A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials.

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Deep learning-based automated speech detection as a marker of social functioning in late-life depression.

BACKGROUND: Late-life depression (LLD) is associated with poor social functioning. However, previous research uses bias-prone self-report scales to measure social functioning and a more objective measure is lacking. We tested a novel wearable device to measure speech that participants encounter as an indicator of social interaction. METHODS: Twenty nine participants with LLD and 29 age-matched controls wore a wrist-worn device continuously for seven days, which recorded their acoustic environment. Acoustic data were automatically analysed using deep learning models that had been developed and validated on an independent speech dataset. Total speech activity and the proportion of speech produced by the device wearer were both detected whilst maintaining participants' privacy. Participants underwent a neuropsychological test battery and clinical and self-report scales to measure severity of depression, general and social functioning. RESULTS: Compared to controls, participants with LLD showed poorer self-reported social and general functioning. Total speech activity was much lower for participants with LLD than controls, with no overlap between groups. The proportion of speech produced by the participants was smaller for LLD than controls. In LLD, both speech measures correlated with attention and psychomotor speed performance but not with depression severity or self-reported social functioning. CONCLUSIONS: Using this device, LLD was associated with lower levels of speech than controls and speech activity was related to psychomotor retardation. We have demonstrated that speech activity measured by wearable technology differentiated LLD from controls with high precision and, in this study, provided an objective measure of an aspect of real-world social functioning in LLD.

Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology.

These updated guidelines from the British Association for Psychopharmacology replace the original version published in 2011. They address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting was held in 2017, involving experts in schizophrenia and its treatment. They were asked to review key areas and consider the strength of the evidence on the risk-benefit balance of pharmacological interventions and the clinical implications, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. The guidelines cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. It is hoped that the practice recommendations presented will support clinical decision making for practitioners, serve as a source of information for patients and carers, and inform quality improvement.

Language in schizophrenia and aphasia: the relationship with non-verbal cognition and thought disorder.

Objective: To determine the relationship between language abnormalities and broader cognitive impairment and thought disorder by examining language and cognition in schizophrenia and aphasia (a primary language disorder).Methods: Cognitive and linguistic profiles were measured with a battery of standardised tests, and compared in a clinical population of n = 50 (n = 30 with schizophrenia and n = 20 with aphasia) and n = 61 non-clinical comparisons (n = 45 healthy controls and n = 16 non-affected first-degree relatives of patients with schizophrenia).Results: Both clinical groups showed linguistic deficits. Verbal impairment was more severe in participants with aphasia, whereas non-verbal performance was more affected in participants with schizophrenia. In schizophrenia, but not in aphasia, verbal and non-verbal performance were associated. Formal thought disorder was associated with impairment in executive function and in grammatical, but not naming, tasks.Conclusion: While patients with schizophrenia and aphasia showed language impairments, the nature and cognitive basis of these impairments may be different; language performance disassociates from broader cognitive functioning in aphasia but may be an intrinsic expression of a broader cognitive impairment in schizophrenia. Thought disorder may represent a core malfunction of grammatical processing. Results suggests that communicative ability may be a valid target in cognitive remediation strategies in schizophrenia.

A UK clinical audit addressing the quality of prescribing of sodium valproate for bipolar disorder in women of childbearing age.

OBJECTIVES: To review prescribing practice concerning valproate, an established human teratogen, for the management of bipolar disorder in women of childbearing age. DESIGN: The Prescribing Observatory for Mental Health conducted a baseline clinical audit in the UK, as part of a quality improvement programme. PARTICIPANTS: Six hundred and forty-eight clinical teams from 55 mental health Trusts submitted retrospective treatment data relating to patients with a diagnosis of bipolar disorder. RESULTS: Of the audit sample of 6705 patients, 3854 were 50 years of age or younger. Valproate was prescribed for 24% of women and 43% men in this age group, and the mean dose of valproate was lower in women (1196 mg) than in men (1391 mg). For only half of such women was there documented evidence that information had been provided on the risks for the unborn child and the need for adequate contraception. Valproate was more often used in men to treat mania and aggression, while the most common treatment targets in women were hypomania and relapse prevention. CONCLUSIONS: Despite explicit recommendations in national treatment guidelines and published safety alerts and warnings regarding the use of valproate in women of childbearing age, current prescribing of this medication to such women in the context of the treatment of bipolar disorder falls short of best practice, particularly with regard to provision of information regarding the risks associated with exposure to valproate during pregnancy. While women younger than 50 years of age were less likely to be prescribed valproate than men in the same age group, and at a lower dosage, it is unclear to what extent this reflects clinicians' concerns about teratogenicity or is driven by perceptions of the indication for valproate, and the dosage required, for the treatment of different phases of the disorder in men and women.

Prevalence of cognitive impairment in major depression and bipolar disorder.

OBJECTIVES: The current study examines prevalence of cognitive impairment in four mood disorder samples, using four definitions of impairment. The impact of premorbid IQ on prevalence was examined, and the influence of treatment response. METHODS: Samples were: (i) 58 inpatients in a current severe depressive episode (unipolar or bipolar), (ii) 69 unmedicated outpatients in a mild to moderate depressive episode (unipolar or bipolar), (iii) 56 outpatients with bipolar disorder, in a depressive episode, and (iv) 63 outpatients with bipolar disorder, currently euthymic. Cognitive assessment was conducted after treatment in Studies 1 (6 weeks of antidepressant treatment commenced on admission) and 2 (16-week course of cognitive behaviour therapy or schema therapy), allowing the impact of treatment response to be assessed. All mood disorder samples were compared with healthy control groups. RESULTS: The prevalence of cognitive impairment was highest for the inpatient depression sample (Study 1), and lowest for the outpatient depression sample (Study 2). Substantial variability in rates was observed depending on the definition of impairment used. Correcting cognitive performance for premorbid IQ had a significant impact on the prevalence of cognitive impairment in the inpatient depression sample. There was minimal evidence that treatment response impacted on prevalence of cognitive impairment, except in the domain of psychomotor speed in inpatients. CONCLUSIONS: As interventions aiming to improve cognitive outcomes in mood disorders receive increasing research focus, the issue of setting a cut-off level of cognitive impairment for screening purposes becomes a priority. This analysis demonstrates important differences in samples likely to be recruited depending on the definition of cognitive impairment and begins to examine the importance of premorbid IQ in determining who is impaired.

Deictic and Propositional Meaning-New Perspectives on Language in Schizophrenia.

Emerging linguistic evidence points at disordered language behavior as a defining characteristic of schizophrenia. In this article, we review this literature and demonstrate how a framework focusing on two core functions of language-reference and propositional meaning-can conceptualize schizophrenic symptoms, identify important variables for risk assessment, diagnosis, and treatment, and inform cognitive behavioral therapy and other remedial approaches. We introduce the linguistic phenomena of deictic anchoring and propositional complexity, explain how they relate to schizophrenic symptoms, and show how they can be tracked in language behavior.

The impact and measurement of social dysfunction in late-life depression: an evaluation of current methods with a focus on wearable technology.

OBJECTIVE: Depression is known to negatively impact social functioning, with patients commonly reporting difficulties maintaining social relationships. Moreover, a large body of evidence suggests poor social functioning is not only present in depression but that social functioning is an important factor in illness course and outcome. In addition, good social relationships can play a protective role against the onset of depressive symptoms, particularly in late-life depression. However, the majority of research in this area has employed self-report measures of social function. This approach is problematic, as due to their reliance on memory, such measures are prone to error from the neurocognitive impairments of depression, as well as mood-congruent biases. METHOD: Narrative review based on searches of the Web of Science and PubMed database(s) from the start of the databases, until the end of 2015. RESULTS: The present review provides an overview of the literature on social functioning in (late-life) depression and discusses the potential for new technologies to improve the measurement of social function in depressed older adults. In particular, the use of wearable technology to collect direct, objective measures of social activity, such as physical activity and speech, is considered. CONCLUSION: In order to develop a greater understanding of social functioning in late-life depression, future research should include the development and validation of more direct, objective measures in conjunction with subjective self-report measures. Copyright © 2016 John Wiley & Sons, Ltd.

The Impact of Target Frequency on Intra-Individual Variability in Euthymic Bipolar Disorder: A Comparison of Two Sustained Attention Tasks.

Greater intra-individual variability (IIV) in reaction time (RT) on a sustained attention task has been reported in patients with bipolar disorder (BD) compared with healthy controls. However, it is unclear whether IIV is task specific, or whether it represents general cross-task impairment in BD. This study aimed to investigate whether IIV occurs in sustained attention tasks with different parameters. Twenty-two patients with BD (currently euthymic) and 17 controls completed two sustained attention tasks on different occasions: a low target frequency (~20%) Vigil continuous performance test (CPT) and a high target frequency (~70%) CPT version A-X (CPT-AX). Variability measures (individual standard deviation and coefficient of variation) were calculated per participant, and ex-Gaussian modeling was also applied. This was supplemented by Vincentile analysis to characterize RT distributions. Results indicated that participants (patients and controls) were generally slower and more variable when completing the Vigil CPT compared with CPT-AX. Significant group differences were also observed in the Vigil CPT, with euthymic BD patients being more variable than controls. This result suggests that IIV in BD demonstrates some degree of task specificity. Further research should incorporate analysis of additional RT distributional models (drift diffusion and fast Fourier transform) to fully characterize the pattern of IIV in BD, as well as its relationship to cognitive processes.

Automatic processing of emotional stimuli in euthymic patients with bipolar disorder.

BACKGROUND: Biased information processing styles are a core feature of cognitive models of unipolar depression (UD). The manic-defence hypothesis (MDH) posits that UD and Bipolar Disorder (BD) are subject partially to the same underlying cognitive processes, which may act as putative vulnerability factors. Previous studies have used experimental paradigms as a way of measuring automatic (non-intentional) processing of emotional information in order to test the MDH with some studies providing some evidence for a negatively biased automatic processing of emotionally-relevant information in BD. However, most prior studies used supraliminal stimuli (i.e. presented above perceptual threshold). Based on the MDH we predicted that subliminally presented negative stimuli will affect performance of patients with BD differently than non-clinical participants, but similarly to what has been observed in prior studies with currently depressed patients. METHODS: The current study used an affective priming paradigm with both supraliminally and subliminally presented emotional images as primes to measure automatic processing. Seventeen euthymic individuals with a BD diagnosis were recruited along with seventeen non-clinical control participants (NCC) matched for age and gender. RESULTS: We found interference (increased response times) due to masked, subliminally presented negative primes in patients with BD when negative prime images were followed by negative targets, but decreased response times (facilitation) in NCCs. LIMITATIONS: We did not include a psychiatric control group and the sample size was small. CONCLUSION: Our findings suggest that euthymic patients with BD do exhibit an affective bias suggesting an increased sensitivity to negative emotional information even when euthymic.

The effect of self-monitoring on Wisconsin Card Sorting Test performance in euthymic patients with bipolar disorder: a pilot study.

OBJECTIVES: Euthymic patients with bipolar disorder (BD) show executive impairment. Assisting cognitive function with non-pharmacological strategies has not been widely explored in BD. In schizophrenia, concomitant verbalisation (self-monitoring) during executive tests improved performance. The present pilot study assesses the effects of self-monitoring whilst completing the Wisconsin Card Sorting Test (WCST) in BD patients. METHODS: Thirty-six euthymic BD patients and 42 healthy controls participated. Twenty patients with BD and 20 controls received standard administration and 16 patients and 22 controls used self-monitoring during the test. RESULTS: ANCOVA revealed a significant "group by administration" interaction. Patients who received the standard administration were significantly worse than healthy controls (trials administered: p = .012, η p (2) = 0.17; trials to first category: p = .046, η p (2) = 0.11; failure to maintain set: p = .003, η p (2) = 0.23). BD patients who self-monitored performed significantly better than patients receiving the standard administration (trials to first category: p = .020, η p (2) = 0.17) and showed no significant differences in performance compared to controls. CONCLUSION: Self-monitoring deserves further investigation as a tool that may be helpful for patients with BD. Further exploration of the utility, generalisability, and stability of the effects of self-monitoring is needed.

Antidepressant augmentation with metyrapone for treatment-resistant depression (the ADD study): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression. METHODS: This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18-65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of ≥18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2-10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1:1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31. FINDINGS: Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 [83%] in the metyrapone and 74 [90%] in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21·7 points [95% CI 19·2-24·4] in the metyrapone group vs 22·6 points [20·1-24·8] in the placebo group; adjusted mean difference of -0·51 points [95% CI -3·48 to 2·46]; p=0·74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug. INTERPRETATION: Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic-pituitary-adrenal axis abnormalities. FUNDING: Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.

Processing of Facial Emotion in Bipolar Depression and Euthymia.

Previous studies of facial emotion processing in bipolar disorder (BD) have reported conflicting findings. In independently conducted studies, we investigate facial emotion labeling in euthymic and depressed BD patients using tasks with static and dynamically morphed images of different emotions displayed at different intensities. Study 1 included 38 euthymic BD patients and 28 controls. Participants completed two tasks: labeling of static images of basic facial emotions (anger, disgust, fear, happy, sad) shown at different expression intensities; the Eyes Test (Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001), which involves recognition of complex emotions using only the eye region of the face. Study 2 included 53 depressed BD patients and 47 controls. Participants completed two tasks: labeling of "dynamic" facial expressions of the same five basic emotions; the Emotional Hexagon test (Young, Perret, Calder, Sprengelmeyer, & Ekman, 2002). There were no significant group differences on any measures of emotion perception/labeling, compared to controls. A significant group by intensity interaction was observed in both emotion labeling tasks (euthymia and depression), although this effect did not survive the addition of measures of executive function/psychomotor speed as covariates. Only 2.6-15.8% of euthymic patients and 7.8-13.7% of depressed patients scored below the 10th percentile of the controls for total emotion recognition accuracy. There was no evidence of specific deficits in facial emotion labeling in euthymic or depressed BD patients. Methodological variations-including mood state, sample size, and the cognitive demands of the tasks-may contribute significantly to the variability in findings between studies.

Childhood trauma in bipolar disorder.

OBJECTIVE: There has been little investigation of early trauma in bipolar disorder despite evidence that stress impacts on the course of this illness. We aimed to compare the rates of childhood trauma in adults with bipolar disorder to a healthy control group, and to investigate the impact of childhood trauma on the clinical course of bipolar disorder. METHODS: Retrospective assessment of childhood trauma was conducted using the Childhood Trauma Questionnaire (CTQ) in 60 outpatients with bipolar disorder being treated for a depressive episode and 55 control participants across two centres in north-east England and New Zealand. RESULTS: Significantly higher rates of childhood trauma were observed in patients with bipolar I and bipolar II disorder compared to controls. Logistic regression, controlling for age and sex, identified emotional neglect to be the only significant CTQ subscale associated with a diagnosis of bipolar disorder. Childhood history of sexual abuse was not a significant predictor. Associations with clinical severity or course were less clear. CONCLUSIONS: Childhood emotional neglect appears to be significantly associated with bipolar disorder. Limitations include the relatively small sample size, which potentially increases the risk of type II errors. Replication of this study is required, with further investigation into the neurobiological consequences of childhood trauma, particularly emotional neglect.

Corpus callosum changes in euthymic bipolar affective disorder.

BACKGROUND: Changes in corpus callosum area and thickness have been reported in bipolar disorder. Imaging and limited neuropathological data suggest possible abnormalities in myelination and/or glial function. AIMS: To compare corpus callosum area, thickness and magnetic resonance imaging (MRI) T1 signal intensity in patients with bipolar disorder and healthy controls. METHOD: A total of 48 patients with euthymic bipolar disorder and 46 healthy controls underwent MRI analysis of callosal midsagittal area, callosal thickness and T1 signal intensity. RESULTS: The bipolar group had smaller overall and subregional callosal areas and correspondingly reduced callosal width than the control group. Age correlated negatively with callosal area in the control group but not in the bipolar group. Signal intensity was higher in women than in men in both groups. Signal intensity was reduced in women, but not in men, in the bipolar group. CONCLUSIONS: Observed differences probably relate to diagnosis rather than mood state and bipolar disorder appears to result in morphometric change that overrides changes seen in normal ageing. Intensity changes are consistent with possible altered myelination or glial function. A gender-dependent factor appears to operate and to interact with diagnosis.

Study protocol for the randomised controlled trial: antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study).

BACKGROUND: Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service. METHODS/DESIGN: Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone. DISCUSSION: Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.

Performance monitoring and executive control of attention in euthymic bipolar disorder: employing the CPT-AX paradigm.

Reduced cognitive test performance has been demonstrated in patients with bipolar disorder (BD), even when euthymic. Several studies have explored aspects of attention, including sustained attention, and reported patients show lower accuracy compared to controls. It is necessary to modify existing attentional paradigms to fully characterise such deficits. The present study sought to examine if there are changes in the profile of performance and error-types during a sustained attention task in BD. Twenty-two euthymic patients with DSM-IV diagnosed BD and 21 healthy controls were recruited. Participants completed a modified CPT-AX paradigm with a high proportion of target trials (70%) with cues and probes presented at continuous intervals. This modification increases the demands on response inhibition and permits the deconstruction of attentional/executive deficits previously described. Overall, BD patients showed significantly poorer target discriminability compared to controls. In block one (first quarter) of the task, patients showed no significant differences to controls, but by the final fourth block (last quarter) they made significantly fewer hits and more errors (both 'AX' misses and 'BX' false alarms). BD patients completed initial stages of the task similarly to controls, but as demands on the attentional system continued difficulties emerged, consistent with problems in context-maintenance.

Negative BOLD response in the hippocampus during short-term spatial memory retrieval.

A parieto-medial temporal pathway is thought to underlie spatial navigation in humans. fMRI was used to assess the role of this pathway, including the hippocampus, in the cognitive processes likely to underlie navigation based on environmental cues. Participants completed a short-term spatial memory task in virtual space, which required no navigation but involved the recognition of a target location from a foil location based on environmental landmarks. The results showed that spatial memory retrieval based on environmental landmarks was indeed associated with increased signal in regions of the parieto-medial temporal pathway, including the superior parietal cortex, the retrosplenial cortex, and the lingual gyrus. However, the hippocampus demonstrated a signal decrease below the fixation baseline during landmark-based retrieval, whereas there was no signal change from baseline during retrieval based on viewer position. In a discussion of the origins of such negative BOLD response in the hippocampus, we consider both a suppression of default activity and an increase in activity without a corresponding boost in CBF as possible mechanisms.

A randomized trial to examine the effect of mifepristone on neuropsychological performance and mood in patients with bipolar depression.

BACKGROUND: Deficits in neuropsychological performance are found in patients with bipolar disorder and represent a potential treatment target for novel therapeutic strategies. We have previously demonstrated a beneficial effect on spatial working memory (SWM) of treatment for 1 week with the progesterone and glucocorticoid receptor antagonist mifepristone, evident 2 weeks after the cessation of treatment. METHODS: We examined the longer-term efficacy of 600 mg/day of mifepristone as an adjunctive treatment, for 1 week, in a placebo-controlled, randomized, double-blind trial in 60 patients with bipolar depression, with SWM as the primary outcome measure. A comparator group of healthy control subjects was also recruited. RESULTS: At baseline, neuropsychological performance of patients was impaired, but hypothalamic-pituitary-adrenal axis function did not differ from that of control subjects. Mifepristone treatment was associated with a time-limited increase in cortisol awakening response and with a sustained improvement in SWM performance, which was evident 7 weeks after the cessation of treatment. The magnitude of this neuropsychological response was predicted by the magnitude of the cortisol response to mifepristone. The response occurred in the absence of a significant improvement in depressed mood. CONCLUSIONS: These data accord with the findings of animal studies and demonstrate that brief treatment with mifepristone is associated with a sustained improvement in SWM, an effect that might be mediated by a persistent enhancement in hippocampal mineralocorticoid receptor function.