The progression trajectory of Bipolar Disorder: results from the application of a staging model over a ten-year observation.

BACKGROUND: Trying to better define Bipolar Disorder (BD) progression, different staging models have been conceptualized, each one emphasizing different aspects of illness. In a previous article we retrospectively applied the main staging models to a sample of 100 bipolar patients at four time points over a ten-year observation. In the present study, focusing on Kupka & Hillegers's model, we aimed to assess the transition of the same sample through the different stages of illness and to explore the potential role of clinical variables on the risk of progression. METHODS: Multistate Model using the mstate package in R and Markov model with stratified hazards were used for statistical analysis. RESULTS: A high hazard of transition from stage 2 to 3 emerged, with a probability of staying in stage 2 decreasing to 14 % after 3 years. BD II was significantly associated with transition from stage 1 to 2, whereas the number of lifetime episodes >3 and the elevated predominant polarity with transition from stage 3 to 4. CONCLUSION: Our results corroborated the evidence on BD progression and contributed to outline its trajectory over time. Further effort may help to define a standardized staging approach towards ever increasing tailored interventions.

Bipolar disorder staging and the impact it has on its management: an update.

INTRODUCTION: The longitudinal course of bipolar disorder (BD) is associated with an active process of neuroprogression, characterized by structural brain alterations and progressive functional impairment. In the last decades, a growing need of a standardized staging model for BD arose, with the aim of a more appropriate definition of stage-specific clinical manifestations and the identification of more customized therapeutic tools. AREAS COVERED: The authors review the literature on clinical aspects, neurobiological correlates and treatment issues related to BD progression. Thereafter, they address the definition, constructs, and evolution of the staging concept, focusing on the clinical applications of BD staging models available in literature. EXPERT OPINION: Although several staging models for BD have been proposed to date, their application in clinical practice is still relatively scant. This may have a detrimental impact on the clinical and therapeutic management of BD, in terms of early and proper diagnosis as well as tailored treatment interventions according to the different stages of illness. Future research efforts should tend to the integration of recent insights on neuroimaging and epigenetic markers, toward a standardized and multidimensional staging model.

The use of antipsychotics in obsessive compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic disease with a prevalence in the general population of around 2%-3%, generally accompanied by a severe impairment of functioning and quality of life. A consistent subgroup of patients may not achieve adequate symptom remission with first-line treatments (i.e., cognitive behavioral therapy, selective serotonin reuptake inhibitors [SSRIs]). The most validated option for treatment-resistant cases relies on the augmentative use of antipsychotics to SSRIs, preferably of the 'second generation'. Indeed, dopamine appears to be crucially involved in OCD neuropathology due to its implication in systems relating to goal-directed behaviour and maladaptive habits. Nevertheless, the mechanism of action of antipsychotics in OCD symptom improvement is still unclear. Risperidone, aripiprazole, and haloperidol seem to be the most useful medications, whereas 'first generation' antipsychotics may be indicated in case of comorbidity with tics and/or Tourette Syndrome. Antipsychotic augmentation may be also related to side-effects, particularly in the long term (e.g., alteration in metabolic profile, sedation, extrapyramidal symptoms). The present mini-review sought to provide the most updated evidence on augmentative antipsychotic use in treatment-resistant patients with OCD, providing a road map for clinicians in daily practice and shedding light on avenues for further research.

Staging models applied in a sample of patients with bipolar disorder: Results from a retrospective cohort study.

BACKGROUND: Bipolar Disorder (BD) is a life-long illness with compelling evidence of progression. Although different staging models have been proposed to evaluate its course, clinical data remain limited. The aim of the present study was to retrospectively assess applicability of available staging approaches and their pattern of progression in a sample of bipolar patients. METHODS: In a naturalistic sample of 100 BD patients, retrospective assessment of clinical stages was performed at four time points over 10 years, according to four staging models. Staging progression with potential associations between stages and unfavourable illness characteristics were analyzed. RESULTS: A pattern of stage worsening emerged for each model, with a significant increase at every time point. Greater stage increases emerged in patients with lower educational level, age at first elevated episode ≤35 years, duration of illness ≤25 years, and duration of untreated illness ≤5 years. Lower stage values were associated with BD II, no psychiatric hospitalization, depressive onset and predominant polarity, ≤three lifetime episodes, age at first mood stabilizer >40 years, duration of illness ≤25 years, and engaged/employed status. Higher stage values were associated with lower age at first elevated episode and mood stabilizing treatment instead. LIMITATIONS: Naturalistic and retrospective design, recruitment at a 2nd level specialistic clinic. CONCLUSIONS: Reported findings support the progressive nature of BD and the application of staging models for early intervention, suggesting a conceptualization of a standardized approach to better characterize patients, predict their clinical course, and deliver tailored treatment options.

Psychological impact of COVID-19 after hospital discharge: A follow-up study on Italian recovered patients.

BACKGROUND: Since COVID-19 outbreak, clinical experience on its management during the acute phase has rapidly grown, including potential effects on the psychopathological dimension. However, still few data are available regarding the impact on survivors' mental health over the long-term. METHODS: A sample of 1457 COVID-19 patients underwent a multidisciplinary follow-up protocol, approximately 3 months after hospital discharge, including a psychological evaluation. The primary outcomes were anxiety, depression, resilience, post-traumatic symptoms, and health-related quality of life. Furthermore, we examined the potential role of hospitalization and delay in the follow-up assessment on the increased burden of illness. RESULTS: Although a general high level of resilience emerged, suggesting most patients relied on their individual and interpersonal resources to face difficulties related to the pandemic, almost one third of the sample reported signs of psychological distress over time, especially post-traumatic symptoms, with anxiety being more represented than depression. Furthermore, hospitalization - regardless of the setting of care - and promptness in follow-up evaluation were found to play a protective role on patients' recovery and mental wellbeing. LIMITATIONS: Selection bias of patients exclusively admitted to the hospital; absence of a control group; psychological assessment relying on self-reported instruments. CONCLUSIONS: The current crisis demands resilience and adjustment resources, either in the acute and post-acute phase. Thus, the clinical effort should aim at relieving the traumatic impact of such condition through timely interventions. Further investigation may address potential predictors of developing a traumatic stress response, in order to identify and promptly treat at-risk subpopulations.

A 6-month follow-up study on response and relapse rates following an acute trial of repetitive transcranial magnetic stimulation in patients with major depression.

BACKGROUND: Little is known about the post-acute effects of repetitive transcranial magnetic stimulation (rTMS) in patients with major depression. The present study focused on the 6-month follow-up of a sample of patients with major depression, after the completion of an acute 4 weeks rTMS trial, with the aim of evaluating response (in terms of sustained and late response) and relapse rates. METHODS: Following the completion of an acute trial of rTMS (T0-T4), 31 drug-resistant depressed patients (bipolar or unipolar) entered a naturalistic follow-up period of 6 months, with three timepoints (T5, T6, and T7) during which they were assessed with the Hamilton Depression Rating Scale and the Young Mania Rating Scale. RESULTS: Results showed that in the 6 months following an acute transcranial magnetic stimulation (TMS) trial, a higher rate of late responders was observed among previously acute TMS nonresponders (63.64%, 7 out of 11) compared to the rate of relapse among those who had acutely responded to TMS (10%, 2 out of 20). In addition, an overall high rate of maintained response (90%) was observed. CONCLUSION: Present findings seem to support the possibility of obtaining a clinical response also after the end of an acute TMS trial in patients with major depression. The concomitant low rate of relapse observed at the end of follow-up along with a high rate of maintained response provides further support to the post-acute efficacy of TMS. Nonetheless, further controlled studies, with larger samples and longer follow-up observation, are needed to confirm the reported results.

Antidepressants in bipolar disorder: Analysis of correlates overall, and in BD-I and BD-II subsamples.

BACKGROUND: Clinical therapeutic approaches to Bipolar Disorders (BDs) include diverse pharmacotherapies, targeting different symptomatic BD presentations. To date, guidelines about pharmacological treatment of BDs have focused on short-term treatment of mood episodes, at the expense of longer-term treatment, especially for (the most common) predominantly depressive polarity patients. METHODS: A database of BD-I and BD-II patients was collected between 2013 and 2019 at the University Psychiatric Clinic of Ospedale Policlinico and Ospedale Luigi Sacco of Milan. Only patients in euthymic phases (no current mood episode) were included in the study. We then analyzed socio-demographic and clinical characteristic overall and in the subgroup BD-I and BD-II, comparing patients taking vs. not taking ADs. RESULTS: Our results showed that approximately 1/3 of BD patients between acute episodes took ADs, also among patients from the subgroup with BD-I, especially those first presenting with a depressive episodes, and those with a most recent depressive (as opposed to elevated, irritable, or mixed) polarity episode. LIMITATIONS: Although patients included in our study were primarily in follow up for Bipolar Disorder, use of ADs could be explained by other comorbidities, such as Anxiety or Eating Disorders. CONCLUSIONS: These data shed light on how managing depressive symptoms is a very important aspect of treating BDs, highlighting the need for wider and more specific studies on the use of ADs in BDs.

Crossing Borders Between Frontotemporal Dementia and Psychiatric Disorders: An Updated Overview.

Frontotemporal dementia (FTD) includes a group of neurocognitive syndromes, clinically characterized by altered behaviors, impairment of language proficiency, and altered executive functioning. FTD is one of the most frequently observed forms of dementia in the elderly population and the most common in presenile age. As for other subtypes of dementia, FTD incidence is constantly on the rise due to the steadily increasing age of the population, and its recognition is now becoming a determinant for clinicians. FTD and psychiatric disorders can overlap in terms of clinical presentations by sharing a common genetic predisposition and neuropathological mechanism in some cases. Nonetheless, this association is often unclear and underestimated. Since its first reports, research into FTD has constantly grown, with the identification of recent findings related to its neuropathology, genetic, clinical, and therapeutic issues. Literature is thriving on this topic, with numerous research articles published in recent years. In the present review, we aimed to provide an updated description of the clinical manifestations that link and potentially confound the diagnosis of FTD and psychiatric disorders in order to improve their differential diagnosis and early detection. In particular, we systematically reviewed the literature, considering articles specifically focused on the behavioral variant FTD, published after 2015 on the PubMed database.

Antipsychotic use in Northern Italian inter-episode bipolar disorder patients: considering both second- and first-generation agents.

Evidence supports increasing antipsychotic use in bipolar disorder, especially second-generation antipsychotics. However, data regarding first-generation antipsychotic contemporary use are limited. We studied 380 Northern Italian bipolar disorder inter-episode patients, grouped according to current antipsychotic use, stratified by bipolar subtype (BDI vs. BDII). Furthermore, we compared first-generation antipsychotic users vs. non-users. In our sample (n = 357), 81.8% were taking antipsychotics (74% second-generation antipsychotics, 24.1% first-generation antipsychotics), with antipsychotic use in BDI significantly more prevalent than in BDII (85.2% vs. 72.0%). Overall, antipsychotic users vs. non-users had higher rates of hypo/manic last episode, lifetime psychiatric hospitalization, psychosis, and current psychotropic use, but lower rates of anxiety disorder main comorbidity and current antidepressant use. First-generation antipsychotic use rates (30.3% in BDI vs. 6.5% in BDII) were associated with more frequently being unpartnered, having elevated first/last episodes, higher lifetime hospitalization, involuntary commitment, psychosis, and psychosocial rehabilitation rates, and more current psychotropic use, but lower Global Assessment Functioning scores and less current antidepressant use. Bipolar disorder patients had robust antipsychotic (second-generation antipsychotic > first-generation antipsychotic) use, consistently with previous reports. FGAs were still prescribed for a substantial group of patients, likely suffering from severe bipolar disorder. Prescriptions need to be monitored to assess their appropriateness and adherence to evidence-based recommendations.

Differential core pharmacotherapy in bipolar I versus bipolar II disorder and European versus American patients not in a syndromal episode.

Assess bipolar disorder subtype and treatment location effects on bipolar disorder core pharmacotherapy. Outpatients not in a syndromal episode referred to the University of Milan and Stanford University Bipolar Disorder Clinics were assessed with SCID for the fourth Edition of the Diagnostic and Statistical Manual of Mood Disorders, and the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation, respectively. Prevalence and clinical correlates of antidepressant, antipsychotic, and mood stabilizer use, in aggregate and individually, were compared in bipolar I (BDI) versus II (BDII) patients in Milan/Stanford and in Milan versus Stanford patients, stratified by subtype. Milan/Stanford pooled BDI versus BDII patients significantly more often took antipsychotic (69.8 versus 44.8%), mood stabilizers (68.6 versus 57.7%), and valproate (40.1 versus 17.5%), and less often took antidepressants (23.1 versus 55.6%) and lamotrigine (9.9 versus 25.2%). Milan versus Stanford patients (stratified by bipolar disorder subtype) significantly more often took antipsychotic (BDI and BDII), antidepressants (BDII), and valproate (BDII), and less often took lamotrigine (BDI). Research regarding bipolar disorder core pharmacotherapy relationships with bipolar subtype and treatment location is warranted to enhance clinical management.

Exploring characteristics associated with first benzodiazepine prescription in patients with affective disorders and related diagnoses.

OBJECTIVE: In patients with affective disorders, benzodiazepines (BZDs) are frequently administered at the onset, sometimes inappropriately. We sought to identify clinical variables associated with first BZD prescription in a large sample of patients with affective disorders. METHODS: Four hundred sixty patients with mood or anxiety disorders attending different psychiatric services were assessed comparing those who received BZD as first treatment (BZD w/) and those who did not (BZD w/o). RESULTS: More than one third (35.7%) of the total sample had received BZDs as first prescription. In relation to mood disorders, BZD w/ subjects more frequently (a) had not a psychiatrist as first therapist, (b) had anxious symptoms at onset, (c) had adjustment disorder as first diagnosis, (d) were treated as outpatients. In relation to specific diagnoses, (a) personal decision of treatment for major depressive disorder, (b) outpatient status for bipolar disorder and (c) longer duration of untreated illness for adjustment disorder were more frequently associated with first BZD prescription. For anxiety disorders, the presence of stressful life events and the diagnoses of panic disorder or specific phobias were more frequently observed in BZD w/ patients. CONCLUSION: Patients with affective disorders frequently received BZDs as first prescription with significant differences between and within mood and anxiety disorders.

Is trazodone more effective than clomipramine in major depressed outpatients? A single-blind study with intravenous and oral administration.

OBJECTIVE: Some antidepressants, such as trazodone or clomipramine, can be administered intravenously in patients with major depressive disorder (MDD), with potential benefits compared to the standard oral treatment, but available data about their efficacy are limited. The present study was aimed to compare the effectiveness of trazodone and clomipramine (intravenous [i.v.] followed by oral administration). METHODS: Some 42 patients with a diagnosis of MDD according to the DSM-5 were selected and treated with i.v. trazodone or clomipramine according to clinical judgment. The Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Montgomery-Åsberg Depression Rating Scale were administered at baseline, after 2 weeks, and after 6 weeks, as well as after 1 week of intravenous antidepressant administration. Raters were blinded to type of treatment. RESULTS: No significant differences were found between treatment groups in terms of effectiveness at endpoint. Borderline statistical significance was found in terms of number of responders in favor of trazodone. In addition, patients treated with trazodone reported fewer total side effects than those treated with clomipramine. CONCLUSION: Both i.v. trazodone and clomipramine are rapid and effective options for improving depressive symptoms, although trazodone appears to be tolerated better. Further studies with larger samples and double-blind conditions are warranted to confirm our results.

Benzodiazepine ingestion as a way to die by suicide and related safety: the case of an elderly patient.

Benzodiazepines (BDZs) are widespread psychotropic compounds, often prescribed as first-line symptomatic option by general practitioners in patients with different psychiatric disorders. Sometimes, however, they contribute to delay the administration of the first appropriate psychopharmacological treatment, thus leading to a longer duration of untreated illness in patients with depressive and anxiety disorders. The well-established pros of BDZs use in clinical practice include efficacy, rapidity of action, versatility, and safety. Among the cons, BDZs can provoke cognitive side-effects, asthenia, and misuse/abuse. Although their overall safety has been traditionally viewed as one of their greatest strengths, BDZs massive ingestion for suicidal purposes may pose, in some cases, serious life-threatening conditions, as described in the present case report. Hence, particular attention needs to be paid in prescribing these compounds to special populations, such as elderly patients. Among these, their prescription should be limited to the short-term and particularly monitored in case of risk factors, as they may be unsafe in case of overdose.

Does initial use of benzodiazepines delay an adequate pharmacological treatment? A multicentre analysis in patients with psychotic and affective disorders.

It is established that delayed effective pharmacotherapy plays a significant role in the overall burden of psychiatric disorders, which are often treated with symptomatic drugs, that is benzodiazepines (BZDs), in relation to their rapid onset of action and safety, despite long-term side effects. We aimed to assess the influence of initial treatment with BZDs on the duration of untreated illness (DUI) and whether specific sociodemographic and clinical factors could influence the choice of BZDs as first treatment in 545 patients affected by schizophrenia, mood and anxiety spectrum disorders. Statistical analyses (one-way analysis of variance and χ) were carried out to compare patients who used BZDs as first treatment (BZD w/) and those who did not (BZD w/o). The overall DUI, irrespective of diagnosis, resulted in significantly longer in BZD w/ versus w/o patients, who also experienced more frequently anxious/depressive symptoms at onset. Furthermore, BZD w/ patients more frequently autonomously decided to look for treatment (mainly refering to psychologists or general practitioners) and experimented more frequently phobias, than BZD w/o ones. The present findings suggest that initial BZDs treatment may prolong the overall DUI, although their prescription seems to be influenced by specific sociodemographic and clinical factors. Further studies are needed to confirm the present findings.

New Directions in the Use of Brain Stimulation Interventions in Patients with Obsessive-Compulsive Disorder.

Obsessive-Compulsive Disorder (OCD) is a highly disabling condition with early onset and chronic course in most of the affected patients. In addition, OCD may show high comorbidity and suicide attempt rates, which worsen the overall burden of the disease for patients and their caregivers. First-line treatments for OCD consist of pro-serotonergic compounds and cognitive-behavioral therapy. Nonetheless, many patients show only limited benefit from such interventions and require additional "next-step" interventions, including augmentative antipsychotics and glutamate-modulating agents. Based on the knowledge about altered neurocircuitry in OCD, brain stimulation techniques, including transcranial magnetic and electrical stimulations (TMS and tDCS) and deep brain stimulation (DBS), have been increasingly investigated over the last decade, revealing positive results for otherwise intractable and treatment-refractory patients. Available evidence in the field is in continuous evolution and professionals actively involved in the management of OCD patients, psychiatrists in particular, need to be updated about latest developments. Through the analysis of controlled studies, meta-analyses, and International treatment guidelines, the present article is aimed at providing the state of the art on the use of brain stimulation techniques for the treatment of OCD.

The impact of psychosis on brain anatomy in bipolar disorder: A structural MRI study.

BACKGROUND: Bipolar disorder (BD) is a major psychiatric illness characterized by heterogeneous symptoms including psychotic features. Up until now, neuroimaging studies investigating cerebral morphology in patients with BD have underestimated the potential impact of psychosis on brain anatomy in BD patients. In this regard, psychotic and non-psychotic BD may represent biologically different subtypes of the disorder, being possibly associated with specific cerebral features. METHODS: In the present study, magnetic resonance imaging (MRI) at 3T was used to identify the neuroanatomical correlates of psychosis in an International sample of BD patients. A large sample of structural MRI data from healthy subjects (HC) and BD patients was collected across two research centers. Voxel based morphometry was used to compare gray matter (GM) volume among psychotic and non-psychotic BD patients and HC. RESULTS: We found specific structural alterations in the two patient groups, more extended in the psychotic sample. Psychotic patients showed GM volume deficits in left frontal cortex compared to HC, and in right temporo-parietal cortex compared to both HC and non-psychotic patients (p < 0.001, > 100 voxels). Psychotic patients also exhibited enhanced age-related GM volume deficits in a set of subcortical and cortical regions. LIMITATIONS: The integration of multiple datasets may have affected the results. CONCLUSIONS: Overall, our results confirm the importance of classifying BD based on psychosis. The knowledge of the neuronal bases of psychotic symptomatology in BD can provide a more comprehensive picture of the determinants of BD, in the light of the continuum characteristic of major psychoses.

Clinical characterization of Italian suicide attempters with bipolar disorder.

IntroductionBipolar disorder (BD) is a chronic, highly disabling condition associated with psychiatric/medical comorbidity and substantive morbidity, mortality, and suicide risks. In prior reports, varying parameters have been associated with suicide risk. OBJECTIVES: To evaluate sociodemographic and clinical variables characterizing Italian individuals with BD with versus without prior suicide attempt (PSA). METHODS: A sample of 362 Italian patients categorized as BD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM IV-TR) was assessed and divided in 2 subgroups: with and without PSA. Sociodemographic and clinical variables were compared between prior attempters and non-attempters using corrected multivariate analysis of variance (MANOVA). RESULTS: More than one-fourth of BD patients (26.2%) had a PSA, with approximately one-third (31%) of these having>1 PSA. Depressive polarity at onset, higher number of psychiatric hospitalizations, comorbid alcohol abuse, comorbid eating disorders, and psychiatric poly-comorbidity were significantly more frequent (p<.05) in patients with versus without PSA. Additionally, treatment with lithium, polypharmacotherapy (≥4 current drugs) and previous psychosocial rehabilitation were significantly more often present in patients with versus without PSA. CONCLUSIONS: We found several clinical variables associated with PSA in BD patients. Even though these retrospective findings did not address causality, they could be clinically relevant to better understanding suicidal behavior in BD and adopting proper strategies to prevent suicide in higher risk patients.

Differentiating multiple vs single lifetime suicide attempters with bipolar disorders: A retrospective study.

BACKGROUND: The risk of suicide in Bipolar Disorder (BD) has been estimated up to 20-30 times higher compared with the general population. Previous suicide attempts (SAs) represent a well-established risk factor for further attempts and for death by suicide in patients with psychiatric disorders. However, little is known about the socio-demographic and clinical profile of BD patients with a history of multiple SAs (MSAs). The present study sought to characterize BD patients with MSAs versus single suicide attempt (SSA) within a large Italian sample. METHODS: An original sample of 354 bipolar patients, recruited at the University Clinic and related community services at the Department of Psychiatry, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan (Italy), was screened for the presence of previous SAs (n=95). Socio-demographic and clinical variables were then compared between patients with multiple vs single lifetime suicide attempts. RESULTS: Bipolar patients with MSAs versus SSA had longer bipolar illness duration (26.9±12.6 vs 21.2±12.8years; p=0.05), and more frequently lived alone (38.5% vs 17.2%; p<0.05), had more than one psychiatric comorbidity (39.3% vs 17.5%; p=0.04), and utilized substance ingestion (e.g., overdose) (78.6% vs 47.2%, p=0.009), although the latter was the most common suicide attempt method in both groups. CONCLUSION: Present findings suggest different socio-demographic and clinical characteristics in bipolar patients with MSAs versus SSA. Further investigation is needed to confirm reported data.

Prevalences of autoimmune diseases in schizophrenia, bipolar I and II disorder, and controls.

Previous studies on the relationship between autoimmune diseases, schizophrenia, and bipolar disorder are mainly based on hospital discharge registers with insufficient coverage of outpatient data. Furthermore, data is scant on the prevalence of autoimmune diseases in bipolar subgroups. Here we estimate the self-reported prevalences of autoimmune diseases in schizophrenia, bipolar disorder type I and II, and controls. Lifetime prevalence of autoimmune diseases was assessed through a structured interview in a sample of 9076 patients (schizophrenia N = 5278, bipolar disorder type I N = 1952, type II N = 1846) and 6485 controls. Comparative analyses were performed using logistic regressions. The prevalence of diabetes type 1 did not differ between groups. Hyperthyroidism, hypothyroidism regardless of lithium effects, rheumatoid arthritis, and polymyalgia rheumatica were most common in bipolar disorder. Systemic lupus erythematosus was less common in bipolar disorder than in the other groups. The rate of autoimmune diseases did not differ significantly between bipolar subgroups. We conclude that prevalences of autoimmune diseases show clear differences between schizophrenia and bipolar disorder, but not between the bipolar subgroups.