Using a generative model of affect to characterize affective variability and its response to treatment in bipolar disorder.

The affective variability of bipolar disorder (BD) is thought to qualitatively differ from that of borderline personality disorder (BPD), with changes in affect persisting longer in BD. However, quantitative studies have not been able to confirm this distinction. It has therefore not been possible to accurately quantify how treatments like lithium influence affective variability in BD. We assessed the affective variability associated with BD and BPD as well as the effect of lithium using a computational model that defines two subtypes of variability: affective changes that persist (volatility) and changes that do not (noise). We hypothesized that affective volatility would be raised in the BD group, noise would be raised in the BPD group, and that lithium would impact affective volatility. Daily affect ratings were prospectively collected for up to 3 y from patients with BD or BPD and nonclinical controls. In a separate experimental medicine study, patients with BD were randomized to receive lithium or placebo, with affect ratings collected from week -2 to +4. We found a diagnostically specific pattern of affective variability. Affective volatility was raised in patients with BD, whereas affective noise was raised in patients with BPD. Rather than suppressing affective variability, lithium increased the volatility of positive affect in both studies. These results provide a quantitative measure of the affective variability associated with BD and BPD. They suggest a mechanism of action for lithium, whereby periods of persistently low or high affect are avoided by increasing the volatility of affective responses.

Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial.

BACKGROUND: Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm. OBJECTIVES: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. METHODS: A 6-week randomised, crossover, double-blinded and placebo-controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6. RESULTS: Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid-sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid. CONCLUSIONS: These findings support the administration of hormone therapy that mimics physiology.

Brain activity measured by functional brain imaging predicts breathlessness improvement during pulmonary rehabilitation.

BACKGROUND: Chronic breathlessness in chronic obstructive pulmonary disease (COPD) is effectively treated with pulmonary rehabilitation. However, baseline patient characteristics predicting improvements in breathlessness are unknown. This knowledge may provide better understanding of the mechanisms engaged in treating breathlessness and help to individualise therapy. Increasing evidence supports the role of expectation (ie, placebo and nocebo effects) in breathlessness perception. In this study, we tested functional brain imaging markers of breathlessness expectation as predictors of therapeutic response to pulmonary rehabilitation, and asked whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulated any predictive model. METHODS: Data from 71 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation were analysed (ID: NCT01985750). Baseline variables, including brain-activity, self-report questionnaires responses, clinical measures of respiratory function and drug allocation were used to train machine-learning models to predict the outcome, a minimally clinically relevant change in the Dyspnoea-12 score. RESULTS: Only models that included brain imaging markers of breathlessness-expectation successfully predicted improvements in Dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine was independently associated with breathlessness improvement. Models that included only questionnaires and clinical measures did not predict outcome (sensitivity 0.68, specificity 0.2). CONCLUSIONS: Brain activity to breathlessness related cues is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is key in breathlessness perception. Manipulation of the brain's expectation pathways (either pharmacological or non-pharmacological) therefore merits further testing in the treatment of chronic breathlessness.

Real-world outcomes of concomitant antidepressant and statin use in primary care patients with depression: a population-based cohort study.

BACKGROUND: Antidepressants are licensed for use in depressive disorders, but non-response and poor adherence to treatment affect a considerable number of patients. Pre-clinical and clinical evidence suggest that statins can augment the effects of antidepressants. However, the acceptability and tolerability of combining statins with antidepressants are unclear, and their add-on efficacy has only been shown in small, short-term clinical trials. Observational data can provide complementary information about treatment effects on larger samples over longer follow-ups. In this study, we therefore assessed the real-world acceptability, tolerability, and efficacy of concomitant antidepressant and statin treatment in depression. METHODS: We conducted a population-based cohort study investigating QResearch primary care research database, which comprises the anonymised electronic healthcare records of 35 + million patients over 1574 English general practices. Patients aged 18-100 years, registered between January 1998 and August 2020, diagnosed with a new episode of depression, and commencing an antidepressant were included. Using a between-subject design, we identified two study groups: antidepressant + statin versus antidepressant-only prescriptions. Outcomes of interest included the following: antidepressant treatment discontinuations due to any cause (acceptability) and due to any adverse event (tolerability) and effects on depressive symptoms (efficacy) measured as response, remission, and change in depression score on the Patient Health Questionnaire-9. All outcomes were assessed at 2, 6, and 12 months using multivariable regression analyses, adjusted for relevant confounders, to calculate adjusted odds ratios (aORs) or mean differences (aMDs) with 99% confidence intervals (99% CIs). RESULTS: Compared to antidepressant-only (N 626,335), antidepressant + statin (N 46,482) was associated with higher antidepressant treatment acceptability (aOR2months 0.88, 99% CI 0.85 to 0.91; aOR6months 0.81, 99% CI 0.79 to 0.84; aOR12months 0.78, 99% CI 0.75 to 0.81) and tolerability (aOR2months 0.92, 99% CI 0.87 to 0.98; aOR6months 0.94, 99% CI 0.89 to 0.99, though not long term aOR12 months 1.02, 99% CI 0.97 to 1.06). Efficacy did not differ between groups (range aOR2-12 months 1.00 and 1.02 for response and remission, range aOR2-12 months - 0.01 and - 0.02 for change in depression score). CONCLUSIONS: On real-world data, there is a positive correlation between antidepressant treatment adherence and statin use, partly explained by fewer dropouts due to adverse events. The main limitation of our study is its observational design, which restricts the potential to make causal inferences.

Multispecies probiotic administration reduces emotional salience and improves mood in subjects with moderate depression: a randomised, double-blind, placebo-controlled study.

BACKGROUND: The potential antidepressant properties of probiotics have been suggested, but their influence on the emotional processes that may underlie this effect is unclear. METHODS: Depressed volunteers (n = 71) were recruited into a randomised double-blind, placebo-controlled study to explore the effects of a daily, 4-week intake of a multispecies probiotic or placebo on emotional processing and cognition. Mood, anxiety, positive and negative affect, sleep, salivary cortisol and serum C-reactive peptide (CRP) were assessed before and after supplementation. RESULTS: Compared with placebo, probiotic intake increased accuracy at identifying faces expressing all emotions (+12%, p < 0.05, total n = 51) and vigilance to neutral faces (mean difference between groups = 12.28 ms ± 6.1, p < 0.05, total n = 51). Probiotic supplementation also reduced reward learning (-9%, p < 0.05, total n = 51), and interference word recall on the auditory verbal learning task (-18%, p < 0.05, total n = 50), but did not affect other aspects of cognitive performance. Although actigraphy revealed a significant group × night-time activity interaction, follow up analysis was not significant (p = 0.094). Supplementation did not alter salivary cortisol or circulating CRP concentrations. Probiotic intake significantly reduced (-50% from baseline, p < 0.05, n = 35) depression scores on the Patient Health Questionnaire-9, but these did not correlate with the changes in emotional processing. CONCLUSIONS: The impartiality to positive and negative emotional stimuli or reward after probiotic supplementation have not been observed with conventional antidepressant therapies. Further studies are required to elucidate the significance of these changes with regard to the mood-improving action of the current probiotic.

Online behavioural activation during the COVID-19 pandemic decreases depression and negative affective bias.

BACKGROUND: The COVID-19 pandemic highlighted the need for mental health interventions that can be easily disseminated during a crisis. Behavioural activation (BA) is a cost-effective treatment that can be administered by non-specialists; however, it is unclear whether it is still effective during a time of lockdown and social distancing, when opportunities for positive activity are significantly constrained. METHODS: Between May and October 2020, we randomised 68 UK participants with mild to moderate low mood to either a 4-week online programme of non-specialist administered BA or to a passive control group. Before and after the intervention, we collected self-report data on mood and COVID-related disruption, as well as measuring emotional cognition as an objective marker of risk for depression. RESULTS: In comparison to the control group, the BA group showed a significant decrease in depression, anxiety and anhedonia after the intervention, as well as an increase in self-reported activation and social support. Benefits persisted at 1-month follow-up. BA also decreased negative affective bias on several measures of the Facial Emotion Recognition Task and early change in bias was associated with later therapeutic gain. Participants rated the intervention as highly acceptable. CONCLUSION: This study highlights the benefits of online BA that can be administered by non-specialists after brief training. These findings can help inform the policy response towards the rising incidence of mental health problems during a crisis situation such as a pandemic. They also highlight the use of objective cognitive markers of risk across different treatment modalities.

Neuropsychological markers of antidepressant action: a secondary analysis of the ANTLER randomised controlled trial.

BACKGROUND: Antidepressants have been proposed to act via their influence on emotional processing. We investigated the effect of discontinuing maintenance antidepressant treatment on positive and negative self-referential recall and the association between self-referential recall and risk of relapse. METHODS: The ANTLER trial was a large (N = 478) pragmatic double-blind trial investigating the clinical effectiveness of long-term antidepressant treatment for preventing relapse in primary care patients. Participants were randomised to continue their maintenance antidepressants or discontinue via a taper to placebo. We analysed memory for positive and negative personality descriptors, assessed at baseline, 12- and 52-week follow-up. RESULTS: The recall task was completed by 437 participants. There was no evidence of an effect of discontinuation on self-referential recall at 12 [positive recall ratio 1.00, 95% CI (0.90-1.11), p = 0.93; negative recall ratio 1.00 (0.87-1.14), p = 0.87] or 52 weeks [positive recall ratio 1.03 (0.91-1.17), p = 0.62; negative recall ratio 1.00 (0.86-1.15), p = 0.96; ratios larger than one indicate higher recall in the discontinuation group], and no evidence of an association between recall at baseline or 12 weeks and later relapse [baseline, positive hazard ratio (HR) 1.02 (0.93-1.12), p = 0.74; negative HR 1.01 (0.90-1.13), p = 0.87; 12 weeks, positive HR 0.99 (0.89-1.09), p = 0.81; negative HR 0.98 (0.84-1.14), p = 0.78; ratios larger than one indicate a higher frequency of relapse in those with higher recall]. CONCLUSIONS: We found no evidence that discontinuing long-term antidepressants altered self-referential recall or that self-referential recall was associated with risk of relapse. These findings suggest that self-referential recall is not a neuropsychological marker of antidepressant action.

The effect of attention bias modification on depressive symptoms in a comorbid sample: a randomized controlled trial.

BACKGROUND: Studies investigating the long-term effect of attention bias modification (ABM) in clinical samples are lacking. This study investigates the 6-months follow-up effect of ABM on depressive symptoms in participant with major depressive disorder with and without comorbid disorders. METHODS: We conducted a double-blind randomized sham-controlled trial in 101 participants between 19 November 2019, and 17 August 2021. Follow-up ended 3 April 2022. Participants were allocated to ABM or sham condition twice daily for 14 consecutive days. Primary outcomes were the total score on the Beck Depression Inventory-II (BDI-II) at 6 months, mean Brief State Rumination Inventory (BSRI) score post-treatment and reduction in BSRI post-treatment. Secondary outcome was change in attentional bias (AB). The trial was preregistered in ClinicalTrials.gov (#NCT04137367). RESULTS: A total of 118 patients aged 18-65 years were assessed for eligibility, and 101 were randomized and subjected to intention-to-treat analyses. At 6 months, ABM had no effect on depression and anxiety compared to a sham condition. While rumination decreased during the intervention, there was no effect of condition on rumination and AB. Predictor analysis did not reveal differences between participants with ongoing major depressive episode or comorbid anxiety. CONCLUSION: Compared to sham training, there was no effect of ABM on depressive symptoms at 6-months follow-up. Since the intervention failed at modifying AB, it is unclear whether changes in AB are related to long-term outcomes.

Acute neural effects of fluoxetine on emotional regulation in depressed adolescents.

BACKGROUND: Adolescent major depressive disorder (MDD) is associated with disrupted processing of emotional stimuli and difficulties in cognitive reappraisal. Little is known however about how current pharmacotherapies act to modulate the neural mechanisms underlying these key processes. The current study therefore investigated the neural effects of fluoxetine on emotional reactivity and cognitive reappraisal in adolescent depression. METHODS: Thirty-one adolescents with MDD were randomised to acute fluoxetine (10 mg) or placebo. Seventeen healthy adolescents were also recruited but did not receive any treatment for ethical reasons. During functional magnetic resonance imaging (fMRI), participants viewed aversive images and were asked to either experience naturally the emotional state elicited ('Maintain') or to reinterpret the content of the pictures to reduce negative affect ('Reappraise'). Significant activations were identified using whole-brain analysis. RESULTS: No significant group differences were seen when comparing Reappraise and Maintain conditions. However, when compared to healthy controls, depressed adolescents on placebo showed reduced visual activation to aversive pictures irrespective of the condition. The depressed adolescent group on fluoxetine showed the opposite pattern, i.e. increased visuo-cerebellar activity in response to aversive pictures, when compared to depressed adolescents on placebo. CONCLUSIONS: These data suggest that depression in adolescence may be associated with reduced visual processing of aversive imagery and that fluoxetine may act to reduce avoidance of such cues. This could reflect a key mechanism whereby depressed adolescents engage with negative cues previously avoided. Future research combining fMRI with eye-tracking is nonetheless needed to further clarify these effects.

A translational perspective on the anti-anhedonic effect of ketamine and its neural underpinnings.

Anhedonia, a pronounced reduction in interest or pleasure in any of life's daily activities, is a cardinal symptom of major depression. In this Perspective article, we synthesise the recent evidence from rodent, monkey and human neuroimaging literature to highlight how the habenula, a small evolutionarily conserved subcortical structure located in the midbrain, may orchestrate the behavioural expression of anhedonia across fronto-mesolimbic networks. We then review how this circuitry can be modulated by ketamine, an NMDA receptor antagonist with rapid antidepressant properties. We propose that experimental paradigms founded in reinforcement learning and value-based decision-making can usefully probe this network and thereby help elucidate the mechanisms underlying ketamine's rapid antidepressant action.

Cognitive Remediation in Bipolar (CRiB2): study protocol for a randomised controlled trial assessing efficacy and mechanisms of cognitive remediation therapy compared to treatment as usual.

BACKGROUND: A substantial proportion of people with bipolar disorder (BD) experience persistent cognitive difficulties associated with impairments in psychosocial functioning and a poorer disorder course. Emerging evidence suggests that cognitive remediation (CR), a psychological intervention with established efficacy in people with schizophrenia, can also benefit people with BD. Following a proof-of-concept trial showing that CR is feasible and potentially beneficial for people with BD, we are conducting an adequately powered trial in euthymic people with BD to 1) determine whether an individual, therapist-supported, computerised CR can reduce cognitive difficulties and improve functional outcomes; and 2) explore how CR exerts its effects. METHODS: CRiB2 is a two-arm, assessor-blind, multi-site, randomised controlled trial (RCT) comparing CR to treatment-as-usual (TAU). Participants are people with a diagnosis of BD, aged between 18 and 65, with no neurological or current substance use disorder, and currently euthymic. 250 participants will be recruited through primary, secondary, tertiary care, and the community. Participants will be block-randomised (1:1 ratio, stratified by site) to continue with their usual care (TAU) or receive a 12-week course of therapy and usual care (CR + TAU). The intervention comprises one-on-one CR sessions with a therapist supplemented with independent cognitive training for 30-40 h in total. Outcomes will be assessed at 13- and 25-weeks post-randomisation. Efficacy will be examined by intention-to-treat analyses estimating between-group differences in primary (i.e., psychosocial functioning at week 25 measured with the Functional Assessment Short Test) and secondary outcomes (i.e., measures of cognition, mood, patient-defined goals, and quality of life). Global cognition, metacognitive skills, affect fluctuation, and salivary cortisol levels will be evaluated as putative mechanisms of CR through mediation models. DISCUSSION: This study will provide a robust evaluation of efficacy of CR in people with BD and examine the putative mechanisms by which this therapy works. The findings will contribute to determining the clinical utility of CR and potential mechanisms of action. TRIAL REGISTRATION: Cognitive Remediation in Bipolar 2 (CRiB2): ISRCTN registry: https://www.isrctn.com/ISRCTN10362331 . Registered 04 May 2022. Overall trial status: Ongoing; Recruitment status: Recruiting.

AI-based dimensional neuroimaging system for characterizing heterogeneity in brain structure and function in major depressive disorder: COORDINATE-MDD consortium design and rationale.

BACKGROUND: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states. METHODS: We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants. RESULTS: We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites. CONCLUSION: We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project.

Machine learning prediction will be part of future treatment of depression.

Machine learning (ML) is changing the way that medicine is practiced. While already clinically utilised in diagnostic radiology and outcome prediction in intensive care unit, ML approaches in psychiatry remain nascent. Implementing ML algorithms in psychiatry, particularly in the treatment of depression, is significantly more challenging than other areas of medicine in part because of the less demarcated disease nosology and greater variability in practice. Given the current exiguous capacity of clinicians to predict patient and treatment outcomes in depression, there is a significantly greater need for better predictive capability. Early studies have shown promising results. ML predictions were significantly better than chance within the sequenced treatment alternatives to relieve depression (STAR*D) trial (accuracy 64.6%, p < 0.0001) and combining medications to enhance depression outcomes (COMED) randomised Controlled Trial (RCT) (accuracy 59.6%, p = 0.043), with similar results found in larger scale, retrospective studies. The greater flexibility and dimensionality of ML approaches has been demonstrated in studies incorporating diverse input variables including electroencephalography scans, achieving 88% accuracy for treatment response, and cognitive test scores, achieving up to 72% accuracy for treatment response. The predicting response to depression treatment (PReDicT) trial tested ML informed prescribing of antidepressants against standard therapy and found there was both better outcomes for anxiety and functional endpoints despite the algorithm only having a balanced accuracy of 57.5%. Impeding the progress of ML algorithms in psychiatry are pragmatic hurdles, including accuracy, expense, acceptability and comprehensibility, and ethical hurdles, including medicolegal liability, clinical autonomy and data privacy. Notwithstanding impediments, it is clear that ML prediction algorithms will be part of depression treatment in the future and clinicians should be prepared for their arrival.

A co-produced online cultural experience compared to a typical museum website for mental health in people aged 16-24: A proof-of-principle randomised controlled trial.

OBJECTIVE: We aimed to compare a co-produced online intervention encompassing the diverse human stories behind art and artefacts, named Ways of Being (WoB), with a typical museum website, the Ashmolean (Ash) on negative affect (NA), positive affect (PA) and psychological distress (K10). METHODS: In this parallel group RCT, 463 YP aged 16-24 were randomly assigned, 231 to WoB and 232 to Ash. RESULTS: Over the intervention phase (an aggregate score including all post-allocation timepoints to day-five) a group difference was apparent in favour of WoB for NA (WoB-Ash n=448, NA -0.158, p=0.010) but no differences were detected for PA or K10 and differences were not detected at week six. Group differences in NA in favour of WoB were detected in specific subgroups, e.g. ethnic minorities and males. Across participants (from both groups) mean K10 and NA improved between baseline and six weeks despite increased COVID-19 restrictions. Trial recruitment was rapid, retention high and feedback positive with broad geographical, occupational and ethnic diversity. CONCLUSIONS: Online engagement with arts and culture has the potential to impact on mental health in a measurable way in YP with high unmet mental health needs.

Enhanced Taste Recognition Following Subacute Treatment With The Dopamine D2/D3 Receptor Agonist Pramipexole in Healthy Volunteers.

BACKGROUND: Patients with Parkinson's disease (PD) show impaired performance in taste recognition tests, which suggests a possible dopaminergic influence on gustatory functioning. To experimentally test this hypothesis, we assessed whether pharmacological manipulation of dopaminergic signaling in healthy volunteers can affect performance in a standardized taste recognition test. METHODS: Physically and mentally healthy volunteers (n = 40, age 18-43 years) were randomly allocated to treatment with either pramipexole or placebo using a double-blind, parallel-group design. After 12 to 15 days of treatment (dose titrated up from 0.25 mg/d of pramipexole salt to 1.0 mg/d), taste recognition performance was assessed using a standardized and validated assay (taste strip test). Additionally, visual analogue scale ratings of subjective pleasantness and disgustingness of taste samples were obtained. RESULTS: Compared with the placebo group, participants receiving pramipexole showed significantly higher total recognition accuracy (medianpramipexole = 14.0, medianplacebo = 13.0, U = 264.5, P = .04). This was driven by a higher sensitivity for taste in the pramipexole group. Exploratory analysis of pleasantness and disgustingness ratings of appetitive (sweet) vs aversive (bitter) stimuli suggested that pramipexole treatment was associated with overall blunted hedonic responses, but this effect did not survive the inclusion of nausea (a side effect of treatment) as a covariate in the analysis. CONCLUSIONS: Healthy volunteers who received subacute pramipexole treatment exhibited higher taste recognition performance compared with the placebo group. This finding is consistent with a proposed role of the dopaminergic system in gustatory functioning and could have important theoretical and clinical implications.

The effect of sertraline on emotional processing: secondary analyses of the PANDA randomised controlled trial.

BACKGROUND: According to the cognitive neuropsychological model, antidepressants reduce symptoms of depression and anxiety by increasing positive relative to negative information processing. Most studies of whether antidepressants alter emotional processing use small samples of healthy individuals, which lead to low statistical power and selection bias and are difficult to generalise to clinical practice. We tested whether the selective serotonin reuptake inhibitor (SSRI) sertraline altered recall of positive and negative information in a large randomised controlled trial (RCT) of patients with depressive symptoms recruited from primary care. METHODS: The PANDA trial was a pragmatic multicentre double-blind RCT comparing sertraline with placebo. Memory for personality descriptors was tested at baseline and 2 and 6 weeks after randomisation using a computerised emotional categorisation task followed by a free recall. We measured the number of positive and negative words correctly recalled (hits). Poisson mixed models were used to analyse longitudinal associations between treatment allocation and hits. RESULTS: A total of 576 participants (88% of those randomised) completed the recall task at 2 and 6 weeks. We found no evidence that positive or negative hits differed according to treatment allocation at 2 or 6 weeks (adjusted positive hits ratio = 0.97, 95% CI 0.90-1.05, p = 0.52; adjusted negative hits ratio = 0.99, 95% CI 0.90-1.08, p = 0.76). CONCLUSIONS: In the largest individual placebo-controlled trial of an antidepressant not funded by the pharmaceutical industry, we found no evidence that sertraline altered positive or negative recall early in treatment. These findings challenge some assumptions of the cognitive neuropsychological model of antidepressant action.

Neuronal underpinnings of cognitive impairment in bipolar disorder: A large data-driven functional magnetic resonance imaging study.

OBJECTIVES: Cognitive impairment occurs in approximately 50% of remitted patients with bipolar disorder (BD). However, there exists no treatment with replicated and robust efficacy on cognition in BD. This is partially due to limited insight into the neuronal underpinnings of cognitive impairment in these patients. This is the first study to investigate neuronal underpinnings of cognitive impairment in a large functional magnetic resonance imaging (fMRI) dataset comparing neural activity patterns between distinct neurocognitive subgroups of partially or fully remitted patients with BD. METHODS: Patients (n = 153) and healthy controls (HC) (n = 52) underwent neuropsychological assessment and fMRI, during which they performed a verbal N-back working memory (WM) task. Based on hierarchical cluster analysis of neuropsychological test performance, patients were grouped into one of two neurocognitive subgroups (cognitively impaired, n = 91; cognitively normal compared to HC, n = 62) that were compared on WM-related neural activity. RESULTS: Cognitively impaired patients displayed WM-related hypo-activity in left dorsolateral prefrontal cortex and frontal and parietal regions within a cognitive control network (CCN) as well as hyper-activity in the default mode network (DMN) compared to cognitively normal patients. In contrast, cognitively normal patients only exhibited hypo-activity within a small cluster in the superior frontal gyrus relative to HC. CONCLUSIONS: Cognitive impairment in BD seems to originate from a failure to recruit key regions in the CCN and to suppress task-irrelevant DMN activity during cognitive performance. These results highlight modulation of aberrant dorsal prefrontal and DMN activity as a putative target for pro-cognitive treatment in BD.

Statins in depression: a repurposed medical treatment can provide novel insights in mental health.

Depression has a large burden, but the development of new drugs for its treatment has proved difficult. Progresses in neuroscience have highlighted several physiopathological pathways, notably inflammatory and metabolic ones, likely involved in the genesis of depressive symptoms. A novel strategy proposes to repurpose established medical treatments of known safety and to investigate their potential antidepressant activity. Among numerous candidates, growing evidence suggests that statins may have a positive role in the treatment of depressive disorders, although some have raised concerns about possible depressogenic effects of these widely prescribed medications. This narrative review summarises relevant findings from translational studies implicating many interconnected neurobiological and neuropsychological, cardiovascular, endocrine-metabolic, and immunological mechanisms by which statins could influence mood. Also, the most recent clinical investigations on the effects of statins in depression are presented. Overall, the use of statins for the treatment of depressive symptoms cannot be recommended based on the available literature, though this might change as several larger, methodologically robust studies are being conducted. Nevertheless, statins can already be acknowledged as a driver of innovation in mental health, as they provide a novel perspective to the physical health of people with depression and for the development of more precise antidepressant treatments.

Breathlessness in COPD: linking symptom clusters with brain activity.

BACKGROUND: Current models of breathlessness often fail to explain disparities between patients' experiences of breathlessness and objective measures of lung function. While a mechanistic understanding of this discordance has thus far remained elusive, factors such as mood, attention and expectation have all been implicated as important modulators of breathlessness. Therefore, we have developed a model to better understand the relationships between these factors using unsupervised machine learning techniques. Subsequently we examined how expectation-related brain activity differed between these symptom-defined clusters of participants. METHODS: A cohort of 91 participants with mild-to-moderate chronic obstructive pulmonary disease (COPD) underwent functional brain imaging, self-report questionnaires and clinical measures of respiratory function. Unsupervised machine learning techniques of exploratory factor analysis and hierarchical cluster modelling were used to model brain-behaviour-breathlessness links. RESULTS: We successfully stratified participants across four key factors corresponding to mood, symptom burden and two capability measures. Two key groups resulted from this stratification, corresponding to high and low symptom burden. Compared with the high symptom burden group, the low symptom burden group demonstrated significantly greater brain activity within the anterior insula, a key region thought to be involved in monitoring internal bodily sensations (interoception). CONCLUSIONS: This is the largest functional neuroimaging study of COPD to date, and is the first to provide a clear model linking brain, behaviour and breathlessness expectation. Furthermore, it was possible to stratify participants into groups, which then revealed differences in brain activity patterns. Together, these findings highlight the value of multimodal models of breathlessness in identifying behavioural phenotypes and for advancing understanding of differences in breathlessness burden.

Effect of the NMDA receptor partial agonist, d-cycloserine, on emotional processing and autobiographical memory.

BACKGROUND: Studies suggest that d-cycloserine (DCS) may have antidepressant potential through its interaction with the glycine site of the N-methyl-D-aspartate receptor; however, clinical evidence of DCS's efficacy as a treatment for depression is limited. Other evidence suggests that DCS affects emotional learning which may also be relevant for the treatment of depression and anxiety. The aim of the present investigation was to assess the effect of DCS on emotional processing in healthy volunteers and to further characterise its effects on emotional and autobiographical memory. METHODS: Forty healthy volunteers were randomly allocated to a single dose of 250 mg DCS or placebo in a double-blind design. Three hours later, participants performed an Emotional Test Battery [including Facial Expression Recognition Task (FERT), Emotional Categorisation Task (ECAT), Emotional Recall Task (EREC), Facial Dot-Probe Task (FDOT) and Emotional Recognition Memory Task (EMEM)] and an Autobiographical Memory Test (AMT). Also, participants performed the FERT, EREC and AMT tasks again after 24 h in order to assess longer lasting effects of a single dose of DCS. RESULTS: DCS did not significantly affect the FERT, EMEM and FDOT performance but significantly increased emotional memory and classification for positive words v. negative words. Also, DCS enhanced the retrieval of more specific autobiographical memories, and this effect persisted at 24 h. CONCLUSIONS: These findings support the suggestion that low-dose DCS increases specific autobiographical memory retrieval and positive emotional memory. Such effects make it an intriguing agent for further investigation in clinical depression, which is characterised by decreased autobiographical memory specificity and increased negative bias in memory recall. It also underscores the potential role of DCS as an adjunct to cognitive behavioural therapy in depression.