Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension.

About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.

Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

Experience and Reporting of Postnatal Depression Across Cultures: A Comparison Using Anchoring Vignettes of Mothers in the United Kingdom and India.

Postnatal mental health is often assessed using self-assessment questionnaires in epidemiologic research. Differences in response style, influenced by language, culture, and experience, may mean that the same response may not have the same meaning in different settings. These differences need to be identified and accounted for in cross-cultural comparisons. Here we describe the development and application of anchoring vignettes to investigate the cross-cultural functioning of the Edinburgh Postnatal Depression Scale (EPDS) in urban community samples in India (n = 549) and the United Kingdom (n = 828), alongside a UK calibration sample (n = 226). Participants completed the EPDS and anchoring vignettes when their children were 12-24 months old. In an unadjusted item-response theory model, UK mothers reported higher depressive symptoms than Indian mothers (d = 0.48, 95% confidence interval: 0.358, 0.599). Following adjustment for differences in response style, these positions were reversed (d = -0.25, 95% confidence interval: -0.391, -0.103). Response styles vary between India and the United Kingdom, indicating a need to take these differences into account when making cross-cultural comparisons. Anchoring vignettes offer a valid and feasible method for global data harmonization.

Distinct Effects of Major Affective Disorder Diagnoses and Suicidal Symptom Severity on Inhibitory Control Function and Proinflammatory Cytokines: Single-Site Analysis of 800 Adolescents and Adults.

BACKGROUND: Inhibitory control function and proinflammatory cytokines play a role in the pathomechanisms underlying major affective disorders and suicidal behavior. However, the distinct or interactive effects of major affective disorders and suicidal symptom severity on inhibitory control function and proinflammatory cytokines remain unclear. METHODS: This study included 287 patients with bipolar disorder, 344 with major depressive disorder, and 169 healthy controls. We categorized the participants into 3 groups based on Montgomery-Åsberg Depression Rating Scale (MADRS) item 10 (suicidal symptoms) score: 0, 2 or 3, and ≥4. The participants completed the go/no-go task and the measurements for C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) levels. RESULTS: Errors in the go/no-go task were associated with suicidality (P = .040), regardless of the severity of suicidal symptoms and diagnosis. An elevated CRP level was especially associated with a Montgomery-Åsberg Depression Rating Scale item 10 score ≥4 (P = .001). An increased TNF-α level could distinguish bipolar disorder from major depressive disorder (P < .001). DISCUSSION: Our study indicated the distinct effects of major affective disorder diagnosis and suicide symptom severity on inhibitory control function and CRP and TNF-α levels. Importantly, individuals with the poorest inhibitory control function and highest CRP levels had more severe suicidal symptoms.

Assessment of perinatal anxiety: diagnostic accuracy of five measures.

BACKGROUND: Anxiety in pregnancy and after giving birth (the perinatal period) is highly prevalent but under-recognised. Robust methods of assessing perinatal anxiety are essential for services to identify and treat women appropriately. AIMS: To determine which assessment measures are most psychometrically robust and effective at identifying women with perinatal anxiety (primary objective) and depression (secondary objective). METHOD: We conducted a prospective longitudinal cohort study of 2243 women who completed five measures of anxiety and depression (Generalized Anxiety Disorder scale (GAD) two- and seven-item versions; Whooley questions; Clinical Outcomes in Routine Evaluation (CORE-10); and Stirling Antenatal Anxiety Scale (SAAS)) during pregnancy (15 weeks, 22 weeks and 31 weeks) and after birth (6 weeks). To assess diagnostic accuracy a sample of 403 participants completed modules of the Mini-International Neuropsychiatric Interview (MINI). RESULTS: The best diagnostic accuracy for anxiety was shown by the CORE-10 and SAAS. The best diagnostic accuracy for depression was shown by the CORE-10, SAAS and Whooley questions, although the SAAS had lower specificity. The same cut-off scores for each measure were optimal for identifying anxiety or depression (SAAS ≥9; CORE-10 ≥9; Whooley ≥1). All measures were psychometrically robust, with good internal consistency, convergent validity and unidimensional factor structure. CONCLUSIONS: This study identified robust and effective methods of assessing perinatal anxiety and depression. We recommend using the CORE-10 or SAAS to assess perinatal anxiety and the CORE-10 or Whooley questions to assess depression. The GAD-2 and GAD-7 did not perform as well as other measures and optimal cut-offs were lower than currently recommended.

Towards precision in the diagnostic profiling of patients: leveraging symptom dynamics as a clinical characterisation dimension in the assessment of major depressive disorder.

BACKGROUND: International guidelines present overall symptom severity as the key dimension for clinical characterisation of major depressive disorder (MDD). However, differences may reside within severity levels related to how symptoms interact in an individual patient, called symptom dynamics. AIMS: To investigate these individual differences by estimating the proportion of patients that display differences in their symptom dynamics while sharing the same overall symptom severity. METHOD: Participants with MDD (n = 73; mean age 34.6 years, s.d. = 13.1; 56.2% female) rated their baseline symptom severity using the Inventory for Depressive Symptomatology Self-Report (IDS-SR). Momentary indicators for depressive symptoms were then collected through ecological momentary assessments five times per day for 28 days; 8395 observations were conducted (average per person: 115; s.d. = 16.8). Each participant's symptom dynamics were estimated using person-specific dynamic network models. Individual differences in these symptom relationship patterns in groups of participants sharing the same symptom severity levels were estimated using individual network invariance tests. Subsequently, the overall proportion of participants that displayed differential symptom dynamics while sharing the same symptom severity was calculated. A supplementary simulation study was conducted to investigate the accuracy of our methodology against false-positive results. RESULTS: Differential symptom dynamics were identified across 63.0% (95% bootstrapped CI 41.0-82.1) of participants within the same severity group. The average false detection of individual differences was 2.2%. CONCLUSIONS: The majority of participants within the same depressive symptom severity group displayed differential symptom dynamics. Examining symptom dynamics provides information about person-specific psychopathological expression beyond severity levels by revealing how symptoms aggravate each other over time. These results suggest that symptom dynamics may be a promising new dimension for clinical characterisation, warranting replication in independent samples. To inform personalised treatment planning, a next step concerns linking different symptom relationship patterns to treatment response and clinical course, including patterns related to spontaneous recovery and forms of disorder progression.

Cross-cultural validation of the revised Green et al., paranoid thoughts scale.

BACKGROUND: With efforts increasing worldwide to understand and treat paranoia, there is a pressing need for cross-culturally valid assessments of paranoid beliefs. The recently developed Revised Green et al., Paranoid Thoughts Scale (R-GPTS) constitutes an easy to administer self-report assessment of mild ideas of reference and more severe persecutory thoughts. Moreover, it comes with clinical cut-offs for increased usability in research and clinical practice. With multiple translations of the R-GPTS already available and in use, a formal test of its measurement invariance is now needed. METHODS: Using data from a multinational cross-sectional online survey in the UK, USA, Australia, Germany, and Hong Kong (N = 2510), we performed confirmatory factory analyses on the R-GPTS and tested for measurement invariance across sites. RESULTS: We found sufficient fit for the two-factor structure (ideas of reference, persecutory thoughts) of the R-GPTS across cultures. Measurement invariance was found for the persecutory thoughts subscale, indicating that it does measure the same construct across the tested samples in the same way. For ideas of reference, we found no scalar invariance, which was traced back to (mostly higher) item intercepts in the Hong Kong sample. CONCLUSION: We found sufficient invariance for the persecutory thoughts scale, which is of substantial practical importance, as it is used for the screening of clinical paranoia. A direct comparison of the ideas of reference sum-scores between cultures, however, may lead to an over-estimation of these milder forms of paranoia in some (non-western) cultures.

Interleukin-1ß moderates the relationships between middle frontal-mACC/insular connectivity and depressive symptoms in bipolar II depression.

The functional alterations of the brain in bipolar II depression (BDII-D) and their clinical and inflammatory associations are understudied. We aim to investigate the functional brain alterations in BDII-D and their relationships with inflammation, childhood adversity, and psychiatric symptoms, and to examine the moderating effects among these factors. Using z-normalized amplitude of low-frequency fluctuation (zALFF), we assessed the whole-brain resting-state functional activity between 147 BDII-D individuals and 150 healthy controls (HCs). Differential ALFF regions were selected as seeds for functional connectivity analysis to observe brain connectivity alterations resulting from abnormal regional activity. Four inflammatory cytokines including interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and five clinical scales including Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), and Childhood Trauma Questionnaire (CTQ) were tested and assessed in BDII-D. Partial correlations with multiple comparison corrections identified relationships between brain function and inflammation, childhood adversity, and psychiatric symptoms. Moderation analysis was conducted based on correlation results and previous findings. Compared to HCs, BDII-D individuals displayed significantly lower zALFF in the superior and middle frontal gyri (SFG and MFG) and insula, but higher zALFF in the occipital-temporal area. Only the MFG and insula-related connectivity exhibited significant differences between groups. Within BDII-D, lower right insula zALFF value correlated with higher IL-6, CRP, and emotional adversity scores, while lower right MFG zALFF was related to higher CRP and physical abuse scores. Higher right MFG-mid-anterior cingulate cortex (mACC) connectivity was associated with higher IL-1ß. Moreover, IL-1ß moderated associations between higher right MFG-mACC/insula connectivity and greater depressive symptoms. This study reveals that abnormal functional alterations in the right MFG and right insula were associated with elevated inflammation, childhood adversity, and depressive symptoms in BDII-D. IL-1ß may moderate the relationship between MFG-related connectivity and depressive symptoms.

Efficacy and Safety of Adding Lurasidone to Ongoing Therapy With Lithium or Valproate for the Treatment of an Acute Bipolar Depressive Episode: A Post Hoc Analysis of 2 Placebo-Controlled Trials.

PURPOSE: The aim of this study was to compare the efficacy and safety profile of lurasidone combined with either lithium or valproate, in the short-term treatment of patients with bipolar depression. METHODS: Data were pooled from two 6-week, double-blind, placebo-controlled trials of patients with bipolar depression on stable doses of lithium or valproate randomized to lurasidone (20-120 mg/d) or placebo. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impressions Bipolar Scale, and the Quick Inventory of Depressive Symptomatology via self-assessment and were analyzed using a mixed model for repeated measures approach. RESULTS: Notably larger week 6 effect sizes were observed when lurasidone was added to lithium, compared with when lurasidone was added to valproate, on 2 of the 3 depression outcome measures, Montgomery-Åsberg Depression Rating Scale total score (d = 0.45 vs 0.22) and Quick Inventory of Depressive Symptomatology via self-assessment (d = 0.63 vs 0.29); the efficacy advantage was smaller on the Clinical Global Impressions Bipolar Scale depression score (d = 0.34 vs 0.29). Similar adverse event profiles were observed for lurasidone treatment in combination with either lithium or valproate. The most frequently reported events (≥5%) in both groups were nausea, parkinsonism, somnolence, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone combined with either lithium or valproate. CONCLUSIONS: Lurasidone added to either lithium or valproate was found to be an effective treatment for bipolar depression, with a larger antidepressant effect observed when lurasidone was combined with lithium. There were no clinically meaningful differences in the safety or tolerability of lurasidone when used adjunctively with lithium or valproate.

Screening for depression in patients with epilepsy: What are the benefits for physicians and patients in the real-life setting.

OBJECTIVE: Screening for depression in people with epilepsy (PWE) is highly recommended in order to avoid underdiagnosis, misdiagnosis, or delayed diagnosis of this highly impacting comorbidity. Here we evaluated the impact of reporting and suggesting depression via the Beck Depression Inventory (BDI) on medical decision-making, and thereby the value of a depression screening for good medical practice. METHODS: Of 445 BDI data sets, PWE with scores indicating moderate (BDI 19-29) to severe depressive disorder (BDI >29) were extracted and clinical reports were retrospectively reviewed regarding decisions on antidepressants, anti-seizure medications (ASMs), and non-pharmaceutical interventions. RESULTS: Sixty-four PWE (14%; 56% female; mean age 39.7 years) showed elevated BDI scores, with 40 (63%) categorized as moderate depression and 24 (37%) as severe depression. Thirty-nine percent of PWE already had a pre-existing diagnosis of depression and 53% left the clinic with the diagnosis of depression, half of them with antidepressants. High depression scores were associated with any intervention in 53%, interventions with potentially mood affecting ASM in 19%, treatment with antidepressants in 11%, and non-pharmaceutical interventions in 41%. Non-pharmaceutical interventions were related to BDI scores. Changes of potentially mood-affecting ASMs were more frequent in PWE with moderate scores, and introduction of antidepressants appeared as a trend related to higher depression scores. SIGNIFICANCE: The finding of an only weak relation between high depression scores, diagnoses of depression, and treatment consequences questions the diagnosis and treatment pathway and the clinical value of the BDI screening in PWE. Prospective standard procedures need to be established for depression diagnosis and treatment including follow-up evaluations of the validity of the diagnosis and effectiveness of the decisions taken.

The impact of body mass index on the clinical features of bipolar disorder: A STEP-BD study.

INTRODUCTION: The effects of body mass index (BMI) on the core symptoms of bipolar disorder (BD) and its implications for disease trajectory are largely unexplored. OBJECTIVE: To examine whether BMI impacted hospitalization rate, medical and psychiatric comorbidities, and core symptom domains such as depression and suicidality in BD. METHODS: Participants (15 years and older) were 2790 BD outpatients enrolled in the longitudinal STEP-BD study; all met DSM-IV criteria for BD-I, BD-II, cyclothymia, BD NOS, or schizoaffective disorder, bipolar subtype. BMI, demographic information, psychiatric and medical comorbidities, and other clinical variables such as bipolarity index, history of electroconvulsive therapy (ECT), and history of suicide attempts were collected at baseline. Longitudinal changes in Montgomery-Åsberg Depression Rating Scale (MADRS) score, Young Mania Rating Scale (YMRS) score, and hospitalizations during the study were also assessed. Depending on the variable of interest, odds-ratios, regression analyses, factor analyses, and graph analyses were applied. RESULTS: A robust increase in psychiatric and medical comorbidities was observed, particularly for baseline BMIs >35. A significant relationship was noted between higher BMI and history of suicide attempts, and individuals with BMIs >40 had the highest prevalence of suicide attempts. Obese and overweight individuals had a higher bipolarity index (a questionnaire measuring disease severity) and were more likely to have received ECT. Higher BMIs correlated with worsening trajectory of core depression symptoms and with worsening lassitude and inability to feel. CONCLUSIONS: In BD participants, elevated BMI was associated with worsening clinical features, including higher rates of suicidality, comorbidities, and core depression symptoms.

Dynamic time warp analysis of individual symptom trajectories in individuals with bipolar disorder.

BACKGROUND: Manic and depressive mood states in bipolar disorder (BD) may emerge from the non-linear relations between constantly changing mood symptoms exhibited as a complex dynamic system. Dynamic Time Warp (DTW) is an algorithm that may capture symptom interactions from panel data with sparse observations over time. METHODS: The Young Mania Rating Scale and Quick Inventory of Depressive Symptomatology were repeatedly assessed in 141 individuals with BD, with on average 5.5 assessments per subject every 3-6 months. Dynamic Time Warp calculated the distance between each of the 27 × 27 pairs of standardized symptom scores. The changing profile of standardized symptom scores of BD participants was analyzed in individual subjects, yielding symptom dimensions in aggregated group-level analyses. Using an asymmetric time-window, symptom changes that preceded other symptom changes (i.e., Granger causality) yielded a directed network. RESULTS: The mean age of the BD participants was 40.1 (SD 13.5) years old, and 60% were female participants. Idiographic symptom networks were highly variable between subjects. Yet, nomothetic analyses showed five symptom dimensions: core (hypo)mania (6 items), dysphoric mania (5 items), lethargy (7 items), somatic/suicidality (6 items), and sleep (3 items). Symptoms of the "Lethargy" dimension showed the highest out-strength, and its changes preceded those of "somatic/suicidality," while changes in "core (hypo)mania" preceded those of "dysphoric mania." CONCLUSION: Dynamic Time Warp may help to capture meaningful BD symptom interactions from panel data with sparse observations. It may increase insight into the temporal dynamics of symptoms, as those with high out-strength (rather than high in-strength) could be promising targets for intervention.

Validity of the DSM-5 Mixed Features Specifier Interview.

OBJECTIVES: To examine the reliability and validity of a semi-structured interview assessing the features of the DSM-5 mixed features specifier. Our goal was to develop an instrument that could be used for both diagnostic and severity measurement purposes. METHODS: Four hundred fifty-nine psychiatric patients in a depressive episode were interviewed by a trained diagnostic rater who administered semi-structured interviews including the DSM-5 Mixed Features Specifier Interview (DMSI). We examined the inter-rater reliability and psychometric properties of the DMSI. The patients were rated on clinician rating scales of depression, anxiety, and irritability, and measures of psychosocial functioning, suicidality, and family history of bipolar disorder. RESULTS: The DMSI had excellent joint-interview interrater reliability. More than twice as many patients met the DSM-5 mixed features specifier criteria during the week before the assessment than for the majority of the episode (9.4% vs. 3.9%). DMSI total scores were more highly correlated with a clinician-rated measure of manic symptoms than with measures of depression and anxiety. More patients with bipolar depression met the mixed features specifier than patients with MDD. Amongst patients with MDD, those with mixed features more frequently had a family history of bipolar disorder, were more frequently diagnosed with anxiety disorders, attention deficit disorder, and borderline personality disorder, more frequently had attempted suicide, and were more severely depressed, anxious, and irritable. CONCLUSION: The DMSI is a reliable and valid measure of the presence of the DSM-5 mixed features specifier in depressed patients as well as the severity of the features of the specifier.

Anhedonia in bipolar depression treated with ketamine.

BACKGROUND: Bipolar depression is the major cause of morbidity in patients with bipolar disorder. It affects psychosocial functioning and markedly impairs occupational productivity. Anhedonia is one of the most debilitating symptoms of depression contributing to treatment resistance. It correlates with suicidality, low quality of life, social withdrawal, and poor treatment response. Currently, there is no approved treatment specifically targeting anhedonia. Emerging evidence suggests that ketamine possesses anti-anhedonic properties in individuals with depression. OBJECTIVES: The aim of this naturalistic open-label study was to investigate the effect of add-on ketamine treatment on anhedonia in treatment resistant bipolar depression. METHODS: Our main interest was the change in patient-reported (Snaith-Hamilton Pleasure Scale) and rater-based anhedonia measure (Montgomery-Åsberg Depression Rating Scale-anhedonia subscale). The secondary aim was to analyze the score change in three Inventory of Depressive Symptomatology-Self Report (IDS-SR) domains: mood/cognition, anxiety/somatic, and sleep. Patients underwent assessments at several time points, including baseline, after the third, fifth, and seventh ketamine infusions. Additionally, a follow-up assessment was conducted 1 week following the final ketamine administration. RESULTS: We found improvement in anhedonia symptoms according to both patient-reported and rater-based measures. The improvement in IDS-SR domains was most prominent in anxiety/somatic factor and mood/cognition factor, improvement in sleep factor was not observed. No serious adverse events occurred. CONCLUSION: Add-on ketamine seems to be a good choice for the treatment of anhedonia in treatment resistant bipolar depression. It also showed a good effect in reducing symptoms of anxiety in this group of patients. Considering unmet needs and the detrimental effect of anhedonia and anxiety, more studies are needed on ketamine treatment in resistant bipolar depression.

Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder.

INTRODUCTION: Cariprazine treats acute manic and depressive episodes in bipolar I disorder (BP-I), but its efficacy in preventing relapse of mood episode remains unknown. METHODS: In this phase 3b, double-blind, placebo-controlled study, patients with BP-I with acute manic or depressive episodes (each with/without mixed features), were treated with cariprazine 3.0 mg/day during a 16-week open-label treatment period; those who achieved stable remission within 8 weeks and remained stable for at least another 8 weeks were randomized to receive cariprazine 1.5 or 3.0 mg per day or placebo in the double-blind treatment period for up to 39 weeks. The primary efficacy endpoint was time to relapse of any mood episode. Adverse events (AEs) were assessed. RESULTS: Patients (440/896) enrolled in the open-label treatment period achieved stability criteria and were randomized to receive cariprazine 3.0 mg/day (n = 148), cariprazine 1.5 mg/day (n = 147), or placebo (n = 145) in the double-blind treatment period. Relapse rates were 17.9%, 16.8%, and 19.7% in the cariprazine 3.0 mg/day, cariprazine 1.5 mg/day, and placebo groups, respectively. Neither dose of cariprazine was more effective than placebo on the primary outcome (3.0 mg/day: HR = 0.89, [95% CI: 0.5, 1.5]; 1.5 mg/day: HR = 0.83, 95% CI [0.5, 1.4]). The most frequently reported AEs (≥5%) were akathisia, headache, insomnia, and nausea in the open-label treatment period and increased weight and insomnia in the double-blind treatment period. In the open-label and double-blind treatment periods, 7.5% and 1.6% of patients experienced an AE leading to discontinuation. CONCLUSION: Cariprazine was not superior to placebo in the prevention of relapses in this study. Relapse rates were unusually low in the placebo group. Cariprazine was well-tolerated.

Study of the different sleep disturbances during the prodromal phase of depression and mania in bipolar disorders.

BACKGROUND: One of the challenges in bipolar disorder (BD) lies in early detection of the illness and its recurrences, to improve prognosis. Sleep disturbances (SD) have been proposed as reliable predictive markers of conversion. While preliminary studies have explored the relationship between SD and the onset of mood episodes, the results remain heterogeneous and a few have specifically examined patients' perception of prodromal symptoms and their progression until the episode occurs. Identifying prodromes represents a crucial clinical challenge, as it enables early intervention, thereby reducing the severity of BD. Therefore, the objective of this study is to better characterize and evaluate the progressive nature of SD as prodromal symptoms of mood episodes, and patients' perception of it. METHODS: Patients diagnosed with BD, either hospitalized or seeking treatment for a (hypo)manic or depressive episode benefited from standardized questionnaires, structured interviews, and self-report questionnaires to evaluate SD prior to the current episode, as well as sociodemographic and clinical information. RESULTS: Out of the 41 patients included, 59% spontaneously reported SD prior to the episode, appearing 90 days before depression and 35 days before mania (pre-indexed/spontaneous reports: 51.22% insomnia complaints, 4.88% hypersomnolence complaints, 7.32% parasomnias, 2.44% sleep movements). After inquiry about specific SD, the percentage of patients reporting prodromal SD increased significantly to 83%, appearing 210 days before depression and 112.5 days before mania (post-indexed reports: 75.61% presented with insomnia complaints appearing 150 days before depression and 20 days before mania, 46.34% had hypersomnolence complaints appearing 60 days before depression, 43.9% had parasomnias appearing 210 days before depression and 22.5 days before mania, 36.59% had sleep movements appearing 120 days before depression and 150 days before mania). Of note, bruxism appeared in 35% of patients before mania, and restless legs syndrome in 20% of patients before depression. CONCLUSION: This study highlights the very high prevalence of SD prior to a mood episode in patients with BD with differences between depressive and manic episodes. The more systematic screening of sleep alterations of the prodromal phase improved the recognition and characterization of different symptoms onset by patients. This underscores the need for precise questioning regarding sleep patterns in patients, to better identify the moment of transition toward a mood episode, referred to as "Chronos syndrome". The study emphasizes the importance of educating patients about the disorder and its sleep prodromal symptoms to facilitate early intervention and prevent recurrences.

Sex-dependent associations of serum BDNF, glycolipid metabolism and cognitive impairments in Parkinson's disease with depression: a comprehensive analysis.

Brain-derived neurotrophic factor (BDNF) and glycolipid metabolism have been implicated in cognitive impairments and depression among Parkinson's disease (PD). However, the role of sex differences in this relationship remains elusive. This study aimed to investigate the potential sex differences in the link between serum BDNF levels, glycolipid metabolism and cognitive performance among depressive PD patients. PD patients comprising 108 individuals with depression and 108 without depression were recruited for this study. Cognitive function was assessed using the Montreal Cognitive Assessment Beijing version (MOCA-BJ). The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HAMD-17), while motor symptoms were evaluated using the Revised Hoehn and Yahr rating scale (H-Y) and the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). Laboratory testing and enzyme-linked immunosorbent assay (ELISA) are used to measure serum levels of glycolipid metabolism and BDNF. Females showed superior performance in delayed recall (all p < 0.05), male PD patients exhibited higher scores in naming tasks compared to females in non-depression group. There was no sex differences in serum BDNF levels between depression and non-depression groups. Liner regression analysis indicated BDNF as an independent risk factor for language deficits in male PD patients with depression (p < 0.05), while cholesterol (CHOL) emerged as a cognitive influencing factor, particularly in delayed recall among male PD patients with depression (p < 0.05). Our study reveals extensive cognitive impairments in PD patients with depression. Moreover, BDNF and CHOL may contribute to the pathological mechanisms underlying cognitive deficits, particularly in male patients with depression.

Psychological impact of life events in systemic lupus erythematosus patients - Differences between flares and remission.

BACKGROUND: Stress has been linked to worsening symptoms and increased disease activity in patients with Systemic lupus erythematosus (SLE). Life-events are individual stress points, and there is conflicting evidence regarding their role in SLE activity and disease perception. METHODS: Adult SLE patients were recruited for the study. Clinical and laboratory features of SLE were recorded, and previous diagnosis of anxiety or depression were retrieved from patients' electronic charts. Flares were defined by the Systemic Lupus Erythematosus Disease Activity (SLEDAI) flare Index, and flares during the previous year were documented. During a routine visit, they completed validated Portuguese translations of the 10-item Perceived Stress Scale (PSS-10), Hospital Anxiety and Depression Scale (HADS) and Life Experience Survey (LES) for the previous year. RESULTS: A total of 47 female SLE patients were recruited. Ten patients (21.3%) had experienced recent flares. Patients with recent flares reported fewer life events, with lower positive, negative, and total weightings sums compared to those without recent flares. Although 42.2% of patients perceived pathological levels of stress in the previous month, 48.9% had anxiety symptoms, and 34% were at high risk for an anxiety disorder, these psychometric measures did not differ significantly between the recent flare and no-flare groups. CONCLUSIONS: There is a high prevalence of pathological levels of stress among SLE patients. SLE patients with recent flares report less psychological impact from life events, both positive and negative, independent of other psychological or pharmacological factors.

Evaluation of depressive and anxiety symptoms in childhood-onset systemic lupus erythematosus: Frequency, course, and associated risk factors.

BACKGROUND: Depressive and anxiety symptoms are common in childhood-onset systemic lupus erythematosus (cSLE), yet their etiology and course remain unclear. We investigated the frequency of depressive and anxiety symptoms longitudinally in youth with cSLE, and associated socio-demographic and disease factors. METHODS: Participants 8-18 years with cSLE completed baseline measures [demographic questionnaire, Center for Epidemiologic Studies Depression Scale for Children (CES-DC), Screen for Childhood Anxiety Related Disorders (SCARED), and psychiatric interview] and follow-up measures (CES-DC and SCARED) > 6 months later. Prevalence of clinically significant depressive (score >15 on CES-DC) or anxiety symptoms (score ≥25 on SCARED) was calculated at baseline and follow-up. Baseline psychiatric interview diagnoses were tabulated. Relationships between socio-demographics (neighborhood-level material deprivation, ethnic concentration, adverse childhood event history, psychiatric condition in a first-degree relative), disease-related factors (disease duration, major organ disease, disease activity, glucocorticoid use, comorbid medical condition) and baseline depressive and anxiety scores, were examined in linear regression models. Factors with univariate associations with p < 0.2 were included in multivariable adjusted models. RESULTS: At baseline, of 51 participants with a mean disease duration of 4.3 years (SD 2.7), 35% (n = 18) and 35% (n = 18) had clinically significant depressive and anxiety symptoms, respectively. Anxiety disorder was diagnosed by psychiatric interview in 14% (n = 7), depressive disorders in 6% (n = 3), and post-traumatic stress disorder in 4% (n = 2). Adverse childhood events and first-degree relative with psychiatric condition were present in 40% (n = 20) and 37% (n = 18), respectively. In multivariable regression analysis, baseline depressive symptoms were positively correlated with neighbourhood-level material deprivation (ß = 4.2, 95% CI [1.0, 7.3], p = 0.01) and psychiatric condition in a first-degree relative (ß = 7.3, 95% CI [2.2, 12.4], p = 0.006). No associations were found between baseline anxiety scores and patient factors. At a median follow-up of 13.5 months (IQR 10.5, 18) for CES-DC (n = 34) and SCARED (n = 44), depressive and anxiety symptoms were persistent (18%, n = 6; 16%, n = 7), and newly present (24%, n = 8; 16% n = 7) at follow-up. CONCLUSION: In this sample, depressive and anxiety symptoms were prevalent and persistent. Depressive symptoms correlated with neighborhood-level material deprivation, and family psychiatric history. These findings support routine psychosocial assessment in cSLE, and provision of appropriate resources.

The relationship between female orgasmic disorder, attention-deficit/hyperactivity disorder, and depression in Dominican women.

BACKGROUND: Female orgasmic disorder is listed in the DSM-5 and is defined as the persistent or recurrent inability to have an orgasm. Many depressed women may experience sexual dysfunction, including female orgasmic disorder. AIM: The study sought to analyze the relationship between depressive disorders and attention-deficit/hyperactivity disorder (ADHD) and their influence on the development of female orgasmic disorder. METHODS: A total of 221 Dominican women participated in this case-control study. The case group consisted of 107 women diagnosed with female orgasmic disorder, while the control group consisted of 114 women without any sexual dysfunction. OUTCOMES: The diagnosis of ADHD was obtained from the participants' medical records, previously conducted using the DSM-5-TR criteria. The Beck Depression Inventory II was used to assess the severity of depressive symptoms in both groups. RESULTS: There was a significant relationship between female orgasmic disorder and ADHD and depression. The results of multiple logistic regression indicated that the highest risk of female orgasmic disorder was observed in women with ADHD (odds ratio [OR], 4.91; 95% confidence interval [CI], 2.46-9.20; P < .001), women with severe depression (OR, 2.50; 95% CI, 1.08-6.96; P = .04), and women who had sexual intercourse that focused on penetration (OR, 2.02; 95% CI, 1.03-3.98; P = .04). CLINICAL IMPLICATIONS: These findings may have important implications for the prevention and treatment of sexual disorders in women. STRENGTHS AND LIMITATIONS: This design selected all diagnosed cases of female orgasmic disorder and did not select a specific subgroup. However, some limitations must be considered. This study was conducted in a single clinic, although it should be noted that it is the main clinic for the treatment of sexual dysfunction in the country. A further limitation could be that this type of study design does not allow for statements about causality to be made. CONCLUSION: There is an increased risk of female orgasmic disorder in women with ADHD, with severe depression, and who engage in penetrative sex.