The interplay between mentalization, personality traits and burnout in psychiatry training: Results from a large multicenter controlled study.

BACKGROUND: A better characterization of educational processes during psychiatry training is needed, both to foster personal resilience and occupational proficiency. METHODS: An adequate coverage of medical residents at the national level was reached (41.86% of the total reference population, 29 out of 36 training centers-80.55%). Controls were recruited among residents in other medical specialties. All participants were assessed by questionnaires to evaluate early life experiences, attachment style, personality traits, coping strategies, emotional competencies. A Structural Equation Model (SEM) framework was employed to investigate the interplay between individual factors. RESULTS: A total sample of 936 people was recruited (87.9% response-rate; 645 residents in psychiatry, 291 other medical residents). Psychiatry trainees reported a higher prevalence of adverse childhood experiences (emotional abuse, emotional neglect, physical neglect), greater attachment insecurity (anxious or avoidant) in comparison to other medical trainees. Psychiatry residents also reported higher social support-seeking as a coping strategy, lower problem-orientation, and lower transcendence. Lower neuroticism, higher openness to experience, and higher emotional awareness were also observed in psychiatry trainees. Psychiatry training was associated with a redefinition of conflict management skills as a function of seniority. The SEM model provided support for an interplay between early traumatic experiences, mentalization skills (coping strategies, emotion regulation), interpersonal competencies and occupational distress. CONCLUSIONS: The findings of the present study supported a theoretical model based on mentalization theory for the interactions between personal and relational competencies in psychiatry training, thus providing potential target of remodulation and redefinition of this specific process of education.

Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

Objective: Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as "borderline." Methods: Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the "borderline" individual with moderate anxiety and obsessive-compulsive traits. Results: The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a "borderline" phenotype that, if combined with a heterozygous missense variant in ZNF92, is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. Conclusions: Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92.

Two-Injection Start Regimen of Long-Acting Aripiprazole in 133 Patients With Schizophrenia.

PURPOSE/BACKGROUND: Based on a population-pharmacokinetic model, the European Medicines Agency has recently approved a simplified starting strategy of aripiprazole once a month (AOM), injectable and long-acting antipsychotic, with two 400 mg injections and a single oral 20 mg dose of aripiprazole, administered on the same day, instead of 1 injection and 14 daily administrations of concurrent oral aripiprazole. However, to our knowledge, no previous study has reported the safety and tolerability of this regimen in real-world patients. METHODS/PROCEDURES: We retrospectively reviewed medical records of 133 patients who received the newly approved 2-injection start regimen as part of their standard care in 10 Italian clinical centers. FINDINGS/RESULTS: Adverse effects were mild or moderate, with no clinically evident difference from the adverse effects observed in previous trials where AOM was started with a single injection followed by 14 days of orally administered aripiprazole. None of the patients who started AOM after the 2-injection start regimen experienced severe adverse effects or severe adverse effects. IMPLICATIONS/CONCLUSIONS: The coadministration of 2 injections of 400 mg aripiprazole and 20 mg oral aripiprazole was not associated with safety concerns beyond those reported after a single injection followed by 14 days of orally administered aripiprazole. Our results should be interpreted with caution, due to the limited sample size and to the retrospective design of the study.

Effectiveness of light therapy as adjunctive treatment in bipolar depression: A pilot study.

BACKGROUND: About 1 and 4 % of people suffering from depression is affected by bipolar disorder. Few patients respond to the first-line antidepressants, and a 4-week latency pharmacological treatment period has been observed. This pilot study aimed to evaluate the effectiveness and safety of bright light therapy (BLT) in accelerating and increasing therapeutic response in patients with bipolar depression. METHODS: A pilot study was conducted. Patients with bipolar depression, already treated with antidepressants, were included. The treatment group was composed of patients treated with antidepressants combined with BLT (30 min/4 days a week at 10,000 lx for eight weeks). The control group included patients treated with antidepressants with exposure to red light (30 min/4 days a week at a red light for eight weeks). MADRS, HAMD-17, CGI-S, FSS, and QoLS were collected at the baseline and after 4 and 8 weeks of treatments. RESULTS: Forty-one patients (18 males and 23 females; mean age 49.1 ± 15 years) were included in the study. After four weeks, MADRS and HAMD-17 scores in treatment groups were significantly lower than those reported in the control group (p < 0.001). After eight weeks, all scales except FSS reported significantly lower values in patients treated with BLT (p < 0.0001). LIMITATIONS: Small sample size and significant heterogeneity in the antidepressant treatments. CONCLUSION: BLT has shown reliable effectiveness and safety in treating patients with bipolar depression and should be considered a clinically relevant approach in accelerating patients' therapeutic response and reducing the impact of long-lasting therapy.

Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder.

OBJECTIVE: Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as "borderline." METHODS: Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the "borderline" individual with moderate anxiety and obsessive-compulsive traits. RESULTS: The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a "borderline" phenotype that, if combined with a heterozygous missense variant in ZNF92, is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. CONCLUSIONS: Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92.

Neuroticism and Conscientiousness Moderate the Effect of Oral Medication Beliefs on Adherence of People with Mental Illness during the Pandemic.

BACKGROUND: After the declaration of the pandemic status in several countries, the continuity of face-to-face visits in psychiatric facilities has been delayed or even interrupted to reduce viral spread. Little is known about the personality factors associated with medication beliefs and adherence amongst individuals with mental illness during the COVID-19 pandemic. This brief report describes a preliminary naturalistic longitudinal study that explored whether the Big Five personality traits prospectively moderate the effects of medication beliefs on changes in adherence during the pandemic for a group of outpatients with psychosis or bipolar disorder. METHODS: Thirteen outpatients undergoing routine face-to-face follow-up assessments during the pandemic were included (41 observations overall) and completed the Revised Italian Version of the Ten-Item Personality Inventory, the Beliefs about Medicines Questionnaire, the Morisky Medication Adherence Scale-8-item and the Beck Depression Inventory-II. RESULTS: Participants had stronger concerns about their psychiatric medications rather than beliefs about their necessity, and adherence to medications was generally low. Participants who had more necessity beliefs than concerns had better adherence to medications. People scoring higher in Conscientiousness and Neuroticism traits and more concerned about the medication side effects had poorer adherence. CONCLUSIONS: These preliminary data suggest the importance of a careful assessment of the adherence to medications amongst people with psychosis/bipolar disorder during the pandemic. Interventions aimed to improve adherence might focus on patients' medication beliefs and their Conscientiousness and Neuroticism personality traits.

Treatment persistence with aripiprazole once monthly: a 4-year follow-up.

OBJECTIVES: Treatment persistence refers to the act of continuing a treatment as prescribed and reflects the patient's or doctor's judgment about efficacy, tolerability, and acceptability. In patients with schizophrenia, antipsychotic persistence is often poor, because of issues such as lack or loss of efficacy, side effects, and poor adherence, which is often related to the degree to which patients find the medication and overall intervention to be helpful, tolerable, fair, reasonable, appropriate, and consistent with expectations of treatment. Despite the poor antipsychotic persistence that has been reported to date in patients with schizophrenia, we previously observed a relatively high (86%) 6 months persistence with aripiprazole once-monthly (AOM) in a group of patients with schizophrenia, treated in the real world Italian clinical practice. The present study explores the longer term persistence with AOM, over a mean follow-up period of 48 months. METHODS: This was a multicenter, retrospective, non-interventional follow-up study, aimed at evaluating the longer term persistence with AOM in a group of patients with schizophrenia who had already shown persistence over a period of at least 6 months. The study included 161 individuals who had participated in our previous study, where 86% of participating individuals had shown persistence with AOM for at least 6 months. Non-persistence was defined as discontinuing the medication for any reason. Baseline demographic and clinical characteristics of patients who continued AOM were then compared to those of patients who discontinued the medication. RESULTS: Study subjects were predominantly male (64.4%) and their mean age was 39.7 (SD: 12.24). Treatment persistence with AOM was 69.6% and 112 out of 161 patients were still receiving AOM treatment at the last follow-up visit. The mean duration of AOM treatment until the last recorded observation was 55.87 months (median 56.17, SD6.23) for the 112 persistent patients and 32.23 (median 28.68.SD 15.09) months for the 49 non-persistent individuals. The mean observation period for all patients (persistent and non-persistent) was 48.78 months (median 52.54, SD 14.64). For non-persistent subjects, the observation period ended with the discontinuation of AOM. Subjects treated with AOM at 400 mg presented a 69.6% lower risk of all-cause treatment discontinuation when compared with patients treated with 300 mg (HR: 0.314; 95% confidence interval [CI] 0.162-0.608; P = 0.001). The main reasons for discontinuation were lack of efficacy (30.6%), patient/caregiver choice (18.4%), physician's choice (16.3%), non-adherence (12.2%) and inconvenience (6.1%). Only 3 patients (6.1%) discontinued AOM for tolerability issues. CONCLUSIONS: In subjects with schizophrenia, who had already shown a 6 months persistence with AOM, a high number of patients (69.6%) continued to be persistent over a 4-year follow-up period. This may reflect a favourable profile of efficacy, tolerability, and acceptability. Larger and prospective studies are warranted to confirm our observations.

High depression symptomatology and mental pain characterize suicidal psychiatric patients.

BACKGROUND: Symptoms of depression are transdiagnostic heterogenous features frequently assessed in psychiatric disorders, that impact the response to first-line treatment and are associated with higher suicide risk. This study assessed whether severe mental pain could characterize a specific phenotype of severely depressed high-risk psychiatric patients. We also aimed to analyze differences in treatments administered. METHODS: 2,297 adult patients (1,404 females and 893 males; mean age = 43.25 years, SD = 15.15) treated in several Italian psychiatric departments. Patients were assessed for psychiatric diagnoses, mental pain, symptoms of depression, hopelessness, and suicide risk. RESULTS: More than 23% of the patients reported high depression symptomatology and high mental pain (HI DEP/HI PAIN). Compared to patients with lower symptoms of depression, HI DEP/HI PAIN is more frequent among females admitted to an inpatient department and is associated with higher hopelessness and suicide risk. In addition, HI DEP/HI PAIN (compared to both patients with lower symptoms of depression and patients with higher symptoms of depression but lower mental pain) were more frequently diagnosed in patients with personality disorders and had different treatments. CONCLUSIONS: Patients reporting severe symptoms of depression and high mental pain presented a mixture of particular dangerousness (high trait hopelessness and the presence of suicide ideation with more frequency and less controllability and previous suicide behaviors). The presence of severe mental pain may act synergically in expressing a clinical phenotype that is likewise treated with a more complex therapeutic regime than that administered to those experiencing symptoms of depression without mental pain.

Radiofrequency echographic multispectrometry (REMS): an innovative technique for the assessment of bone status in young women with anorexia nervosa.

PURPOSE: Reduced bone mineral density (BMD) and increase risk of fragility fracture are common complication of anorexia nervosa (AN). BMD by dual-energy X-ray absorptiometry (DXA) present several limits in subjects with AN. This study aimed to evaluate the usefulness of the new Radiofrequency echographic multispectrometry (REMS) technique in the assessment of bone status in young women with AN. METHODS: In a cohort of 50 subjects with restrictive AN and in 30 healthy controls, we measured BMD at the lumbar spine (LS-BMD), at femoral neck (FN-BMD) and total hip (TH-BMD) using both DXA and REMS technique. RESULTS: BMD evaluated by DXA and REMS technique at all measurement sites were all significantly (p < 0.01) lower in subjects suffering from AN subjects than in controls. Good correlations were detected between BMD by DXA and BMD by REMS measurements at LS (r = 0.64, p < 0.01) at FN (r = 0.86, p < 0.01) and at TH (r = 0.84, p < 0.01) in subjects suffering from AN. Moreover, Bland-Altman analysis confirmed the good agreement between the two techniques. The subjects suffering from AN with previous vertebral fragility fractures presented lower values of both BMD-LS and BMD-TH by DXA and by REMS with respect to those without fractures; however, the difference was significant only for BMD-TH by REMS (p < 0.05). CONCLUSIONS: Our data suggest that REMS technique due to its characteristic of precision and reproducibility may represent an important tool for the evaluation of the changes in bone status in AN young women, especially during the fertile age and in case of pregnancy and breastfeeding. LEVEL OF EVIDENCE: Level of evidence: level III cohort study.

Effectiveness and Tolerability of Supratherapeutic Dosing of Vortioxetine in Patients With Treatment-Resistant Depression.

Objective: To evaluate the effectiveness and tolerability of vortioxetine at supratherapeutic dosages in patients with treatment-resistant depression.Methods: A retrospective observational naturalistic study was conducted in 56 depressed patients resistant to standard care treatment from September 2020 to April 2021. Effectiveness of the vortioxetine treatments was evaluated through Clinical Global Impressions (CGI) score, comparing CGI values at the beginning (T0) of the vortioxetine treatment with CGI values at the earliest of these 2 time points (T1): (1) 8 weeks of treatment with supratherapeutic dosages and (2) day of vortioxetine discontinuation or daily dosage reduction to ≤ 20 mg due to side effects. The tolerability and safe of vortioxetine were also monitored.Results: Fifty-six patients (32 females and 24 males, mean ± SD age of 51.1 ± 9.3 years) were included in the study. Thirty-seven patients received vortioxetine 30 mg/d, while 19 patients were treated with a 40-mg/d dosage. CGI scores significantly decreased (P < .001) in patients treated with 30 mg/d and 40 mg/d, respectively. No severe side effects were reported. Weight gain and nausea were the most common reported side effects. Nausea and limited efficacy were recorded as the most frequent reasons for vortioxetine dose reduction. None of the patients required vortioxetine discontinuation.Conclusions: Supratherapeutic doses of vortioxetine were relatively well-tolerated and effective in patients with treatment-resistant depression.

Exploration of mood spectrum symptoms during a major depressive episode: The impact of contrapolarity-Results from a transdiagnostic cluster analysis on an Italian sample of unipolar and bipolar patients.

BACKGROUND: Subthreshold hypomania during a major depressive episode challenges the bipolar-unipolar dichotomy. In our study we employed a cross-diagnostic cluster analysis - to identify distinct subgroups within a cohort of depressed patients. METHODS: A k-means cluster analysis- based on the domain scores of the Mood Spectrum Self-Report (MOODS-SR) questionnaire-was performed on a data set of 300 adults with either bipolar or unipolar depression. After identifying groups, between-clusters comparisons were conducted on MOODS-SR domains and factors and on a set of sociodemographic, clinical and psychometric variables. RESULTS: Three clusters were identified: one with intermediate depressive and poor manic symptomatology (Mild), one with severe depressive and poor manic symptomatology (Moderate), and a third one with severe depressive and intermediate manic symptomatology (Mixed). Across the clusters, bipolar patients were significantly less represented in the Mild one, while the DSM-5 "Mixed features" specifier did not differentiate the groups. When compared to the other patients, those of Mixed cluster exhibited a stronger association with most of the illness-severity, quality of life, and outcomes measures considered. After performing pairwise comparisons significant differences between "Mixed" and "Moderate" clusters were restricted to: current and disease-onset age, psychotic ideation, suicidal attempts, hospitalization numbers, impulsivity levels and comorbidity for Cluster B personality disorder. CONCLUSIONS: In the present study, a clustering approach based on a spectrum exploration of mood symptomatology led to the identification of three transdiagnostic groups of patients. Consistent with our hypothesis, the magnitude of subthreshold (hypo)manic symptoms was related to a greater clinical severity, regardless of the main categorical diagnosis.

The interplay between acute post-traumatic stress, depressive and anxiety symptoms on healthcare workers functioning during the COVID-19 emergency: A multicenter study comparing regions with increasing pandemic incidence.

BACKGROUND: Healthcare workers (HCWs) deployed to the frontline during the COVID-19 pandemic are at risk for developing mental disorders, with a possible impact on their wellbeing and functioning. The present study aimed at investigating post-traumatic stress symptoms (PTSS), anxiety and depressive symptoms and their relationships with impairment in the functioning impairment among frontline HCWs from three Italian regions differently exposed to the first wave of the COVID-19 emergency: Tuscany (low), Emilia-Romagna (medium) and Lombardy (high). METHODS: 514 frontline HCWs were consecutively enrolled in hospital units devoted to the treatment of COVID-19 patients. They completed the IES-R, PHQ-9 and GAD-7 to assess PTSS, depressive and anxiety symptoms respectively, and the WSAS to investigate functioning impairment. RESULTS: A total of 23.5% of HCWs reported severe PTSS, 22.4% moderate-severe anxiety symptoms, 19.3% moderate-severe depressive symptoms and 22.8% impairment in global functioning. HCWs from the higher-exposure regions reported significantly higher scores in all instruments than those from lower-exposure regions. In a multiple linear regression model, PTSS, depressive and anxiety symptoms presented a significant positive association with the functioning impairment. Both PTSS and depression resulted to be independently related to functioning impairment. LIMITATIONS: The cross-sectional design and the use of self-report instruments. CONCLUSIONS: Depressive and PTSS appear to be the greatest contributors to functioning impairment in HCWs exposed to a massive stressful sanitary event as the COVID-19 pandemic. A more accurate assessment of work-related mental health outcomes in such population could help planning effective prevention strategies and therapeutic interventions.

Which mixed depression model? A comparison between DSM-5-defined mixed features and Koukopoulos' criteria.

BACKGROUND: The criteria of the Diagnostic and Statistical Manual of Mental Disorders 5th edition "with mixed features specifier" (DSM-5 MFS) are considered controversial since they include only typical manic symptoms. By contrast, Koukopoulos developed an alternative model of mixed depression (MxD) focusing primarily on the excitatory component. OBJECTIVE: To compare DSM-5 MFS and Koukopoulos' MxD (KMxD) in terms of prevalence, associated clinical variables, and discriminative capacity for bipolar depression in patients with major depressive episode (MDE). METHODS: A total of 300 patients with MDE-155 with major depressive disorder and 145 with bipolar disorder (BD)-were recruited. The discriminative capacity of DSM-5 MFS and KMxD criteria for BD was estimated using the area under the curves of receiver operating characteristic (ROC_AUC). The clinical variables associated with these two diagnostic constructs were assessed by performing a logistic regression. RESULTS: A total of 44 and 165 patients met the DSM-5 MFS and KMxD criteria, respectively. The ROC_AUCs and their confidence intervals for BD according to DSM-5 MFS and KMxD were 77.0% (72.0%-82.1%) and 71.9% (66.2%-77.7%), respectively. The optimal thresholds (combining sensitivity and specificity measures) for BD diagnosis were ≥1 (77%/68%) for DSM-5 MFS and ≥3 symptoms (78%/66%) for KMxD. However, considering the DSM-5 MFS cut-off (≥3 symptoms), the specificity (97%) increased at the expense of sensitivity (26%). CONCLUSIONS: KMxD and DSM-5-MFS showed an overlapping discriminative capacity for bipolar depression. The current diagnostic threshold of DSM-5 MFS did not prove to be very inclusive, if compared with the greater diagnostic sensitivity of KMxD, which also yielded better association with clinical variables related to mixedness.

Biomarkers, Inflammation, and Bipolar Disorder: Association Between the Improvement of Bipolar Disorder Severity and the Improvement in C-Reactive Protein Levels After 7 Days of Inpatient Treatment.

Introduction: Compared to the general population, people with severe mental illness (SMI) have a poorer health status and a higher mortality rate, with a 10-20-year reduction in life expectancy. Excess mortality and morbidity in SMI have been explained by intertwined components. Inflammatory processes could increase the morbidity and mortality risk in patients with bipolar disorder (BD) because of a bidirectional interaction between BD and conditions related to inflammation. This pilot study aimed to evaluate the relationship between C-Reactive-Protein (CRP) and bipolar disorder severity. Methods: A retrospective observational study was conducted on 61 hospitalized patients with bipolar disorder. CRP was measured at admission to inpatient treatment (T0) and after seven days from the admission (T1). Clinical Global Impression for Depression, Mania and Overall Bipolar Illness were recorded at T0 and T1. Comparisons among the recorded CRP values were determined through the paired t-test. Correlations between CRP and CGI scores were determined through Spearman's correlation coefficient at T0 and T1. Results: A statistically significant decrease in CRP values was observed after 7 days of hospitalization (p < 0.001) and positive significant correlations emerged between CRP and CGI scores at T0 and T1. Conclusion: Patients admitted to the inpatient unit reported a statistically significant decrease of CRP values during the first 7 days of treatment. Although the direction of the relationship between BP severity and inflammation status continues to remain unclear, this study showed a relationship between the improvement of bipolar disease symptoms and the improvement of the inflammatory marker CRP.

A new approach for seasonal pattern: is it related to bipolarity dimension? Findings from an Italian multicenter study.

OBJECTIVE: The aims of this study were to assess the impact of seasonal pattern on several clinical dimensions in inpatients with a current major depressive episode and to evaluate clinical differences between unipolar and bipolar depression according to seasonal pattern. METHODS: Study participants were 300 patients affected by major depressive disorder (MDD) or bipolar disorder (BD) currently experiencing a major depressive episode (MDE) and were recruited at three University Medical Centres in Italy. All study subjects completed several evaluation scales for depressive and hypomanic symptoms, quality of life and functioning, impulsiveness, and seasonal pattern. RESULTS: Several differences between BD with and without seasonal pattern, MDD with and without seasonal pattern but in particular between BD and MDD with seasonal pattern were found. Patients with MDE with seasonal pattern had more frequently received a longitudinal diagnosis of BD. CONCLUSIONS: A large number of patients with BD and seasonal pattern, but also a considerable number of patients with MDD and seasonal pattern, endorsed manic items during a current MDE. Seasonal pattern should be associated with a concept of bipolarity in mood disorders and not only related to bipolar disorder. A correct identification of seasonal patterns may lead to the implementation of personalised pharmacological treatment approaches.KEY POINTSHigh prevalence of mixed features in mood disorders with seasonal pattern, supporting the need for a dimensional approach to major depressive disorder and bipolar disorder.Significant percentage of patients with a primary diagnosis of major depressive disorder had seasonal pattern.Significant percentage of patients with a primary diagnosis of major depressive disorder reported (hypo)manic symptomatology.

S-Adenosylmethionine (SAMe) in major depressive disorder (MDD): a clinician-oriented systematic review.

BACKGROUND: Major depressive disorder (MDD) is a recurrent illness with high rates of chronicity, treatment-resistance, and significant economic impact. S-Adenosylmethionine (SAMe), a molecule that is formed naturally in the human body, has shown antidepressant effects and may expand the available options for treating MDD. This systematic review examines the evidence concerning the efficacy of SAMe as monotherapy or in combination with antidepressants. METHODS: A systematic search in Medline, Psychinfo, AMED, and Cochrane Controlled Trials Register was conducted for any reference recorded up to March 2020. Double-blind, randomised controlled trials, comparing the antidepressant efficacy of SAMe to placebo or/and to other antidepressants, were selected. Two authors evaluated each study independently and then, reconciled findings. RESULTS: Eight trials, with a total of 11 arms and 1011 subjects, evaluating the efficacy of SAMe used as monotherapy or as adjunctive therapy (512 individuals), were included in this review. The study duration ranged between 2 and 12 weeks and the daily dose of SAMe varied from 200 to 3200 mg. Five comparisons evaluated the differences between SAMe and placebo and SAMe resulted significantly better than placebo in three of these studies. Four comparisons evaluated the differences between SAMe and other antidepressants (imipramine or escitalopram) and showed no significant difference. One study showed that SAMe was significantly better than placebo in accelerating the response to imipramine from day 4 to day 12, but the mean scores were not statistically different at the day 14 endpoint. One study showed that SAMe combined with serotonin reuptake inhibitors (SSRI) was better than PBO combined with SSRI. The studies reported only mild, transient or non-clinically relevant side effects. CONCLUSIONS: The existing trials of SAMe, used as monotherapy or add on to another antidepressants, have shown encouraging and generally positive results. However, more evidence is necessary before definitive conclusions can be drawn. Larger, double-blind randomised controlled studies are warranted to confirm the antidepressant effectiveness of SAMe.

Advances in treatment for postpartum major depressive disorder.

Introduction: Postpartum depressive disorder (PPD) is a burdensome medical condition. To date, only one treatment (Brexanolone) has undergone registrational trials and is approved in the United States with an indication for the treatment of PPD. However, other treatments are prescribed and have been tested for this condition. Herein, the authors review the available scientific evidence pertaining to the somatic treatments of PPD. Areas covered: The authors evaluate the published open-label and randomized controlled trials (RCTs), examine the biological mechanisms of PPD treatments, and evaluate how the available data translates into information that may be useful for clinical practice. Expert opinion: Antidepressants have long been the mainstay of PPD treatment, despite the limited evidence from randomized clinical trials that supports this practice. Brexanolone improves treatment options for women with PPD. However, the relatively burdensome administration and monitoring protocol, along with the high cost of the medication, limit the possibility for an extensive use of this medication. Large, randomized, controlled trials of hormonal treatments in patients with PPD are warranted. Also, treatment with mood stabilizers and/or antipsychotics in women with major depressive disorder, who meet the DSM-5 mixed features specifiers in the post-partum period, should be tested in controlled clinical trials.

Human CRY1 variants associate with attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.

Mood spectrum symptoms during a major depressive episode: Differences between 145 patients with bipolar disorder and 155 patients with major depressive disorder. Arguments for a dimensional approach.

BACKGROUND: Several studies have challenged the traditional unipolar-bipolar dichotomy in favor of a more dimensional approach. OBJECTIVE: To evaluate the differences in mood spectrum between patients with bipolar disorder (BD) and major depressive disorder (MDD) during a major depressive episode (MDE). METHOD: Study participants were 145 patients with BD and 155 patients with MDD recruited at three University Medical Centers in Italy. All study subjects met Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for MDE and completed the Mood Spectrum-Self-Report-Last Month questionnaire. RESULTS: Patients with BD endorsed more items in the mood manic/hypomanic and energy depressive subdomains of the MOODS-SR questionnaire. Significant differences were also found for specific depressive and manic items, which were more frequently endorsed by patients with BD. A large number of patients with BD, but also a considerable number of patients with MDD, endorsed manic items during a depressive episode. CONCLUSIONS: There are differences between BD and MDD in terms of the number and type of mood spectrum items that are endorsed during a MDE, which may help to identify patients with BD when a retrospective assessment of a history of mania or hypomania is not possible or not reliable. A high number of patients with BD and a considerable number of patients with MDD endorsed several items in the manic section of the mood, energy, and cognition domains, this confirming the centrality of mixed features in patients with mood disorders and the need for a unitary, dimensional, descriptive and dynamic approach to MDD and BD, such as the recently proposed ACE (Activity, Cognition, Energy) model.