Publications by authors named "Michele Fornaro"

216 Publications

Implications of the COVID-19 pandemic for people with bipolar disorders: A scoping review.

J Affect Disord 2021 Sep 4;295:740-751. Epub 2021 Sep 4.

IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia. Electronic address:

Introduction: The COVID-19 (coronavirus disease 2019)-related pandemic represents a global source of societal and health burden. Yet, the impact of the pandemic on people with severe mental illness, including bipolar disorder (BD), remains unclear, warranting scoping review on the matter.

Methods: The MEDLINE and EMBASE databases were systematically searched from inception up to April 24, 2021, adopting broad inclusion criteria to assess a variety of clinical and public health themes related to people with a primary diagnosis of BD during the COVID-19 pandemics. The present work complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) registered in the Open Science Framework (OSF) repository (https://osf.io/7evpx/).

Results: Fourteen papers informed the present scoping review. Four major themes were identified: (i) impact of COVID-19-related stressors on BD; (ii) impact of COVID-19 on mental health service utilization among people with BD; (iii) impact of BD on the risk of acquiring SARS-CoV-2 infection; (iv) engagement in preventative behaviors among people with BD. Additional themes warranting further research were nonetheless detected.

Limitations: Further original studies are needed.

Conclusion: The present study confirmed the high-vulnerability hypothesis concerning people with BD versus the general population, reinforcing the need for further research related to the COVID-19 pandemic. Additional information is warranted to compare the impact of the pandemic period among BD people against pre-pandemic records, the general population, and other severe mental illnesses, namely people with schizophrenia or major depressive disorder, to inform the public health and the delivery of patient-tailored interventions.
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http://dx.doi.org/10.1016/j.jad.2021.08.091DOI Listing
September 2021

Implications of the COVID-19 pandemic for people with bipolar disorders: A scoping review.

J Affect Disord 2021 Sep 4;295:740-751. Epub 2021 Sep 4.

IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia. Electronic address:

Introduction: The COVID-19 (coronavirus disease 2019)-related pandemic represents a global source of societal and health burden. Yet, the impact of the pandemic on people with severe mental illness, including bipolar disorder (BD), remains unclear, warranting scoping review on the matter.

Methods: The MEDLINE and EMBASE databases were systematically searched from inception up to April 24, 2021, adopting broad inclusion criteria to assess a variety of clinical and public health themes related to people with a primary diagnosis of BD during the COVID-19 pandemics. The present work complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) registered in the Open Science Framework (OSF) repository (https://osf.io/7evpx/).

Results: Fourteen papers informed the present scoping review. Four major themes were identified: (i) impact of COVID-19-related stressors on BD; (ii) impact of COVID-19 on mental health service utilization among people with BD; (iii) impact of BD on the risk of acquiring SARS-CoV-2 infection; (iv) engagement in preventative behaviors among people with BD. Additional themes warranting further research were nonetheless detected.

Limitations: Further original studies are needed.

Conclusion: The present study confirmed the high-vulnerability hypothesis concerning people with BD versus the general population, reinforcing the need for further research related to the COVID-19 pandemic. Additional information is warranted to compare the impact of the pandemic period among BD people against pre-pandemic records, the general population, and other severe mental illnesses, namely people with schizophrenia or major depressive disorder, to inform the public health and the delivery of patient-tailored interventions.
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http://dx.doi.org/10.1016/j.jad.2021.08.091DOI Listing
September 2021

Peripheral levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: A meta-analysis of mean differences and variability.

Brain Behav Immun 2021 Jul 28. Epub 2021 Jul 28.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, 75 Pigdon's Road, Waurn Ponds, Geelong, VIC 3216, Australia. Electronic address:

Importance: It is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls.

Objective: To run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity.

Data Sources: Systematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020.

Study Selection: Case-control studies reporting inflammatory mediators' levels in BD and controls.

Data Extraction And Synthesis: Summary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge's g).

Main Outcomes And Measures: Co-primary outcomes were inflammatory mediators' levels (Hedge's g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls.

Results: Out of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g = 0.70, 95% CI 0.31-1.09, k = 37, BD = 2,215 vs HC = 3,750), IL-6 (g = 0.81, 95% CI 0.46-1.16, k = 45, BD = 1,956 vs HC = 4,106), TNF-α (g = 0.49, 95% CI 0.19-0.78, k = 49, BD = 2,231 vs HC = 3,017) were elevated in subjects with BD vs HC, but not IL-1β (g = -0.28, 95% CI -0.68-0.12, k = 4, BD = 87 vs HC = 66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels.

Conclusions And Relevance: Peripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.
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http://dx.doi.org/10.1016/j.bbi.2021.07.014DOI Listing
July 2021

In Memory of Hagop Akiskal.

Clin Pract Epidemiol Ment Health 2021 31;17:48-51. Epub 2021 May 31.

Department of Psychiatry and Clinical Psychology, Faculty of Medicine, Balamand University, Beirut, Lebanon.

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http://dx.doi.org/10.2174/1745017902117010048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227446PMC
May 2021

New Pharmacological Targets for the Treatment of Schizophrenia: A Literature Review.

Curr Top Med Chem 2021 Jun 30. Epub 2021 Jun 30.

Department of Mental Health, ASL Teramo, Teramo, Italy.

Background: The pharmacological treatment of schizophrenia is currently based on the employment of anti-psychotic medications showing an antagonism of dopaminergic and serotoninergic. 20-40% of patients are drug-resistant or residually symptomatic in the long-term anti-psychotic treatment, and new strategies are needed for improving their functional and cognitive impairment.

Methods: This systematic review summarized the evidence from the literature regarding the newer pharmacological targets proposed for the treatment of psychosis. We included 128 peer-reviewed articles and 5 other relevant sources published from 2002 to 2020 on PubMed EMBASE, The Cochrane Library, Google Scholar.

Results: It has extensively described the possible role of glutamate and its receptors as targets of the anti-psychotic mechanism of action. Glutamatergic neurotransmission and NMDA receptors hypofunction are involved in the neurobiological explanatory model of psychosis and possibly targeted for the successful treatment of cognitive and residual symptoms. The results show efficacy of D-cycloserine (antagonist at the Glycine site of the NMDA-R) in the treatment of negative symptoms of schizophrenia as well as Memantine (NMDA: Receptor antagonist) on cognition and psychopathology. The putative anti-psychotic effect of cannabidiol on positive symptoms and cognition will also be discussed, even if more evidence is required. The action on serotoninergic and GABAergic receptors will be considered a new pharmacological target, with a possible efficacy of Vabicaserin on symptoms of psychosis. Mynocicline has shown improvements in cognitive symptoms in schizophrenia as well as Erythropoietin. Oxytocin reported an antipsychotic-like effect and COX-2 inhibitors reported a reduction of positive symptoms of psychosis in the first episode of illness.

Conclusion: This narrative report suggests a promising role of new agents in the treatment of Schizophrenia, even if more research is needed to approve their clinical employment.
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http://dx.doi.org/10.2174/1568026621666210701103147DOI Listing
June 2021

New Pharmacological Targets for the Treatment of Schizophrenia: A Literature Review.

Curr Top Med Chem 2021 Jun 30. Epub 2021 Jun 30.

Department of Mental Health, ASL Teramo, Teramo, Italy.

Background: The pharmacological treatment of schizophrenia is currently based on the employment of anti-psychotic medications showing an antagonism of dopaminergic and serotoninergic. 20-40% of patients are drug-resistant or residually symptomatic in the long-term anti-psychotic treatment, and new strategies are needed for improving their functional and cognitive impairment.

Methods: This systematic review summarized the evidence from the literature regarding the newer pharmacological targets proposed for the treatment of psychosis. We included 128 peer-reviewed articles and 5 other relevant sources published from 2002 to 2020 on PubMed EMBASE, The Cochrane Library, Google Scholar.

Results: It has extensively described the possible role of glutamate and its receptors as targets of the anti-psychotic mechanism of action. Glutamatergic neurotransmission and NMDA receptors hypofunction are involved in the neurobiological explanatory model of psychosis and possibly targeted for the successful treatment of cognitive and residual symptoms. The results show efficacy of D-cycloserine (antagonist at the Glycine site of the NMDA-R) in the treatment of negative symptoms of schizophrenia as well as Memantine (NMDA: Receptor antagonist) on cognition and psychopathology. The putative anti-psychotic effect of cannabidiol on positive symptoms and cognition will also be discussed, even if more evidence is required. The action on serotoninergic and GABAergic receptors will be considered a new pharmacological target, with a possible efficacy of Vabicaserin on symptoms of psychosis. Mynocicline has shown improvements in cognitive symptoms in schizophrenia as well as Erythropoietin. Oxytocin reported an antipsychotic-like effect and COX-2 inhibitors reported a reduction of positive symptoms of psychosis in the first episode of illness.

Conclusion: This narrative report suggests a promising role of new agents in the treatment of Schizophrenia, even if more research is needed to approve their clinical employment.
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http://dx.doi.org/10.2174/1568026621666210701103147DOI Listing
June 2021

New Pharmacological Targets for the Treatment of Schizophrenia: A Literature Review.

Curr Top Med Chem 2021 Jun 30. Epub 2021 Jun 30.

Department of Mental Health, ASL Teramo, Teramo, Italy.

Background: The pharmacological treatment of schizophrenia is currently based on the employment of anti-psychotic medications showing an antagonism of dopaminergic and serotoninergic. 20-40% of patients are drug-resistant or residually symptomatic in the long-term anti-psychotic treatment, and new strategies are needed for improving their functional and cognitive impairment.

Methods: This systematic review summarized the evidence from the literature regarding the newer pharmacological targets proposed for the treatment of psychosis. We included 128 peer-reviewed articles and 5 other relevant sources published from 2002 to 2020 on PubMed EMBASE, The Cochrane Library, Google Scholar.

Results: It has extensively described the possible role of glutamate and its receptors as targets of the anti-psychotic mechanism of action. Glutamatergic neurotransmission and NMDA receptors hypofunction are involved in the neurobiological explanatory model of psychosis and possibly targeted for the successful treatment of cognitive and residual symptoms. The results show efficacy of D-cycloserine (antagonist at the Glycine site of the NMDA-R) in the treatment of negative symptoms of schizophrenia as well as Memantine (NMDA: Receptor antagonist) on cognition and psychopathology. The putative anti-psychotic effect of cannabidiol on positive symptoms and cognition will also be discussed, even if more evidence is required. The action on serotoninergic and GABAergic receptors will be considered a new pharmacological target, with a possible efficacy of Vabicaserin on symptoms of psychosis. Mynocicline has shown improvements in cognitive symptoms in schizophrenia as well as Erythropoietin. Oxytocin reported an antipsychotic-like effect and COX-2 inhibitors reported a reduction of positive symptoms of psychosis in the first episode of illness.

Conclusion: This narrative report suggests a promising role of new agents in the treatment of Schizophrenia, even if more research is needed to approve their clinical employment.
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http://dx.doi.org/10.2174/1568026621666210701103147DOI Listing
June 2021

Erratum: Mediterranean Diet and its Benefits on Health and Mental Health: A Literature Review.

Clin Pract Epidemiol Ment Health 2021 26;17. Epub 2021 Mar 26.

Institute of Psychiatry, King's College, London, UK.

[This corrects the article on p. 156 in vol. 16, PMID: 7536728.].
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http://dx.doi.org/10.2174/1745017902117010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097401PMC
March 2021

Efficacy and acceptability of pharmacological, psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review.

World Psychiatry 2021 Jun;20(2):244-275

Neurosciences Department, University of Padua, Padua, Italy.

Top-tier evidence on the safety/tolerability of 80 medications in children/adolescents with mental disorders has recently been reviewed in this jour-nal. To guide clinical practice, such data must be combined with evidence on efficacy and acceptability. Besides medications, psychosocial inter-ventions and brain stimulation techniques are treatment options for children/adolescents with mental disorders. For this umbrella review, we systematically searched network meta-analyses (NMAs) and meta-analyses (MAs) of randomized controlled trials (RCTs) evaluating 48 medications, 20 psychosocial interventions, and four brain stimulation techniques in children/adolescents with 52 different mental disorders or groups of mental disorders, reporting on 20 different efficacy/acceptability outcomes. Co-primary outcomes were disease-specific symptom reduction and all-cause discontinuation ("acceptability"). We included 14 NMAs and 90 MAs, reporting on 15 mental disorders or groups of mental disorders. Overall, 21 medications outperformed placebo regarding the co-primary outcomes, and three psychosocial interventions did so (while seven outperformed waiting list/no treatment). Based on the meta-analytic evidence, the most convincing efficacy profile emerged for amphetamines, methylphenidate and, to a smaller extent, behavioral therapy in attention-deficit/hyperactivity disorder; aripiprazole, risperidone and several psychosocial interventions in autism; risperidone and behavioral interventions in disruptive behavior disorders; several antipsychotics in schizophrenia spectrum disorders; fluoxetine, the combination of fluoxetine and cognitive behavioral therapy (CBT), and interpersonal therapy in depression; aripiprazole in mania; fluoxetine and group CBT in anxiety disorders; fluoxetine/selective serotonin reuptake inhibitors, CBT, and behavioral therapy with exposure and response prevention in obsessive-compulsive disorder; CBT in post-traumatic stress disorder; imipramine and alarm behavioral intervention in enuresis; behavioral therapy in encopresis; and family therapy in anorexia nervosa. Results from this umbrella review of interventions for mental disorders in children/adolescents provide evidence-based information for clinical decision making.
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http://dx.doi.org/10.1002/wps.20881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129843PMC
June 2021

Relationships between early age at onset of psychotic symptoms and treatment resistant schizophrenia.

Early Interv Psychiatry 2021 May 16. Epub 2021 May 16.

Section of Psychiatry - Unit on Treatment Resistant Psychosis, and Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine Federico II, Naples, Italy.

Aim: Early age at schizophrenia onset (EOS) has been associated with a worse clinical course, although previous studies reported substantial heterogeneity. Despite the relevance of the subject, the relationship between the age of onset and treatment resistant schizophrenia (TRS) is less clear.

Methods: We screened 197 non-affective psychotic patients. Of these, 99 suffered from schizophrenia and were putative TRS and were included in a prospective 4-to-8-week trial to assess their response to antipsychotics. According to status (TRS/nonTRS) and age-at-onset (early: ≤18 years, EOS; adult: >18 years, adult onset schizophrenia [AOS]) patients were subdivided in EOS-TRS, EOS-nonTRS, AOS-TRS, AOS-nonTRS. Multiple clinical variables were measured and compared by analysis of covariance (ANCOVA), using age as a covariate. Two-way analysis of variance (ANOVA) was used to assess whether significant differences were attributable to TRS status or age-at-onset.

Results: The rate of TRS patients was significantly higher in EOS compared to AOS. At the ANCOVA, EOS-TRS had significantly worse clinical, cognitive, and psychosocial outcomes compared to the other groups. Overall, EOS-TRS were more impaired than EOS-nonTRS, while significant differences with AOS-TRS were less consistent, albeit appreciable. Two-way ANOVA demonstrated that, in the majority of the investigated variables, the significant differences among groups were attributable to the TRS status effect rather than to age-at-onset or combined effects.

Conclusions: These results suggest that refractoriness to antipsychotics may be strongly linked to the early onset of psychotic symptoms, possibly as a result of common neurobiology.
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http://dx.doi.org/10.1111/eip.13174DOI Listing
May 2021

Relationships between early age at onset of psychotic symptoms and treatment resistant schizophrenia.

Early Interv Psychiatry 2021 May 16. Epub 2021 May 16.

Section of Psychiatry - Unit on Treatment Resistant Psychosis, and Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine Federico II, Naples, Italy.

Aim: Early age at schizophrenia onset (EOS) has been associated with a worse clinical course, although previous studies reported substantial heterogeneity. Despite the relevance of the subject, the relationship between the age of onset and treatment resistant schizophrenia (TRS) is less clear.

Methods: We screened 197 non-affective psychotic patients. Of these, 99 suffered from schizophrenia and were putative TRS and were included in a prospective 4-to-8-week trial to assess their response to antipsychotics. According to status (TRS/nonTRS) and age-at-onset (early: ≤18 years, EOS; adult: >18 years, adult onset schizophrenia [AOS]) patients were subdivided in EOS-TRS, EOS-nonTRS, AOS-TRS, AOS-nonTRS. Multiple clinical variables were measured and compared by analysis of covariance (ANCOVA), using age as a covariate. Two-way analysis of variance (ANOVA) was used to assess whether significant differences were attributable to TRS status or age-at-onset.

Results: The rate of TRS patients was significantly higher in EOS compared to AOS. At the ANCOVA, EOS-TRS had significantly worse clinical, cognitive, and psychosocial outcomes compared to the other groups. Overall, EOS-TRS were more impaired than EOS-nonTRS, while significant differences with AOS-TRS were less consistent, albeit appreciable. Two-way ANOVA demonstrated that, in the majority of the investigated variables, the significant differences among groups were attributable to the TRS status effect rather than to age-at-onset or combined effects.

Conclusions: These results suggest that refractoriness to antipsychotics may be strongly linked to the early onset of psychotic symptoms, possibly as a result of common neurobiology.
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http://dx.doi.org/10.1111/eip.13174DOI Listing
May 2021

Gut Microbiota and Bipolar Disorder: An Overview on a Novel Biomarker for Diagnosis and Treatment.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

NHS, Department of Mental Health, Psychiatric Service for Diagnosis and Treatment, Hospital "G. Mazzini", ASL 4, 64100 Teramo, Italy.

The gut microbiota is the set of microorganisms that colonize the gastrointestinal tract of living creatures, establishing a bidirectional symbiotic relationship that is essential for maintaining homeostasis, for their growth and digestive processes. Growing evidence supports its involvement in the intercommunication system between the gut and the brain, so that it is called the gut-brain-microbiota axis. It is involved in the regulation of the functions of the Central Nervous System (CNS), behavior, mood and anxiety and, therefore, its implication in the pathogenesis of neuropsychiatric disorders. In this paper, we focused on the possible correlations between the gut microbiota and Bipolar Disorder (BD), in order to determine its role in the pathogenesis and in the clinical management of BD. Current literature supports a possible relationship between the compositional alterations of the intestinal microbiota and BD. Moreover, due to its impact on psychopharmacological treatment absorption, by acting on the composition of the microbiota beneficial effects can be obtained on BD symptoms. Finally, we discussed the potential of correcting gut microbiota alteration as a novel augmentation strategy in BD. Future studies are necessary to better clarify the relevance of gut microbiota alterations as state and disease biomarkers of BD.
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http://dx.doi.org/10.3390/ijms22073723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038247PMC
April 2021

Gut Microbiota and Bipolar Disorder: An Overview on a Novel Biomarker for Diagnosis and Treatment.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

NHS, Department of Mental Health, Psychiatric Service for Diagnosis and Treatment, Hospital "G. Mazzini", ASL 4, 64100 Teramo, Italy.

The gut microbiota is the set of microorganisms that colonize the gastrointestinal tract of living creatures, establishing a bidirectional symbiotic relationship that is essential for maintaining homeostasis, for their growth and digestive processes. Growing evidence supports its involvement in the intercommunication system between the gut and the brain, so that it is called the gut-brain-microbiota axis. It is involved in the regulation of the functions of the Central Nervous System (CNS), behavior, mood and anxiety and, therefore, its implication in the pathogenesis of neuropsychiatric disorders. In this paper, we focused on the possible correlations between the gut microbiota and Bipolar Disorder (BD), in order to determine its role in the pathogenesis and in the clinical management of BD. Current literature supports a possible relationship between the compositional alterations of the intestinal microbiota and BD. Moreover, due to its impact on psychopharmacological treatment absorption, by acting on the composition of the microbiota beneficial effects can be obtained on BD symptoms. Finally, we discussed the potential of correcting gut microbiota alteration as a novel augmentation strategy in BD. Future studies are necessary to better clarify the relevance of gut microbiota alterations as state and disease biomarkers of BD.
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http://dx.doi.org/10.3390/ijms22073723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038247PMC
April 2021

Dynamic Environmental Physical Cues Activate Mechanosensitive Responses in the Repair Schwann Cell Phenotype.

Cells 2021 02 17;10(2). Epub 2021 Feb 17.

Department of Anatomy, College of Graduate Studies (CGS), Midwestern University, Downers Grove, IL 60515, USA.

Schwann cells plastically change in response to nerve injury to become a newly reconfigured repair phenotype. This cell is equipped to sense and interact with the evolving and unusual physical conditions characterizing the injured nerve environment and activate intracellular adaptive reprogramming as a consequence of external stimuli. Summarizing the literature contributions on this matter, this review is aimed at highlighting the importance of the environmental cues of the regenerating nerve as key factors to induce morphological and functional changes in the Schwann cell population. We identified four different microenvironments characterized by physical cues the Schwann cells sense via interposition of the extracellular matrix. We discussed how the physical cues of the microenvironment initiate changes in Schwann cell behavior, from wrapping the axon to becoming a multifunctional denervated repair cell and back to reestablishing contact with regenerated axons.
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http://dx.doi.org/10.3390/cells10020425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922665PMC
February 2021

Cariprazine Add-on in Inadequate Clozapine Response: A Report on Two Cases.

Clin Psychopharmacol Neurosci 2021 Feb;19(1):174-178

Department of Neurosciences and Imaging, Chair of Psychiatry, University "G. d'Annunzio," Chieti, Italy.

Cariprazine is a novel antipsychotic drug that exerts partial agonism of dopamine D/D receptors with preferential binding to the D receptor, antagonism of 5HT receptors, and partial agonism of 5HT. Currently, cariprazine has shown clinical efficacy in patients with schizophrenia and with bipolar disorder, as well as adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD. In the present case series, we report on two patients with treatment-resistant schizophrenia and partial response to clozapine who benefit from combination with cariprazine. The effects of cariprazine combination were remarkable also concerning the adverse metabolic effects of clozapine.
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http://dx.doi.org/10.9758/cpn.2021.19.1.174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851462PMC
February 2021

There are no "side" effects, just "core" effects of antipsychotic pharmacotherapy.

Authors:
Michele Fornaro

Acta Psychiatr Scand 2021 02;143(2):99-100

Section of Psychiatry - Department of Neuroscience, Reproductive Sciences, and Dentistry, University School of Medicine Federico II, Naples, Italy.

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http://dx.doi.org/10.1111/acps.13271DOI Listing
February 2021

Case of aripiprazole long-acting-related akathisia successfully managed with carvedilol: A case report.

Psychiatry Clin Neurosci 2021 Mar 14;75(3):114-115. Epub 2021 Jan 14.

Department of Neurosciences and Imaging, University "G. D'Annunzio" Chieti, Chieti, Italy.

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http://dx.doi.org/10.1111/pcn.13189DOI Listing
March 2021

The shocking attitude toward electroconvulsive therapy in Italy.

CNS Spectr 2020 Dec 4:1-3. Epub 2020 Dec 4.

Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy.

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http://dx.doi.org/10.1017/S1092852920002059DOI Listing
December 2020

The shocking attitude toward electroconvulsive therapy in Italy.

CNS Spectr 2020 Dec 4:1-3. Epub 2020 Dec 4.

Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy.

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http://dx.doi.org/10.1017/S1092852920002059DOI Listing
December 2020

Overcoming the Use of Mechanical Restraints in Psychiatry: A New Challenge in the Everyday Clinical Practice at the Time of COVID-19.

J Clin Med 2020 Nov 23;9(11). Epub 2020 Nov 23.

Department of Neurosciences and Imaging, University "G. D'Annunzio", 66100 Chieti, Italy.

Restraining interventions, which comprise physical (PR) and mechanical restraint (MR), have a long history in mental health services [...].
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http://dx.doi.org/10.3390/jcm9113774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700144PMC
November 2020

The prevalence, odds and predictors of lifespan comorbid eating disorder among people with a primary diagnosis of bipolar disorders, and vice-versa: Systematic review and meta-analysis.

J Affect Disord 2021 02 13;280(Pt A):409-431. Epub 2020 Nov 13.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada.

Background: There are scarce and discrepant data about the prevalence and correlates of co-occurring eating disorders (EDs) among people with a primary diagnosis of bipolar disorder (BD), and vice-versa, compelling a systematic review and meta-analysis on the matter.

Methods: MEDLINE/PsycINFO databases were systematically searched for original studies documenting BD⇌ED comorbidity across the lifespan, from inception up until April 20, 2020. Random-effects meta-analysis and meta-regression analyses were conducted, accounting for multiple moderators.

Results: Thirty-six studies involved 15,084 primary BD patients. Eleven studies encompassed 15,146 people with primary EDs. Binge eating disorder (BED) occurred in 12.5% (95%C.I.=9.4-16.6%, I=93.48%) of BDs, while 9.1% (95%C.I.=3.3-22.6%) of BEDs endorsed BD. Bulimia Nervosa (BN) occurred in 7.4% (95%C.I.=6-10%) of people with BD, whereas 6.7% (95%C.I.=12-29.2%) of subjects with BN had a diagnosis of BD. Anorexia Nervosa (AN) occurred in 3.8% (95%C.I.=2-6%) of people with BDs; 2% (95%C.I.=1-2%) of BD patients had a diagnosis of AN. Overall, BD patients with EDs had higher odds of being female vs. non-ED controls. Several moderators yielded statistically significant differences both within- and between different types of BDs and EDs.

Limitations: Scant longitudinal studies, especially across different EDs and pediatric samples. High heterogeneity despite subgroup comparisons. Limited discrimination of the quality of the evidence.

Conclusions: The rates of BD⇌ED comorbidity vary across different diagnostic groups, more than they do according to the "direction" of BD⇌ED. Further primary studies should focus on the risks, chronology, clinical impact, and management of the onset of intertwined BD⇌ED across different ages, promoting a continuum approach.
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http://dx.doi.org/10.1016/j.jad.2020.11.015DOI Listing
February 2021

Environmental risk factors, protective factors, and peripheral biomarkers for ADHD: an umbrella review.

Lancet Psychiatry 2020 11;7(11):955-970

Early Psychosis: Interventions and Clinical-Detection Lab, Department of Psychosis Studies, King's College London, London, UK; Outreach and Support in South London (OASIS) Service, South London and Maudsley NHS Foundation Trust, London, UK; National Institute of Health Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

Background: Many potential environmental risk factors, environmental protective factors, and peripheral biomarkers for ADHD have been investigated, but the consistency and magnitude of their effects are unclear. We aimed to systematically appraise the published evidence of association between potential risk factors, protective factors, or peripheral biomarkers, and ADHD.

Methods: In this umbrella review of meta-analyses, we searched PubMed including MEDLINE, Embase, and the Cochrane Database of Systematic Reviews, from database inception to Oct 31, 2019, and screened the references of relevant articles. We included systematic reviews that provided meta-analyses of observational studies that examined associations of potential environmental risk factors, environmental protective factors, or peripheral biomarkers with diagnosis of ADHD. We included meta-analyses that used categorical ADHD diagnosis criteria according to DSM, hyperkinetic disorder according to ICD, or criteria that were less rigorous than DSM or ICD, such as self-report. We excluded articles that did not examine environmental risk factors, environmental protective factors, or peripheral biomarkers of ADHD; articles that did not include a meta-analysis; and articles that did not present enough data for re-analysis. We excluded non-human studies, primary studies, genetic studies, and conference abstracts. We calculated summary effect estimates (odds ratio [OR], relative risk [RR], weighted mean difference [WMD], Cohen's d, and Hedges' g), 95% CI, heterogeneity I statistic, 95% prediction interval, small study effects, and excess significance biases. We did analyses under credibility ceilings, and assessed the quality of the meta-analyses with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). This study is registered with PROSPERO, number CRD42019145032.

Findings: We identified 1839 articles, of which 35 were eligible for inclusion. These 35 articles yielded 63 meta-analyses encompassing 40 environmental risk factors and environmental protective factors (median cases 16 850, median population 91 954) and 23 peripheral biomarkers (median cases 175, median controls 187). Evidence of association was convincing (class I) for maternal pre-pregnancy obesity (OR 1·63, 95% CI 1·49 to 1·77), childhood eczema (1·31, 1·20 to 1·44), hypertensive disorders during pregnancy (1·29, 1·22 to 1·36), pre-eclampsia (1·28, 1·21 to 1·35), and maternal acetaminophen exposure during pregnancy (RR 1·25, 95% CI 1·17 to 1·34). Evidence of association was highly suggestive (class II) for maternal smoking during pregnancy (OR 1·6, 95% CI 1·45 to 1·76), childhood asthma (1·51, 1·4 to 1·63), maternal pre-pregnancy overweight (1·28, 1·21 to 1·35), and serum vitamin D (WMD -6·93, 95% CI -9·34 to -4·51).

Interpretation: Maternal pre-pregnancy obesity and overweight; pre-eclampsia, hypertension, acetaminophen exposure, and smoking during pregnancy; and childhood atopic diseases were strongly associated with ADHD. Previous familial studies suggest that maternal pre-pregnancy obesity, overweight, and smoking during pregnancy are confounded by familial or genetic factors, and further high-quality studies are therefore required to establish causality.

Funding: None.
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http://dx.doi.org/10.1016/S2215-0366(20)30312-6DOI Listing
November 2020

Editorial: "No Words for Feelings, Yet!" Exploring Alexithymia, Disorder of Affect Regulation, and the "Mind-Body" Connection.

Front Psychiatry 2020 18;11:593462. Epub 2020 Sep 18.

Section of Psychiatry, Department of Clinical Neurosciences/DIMSC, Polytechnic University of Ancona, Ancona, Italy.

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http://dx.doi.org/10.3389/fpsyt.2020.593462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530238PMC
September 2020

Mediterranean Diet and its Benefits on Health and Mental Health: A Literature Review.

Clin Pract Epidemiol Ment Health 2020 30;16(Suppl-1):156-164. Epub 2020 Jul 30.

Institute of Psychiatry, King's College, London, UK.

Mediterranean Diet (MD) is currently considered one of the most healthy dietary models worldwide. It is generally based on the daily intake of fruit and vegetables, whole grains, legumes, nuts, fish, white meats, and olive oil. It may also include moderate consumption of fermented dairy products, a low intake of red meat, and red/white wine during the main course. Even if the effect of MD on cancer prevention as well as on human metabolic and cardiovascular balance has been discussed, including the quality of life of the exposed population, the putative effects on mental health are still not properly investigated. This narrative review reports on some emerging pieces of evidence on the possible impact of MD on general health and the outcome of psychiatric disorders (., major depression, anxiety) and encourages further studies to test the benefits of healthy food selection on the health of the general population.
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http://dx.doi.org/10.2174/1745017902016010156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536728PMC
July 2020

Longitudinal Course of Depressive, Anxiety, and Posttraumatic Stress Disorder Symptoms After Heart Surgery: A Meta-Analysis of 94 Studies.

Psychosom Med 2021 01;83(1):85-93

From the Neurosciences Department (Rosson, Miola, Gentile, Favaro, Solmi), University of Padua, Padua; Department of Mental Health (Monaco), Residential Eating Disorder Unit "Mariconda," ASL Salerno; Department of Medicine (Cascino, Marciello), Surgery and Dentistry "Scuola Medica Salernitana," Section of Neurosciences, University of Salerno, Salerno, Italy; Physiotherapy Department (Stubbs), South London and Maudsley National Health Services Foundation Trust; Department of Psychological Medicine (Stubbs), Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Department of Psychiatry (Correll), The Zucker Hillside Hospital, Northwell Health, Glen Oaks; Department of Psychiatry and Molecular Medicine (Correll), Zucker School of Medicine at Hofstra/Northwell, Hempstead; The Feinstein Institute for Medical Research (Correll), Center for Psychiatric Neuroscience, Manhasset, New York; Department of Child and Adolescent Psychiatry (Correll), Charité Universitätsmedizin Berlin, Berlin, Germany; Division of Psychology and Mental Health, Faculty of Biology, Medicine and Health (Firth), University of Manchester, Manchester, United Kingdom; NICM Health Research Institute, School of Science and Health (Firth), University of Western Sydney, Sydney; Centre for Youth Mental Health, University of Melbourne (Firth), Melbourne, Australia; Department of Child and Adolescent Psychiatry (Ermis), Dokuz Eylul University, İzmir, Turkey; Cardio-Thoracic Surgery Department (Perrotti), University Hospital Jean Minjoz; EA 3920, University of Franche-Comté (Perrotti), Besançon, France; Centre for Addiction and Mental Health (CAMH) (Carvalho); Department of Psychiatry (Carvalho), University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry and Psychotherapy (Brunoni), University Hospital, LMU Munich, Munich, Germany; Service of Interdisciplinary Neuromodulation, Department of Psychiatry, Laboratory of Neurosciences (LIM-27) and National Institute of Biomarkers in Neuropsychiatry (INBioN), Institute of Psychiatry (Brunoni), University of Sao Paulo; Hospital Universitario, Departamento de Clínica Médica (Brunoni), Faculdade de Medicina da USP, São Paulo, Brazil; Early Psychosis: Interventions and Clinical-detection (EPIC) Laboratory, Department of Psychosis Studies (Fusar-Poli, Solmi), Institute of Psychiatry, Psychology and Neuroscience, King's College London; OASIS Service, South London and Maudsley NHS Foundation Trust (Fusar-Poli), London, United Kingdom; Department of Brain and Behavioral Sciences (Fusar-Poli), University of Pavia, Pavia, Italy; National Institute for Health Research, Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust (Fusar-Poli), London, United Kingdom; Neuroscience, Reproductive Science and Odontostolmatology, Section of Psychiatry (Fornaro), University School of Medicine Federico II, Naples; Neuroscience Centre (Favaro, Solmi) and Department of General Psychology (Granziol), University of Padua; and Psychiatry Unit (Pigato), Padua University Hospital, Padua, Italy.

Objective: This study aimed to analyze the longitudinal course of depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms in patients with cardiac disease after heart surgery (HS).

Methods: We conducted a systematic review and random-effects meta-analysis of cohort studies in patients undergoing HS, measuring anxiety, depressive, and PTSD symptoms before and at least 30 days thereafter. Subgroup and meta-regression analyses, investigation of publication bias, and quality assessment were undertaken.

Results: We included 94 studies relating to 15,561 patients. HS included coronary artery bypass graft surgery, valve replacement, implantable cardioverter-defibrillator placement, left ventricular assist device placement, heart transplantation, and other types of HS. Across studies, symptoms of depression (g = 0.32; 95% confidence interval [CI] = 0.25 to 0.39; p < .001) and anxiety improved after HS (g = 0.52; 95% CI = 0.43 to 0.62; p < .001), whereas PTSD symptoms worsened (g = -0.42; 95% CI = -0.80 to -0.04; p = .032). The reduction of depression and anxiety levels was more pronounced for patients with underlying coronary artery disease and heart failure and persisted for 1 year after HS, whereas the increase in PTSD symptoms returned to baseline after 6 months. Depression improvement was inversely associated with older age, diabetes, hypertension, and dyslipidemia and positively with baseline heart failure. No additional clinical or demographic variables were associated with the course of anxiety symptoms. Quality of included studies was low overall. Publication bias was nonsignificant.

Conclusions: Depressive and anxiety symptoms improve for 1 year after HS, whereas PTSD symptoms might worsen. Older patients and those with metabolic comorbidities, valve disease, or ventricular arrhythmias are at higher risk for continued depressive and anxiety symptoms and should be monitored closely.
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http://dx.doi.org/10.1097/PSY.0000000000000872DOI Listing
January 2021

Preclinical Considerations about Affective Disorders and Pain: A Broadly Intertwined, yet Often Under-Explored, Relationship Having Major Clinical Implications.

Medicina (Kaunas) 2020 Sep 25;56(10). Epub 2020 Sep 25.

Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10027, USA.

Pain, a distinctive undesirable experience, encompasses several different and fluctuating presentations across varying mood disorders. Therefore, the present narrative review aimed to shed further light on the matter, accounting for both experimental animal models and clinical observations about major depressive disorder (MDD) pathology. Major databases were inquired from inception until April 2016 for records about MDD and pain. Pain and MDD are tightly associated with each other in a bi-directional fashion. Several cross-sectional and retrospective studies indicated a high presence of pain in the context of mood disorders, including MDD (up to 65%), but also increased prevalence rates in the case of mood disorders documented among people with a primary diagnosis of either psychological or somatic pain (prevalence rates exceeding 45%). The clinical implications of these observations suggest the need to account for mood and pain manifestations as a whole rather than distinct entities in order to deliver more effective interventions. Narrative review, lack of systematic control groups (e.g., people with the primary diagnosis at review, but not the associated comorbidity as a study) to allow reliable comparisons. Prevalence rates and clinical features associated with pain varied across different studies as corresponding operational definitions did. Pain may have a detrimental effect on the course of mood disorders-the opposite holds. Promoting a timely recognition and management of such an often neglected comorbidity would therefore represent a primary goal toward the delivery of effective, multi-disciplinary care.
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http://dx.doi.org/10.3390/medicina56100504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600172PMC
September 2020

Preclinical Considerations about Affective Disorders and Pain: A Broadly Intertwined, yet Often Under-Explored, Relationship Having Major Clinical Implications.

Medicina (Kaunas) 2020 Sep 25;56(10). Epub 2020 Sep 25.

Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10027, USA.

Pain, a distinctive undesirable experience, encompasses several different and fluctuating presentations across varying mood disorders. Therefore, the present narrative review aimed to shed further light on the matter, accounting for both experimental animal models and clinical observations about major depressive disorder (MDD) pathology. Major databases were inquired from inception until April 2016 for records about MDD and pain. Pain and MDD are tightly associated with each other in a bi-directional fashion. Several cross-sectional and retrospective studies indicated a high presence of pain in the context of mood disorders, including MDD (up to 65%), but also increased prevalence rates in the case of mood disorders documented among people with a primary diagnosis of either psychological or somatic pain (prevalence rates exceeding 45%). The clinical implications of these observations suggest the need to account for mood and pain manifestations as a whole rather than distinct entities in order to deliver more effective interventions. Narrative review, lack of systematic control groups (e.g., people with the primary diagnosis at review, but not the associated comorbidity as a study) to allow reliable comparisons. Prevalence rates and clinical features associated with pain varied across different studies as corresponding operational definitions did. Pain may have a detrimental effect on the course of mood disorders-the opposite holds. Promoting a timely recognition and management of such an often neglected comorbidity would therefore represent a primary goal toward the delivery of effective, multi-disciplinary care.
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http://dx.doi.org/10.3390/medicina56100504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600172PMC
September 2020

The concept and management of acute episodes of treatment-resistant bipolar disorder: a systematic review and exploratory meta-analysis of randomized controlled trials.

J Affect Disord 2020 11 21;276:970-983. Epub 2020 Jul 21.

Federico II University, Section of Psychiatry, Department of Neuroscience, Reproductive Sciences and Dentistry, Naples, Italy.

Background: The definitions of treatment-resistant bipolar disorder (TRBD) have varied across studies. Additionally, its management is clinically challenging. An updated synthesis and appraisal of the available evidence is needed.

Methods: A systematic search of major electronic databases from inception up to May 25th, 2020, was conducted to identify randomized controlled trials (RCTs) of pharmacological and non-pharmacological interventions for the management of TRBD. When sufficient evidence was available, a meta-analysis was conducted.

Results: Seventeen studies (n = 928 patients) were included in the qualitative synthesis. Fourteen studies (n = 803) assessed treatment-resistant acute bipolar depression (TRBD-De), including five neuromodulatory and nine pharmacological trials. Rapid- vs. standard up-titration of clozapine showed promising efficacy for TRBD mania, without significant adverse events. Electroconvulsive therapy (ECT) was confirmed to be similarly effective for TRBD-De as for treatment-resistant unipolar depression: odd ratio, OR = 0.919 (95%C.I. = 0.44-1.917), I = 13.98, p = .822. TRBD-De patients exposed to ketamine at day one post-infusion had high odds of response: OR = 10.682 (95%C.I. = 2.142-53.272), I = 0, p = <.005. The pooled drop-out rate in the ketamine trials was 21.2%. Additional evidence is warranted to confirm the potential efficacy of pramipexole or stimulants for TRBD-De.

Limitations: Publication/measurement bias; exploratory nature of the meta-analyses for interventions that included participants solely with TRBD-De.

Conclusions: Overall, a few interventions are available for TRBD, including pramipexole, ECT, and clozapine, among others. Larger and better-designed trials for TRBD are warranted and should be based on more uniform operational definitions. PROSPERO registration number: CRD42018114567.
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http://dx.doi.org/10.1016/j.jad.2020.07.109DOI Listing
November 2020

Predictors of Treatment Resistance Across Different Clinical Subtypes of Depression: Comparison of Unipolar vs. Bipolar Cases.

Front Psychiatry 2020 15;11:438. Epub 2020 May 15.

Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychosis, Section of Psychiatry, University of Naples Federico II, Naples, Italy.

Objective: Treatment-resistant depression (TRD) and treatment-resistant bipolar depression (TRBD) poses a significant clinical and societal burden, relying on different operational definitions and treatment approaches. The detection of clinical predictors of resistance is elusive, soliciting clinical subtyping of the depressive episodes, which represents the goal of the present study.

Methods: A hundred and thirty-one depressed outpatients underwent psychopathological evaluation using major rating tools, including the Hamilton Rating Scale for Depression, which served for subsequent principal component analysis, followed-up by cluster analysis, with the ultimate goal to fetch different clinical subtypes of depression.

Results: The cluster analysis identified two clinically interpretable, yet distinctive, groups among 53 bipolar (resistant cases = 15, or 28.3%) and 78 unipolar (resistant cases = 20, or 25.6%) patients. Among the MDD patients, cluster "1" included the following components: "Psychic symptoms, depressed mood, suicide, guilty, insomnia" and "genitourinary, gastrointestinal, weight loss, insight". Altogether, with broadly defined "mixed features," this latter cluster correctly predicted treatment outcome in 80.8% cases of MDD. The same "broadly-defined" mixed features of depression (namely, the standard Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition-DSM-5-specifier plus increased energy, psychomotor activity, irritability) correctly classified 71.7% of BD cases, either as TRBD or not.

Limitations: Small sample size and high rate of comorbidity.

Conclusions: Although relying on different operational criteria and treatment history, TRD and TRBD seem to be consistently predicted by broadly defined mixed features among different clinical subtypes of depression, either unipolar or bipolar cases. If replicated by upcoming studies to encompass also biological and neuropsychological measures, the present study may aid in precision medicine and informed pharmacotherapy.
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http://dx.doi.org/10.3389/fpsyt.2020.00438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326075PMC
May 2020
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