, and argue about the potential translational value of this research on the development of effective social policies and successful personalized medicine in disadvantaged societies.
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http://dx.doi.org/10.1016/j.bpsc.2018.09.005DOI Listing
January 2019

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

Early treatment resistance in a Latin-American cohort of patients with schizophrenia.

Schizophr Res 2018 09 9;199:380-385. Epub 2018 Mar 9.

Department of Psychiatry, School of Medicine, Pontificia Universidad Católica de Chile, Chile; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK. Electronic address:

Background: Failure to respond to antipsychotic medication in schizophrenia is a common clinical scenario with significant morbidity. Recent studies have highlighted that many patients present treatment-resistance from disease onset. We here present an analysis of clozapine prescription patterns, used as a real-world proxy marker for treatment-resistance, in a cohort of 1195 patients with schizophrenia from a Latin-American cohort, to explore the timing of emergence of treatment resistance and possible subgroup differences.

Methods: Survival analysis from national databases of clozapine monitoring system, national disease notification registers, and discharges from an early intervention ward.

Results: Echoing previous studies, we found that around 1 in 5 patients diagnosed with schizophrenia were eventually prescribed clozapine, with an over-representation of males and those with a younger onset of psychosis. The annual probability of being prescribed clozapine was highest within the first year (probability of 0.11, 95% confidence interval of 0.093-0.13), compared to 0.018 (0.012-0.024) between years 1 and 5, and 0.006 (0-0.019) after 5years. Age at psychosis onset, gender, dose of clozapine used, and compliance with hematological monitoring at 12months, was not related to the onset of treatment resistance. A similar pattern was observed in a subgroup of 230 patients discharged from an early intervention ward with a diagnosis of non-affective first episode of psychosis.

Conclusions: Our results highlight that treatment resistance is frequently present from the onset of psychosis. Future studies will shed light on the possible different clinical and neurobiological characteristics of this subtype of psychosis.
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http://dx.doi.org/10.1016/j.schres.2018.02.056DOI Listing
September 2018

Tricyclic and selective serotonin-reuptake-inhibitor antidepressants compared with placebo in randomized trials for acute major depression.

J Psychopharmacol 2017 12;31(12):1624-1625

1 International Consortium for Mood and Psychotic Disorder Research, Mailman Research Center, McLean Hospital, Belmont, USA.

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http://dx.doi.org/10.1177/0269881117731294DOI Listing
December 2017

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review.

Ther Clin Risk Manag 2017 29;13:757-777. Epub 2017 Jun 29.

Institute for Clinical Research and Education in Medicine, Padua, Italy.

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 () 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.
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http://dx.doi.org/10.2147/TCRM.S117321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499790PMC
June 2017

Direct comparison of tricyclic and serotonin-reuptake inhibitor antidepressants in randomized head-to-head trials in acute major depression: Systematic review and meta-analysis.

J Psychopharmacol 2017 09 21;31(9):1184-1189. Epub 2017 Jun 21.

1 International Consortium for Mood & Psychotic Disorder Research, Mailman Research Center, McLean Hospital, Belmont, USA.

Background: A comparison across trials conducted over several decades suggested superior efficacy of tricyclic antidepressants (TCAs) over selective serotonin-reuptake inhibitors (SSRIs). However, this outcome may reflect a selective secular decline of responses after randomization to placebo. Remaining uncertainty encouraged direct comparison of the drug-types in trials involving randomized, head-to-head comparisons.

Methods: We systematically identified reports of randomized trials of TCAs versus SSRIs for major depression in several digital databases, and applied standard meta-analytic and multiple-factor regression methods to analyze and pool the findings.

Results: In 89 head-to-head trials, there was no detectable overall difference in responder rates or percent-improvement between TCAs and SSRIs. In addition to non-difference between drug-types, outcomes were unrelated to reporting-year, trial-size or nominal duration, proportion of women participants, initial depression ratings, rating scales, subjects/arm, imipramine-equivalent mg/day drug dose, or dropout rate. Trial size and duration increased significantly over the years 1980-2016.

Conclusions: Previous evidence suggesting superior benefits of TCAs over SSRIs for the treatment of acute major depression is probably an artifact of a selective secular decline in responses to placebo, as no difference was found in a large series of direct comparisons of these antidepressant-types.
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http://dx.doi.org/10.1177/0269881117711709DOI Listing
September 2017

Morbidity in Depressive Disorders.

Psychother Psychosom 2017 10;86(2):65-72. Epub 2017 Feb 10.

International Consortium for Mood and Psychotic Disorder Research, McLean Hospital, Belmont, Mass., USA.

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http://dx.doi.org/10.1159/000448661DOI Listing
April 2018

Psychoeducation in bipolar disorder with a SIMPLe smartphone application: Feasibility, acceptability and satisfaction.

J Affect Disord 2016 Aug 20;200:58-66. Epub 2016 Apr 20.

Mental Health Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.

Background: During the last fifteen years, the possibility of delivering psychoeducation programs through Internet-based platforms have been explored. Studies evaluating those programs have shown good to acceptable retention rates. In this context, we developed a smartphone application (SIMPLe) collecting information about mood symptoms and offering personalized psychoeducation messages. The main aims of this study were to evaluate the feasibility, acceptability and satisfaction of the smartphone application.

Methods: The study was conducted from March to August 2015. Participation in the study was proposed to a consecutive sample of adult patients attending an outpatient mental health clinic. Sociodemographic data, clinical and functional assessments alongside smartphone ownership and uses were collected at baseline and at 3 months' follow-up. A 5 item Likert-scale satisfaction questionnaire was also employed.

Results: 51 participants were initially enrolled in the study, 36 (74%) remained actively using the application after 3 months. The whole sample interacted with the application a mean of 77 days (SD=26.2). During these days they completed 88% of the daily tests. Over 86% of the participants agreed that the experience using the application was satisfactory.

Limitations: The diversity of smartphones operating systems led to a moderate, although representative, sample number. Additionally, the subjective data reporting, narrow time frame of use and stability of the patients could have affected the results.

Conclusions: The results confirm that this particular intervention is feasible and represent a satisfactory and acceptable instrument for the self-management of bipolar disorder as an add-on to the usual treatment but future clinical trials must still probe its efficacy.
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http://dx.doi.org/10.1016/j.jad.2016.04.042DOI Listing
August 2016

Duration of untreated psychosis and acute remission of negative symptoms in a South American first-episode psychosis cohort.

Early Interv Psychiatry 2017 02 9;11(1):77-82. Epub 2015 Aug 9.

Facultad de Medicina, Universidad Finis Terrae, Santiago, Chile.

Aim: To determine the association between duration of untreated psychosis (DUP) and symptoms remission in a hospitalized first-episode psychosis cohort.

Methods: Inpatients with a first-episode non-affective psychosis were recruited. Subjects were divided into two groups of long and short DUP using a 3-month cut-off point, and this was related to remission at 10 weeks of treatment. Multivariate analyses were performed.

Results: Fifty-five inpatients were included. There were no differences in remission rates of positive symptoms. Up to 76.5% of the patients with a short DUP (<3 months) achieved remission of negative symptoms versus 31.6% in the DUP ≥ 3 months group (P = 0.003). After controlling for relevant factors, patients with a shorter DUP were still three times more likely to achieve negative symptoms remission (HR: 3.04, 95% CI 1.2-7.5).

Conclusions: DUP is a prognostic factor that should be considered at an early stage to identify a 'high risk' subgroup of persistent negative symptoms.
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http://dx.doi.org/10.1111/eip.12266DOI Listing
February 2017

Predictors of functional outcome after a manic episode.

J Affect Disord 2015 Aug 2;182:121-5. Epub 2015 May 2.

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

Background: The identification of functional outcome predictors after acute episodes of bipolar disorders (BD) may allow designing appropriate treatment aiming at restoring psychosocial functioning. Our objective was to identify the best functional outcome predictors at a 6-month follow-up after an index manic episode.

Methods: We conducted a naturalistic trial (MANACOR) focusing on the global burden of BD, with special emphasis on manic episode-associated costs. We observed patients with BD seen in services of four hospitals in Catalonia (Spain).The total sample included 169 patients with chronic DSM-IV-TR BD I suffering from an acute manic episode who were followed-up for 6 months. In this subanalysis we report the results of a stepwise multiple regression conducted by entering in the model those clinical and sociodemographic variables that were identified through preliminary bivariate Pearson correlations and using total scores on the Functioning Assessment Short Test (FAST) at the 6-month follow-up as the dependent variable.

Results: Number of previous depressive episodes (Beta=3.25; t=3.23; p=0.002), presence of psychotic symptoms during the manic index episode (Beta=7.007; t=2.2; p=0.031) and the Body Mass Index (BMI) at baseline (Beta=0.62; t=2.09; p=0.041) were best predictors of functional outcome after a manic episode.

Limitations: The main limitations of this study include the retrospective assessment of the episodes, which can be a source of bias, and the 6-month follow-up might have been too short for assessing the course of a chronic illness.

Conclusions: Psychotic symptoms at index episode, number of past depressive episodes, and BMI predict worse outcome after 6 months follow-up after a manic episode, and may constitute the target of specific treatment strategies.
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http://dx.doi.org/10.1016/j.jad.2015.04.043DOI Listing
August 2015

Making sense of DSM-5 mania with depressive features.

Aust N Z J Psychiatry 2015 Jun 5;49(6):540-9. Epub 2015 May 5.

Bipolar Disorders Program, Institute of Neuroscience, Hospital Clínic de Barcelona, IDIBAPS, CIBERSAM, University of Barcelona, Barcelona, Spain

Objective: The assessment of the depressive component during mania has become critical for the accurate diagnosis of mixed states, which were defined very narrowly in the past classification systems before Diagnostic and Statistical Manual of Mental Disorders (5th ed.). The aim of this study was to compare socio-demographic, clinical and therapeutic characteristics, as well as clinical and functional outcomes, between manic patients with and without mixed features to validate the relevance of the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) mixed specifier.

Methods: This is a subanalysis of a multicentre naturalistic study MANía Aguda y COnsumo de Recursos (acute mania and health resource consumption [MANACOR]) on the burden of mania in bipolar patients from four hospitals in Catalonia (Spain). The sample consisted of 169 adult patients presenting a manic episode and systematically assessed during a 6-month period.

Results: A total of 27% (n = 46/169) of manic patients showed mixed features. Total number of episodes (p = 0.027), particularly depressive and mixed, was greater in manic patients with mixed features, as well as depressive onset (p = 0.018), suicide ideation (p = 0.036), rapid cycling (p = 0.035) and personality disorders (p = 0.071). In contrast, a higher percentage of pure manic subjects were inpatients (p = 0.035), started the illness with mania (p = 0.018) and showed family history of bipolar disorder (p = 0.037), congruent psychotic symptoms (p = 0.001) and cannabis use (p = 0.006). At baseline, pure manic patients received more risperidone (p = 0.028), while mixed patients received more valproate (p = 0.049) and antidepressants (p = 0.005). No differences were found in syndromic recovery at the end of the study. However, depressive change was higher in the mixed group (p = 0.010), while manic change was higher in the pure manic group (p = 0.029). At the end of follow-up, the group with mixed features showed a significant trend towards higher psychosocial dysfunction.

Conclusion: A total of 27% of manic patients showed mixed features. Groups differed regarding clinical characteristics, course of illness, psychosocial functioning, prescribed treatment and symptom progress. Depressive symptoms in mania should be routinely assessed and considered to guide treatment.
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http://dx.doi.org/10.1177/0004867415585583DOI Listing
June 2015

Implementing psychosocial evidence-based practices in mental health: are we moving in the right direction?

Front Psychiatry 2015 14;6:51. Epub 2015 Apr 14.

Early Intervention in Psychosis Program, Instituto Psiquiátrico "Dr. José Horwitz Barak" , Santiago , Chile.

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http://dx.doi.org/10.3389/fpsyt.2015.00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396081PMC
April 2015

Self-monitoring and psychoeducation in bipolar patients with a smart-phone application (SIMPLe) project: design, development and studies protocols.

BMC Psychiatry 2015 Mar 20;15:52. Epub 2015 Mar 20.

Bipolar Disorders Unit, Neurosciences Institute, Hospital Clínic de Barcelona, IDIBAPS, CIBERSAM, Universitat de Barcelona, Villarroel 170, 08036, Barcelona, Catalonia, Spain.

Background: New technologies have recently been used for monitoring signs and symptoms of mental health illnesses and particularly have been tested to improve the outcomes in bipolar disorders. Web-based psychoeducational programs for bipolar disorders have also been implemented, yet to our knowledge, none of them have integrated both approaches in one single intervention. The aim of this project is to develop and validate a smartphone application to monitor symptoms and signs and empower the self-management of bipolar disorder, offering customized embedded psychoeducation contents, in order to identify early symptoms and prevent relapses and hospitalizations.

Methods/design: The project will be carried out in three complementary phases, which will include a feasibility study (first phase), a qualitative study (second phase) and a randomized controlled trial (third phase) comparing the smartphone application (SIMPLe) on top of treatment as usual with treatment as usual alone. During the first phase, feasibility and satisfaction will be assessed with the application usage log data and with an electronic survey. Focus groups will be conducted and technical improvements will be incorporated at the second phase. Finally, at the third phase, survival analysis with multivariate data analysis will be performed and relationships between socio-demographic, clinical variables and assessments scores with relapses in each group will be explored.

Discussion: This project could result in a highly available, user-friendly and not costly monitoring and psychoeducational intervention that could improve the outcome of people suffering from bipolar disorders in a practical and secure way.

Trial Registration: Clinical Trials.gov: NCT02258711 (October 2014).
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http://dx.doi.org/10.1186/s12888-015-0437-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379950PMC
March 2015

The real world cost and health resource utilization associated to manic episodes: The MANACOR study.

Rev Psiquiatr Salud Ment 2015 Apr-Jun;8(2):55-64. Epub 2015 Mar 6.

Programa de Trastornos Bipolares, Instituto de Neurociencias, Hospital Clínic de Barcelona, IDIBAPS, CIBERSAM, Universidad de Barcelona, Barcelona, Cataluña, España. Electronic address:

Introduction: Bipolar disorder is a relapsing-remitting condition affecting approximately 1-2% of the population. Even when the treatments available are effective, relapses are still very frequent. Therefore, the burden and cost associated to every new episode of the disorder have relevant implications in public health. The main objective of this study was to estimate the associated health resource consumption and direct costs of manic episodes in a real world clinical setting, taking into consideration clinical variables.

Methods: Bipolar I disorder patients who recently presented an acute manic episode based on DSM-IV criteria were consecutively included. Sociodemographic variables were retrospectively collected and during the 6 following months clinical variables were prospectively assessed (YMRS,HDRS-17,FAST and CGI-BP-M). The health resource consumption and associate cost were estimated based on hospitalization days, pharmacological treatment, emergency department and outpatient consultations.

Results: One hundred sixty-nine patients patients from 4 different university hospitals in Catalonia (Spain) were included. The mean direct cost of the manic episodes was €4,771. The 77% (€3,651) was attributable to hospitalization costs while 14% (€684) was related to pharmacological treatment, 8% (€386) to outpatient visits and only 1% (€50) to emergency room visits. The hospitalization days were the main cost driver. An initial FAST score>41 significantly predicted a higher direct cost.

Conclusions: Our results show the high cost and burden associated with BD and the need to design more cost-efficient strategies in the prevention and management of manic relapses in order to avoid hospital admissions. Poor baseline functioning predicted high costs, indicating the importance of functional assessment in bipolar disorder.
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http://dx.doi.org/10.1016/j.rpsm.2015.01.003DOI Listing
December 2016

Risk factors for rapid cycling in bipolar disorder.

Bipolar Disord 2015 Aug 12;17(5):549-59. Epub 2015 Feb 12.

Bipolar Disorders Program, Clinical Institute of Neurosciences, Hospital Clínic Barcelona, IDIBAPS, CIBERSAM, University of Barcelona, Barcelona, Catalonia, Spain.

Objectives: The aim of this study was to investigate the clinical factors associated with the development of rapid cycling, as well as to elucidate the role of antidepressants.

Methods: The present study (NCT01503489) is a prospective, naturalistic cohort study conducted in a sample of 289 patients diagnosed with bipolar disorder followed and treated for up to 14 years. The patients were divided into two groups on the basis of the development of a rapid cycling course (n = 48) or no development of such a course (n = 241), and compared regarding sociodemographic, clinical, and outcome variables.

Results: Among the 289 patients, 48 (16.6%) developed a rapid cycling course during the follow-up. Several differences were found between the two groups, but after performing Cox regression analysis, only atypical depressive symptoms (p = 0.001), age at onset (p = 0.015), and number of suicide attempts (p = 0.030) persisted as significantly associated with the development of a rapid cycling course.

Conclusions: The development of rapid cycling during the course of bipolar disorder is associated with a tendency to chronicity, with a poorer outcome, and with atypical depressive symptomatology. Our study also suggests that the development of rapid cycling is associated with a higher use of antidepressants.
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http://dx.doi.org/10.1111/bdi.12288DOI Listing
August 2015

e-HCL-32: a useful, valid and user friendly tool in the screening of bipolar II disorder.

Compr Psychiatry 2015 Jan 6;56:283-8. Epub 2014 Sep 6.

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

Background And Objectives: Bipolar type II (BDII) is a frequent disorder with high morbidity and mortality, characterized by depressive and hypomanic episodes. Early diagnosis can be effective in improving long-term prognosis. However, diagnosing BDII is challenging due to the difficulty in detecting past hypomanic episodes. The HCL-32 is a widely used and reliable screening instrument for the detection of past hypomanic episodes. Making this tool available to more patients could help diagnose and treat undetected cases of BDII earlier. New technologies such as the Internet have been previously used for this purpose with favorable outcomes. Accordingly, the objective of this study is to evaluate the acceptability, validity, reliability and equivalence of an online version of this questionnaire.

Methods: From May 2012 to March 2013, 52 participants attending an outpatient mental health clinic completed a paper version of the HCL-32 (HCL-32) and its online version (e-HCL-32) within two weeks. After its completion, they were asked to answer a brief satisfaction survey.

Results: No differences were found (HCL-32 mean total score=17.73 (SD=7.37), e-HCL-32 mean total score=18.28 (SD=7.09). T=-1.720, p=0.092, 95% CI=-1.21 to 0.09) between the results of the paper and pencil HCL-32 compared to its online version (e-HCL-32). The psychometric properties of the online version of the hypomania checklist (e-HCL-32) were good and comparable to the paper and pencil version. 80% of participants found online questionnaires to be easier to answer and more user-friendly.

Conclusion: The results of this study support the use of an online screening tool for the detection of previous hypomanic episodes (necessary for BDII diagnosis) as it showed to have a similar validity and reliability to the traditional paper and pencil method.
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http://dx.doi.org/10.1016/j.comppsych.2014.09.008DOI Listing
January 2015

Declining efficacy in controlled trials of antidepressants: effects of placebo dropout.

Int J Neuropsychopharmacol 2014 Aug 13;17(8):1343-52. Epub 2014 Mar 13.

Department of Psychiatry,Harvard Medical School,Boston, MA,USA.

Drug-placebo differences (effect-sizes) in controlled trials of antidepressants for major depressive episodes have declined for several decades, in association with selectively increasing clinical improvement associated with placebo-treatment. As these trends require adequate explanation, we tested the hypothesis that decreasing trial-dropout rates may be an important contributor. We gathered reports of peer-reviewed, placebo-controlled trials of antidepressants (1980-2011) by computerized literature searching, and applied meta-analysis, meta-regression and multiple linear regression methods to evaluate associations of dropout rates and other factors of interest, to reporting year and reported efficacy [standardized mean drug-placebo difference (SMD) as Hedges' g-statistic]. In 56 trials meeting inclusion and exclusion criteria, we confirmed significant overall efficacy of antidepressants but declining drug-placebo contrasts over the past three decades. Among other changes, there was a corresponding increase in placebo-associated improvement with a decline in placebo-dropout rate, mainly for lack of efficacy. These effects were found only when last-observation-carried-forward (LOCF) analyses were used. Other trial-design and subject factors, including drug-responses and drug-dropout rates, were much less associated with efficacy. We propose that declining placebo-dropout rates ascribed to inefficacy combined with use of LOCF analyses led to increasing improvement in placebo-arms that contributed to declining antidepressant-placebo contrasts in controlled treatment trials since the 1980s.
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http://dx.doi.org/10.1017/S1461145714000224DOI Listing
August 2014

Early medication discontinuation on long-term recovery outcome in first-episode psychosis.

JAMA Psychiatry 2014 Feb;71(2):206-7

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

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http://dx.doi.org/10.1001/jamapsychiatry.2013.2993DOI Listing
February 2014

Stratified medicine for mental disorders.

Eur Neuropsychopharmacol 2014 Jan 4;24(1):5-50. Epub 2013 Oct 4.

Child and Adolescent Neuropsychiatry Unit & Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.

There is recognition that biomedical research into the causes of mental disorders and their treatment needs to adopt new approaches to research. Novel biomedical techniques have advanced our understanding of how the brain develops and is shaped by behaviour and environment. This has led to the advent of stratified medicine, which translates advances in basic research by targeting aetiological mechanisms underlying mental disorder. The resulting increase in diagnostic precision and targeted treatments may provide a window of opportunity to address the large public health burden, and individual suffering associated with mental disorders. While mental health and mental disorders have significant representation in the "health, demographic change and wellbeing" challenge identified in Horizon 2020, the framework programme for research and innovation of the European Commission (2014-2020), and in national funding agencies, clear advice on a potential strategy for mental health research investment is needed. The development of such a strategy is supported by the EC-funded "Roadmap for Mental Health Research" (ROAMER) which will provide recommendations for a European mental health research strategy integrating the areas of biomedicine, psychology, public health well being, research integration and structuring, and stakeholder participation. Leading experts on biomedical research on mental disorders have provided an assessment of the state of the art in core psychopathological domains, including arousal and stress regulation, affect, cognition social processes, comorbidity and pharmacotherapy. They have identified major advances and promising methods and pointed out gaps to be addressed in order to achieve the promise of a stratified medicine for mental disorders.
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http://dx.doi.org/10.1016/j.euroneuro.2013.09.010DOI Listing
January 2014

The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders.

Am J Psychiatry 2013 Nov;170(11):1249-62

Objective: The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.

Method: An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.

Results: There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.

Conclusions: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
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http://dx.doi.org/10.1176/appi.ajp.2013.13020185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091043PMC
November 2013