Treating depression in patients with borderline personality disorder: clinical clues on the use of antidepressants.

Personality disorders (PD) are described as enduring patterns of markedly deviant and pervasive inner experiences and behaviors, with onset in adolescence, which lead to severe distress or impairment. Patients suffering from major depressive disorder (MDD) display higher rates of comorbidity with personality disorders, often complicating the treatment, and worsening the outcomes. Borderline personality disorder (BPD) is the most common of PD and is frequently associated with MDD, with which shares several features. The most part of research agrees on the fact that comorbid BPD in MDD patients quite doubles the poor response to treatments. Moreover, no treatment strategy stands out currently to emerge as more effective in these cases, thus urging the call for the need of new approaches. Herein, we revise the current literature on BPD, its neurobiology and comorbidity with MDD, as well as the more recent treatment strategies used. Then, based on its pharmacology, we propose a possible role of trazodone as a valuable tool to approach comorbid BPD-MDD.

Effects of mindfulness-based interventions on symptoms and interoception in trauma-related disorders and exposure to traumatic events: Systematic review and meta-analysis.

Interoception is defined as the sense of the internal state of the body. Dysfunctions in interoception are found in several mental disorders, including trauma-related conditions. Mindfulness-Based Interventions (MBIs) have been shown to influence interoceptive processes. Randomised controlled trials (RCTs) have investigated whether MBIs impact symptoms and interoception in patients with trauma-related disorders. We undertook a systematic review and meta-analysis to synthesize these data. We included RCTs with an MBI arm which enrolled adult patients with trauma related-disorders or exposure to a traumatic experience, and addressed changes in interoception and trauma-related symptoms. A random-effects multivariate meta-analytic model was performed to quantify group differences in score change from baseline to follow-up. Twelve studies were included in the systematic review, and eleven in the meta-analysis. Overall, MBIs showed small to moderate positive effects on both interoception and symptoms. Despite a high heterogeneity in results, sensitivity analyses confirmed the robustness of the findings. We conclude that the efficacy of MBIs on trauma-related symptoms and interoception is supported by randomised evidence. However, further research is needed to understand whether changes in interoception might underpin the effectiveness of MBIs in trauma-related disorders.

First episode psychosis during the Covid-19 pandemic in Milan, Italy: Diagnostic outcomes at 1-year follow-up.

An influence of the Covid-19 pandemic on First Episode Psychosis (FEP) has been hypothesized. We previously reported an increase of FEP during the early stages of the pandemic in Milan, Italy. Here we report a 1-year follow-up of the same cohort and comparison with a FEP cohort from 2019. The higher proportion of non-chronic psychoses observed during the pandemic (58.62% in 2020 vs 43,75% in 2019) should be confirmed in larger cohorts over a longer follow-up period.

Impact of the first Covid-19 pandemic wave on first episode psychosis in Milan, italy.

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic appears to increase risk for mental illness, either directly due to inflammation caused by the virus or indirectly due to related psychosocial stress, resulting in the development of both anxious-depressive and psychotic symptoms. The purpose of the present study was to assess the frequency and characteristics of all patients with First Episodes Psychosis (FEP) without COVID-19 infection hospitalized in the first four months since lockdown in Milan. We recruited sixty-two patients hospitalized between March 8 to July 8, 2020 versus those first  hospitalized in the same period in 2019. The two subgroups were compared for sociodemographic variables and clinical characteristics of the episodes. Patients with FEP in 2020 were significantly older than patients with FEP in 2021, and presented with significantly less substances abuse. Interestingly, patients presenting with FEP in 2020 were significantly older than patients with FEP in 2019. These data are compatible with the greater vulnerability to stressful factors during the pandemic, as well as with the greater concern regarding a possible COVID-19 infection producing brain damage causing the FEP.

Manifesto for a European research network into Problematic Usage of the Internet.

The Internet is now all-pervasive across much of the globe. While it has positive uses (e.g. prompt access to information, rapid news dissemination), many individuals develop Problematic Use of the Internet (PUI), an umbrella term incorporating a range of repetitive impairing behaviours. The Internet can act as a conduit for, and may contribute to, functionally impairing behaviours including excessive and compulsive video gaming, compulsive sexual behaviour, buying, gambling, streaming or social networks use. There is growing public and National health authority concern about the health and societal costs of PUI across the lifespan. Gaming Disorder is being considered for inclusion as a mental disorder in diagnostic classification systems, and was listed in the ICD-11 version released for consideration by Member States (http://www.who.int/classifications/icd/revision/timeline/en/). More research is needed into disorder definitions, validation of clinical tools, prevalence, clinical parameters, brain-based biology, socio-health-economic impact, and empirically validated intervention and policy approaches. Potential cultural differences in the magnitudes and natures of types and patterns of PUI need to be better understood, to inform optimal health policy and service development. To this end, the EU under Horizon 2020 has launched a new four-year European Cooperation in Science and Technology (COST) Action Programme (CA 16207), bringing together scientists and clinicians from across the fields of impulsive, compulsive, and addictive disorders, to advance networked interdisciplinary research into PUI across Europe and beyond, ultimately seeking to inform regulatory policies and clinical practice. This paper describes nine critical and achievable research priorities identified by the Network, needed in order to advance understanding of PUI, with a view towards identifying vulnerable individuals for early intervention. The network shall enable collaborative research networks, shared multinational databases, multicentre studies and joint publications.

Obsessive-compulsive disorder in the elderly: A report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS).

INTRODUCTION: Obsessive-compulsive disorder (OCD) is a highly disabling condition, with frequent early onset. Adult/adolescent OCD has been extensively investigated, but little is known about prevalence and clinical characterization of geriatric patients with OCD (G-OCD≥65years). The present study aimed to assess prevalence of G-OCD and associated socio-demographic and clinical correlates in a large international sample. METHODS: Data from 416 outpatients, participating in the ICOCS network, were assessed and categorized into 2 groups, age

Structural and metabolic differentiation between bipolar disorder with psychosis and substance-induced psychosis: An integrated MRI/PET study.

BACKGROUND: Bipolar disorder (BD) may be characterized by the presence of psychotic symptoms and comorbid substance abuse. In this context, structural and metabolic dysfunctions have been reported in both BD with psychosis and addiction, separately. In this study, we aimed at identifying neural substrates differentiating psychotic BD, with or without substance abuse, versus substance-induced psychosis (SIP) by coupling, for the first time, magnetic resonance imaging (MRI) and positron emission tomography (PET). METHODS: Twenty-seven BD type I psychotic patients with (n=10) or without (n=17) substance abuse, 16 SIP patients and 54 healthy controls were enrolled in this study. 3T MRI and 18-FDG-PET scanning were acquired. RESULTS: Gray matter (GM) volume and cerebral metabolism reductions in temporal cortices were observed in all patients compared to healthy controls. Moreover, a distinct pattern of fronto-limbic alterations were found in patients with substance abuse. Specifically, BD patients with substance abuse showed volume reductions in ventrolateral prefrontal cortex, anterior cingulate, insula and thalamus, whereas SIP patients in dorsolateral prefrontal cortex and posterior cingulate. Common alterations in cerebellum, parahippocampus and posterior cingulate were found in both BD with substance abuse and SIP. Finally, a unique pattern of GM volumes reduction, with concomitant increased of striatal metabolism, were observed in SIP patients. CONCLUSIONS: These findings contribute to shed light on the identification of common and distinct neural markers associated with bipolar psychosis and substance abuse. Future longitudinal studies should explore the effect of single substances of abuse in patients at the first-episode of BD and substance-induced psychosis.

Augmentative repetitive Transcranial Magnetic Stimulation (rTMS) in the acute treatment of poor responder depressed patients: a comparison study between high and low frequency stimulation.

BACKGROUND: While the efficacy of repetitive transcranial magnetic stimulation (rTMS) in Major Depressive Disorder (MDD) is well established, the debate is still open in relation to bipolar depression and to a possible different effectiveness of high vs. low stimulation. The present study was aimed to assess and compare the efficacy and tolerability of different protocols of augmentative rTMS in a sample of patients with current Major Depressive Episode (MDE), poor drug response/treatment resistance and a diagnosis of MDD or bipolar disorder. METHODS: Thirty-three patients were recruited in a 4-week, blind-rater, rTMS trial and randomised to the following three groups of stimulation: (1) (n=10) right dorsolateral prefrontal cortex (DLPFC) 1 HZ, 110% of the motor threshold (MT), 420 stimuli/day; (2) (n=10) right DLPFC, 1Hz, 110% MT, 900 stimuli/day; (3) (n=13) left DLPFC, 10Hz, 80% MT, 750 stimuli/day. RESULTS: Twenty-nine patients completed the treatment, showing a significant reduction of primary outcome measures (HAM-D, MADRS and CGI-S total scores: t=8.1, P<0.001; t=8.6, P<0.001; t=4.6, P<0.001 respectively). No significant differences in terms of efficacy and tolerability were found between high vs. low frequency and between unipolar and bipolar patients. Side effects were reported by 21% of the sample. One of the 4 dropouts was caused by a hypomanic switch. CONCLUSIONS: Augmentative rTMS appeared to be effective and well tolerated for the acute treatment of unipolar and bipolar depression with features of poor drug response/treatment resistance, showing a comparable effectiveness profile between protocols of high and low frequency stimulation.

Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal.

Discovered in the late 1950s by Leo Sternbach, the first benzodiazepine (BZD) chlordiazepoxide was followed by several congeners, which rapidly constituted one of the largest and most widely prescribed classes of psychotropic compounds. After 50 years, BZDs are still routinely utilized not only in psychiatry but, more generally, in the whole of medicine. Despite their high therapeutic index which makes BZDs safer than other compounds like barbiturates, as well as their rapidity of onset, psychiatrists and family physicians are well aware about the controversy that surrounds the wide use - often not adequately based on scientific evidence - of BZDs in many psychiatric disorders. In this overview of international treatment guidelines, systematic reviews and randomized clinical trials, the aim was to provide a critical appraisal of the current use and role of BZDs in psychiatric disorders and their disadvantages, with specific emphasis on anxiety and affective disorders, sleep disorders, alcohol withdrawal, violent and aggressive behaviours in psychoses, and neuroleptic-induced disorders. In addition, specific emphasis has been given to the extent of usage of BZDs and its appropriateness through the assessment of available international surveys. Finally, the entire spectrum of BZD-related adverse effects including psychomotor effects, use in the elderly, paradoxical reactions, tolerance and rebound, teratologic risk, dependence, withdrawal and abuse issues was examined in detail.

Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the Major Depressive Episode: findings from a naturalistic study.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive, neuromodulatory technique with an emerging role for treating major depression. OBJECTIVE: To investigate the interactions between tDCS and drug therapy in unipolar and bipolar depressed patients who were refractory for at least one pharmacological treatment. METHODS: This was a naturalistic study using data from 54 female and 28 male patients (mean age of 54 years) that consecutively visited our psychiatric unit. They received active tDCS (five consecutive days, 2mA, anodal stimulation over the left and cathodal over the right dorsolateral prefrontal cortex, twice a day, 20minutes). The outcome variable (mood) was evaluated using the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS). Predictor variables were age, gender, disorder and pharmacological treatment (seven dummy variables). We performed univariate and multivariate analyses as to identify predictors associated to the outcome. RESULTS: After 5 days of treatment, BDI and HDRS scores decreased significantly (29%±36%, 18%±9%, respectively, P<0.01 for both). Benzodiazepine use was independently associated with a worse outcome in both univariate (ß=4.92, P<0.01) and multivariate (ß=5.8, P<0.01) analyses; whereas use of dual-reuptake inhibitors positively changed tDCS effects in the multivariate model (ß=-4.7, P=0.02). A similar trend was observed for tricyclics (ß=-4, P=0.06) but not for antipsychotics, non-benzodiazepine anticonvulsants and other drugs. CONCLUSION: tDCS over the DLPFC acutely improved depressive symptoms. Besides the inherent limitations of our naturalistic design, our results suggest that tDCS effects might vary according to prior pharmacological treatment, notably benzodiazepines and some antidepressant classes. This issue should be further explored in controlled studies.

Pin1 contribution to Alzheimer's disease: transcriptional and epigenetic mechanisms in patients with late-onset Alzheimer's disease.

BACKGROUND: Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer's disease (AD) although the molecular basis of their coexistence remains elusive. The peptidyl-prolyl cis/trans isomerase Pin1 acts on both tau and amyloid precursor protein to regulate their functions by influencing tau phosphorylation and amyloid precursor protein processing. OBJECTIVE: In order to identify potential biomarkers for AD in easily accessible cells and to gain insight into the relationship between the brain and peripheral compartments in AD pathology, we investigated Pin1 expression and activity in the peripheral blood mononuclear cells of subjects with late-onset AD (LOAD) and age-matched controls (CT). METHODS: Gene and protein expression, promoter methylation, Ser(16) phosphorylation and activity of Pin1 were evaluated in 32 samples from subjects with LOAD and in 28 samples from CT. RESULTS: In LOAD subjects, there was a statistically significant reduction in Ser(16) phosphorylation (-30%; p = 0.041) and promoter methylation (-8%; p = 0.001), whereas Pin1 expression was significantly increased (+74%; p = 0.018). CONCLUSION: The modifications of Pin1 found in LOAD subjects support its involvement in the pathogenesis of the disease with an important role being played by epigenetic mechanisms.

Transcranial direct current stimulation for the outpatient treatment of poor-responder depressed patients.

Transcranial direct current stimulation (tDCS) is a selective, painless, brain stimulation technique that allows the electric stimulation of specific cortical regions. TDCS has been recently used as investigational intervention for major depression and treatment resistant depression (TRD) with encouraging results. The present study was aimed to investigate the efficacy and tolerability of tDCS in major depressives with poor response to pharmacological treatment. Twenty-three depressed patients, with a diagnosis of major depressive disorder or bipolar disorder, were treated with augmentative tDCS for 5 days, two sessions per day in a blind-rater trial. The course of depressive symptoms was analyzed using repeated measures ANOVA for HAM-D and MADRS total scores. A qualitative analysis on the basis of the HAM-D response was performed as well. Both analyses were conducted at three time-points: T0 (baseline), T1 (endpoint tDCS) and T2 (end of the first week of follow-up). All patients completed the trial without relevant side-effects. A significant reduction of HAM-D and MADRS total scores was observed during the study (P<0.0001). Treatment response (endpoint HAM-D reduction ≥50%) was obtained by four patients (17.4%) at T1 and by seven patients (30.4%) at T2 and remission (endpoint HAM-D<8) by three patients (13.0%) at T1 and by four subjects (17.4%) at T2. Present findings support the efficacy and good tolerability of tDCS in the acute treatment of patients with TRD with clinical benefit being progressive and extended to the first week of follow-up. Further sham-controlled trials with longer follow-up are needed to confirm present results.

Duration of untreated illness as a predictor of treatment response and remission in obsessive-compulsive disorder.

OBJECTIVES: The Duration of Untreated Illness (DUI), defined as the time elapsing between the onset of a disorder and the beginning of the first pharmacological treatment, has been increasingly investigated as a predictor of outcome and course across different psychiatric disorders. Purpose of this naturalistic study was to evaluate the influence of DUI on treatment response and remission in a sample of patients with obsessive-compulsive disorder (OCD). METHODS: Sixty-six outpatients with a DSM-IV diagnosis of OCD were included in the study. Patients received, according to their clinical conditions, an open pharmacological treatment of 12 weeks and were evaluated by the administration of the Yale Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and endpoint. Treatment response was defined as a decrease .25% on Y-BOCS score compared to baseline, while remission was defined as an endpoint Y-BOCS total score #10. A logistic regression was performed considering DUI as the independent continuous variable and treatment response and remission as the dependent variables. Moreover, the sample was divided into two groups according to a categorical cut-off for the DUI of 24 months and odds ratios (OR) were calculated on the basis of the same variables. RESULTS: DUI, considered as a continuous variable, was not predictive of treatment response (OR51.00, P50.15) nor remission (OR51.00, P50.59). When considered as a categorical variable, however, a DUI # 24 months was predictive of treatment response (OR50.27, P50.03). CONCLUSIONS: Results from the present naturalistic study suggest a complicated relationship between DUI and treatment outcome in OCD encouraging further investigation with larger samples in order to better define long versus short DUI in this condition.

Quetiapine and classical mood stabilizers in the long-term treatment of Bipolar Disorder: a 4-year follow-up naturalistic study.

BACKGROUND: The aim of this naturalistic study was to compare the effectiveness of quetiapine and classical mood stabilizers, as mono- or combination therapy, in the long-term treatment of Bipolar Disorder (BD). METHODS: 232 DSM-IV BD I (n=91) or BD II (n=141) patients, treated and followed up for four years, were studied. Mood stabilizers were chosen by the treating psychiatrists on the basis of their clinical judgement. The sample was subdivided into 6 treatment groups: quetiapine (n=41), lithium (n=39), sodium valproate (n=73), lamotrigine (n=31), quetiapine plus lithium (n=25), and quetiapine plus sodium valproate (n=23). Throughout the 4-year follow-up period patients were assessed monthly, or whenever a recurrence occurred, by the administration of HAMD-21 and of the YMRS. Primary outcome measures were the duration of euthymia and the cumulative proportion of subjects who maintained euthymia. Kaplan-Meier survival analyses were done to tabulate and compare the differences in survival distributions across the different treatment groups (Log-Rank Mantel-Cox test). RESULTS: The combined treatments with quetiapine plus lithium or sodium valproate were more effective overall in maintaining euthymia, (percentages of patients who maintained euthymia: 29.3% for quetiapine, 46.2% for lithium, 32.9% for sodium valproate, 41.9% lamotrigine, 80% for quetiapine plus lithium, and 78.3% for quetiapine plus sodium valproate). In addition, quetiapine monotherapy was as effective as lithium monotherapy or combination treatment with lithium or sodium valproate in preventing the recurrence of major depressive episodes. LIMITATION: The main limitations of the study are the lack of randomized, controlled conditions and the low doses of quetiapine used. CONCLUSION: If the results from this study will be replicated, there will be important implications for the use of quetiapine in the long-term treatment of BD.

Duration of untreated illness in major depressive disorder: a naturalistic study.

BACKGROUND: Most of the studies on the duration of untreated illness (DUI) as a possible predictor of the clinical outcome and the course have focused on the psychotic disorders. The present naturalistic study was aimed to evaluate the possible relationship between the DUI and some clinical characteristics of a sample of patients with major depressive disorder (MDD). METHODS: Sixty-eight patients with MDD, according to the Diagnostic and Statistical Manual of Mental Disorders, IV Edition, Text Revision (DSM-IV-TR) criteria, followed-up for 4 years, were selected, interviewed and their clinical charts reviewed. The DUI was defined as the interval between the onset of the first major depressive episode and the first adequate antidepressant treatment. The sample was divided in two groups according to a DUI 12 months (n = 23). The main demographic and clinical course variables were compared between the two groups using t-tests or chi-squared tests. RESULTS: Patients with a DUI > 12 months were more frequently women (chi2 = 4.005, p = 0.045), had an earlier onset (t = 2.515, p = 0.014), a longer duration of illness (t = -2.483, p = 0.016), a higher number of recurrences (t = -2.262, p = 0.027) and had more frequently comorbid Axis I disorders with onset later than MDD (chi2 = 5.595, p = 0.05). CONCLUSIONS: These findings suggest that a longer DUI may negatively influence the clinical course of MDD. Further studies on larger samples are warranted to confirm these preliminary results.

Diagnosis and treatment of obsessive-compulsive disorder and related disorders.

Obsessive-compulsive disorder (OCD) is currently recognised as one of the most common psychiatric disorders as well as one of the most disabling of all medical disorders. Obsessive-compulsive related disorders (OCRDs), often comorbid with OCD, include many distinct psychiatric conditions (i.e. some somatoform disorders, eating disorders, impulse control disorders and some neurological conditions) which have overlapping symptoms and compulsive qualities with OCD. Although effective treatments exist, OCD and related disorders are often underdiagnosed and undertreated. Serotonin reuptake inhibitors (SRIs) and cognitive behavioural therapy (CBT) represent the first-line treatment for OCD and related disorders. However, the time and the doses of the medications used in the treatment of OCD and related disorders differ from those recommended in depressive disorders. In addition, remission is not common for patients with OCD and related disorders in clinical practice, and poor responders as well as refractory cases may benefit from different treatment strategies including integrated treatment, pharmacological augmentation and brain stimulation techniques.

Common alterations in the serotonin transporter in platelets and lymphocytes of psychotic patients.

INTRODUCTION: Given the controversial data concerning the role of the serotonin (5-HT) transporter in psychosis, our study was aimed to investigate this structure by means of the measurements of the re-uptake kinetics and of the protein density, in both platelets and lymphocytes of 25 out- and inpatients with different psychotic disorders. METHODS: Diagnoses, according to DSM-IV criteria, were bipolar 1 disorders with mood incongruent psychotic features (14), mixed states (7) and schizophrenia (4). Twenty-five matched healthy subjects were also selected as the control group. Platelet and lymphocyte membranes were prepared according to standardized protocols, as were the [3H]5HT re-uptake and [3H]paroxetine ([3H]Par) binding. RESULTS: The results of this study showed a decreased density of the [3H]Par binding sites coupled with a reduced velocity of [3H]5-HT re-uptake in both platelets and lymphocytes of psychotic patients, as compared with healthy control subjects. CONCLUSION: These findings would suggest a general abnormality of the 5-HT system in psychotic patients, probably not confined only to the brain.