Modafinil for Severe Fatigue in Inflammatory Bowel Disease: A Prospective Case Series.

Fatigue is highly prevalent in patients with IBD, affecting 72% of patients with active inflammatory bowel disease (IBD) and 47% in remission, and is associated with poor quality of life and significantly wider costs.1 However, understanding the mechanisms of IBD fatigue remains limited, as reflected in a lack of effective treatments.1.

Is it now time to prepare psychiatry for a psychedelic future?

Australia has just rescheduled two drugs controlled under the United Nations Psychotropic Drug Conventions, psilocybin and MDMA, as treatments for treatment-resistant depression and post-traumatic stress disorder respectively. This feature explores the reasons for these developments, the opportunities and challenges they provide to psychiatry communities and how along with health systems these communities might respond to these developments.

Neural responses to facial emotions and subsequent clinical outcomes in difficult-to-treat depression.

BACKGROUND: Amygdala and dorsal anterior cingulate cortex responses to facial emotions have shown promise in predicting treatment response in medication-free major depressive disorder (MDD). Here, we examined their role in the pathophysiology of clinical outcomes in more chronic, difficult-to-treat forms of MDD. METHODS: Forty-five people with current MDD who had not responded to ⩾2 serotonergic antidepressants (n = 42, meeting pre-defined fMRI minimum quality thresholds) were enrolled and followed up over four months of standard primary care. Prior to medication review, subliminal facial emotion fMRI was used to extract blood-oxygen level-dependent effects for sad v. happy faces from two pre-registered a priori defined regions: bilateral amygdala and dorsal/pregenual anterior cingulate cortex. Clinical outcome was the percentage change on the self-reported Quick Inventory of Depressive Symptomatology (16-item). RESULTS: We corroborated our pre-registered hypothesis (NCT04342299) that lower bilateral amygdala activation for sad v. happy faces predicted favorable clinical outcomes (rs[38] = 0.40, p = 0.01). In contrast, there was no effect for dorsal/pregenual anterior cingulate cortex activation (rs[38] = 0.18, p = 0.29), nor when using voxel-based whole-brain analyses (voxel-based Family-Wise Error-corrected p < 0.05). Predictive effects were mainly driven by the right amygdala whose response to happy faces was reduced in patients with higher anxiety levels. CONCLUSIONS: We confirmed the prediction that a lower amygdala response to negative v. positive facial expressions might be an adaptive neural signature, which predicts subsequent symptom improvement also in difficult-to-treat MDD. Anxiety reduced adaptive amygdala responses.

Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Aticaprant: (a κ-opioid receptor antagonist) for major depressive disorder.

INTRODUCTION: Major depression is a common, disabling mental health condition associated with the highest disease burden for any neuropsychiatric disorder worldwide, according to the WHO. Due to the imperfect efficacy and tolerability profiles of existing treatments, investigational compounds in novel treatment classes are needed. Opioid-receptor antagonists are a potential new class of treatments currently under investigation. AREAS COVERED: Major depressive disorder is first overviewed. Existing treatments, both their mechanisms of action and their place within the antidepressant space, are discussed herein. Then, the profile of Aticaprant and the wider context of kappa-opioid antagonism for depression are discussed in focus. EXPERT OPINION: Early evidence indicates that Aticaprant may possess desirable pharmacodynamic and pharmacokinetic properties. A lack of convincing efficacy data at the time of writing precludes any definitive statement on its potential as an antidepressant.

Sleep-wake variations of electrodermal activity in bipolar disorder.

BACKGROUND: Affective states influence the sympathetic nervous system, inducing variations in electrodermal activity (EDA), however, EDA association with bipolar disorder (BD) remains uncertain in real-world settings due to confounders like physical activity and temperature. We analysed EDA separately during sleep and wakefulness due to varying confounders and potential differences in mood state discrimination capacities. METHODS: We monitored EDA from 102 participants with BD including 35 manic, 29 depressive, 38 euthymic patients, and 38 healthy controls (HC), for 48 h. Fifteen EDA features were inferred by mixed-effect models for repeated measures considering sleep state, group and covariates. RESULTS: Thirteen EDA feature models were significantly influenced by sleep state, notably including phasic peaks (p < 0.001). During wakefulness, phasic peaks showed different values for mania (M [SD] = 6.49 [5.74, 7.23]), euthymia (5.89 [4.83, 6.94]), HC (3.04 [1.65, 4.42]), and depression (3.00 [2.07, 3.92]). Four phasic features during wakefulness better discriminated between HC and mania or euthymia, and between depression and euthymia or mania, compared to sleep. Mixed symptoms, average skin temperature, and anticholinergic medication affected the models, while sex and age did not. CONCLUSION: EDA measured from awake recordings better distinguished between BD states than sleep recordings, when controlled by confounders.

Cognitive correlates of psychopathology in functional/dissociative seizures and non-lesional epilepsy: An exploratory study.

OBJECTIVE: To explore the relationship between cognitive functioning and psychopathological features in Functional/Dissociative Seizures (FDS), and test whether this differs from that observed in epilepsy. METHODS: We recruited a cross-sectional sample of adults (age > 18) with a diagnosis of non-lesional epilepsy or FDS between January 2021 and July 2022 (n = 73). Participants completed a series of psychiatric questionnaires and neuropsychological measures. Spearman's Correlation Coefficient was computed between each of the psychiatric and cognitive measures in each group. Fisher's Z test of significance for independent correlation coefficients then tested the significance of the difference between correlation coefficients for the two groups. RESULTS: There were no group differences in neuropsychological test scores. However, people with FDS reported higher seizure severity, depression levels, number of medically unexplained somatic symptoms, and exposure to traumatic events compared to epilepsy. Results of the Fisher's Z-test revealed significant differences in correlation coefficients between groups in two instances. First, in the association between the number of traumatic experiences and cognitive switching (z = 2.77, p = 0.006); the number of traumatic experiences were positively associated with cognitive switching in epilepsy but showed a non-significant negative trend in FDS. Secondly, in the association between vocabulary abilities and the number of medically unexplained symptoms (z = -2.71; p = 0.007); higher vocabulary ability was associated with fewer somatic symptoms in epilepsy, while no such correlation was observed in FDS. SIGNIFICANCE: This study provides preliminary evidence for the complex interplay between cognitive functioning and psychopathology in FDS and epilepsy. Neurocognitive functioning such as vocabulary abilities or attentional switching may play a role in the expression or maintenance of pathological features of FDS.

Activation of the interleukin-23/Th17 axis in major depression: a systematic review and meta-analysis.

The interleukin-23/Th17 axis is a promising modifiable target for depression. However, its association with depression has not been systematically evaluated. We systematically searched four databases (EMBASE, Web of Science, Pubmed and PsycINFO) for studies comparing patients with major depression and healthy controls for plasma/serum levels of Th17 cells and their canonical cytokines (interleukin-17A [IL-17A], IL-22, granulocyte macrophage colony stimulating factor [GM-CSF]). We also compared counts of Th1, Th2 and Th9 cells between depressed/non-depressed patients and their respective canonical cytokines. We performed random-effects meta-analysis of the standardised mean difference (SMD) in immune measures between groups. Risk of bias was assessed using the Newcastle-Ottawa scale. Of 3154 studies screened, 36 studies were included in meta-analysis. Patients with depression had elevated IL-17A compared to controls (SMD = 0.80 [95% CI 0.03 to 1.58], p = 0.042), an association moderated by antidepressant use (Z = 2.12, p = 0.034). Patients with depression had elevated GM-CSF (SMD = 0.54 [95% CI 0.16 to 0.91], p = 0.0047), and a trend towards higher Th17 counts (SMD = 0.44 [- 0.01 to 0.88], p = 0.052). Whilst the Th2-associated cytokine IL-5 was elevated in depression (SMD = 0.36 [95% CI 0.05 to 0.66], p = 0.02), Th2 cell counts (p = 0.97), Th1 cell counts (p = 0.17) and interferon-γ (p = 0.22) were not. Data for Th9 cells, IL-9 and IL-22 were insufficient for meta-analysis. Respectively, 22, 25 and 5 studies were good, fair and poor in quality. Patients with major depression show peripheral over-activation of the IL-23/Th17 axis. Future interventional studies should test whether this is a modifiable target for depression.

Ketamine cystitis following ketamine therapy for treatment-resistant depression - case report.

BACKGROUND: Ketamine is a novel and exciting putative antidepressant medication for patients with treatment-resistant depression. A complication commonly seen in frequent and heavy recreational use of ketamine is ulcerative cystitis, which presents with lower urinary tract symptoms (LUTS) and upper renal tract damage and can be seen in over 25% of regular users. Although Ketamine-induced cystitis (KIC) is a recognised complication in recreational use of ketamine, its occurrence in therapeutic use of ketamine in depression has so far not been reported. The exact pathogenesis of KIC is currently unknown, making treatment and prevention advice much more difficult. Early diagnosis of KIC and immediate cessation of ketamine has been shown to improve adverse urinary tract symptoms and prevent further damage. CASE PRESENTATION: We present a case of a 28-year-old female who was started on ketamine treatment for depression, and who then developed symptoms of KIC, which was confirmed by urine microscopy, culture and analysis. CONCLUSIONS: To our knowledge, this is the first reported case of KIC in a patient receiving treatment-dose ketamine as part of their antidepressant therapy.

Olanzapine for young PEople with aNorexia nervosa (OPEN): A protocol for an open-label feasibility study.

INTRODUCTION: Antipsychotics are routinely prescribed off-label for anorexia nervosa (AN) despite limited evidence. This article presents a protocol of a study aiming to assess the feasibility of a future definitive trial on olanzapine in young people with AN. METHODS AND ANALYSIS: In an open-label, one-armed feasibility study, 55 patients with AN or atypical AN, aged 12-24, receiving outpatient, inpatient or day-care treatment who are considered for olanzapine treatment will be recruited from NHS sites based in England. Assessments will be conducted at screening, baseline and at 8-, 16 weeks, 6- and 12 months. Primary feasibility parameters will be proportions of patients who agree to take olanzapine and who adhere to treatment and complete study assessments. Qualitative methods will be used to explore acceptability of the intervention and study design. Secondary feasibility parameters will be changes in body mass index, psychopathology, side effects, health-related quality of life, carer burden and proportion of participants who would enrol in a future randomised controlled trial. The study is funded by the National Institute for Health Research via Health Technology Assessment programme. DISCUSSION: Olanzapine for young PEople with aNorexia nervosa will inform a future randomised controlled trial on the efficacy and safety of prescribing olanzapine in young people with AN.

Cognitive improvement in late-life depression treated with vortioxetine and duloxetine in an eight-week randomized controlled trial: The role of age at first onset and change in depressive symptoms.

BACKGROUND: Age at first onset of depression as a clinical factor affecting cognitive improvement in late life depression was investigated. METHODS: This is a secondary analysis of an eight-week randomized controlled trial involving 452 elderly patients treated by vortioxetine, duloxetine or placebo (1:1:1). Patients were subcategorized into early-onset (LLD-EO) and late-onset (LLD-LO) groups divided by onset age of 50. Cognitive performance was assessed by composite score of Digit Symbol Substitution Test (DSST) and the Rey Auditory Verbal Learning Test (RAVLT) tasks, while depressive symptoms were assessed by Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Vortioxetine and duloxetine exhibited advantages versus placebo in improving cognitive performance in the LLD-LO group, yet not in the LLD-EO group after eight weeks. Patients in the LLD-EO group showed overall advantage to placebo in depressive symptoms before endpoint (week 8) of treatment, while patients in the LLO-LO group showed no advantage until endpoint. Path analysis suggested a direct effect of vortioxetine (B = 0.656, p = .036) and duloxetine (B = 0.726, p = .028) on improving cognition in the LLD-LO group, yet in all-patients treated set both medications improved cognition indirectly through changes of depressive symptoms. LIMITATION: Reliability of clinical history could raise caution as it was collected by subjective recall of patients. CONCLUSION: Age at first onset might affect cognitive improvement as well as change in depressive symptoms and its mediation towards cognitive improvement in late life depression treated with vortioxetine and duloxetine.

Guidelines for ketamine use in clinical psychiatry practice.

In this editorial, we emphasise the efficacy and challenges of using ketamine in treatment-resistant depression. We highlight the need for comprehensive evidence-based guidelines to manage the use of both licensed and off-licence ketamine formulations and discuss recent efforts by Beaglehole et al to develop ketamine guidelines in New Zealand. We finally advocate for national registries to monitor ketamine therapy, ensuring its responsible and effective use in the management of depression.

Antidepressant treatment in inflammatory bowel disease: a systematic review and meta-analysis.

Around 25% of patients with inflammatory bowel disease (IBD) have depressive symptoms, yet antidepressants have been poorly studied in IBD. We systematically searched IBD studies testing antidepressants in four databases. Outcomes were depressive symptoms, anxiety, IBD disease activity, quality of life (QoL) and adverse events. For randomized controlled trials (RCTs), we performed random-effects meta-analysis of the standardized mean difference (SMD) in posttreatment scores between antidepressant and placebo groups. Risk of bias was assessed using the Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group tool (clinical trials) and Newcastle-Ottawa scale (cohort studies). We included 11 studies ( n  = 327): three placebo-controlled RCTs, two nonrandomized trials, and six other study types. In the pooled analysis, antidepressants improved depressive symptoms [SMD = -0.71 (95% confidence interval (CI) -1.32 to -0.10), P  = 0.02, I2  = 51%] and QoL [SMD = 0.88 (95% CI 0.30-1.45), P  = 0.003, I2  = 44%] more than placebo. Serotonin and noradrenaline reuptake inhibitors (SNRIs) alone improved depressive symptoms [SMD = -0.95 (95% CI -1.45 to -0.45, P  < 0.001, I2  = 11%], anxiety [SMD = -0.92 (95% CI 1.72 to -0.13), P  = 0.023, I2  = 65%] and QoL [SMD = 1.14 (95% CI 0.66-1.62), P  < 0.001, I2  = 0%]. The three RCTs were of good quality. In conclusion, based on three small but good-quality studies, antidepressants improve depressive symptoms and QoL compared to placebo in IBD. SNRI antidepressants may also improve anxiety. A fully powered study of antidepressants in IBD is needed.

Sociodemographic and clinical risk factors for suicidal ideation and suicide attempt in functional/dissociative seizures and epilepsy: a large cohort study.

BACKGROUND: People with functional/dissociative seizures (FDS) are at elevated suicidality risk. OBJECTIVE: To identify risk factors for suicidality in FDS or epilepsy. METHODS: Retrospective cohort study from the UK's largest tertiary mental healthcare provider, with linked national admission data from the Hospital Episode Statistics. Participants were 2383 people with a primary or secondary diagnosis of FDS or epilepsy attending between 01 January 2007 and 18 June 2021. Outcomes were a first report of suicidal ideation and a first hospital admission for suicide attempt (International Classification of Diseases, version 10: X60-X84). Demographic and clinical risk factors were assessed using multivariable bias-reduced binomial-response generalised linear models. FINDINGS: In both groups, ethnic minorities had significantly reduced odds of hospitalisation following suicide attempt (OR: 0.45-0.49). Disorder-specific risk factors were gender, age and comorbidity profile. In FDS, both genders had similar suicidality risk; younger age was a risk factor for both outcomes (OR: 0.16-1.91). A diagnosis of depression or personality disorders was associated with higher odds of suicidal ideation (OR: 1.91-3.01). In epilepsy, females had higher odds of suicide attempt-related hospitalisation (OR: 1.64). Age had a quadratic association with both outcomes (OR: 0.88-1.06). A substance abuse disorder was associated with higher suicidal ideation (OR: 2.67). Developmental disorders lowered the risk (OR: 0.16-0.24). CONCLUSIONS: This is the first study systematically reporting risk factors for suicidality in people with FDS. Results for the large epilepsy cohort complement previous studies and will be useful in future meta-analyses. CLINICAL IMPLICATIONS: Risk factors identified will help identify higher-risk groups in clinical settings.

Effect of childhood emotional abuse on depression and anxiety in adulthood is partially mediated by neuroticism: Evidence from a large online sample.

Childhood trauma is widely recognized as a potential risk factor for psychiatric illness in adulthood, yet the precise mechanisms underlying this relationship remain incompletely understood. One proposed mechanism involves the impact of childhood trauma on personality development, particularly in relation to neuroticism, which may subsequently heighten susceptibility to psychiatric disorders. In this study, we aimed to investigate this hypothesis through an online survey involving 1116 participants (232 male, 21 %). Participants completed the Childhood Trauma Questionnaire (CTQ), assessing emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect, along with the Trait Self-Description Inventory (TSDI) for personality assessment and the PHQ-9 and GAD-7 clinical questionnaires for depression and anxiety symptoms evaluation, respectively. Our analyses revealed significant positive correlations between all facets of childhood trauma and neuroticism (all p < .01). Linear regression analysis demonstrated that emotional abuse significantly contributed to neuroticism (ß = 0.267, p < .05), openness (ß = 0.142, p < .05), and agreeableness (ß = 0.089, p < .05), while sexual abuse was associated with agreeableness (ß = 0.137, p < .01) Emotional neglect was negatively correlated with conscientiousness (ß = -0.090, p < .01), extroversion (ß = -0.109, p < .01) and agreeableness (ß = -0.154, p < .01). Furthermore, linear regression analysis revealed that emotional abuse was positively and significantly correlated with PHQ-9 and GAD-7 scores (r = 0.330, p < .01 and r = 0.327, p < .01, respectively). Mediation analysis supported a significant mediating role of neuroticism in the association between childhood emotional abuse and both depression (PHQ-9) (z = 8.681, p < .01) and anxiety (GAD-7) (z = 9.206, p < .01). Notably, the correlation between childhood emotional abuse and psychiatric symptoms was attenuated but not eliminated after controlling for neuroticism, suggesting partial mediation. While our cross-sectional design precludes causal inference, our findings support the notion that childhood emotional abuse may contribute to increased neuroticism, thereby elevating vulnerability to affective disorders in adulthood. These results underscore the importance of considering personality factors in understanding the long-term consequences of childhood trauma on mental health outcomes.

Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial.

Ketamine has rapid-onset antidepressant activity in patients with treatment-resistant major depression (TRD). The safety and tolerability of racemic ketamine may be improved if given orally, as an extended-release tablet (R-107), compared with other routes of administration. In this phase 2 multicenter clinical trial, male and female adult patients with TRD and Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥20 received open-label R-107 tablets 120 mg per day for 5 days and were assessed on day 8 (enrichment phase). On day 8, responders (MADRS scores ≤12 and reduction ≥50%) were randomized on a 1:1:1:1:1 basis to receive double-blind R-107 doses of 30, 60, 120 or 180 mg, or placebo, twice weekly for a further 12 weeks. Nonresponders on day 8 exited the study. The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 13 weeks, starting with the 180 mg dose, using a fixed sequence step-down closed test procedure. Between May 2019 and August 2021, 329 individuals were screened for eligibility, 231 entered the open-label enrichment phase (days 1-8) and 168 responders were randomized to double-blind treatment. The primary objective was met; the least square mean difference of MADRS score for the 180 mg tablet group and placebo was -6.1 (95% confidence interval 1.0 to 11.16, P = 0.019) at 13 weeks. Relapse rates during double-blind treatment showed a dose response from 70.6% for placebo to 42.9% for 180 mg. Tolerability was excellent, with no changes in blood pressure, minimal reports of sedation and minimal dissociation. The most common adverse events were headache, dizziness and anxiety. During the randomized phase of the study, most patient dosing occurred at home. R-107 tablets were effective, safe and well tolerated in a patient population with TRD, enriched for initial response to R-107 tablets. ClinicalTrials.gov registration: ACTRN12618001042235 .

The Role of Subgenual Resting-State Connectivity Networks in Predicting Prognosis in Major Depressive Disorder.

Background: A seminal study found higher subgenual frontal cortex resting-state connectivity with 2 left ventral frontal regions and the dorsal midbrain to predict better response to psychotherapy versus medication in individuals with treatment-naïve major depressive disorder (MDD). Here, we examined whether these subgenual networks also play a role in the pathophysiology of clinical outcomes in MDD with early treatment resistance in primary care. Methods: Forty-five people with current MDD who had not responded to ≥2 serotonergic antidepressants (n = 43, meeting predefined functional magnetic resonance imaging minimum quality thresholds) were enrolled and followed over 4 months of standard care. Functional magnetic resonance imaging resting-state connectivity between the preregistered subgenual frontal cortex seed and 3 previously identified left ventromedial, ventrolateral prefrontal/insula, and dorsal midbrain regions was extracted. The clinical outcome was the percentage change on the self-reported 16-item Quick Inventory of Depressive Symptomatology. Results: We observed a reversal of our preregistered hypothesis in that higher resting-state connectivity between the subgenual cortex and the a priori ventrolateral prefrontal/insula region predicted favorable rather than unfavorable clinical outcomes (rs39 = -0.43, p = .006). This generalized to the sample including participants with suboptimal functional magnetic resonance imaging quality (rs43 = -0.35, p = .02). In contrast, no effects (rs39 = 0.12, rs39 = -0.01) were found for connectivity with the other 2 preregistered regions or in a whole-brain analysis (voxel-based familywise error-corrected p < .05). Conclusions: Subgenual connectivity with the ventrolateral prefrontal cortex/insula is relevant for subsequent clinical outcomes in current MDD with early treatment resistance. Its positive association with favorable outcomes could be explained primarily by psychosocial rather than the expected pharmacological changes during the follow-up period.

Evidence has shown that connectivity of the subgenual cortex, a frontal midline brain region, with 3 other brain regions can predict whether people with never-treated depression benefit more from psychological or medication-based treatments. Here, using resting-state fMRI, we show that subgenual connections with one of these regions, the left ventrolateral prefrontal/insula, also predict future average depression levels in people with difficult-to-treat depression. These data suggest that functional connectivity between these regions may be linked to clinical outcomes in major depressive disorder.