A double-blind, randomized, placebo-controlled plus open trial of adjunctive suvorexant for treatment-resistant insomnia in patients with bipolar disorder.

BACKGROUND: Sleep pattern alteration is a core feature of bipolar disorder (BD), often challenging to treat and affecting clinical outcomes. Suvorexant, a hypnotic agent that decreases wakefulness, has shown promising results in treating primary insomnia. To date, data on its use in BD are lacking. This study evaluated the efficacy and tolerability of adjunctive suvorexant for treatment-resistant insomnia in BD patients. METHODS: Thirty-six BD outpatients (19 BDI, 69.4% female, 48.9 [±15.2] years) were randomized for 1 week to double-blind suvorexant (10-20 mg/day) versus placebo. Then, all subjects who completed the randomized phase were offered open suvorexant for 3 months. Subjective total sleep time (sTST) and objective total sleep time (oTST) were assessed. RESULTS: During the randomized control trial (RCT) phase, an overall increase in the oTST emerged, which was statistically significant for the Cole-Kripke algorithm (p = 0.035). The comparison between the suvorexant and placebo groups was limited by significant differences between measurements at baseline. During the open phase, no significant improvement was detected relative to either sTST and oTST. No adverse events nor major intolerances were reported. DISCUSSION: Efficacy results are inconsistent. During the RCT phase, only a small increase in the objective oTST emerged, while during the open phase, no significant improvement was detected. While this is the first ever study of suvorexant in BD-related insomnia, the limitation of the small sample and the high rate of dropouts limits the generalizability of these findings. Larger studies are needed to assess suvorexant in treating BD-related insomnia.

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 relationship among posttraumatic stress disorder, posttraumatic growth, and suicidal ideation among Italian healthcare workers during the first wave of COVID-19 pandemic.

OBJECTIVE: The COVID-19 pandemic impacted mental health across different groups, including healthcare workers (HWs). To date, few studies focused on potential positive aspects that may follow the exposure to the pandemic. We investigated the prevalence of posttraumatic stress disorder (PTSD) in Italian HWs and whether posttraumatic growth (PTG) dimensions affected the risk of suicidal ideation (SI) during the first COVID-19 wave. METHODS: An online self-report survey was conducted between April and May 2020. Sociodemographic data, information about COVID-19-related stressful events, Impact of the Event Scale-revised, and Post-Traumatic Growth Inventory-Short Form (PTGI-SF) scores were collected and compared between participants. Patient Health Questionnaire-9 scores were also collected to assess SI through item 9. Multivariate logistic regression was used to assess the relationship between PTGI and SI. RESULTS: Among 948 HWs, 257 (27.0%) reported a provisional PTSD diagnosis. The median PTGI-SF score was 24. Participants reporting PTSD symptoms had higher scores in the Spiritual change, Appreciation of life, and New possibilities domains, and in the total PTG scale. A total of 100 HWs (10.8%) screened positive for SI. Improvements in Relating to others domain of PTGI-SF (odds ratioOR: .46; 95% confidence interval: .25-.85) were associated with lower odds of SI. CONCLUSIONS: COVID-19 pandemic has been indicated as a risk factor for SI, also among HWs. PTG may have a protective role on suicide risk. Improvements in Relating to others domain reduced odds of SI, consistently with the role of loneliness and lack of connectedness with others in enhancing suicidal risk.

Relevance of pharmacogenetic analyses and therapeutic drug monitoring of antidepressants for an individualized treatment of peripartum psychopathology.

OBJECTIVE: Psychiatric disorders burden the peripartum period, often requiring psychopharmacological treatment, including antidepressants. Efficacy and tolerability of antidepressants are influenced by the physiological changes of the peripartum and individual metabolic profiles, which in turn can be modified by pregnancy. The objective of this study is to assess the relationship between antidepressants' pharmacokinetic profiles during pregnancy and individual metabolic profiles, along with the efficacy of the treatment. METHODS: In total 87 outpatients with diagnoses of bipolar disorder, major depression, anxiety, obsessive-compulsive disorder and post-traumatic stress disorder who required antidepressant treatment during pregnancy were recruited. Genotyping analysis of hepatic cytochrome P450 (CYPs) individual isoforms was performed. Antidepressants' blood concentrations and psychometric assessments were collected at five time points. Antidepressants' cord blood concentrations were assessed at birth. RESULTS: Sertraline showed greater stability in plasma concentrations and a lower placental penetrance index. Most of the antidepressants' concentrations below the therapeutic range were found in women with an extensive/ultrarapid metabolic profile. Antidepressants mainly metabolized by CYP2C19 were less frequently below the therapeutic range compared with antidepressants metabolized by CYP2D6. CONCLUSIONS: Pregnancy modulates cytochrome activity and drugs' pharmacokinetics. Genotyping analysis of CYPs isoforms and therapeutic drug monitoring might be used to guide clinicians in a well-tolerated treatment of psychiatric symptoms in pregnant women.

Barriers to the use of three-month Paliperidone Palmitate formulation: a study from an Italian real-world setting.

BACKGROUND: Long-acting injectable paliperidone can improve adherence in psychotic patients and reduce relapses and healthcare resource utilization (HRU). This study compares the effectiveness of the three-monthly paliperidone palmitate (PP3M) with the one-monthly formulation (PP1M) and investigates reasons that hinder the use of PP3M in real-world settings. METHODS: The authors conducted a three-phase observational study. For subjects recruited from six psychiatric services in Milan, HRU outcomes of PP3M prescription were evaluated through a 12-month mirror-image design (phase 1) and a comparison of HRU of PP1M-only subjects and PP3M subjects during the year prior to PP3M initiation (phase 2). Lastly, they conducted a survey among physicians concerning reasons for not switching to PP3M (phase 3). RESULTS: A total of 119 subjects (61 on PP3M and 58 on PP1M) were included. One year after PP3M initiation, outpatients' visits decreased significantly. Comparing PP3M with PP1M subjects, no significant difference was found in HRU. Perception of patient's unstable clinical condition was the main reason for maintaining PP1M (32.8%), followed by the need for monthly monitoring (19.7%). CONCLUSION: PP3M initiation was associated with an overall HRU reduction. Subjects switched to PP3M had similar HRU when compared to those who did not, suggesting similar clinical conditions in both groups.

Gender impact on the outcome of rehabilitation programs in psychiatry: Brief report from a metropolitan residential rehabilitative service.

Background: Differences based on gender in the presentation and outcome of many psychiatric conditions have been highlighted in the past years. Moreover, women are often underrepresented in research samples, thus leading to a poorer understanding and addressing of their needs. As regards psychiatric rehabilitation, few studies have focused on the influence of gender on the outcomes of rehabilitation programs. Objectives: This study aimed to analyze the impact of gender on socio-demographic and clinical characteristics, as well as on main rehabilitation outcomes, in a sample of subjects undergoing rehabilitation programs in a metropolitan residential service. Methods: We collected socio-demographic, clinical variables and rehabilitation outcomes of all subjects discharged from the metropolitan residential rehabilitative service of the Luigi Sacco Hospital in Milan, Italy, from January 2015 to December 2021. Gender differences were analyzed through t-test and chi-square for continuous and categorical variables, respectively. Results: In a total sample of 129 subjects equally distributed for gender (50.4% women), all subjects improved after their rehabilitation program, as measured through specific psychometric scales. However, women had a higher proportion of discharges to their own household (52.3% vs. 25% of men). They also showed higher educational status (53.8% completed high school vs. 31.3% of men). Clinically, they showed longer duration of untreated illness (3.6 ± 7.31 vs. 1.06 ± 2.35 years) and lower frequency of substance use disorders compared to men (6.4% vs. 35.9%). Conclusion: The main result of this study shows, in light of an equal improvement in psychopathological and psychosocial functioning after the rehabilitation program, better outcomes in women compared to men, with a higher frequency of return to their own household after the completion of a rehabilitation program compared to men.

The Impact of COVID-19 Pandemic First Wave on Healthcare Workers: A New Perspective from Qualifying PTSD Criterion A to Assessing Post-Traumatic Growth.

Post-traumatic growth (PTG) and specific traumatic events have been poorly explored in the literature focusing on post-traumatic stress disorder (PTSD) among healthcare workers (HWs) tackling the COVID-19 pandemic. In a large sample of Italian HWs, we investigated the kinds of traumatic events and whether PTG affects the risk of PTSD, along with its prevalence and features, during the first COVID-19 wave. COVID-19-related stressful events, Impact of Event Scale-Revised (IES-R) and PTG Inventory-Short Form (PTGI-SF) scores were collected through an online survey. Out of 930 HWs included in the final sample, 257 (27.6%) received a provisional PTSD diagnosis based on IES-R scores. Events referring to the overall pandemic (40%) and to a threat to a family member (31%) were reported as the most stressful events. Female sex, previous mental disorders, job seniority, unusual exposure to sufferance and experiencing a threat to one's family significantly increased the provisional PTSD diagnosis' risk, while being a physician, the availability of personal protective equipment and moderate/greater scores on the PTGI-SF spiritual change domain were found to be protective factors.

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.

The impact of COVID-19 on the psychiatric emergency departments of two Italian hospitals in Milan.

During the first wave of the SARS-CoV-2 contagion in Italy, mental health care services continuity has been granted to the general population. Emergent and urgent conditions, however, are managed in collaboration with Emergency Departments (EDs). This collaboration may have suffered from the overload of the EDs due to the high number of SARS-CoV-2 positive patients. In this perspective, we analysed the possible impact of COVID-19 on the EDs accesses of psychiatric patients in two of the main hospitals of Milan, the "Luigi Sacco" Hospital and the "Fatebenefratelli" Hospital, comparing their admissions between the periods of March, April and May 2019 and 2020. We found a significant reduction in the number of evaluated patients in 2020 in both EDs. Emergency Medical Services (EMSs) brought a significant lower number of patients to the ED of Sacco Hospital during 2020, while this number increased for the ED of Fatebenefratelli Hospital, confirming the hypothesis that the overload of the Sacco Hospital ED significantly influenced the possibility to receive a psychiatric evaluation there. Moreover, we found a significant difference between diagnosis at discharge of the different samples.

Assessing response, remission, and treatment resistance in patients with obsessive-compulsive disorder with and without tic disorders: results from a multicenter study.

BACKGROUND: Highlighting the relationship between obsessive-compulsive disorder (OCD) and tic disorder (TD), two highly disabling, comorbid, and difficult-to-treat conditions, Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) acknowledged a new "tic-related" specifier for OCD, ie, obsessive-compulsive tic-related disorder (OCTD). As patients with OCTD may frequently show poor treatment response, the aim of this multicenter study was to investigate rates and clinical correlates of response, remission, and treatment resistance in a large multicenter sample of OCD patients with versus without tics. METHODS: A sample of 398 patients with a DSM-5 diagnosis of OCD with and without comorbid TD was assessed from 10 different psychiatric departments across Italy. For the purpose of the study, treatment response profiles in the whole sample were analyzed comparing the rates of response, remission, and treatment-resistance as well as related clinical features. Multivariate logistic regressions were performed to identify possible factors associated with treatment response. RESULTS: The remission group was associated with later ages of onset of TD and OCD. Moreover, significantly higher rates of psychiatric comorbidities, TD, and lifetime suicidal ideation and attempts emerged in the treatment-resistant group, with larger degrees of perceived worsened quality of life and family involvement. CONCLUSIONS: Although remission was associated with later ages of OCD and TD onset, specific clinical factors, such as early onset and presence of psychiatric comorbidities and concomitant TD, predicted a worse treatment response with a significant impairment in quality of life for both patients and their caregivers, suggesting a worse profile of treatment response for patients with OCTD.

Do adolescents and young adults accessing the Emergency Room with substance use receive poor therapeutic indications at discharge? An observational retrospective study.

PURPOSE: Emergency rooms (ERs) are usually the first point of contact with mental health services for adolescents with Substance Use Disorders (SUDs). However, only a minority of them receives proper treatment and follow-up indications, increasing the risk of relapses and poor prognosis. In this perspective, we sought to characterize and compare socio-demographic and clinical characteristics of adolescents with vs without SUDs accessing the ER, assessing potential differences in terms of discharge instructions. METHODS: A sample of 557 ER accesses of patients aged 15-25 years old in need of a psychiatric evaluation or with a psychiatric diagnosis at discharge was retrospectively analyzed. Patients were divided in two subgroups according to the presence of SUDs. RESULTS: About 32.1% of patients had SUDs when accessing the ER. Among these, 62% were unknown to any psychiatric services and 57% were at their psychiatric onset. Nevertheless, considering discharge instructions, patients with current substance use received less therapeutic indication or were less frequently referred to psychiatric facilities, than those without substance use (57.8% vs 42.2%, P = .002). CONCLUSIONS: Substance abuse is strongly linked to psychopathology and ER accesses in young patients. However, we observed a large rate of SUDs patients unknown by any specialized mental health service, who received poor therapeutic and follow-up instructions at discharge. Improving communication between ER operators and young patients with SUDs could longitudinally reduce the risk of addiction and related disability, morbidity and mortality.

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.

Has Bipolar Disorder become a predominantly female gender related condition? Analysis of recently published large sample studies.

Bipolar Disorders (BD) are disabling and severe psychiatric disorders, commonly perceived as equally affecting both men and women. The prevalence of BD in the general population has been growing over the last decade, however, few epidemiological studies are available regarding BD gender distribution, leaving unanswered the question whether the often reported increment of BD diagnosis could be gender specific. In fact, BD in female patients can often be misdiagnosed as MDD, leaving such women non correctly treated for longer times than their male counterparts. From this perspective, we searched literature for large sample (> 1000 subjects) studies published in the last decade (2010 onward) on BD patients. We included ten large sample studies that reported the gender distribution of their samples, and we therefore analysed them. Our results show a higher preponderance of female patients in every sample and sub-sample of BDI and BDII, supporting our hypothesis of an increase in BD diagnosis in females. BD in women presents with higher rates of rapid cycling, depressive polarity and suicide attempts, characteristics of non inferior severity compared to males; prompt recognition and adequate treatment of BD is therefore crucial to reduce risks and improve quality of life of affected women. In this regard, our results could lead the way for national or international epidemiological studies with the aim of more accurately assessing gender-specific prevalence of BD.

Correlation between pharmacokinetics and pharmacogenetics of Selective Serotonin Reuptake Inhibitors and Selective Serotonin and Noradrenaline Reuptake Inhibitors and maternal and neonatal outcomes: Results from a naturalistic study in patients with affective disorders.

OBJECTIVE: Some studies have linked the use of selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors (SSRIs/SNRIs) to the risk of perinatal complications. This study explored the relationship between pharmacokinetics and pharmacogenetics, SSRIs/SNRIs tolerability and effectiveness and maternal and newborn outcomes. METHODS: Fifty-five pregnant women with Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnoses of affective disorders, treated with SSRIs/SNRIs, were recruited and, during the third trimester, their blood samples were collected for pharmacokinetic and pharmacogenetic analyses. Plasma levels and metabolic phenotypes were then related to different obstetrical and maternal outcomes. RESULTS: The pharmacokinetic data were more stable for Sertraline, Citalopram, and Escitalopram compared to other molecules (p = 0.009). The occurrence of postnatal adaptation syndrome onset was associated with higher plasma levels for Sertraline (median at delivery: 16.7 vs. 10.5 ng/ml), but not for fluoxetine and venlafaxine. Finally, the subgroup within range plasma concentrations had less blood loss than the below range subgroup (p = 0.030). CONCLUSIONS: Plasma levels of Sertraline, Citalopram and Escitalopram were more frequently in range in late pregnancy when compared to other drugs. Drug plasma concentrations do not strictly correlate with worse perinatal outcomes, but with possible differences between the different drugs.