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Excessive negative self-referential processing plays an important role in the development and maintenance of major depressive disorder (MDD). Current measures of self-reflection are limited to self-report questionnaires and invoking imagined states, which may not be suitable for all populations.
The current study aimed to pilot a new measure of self-reflection, the Fake IQ Test (FIQT).
Participants with MDD and unaffected controls completed a behavioural (experiment 1, n = 50) and functional magnetic resonance imaging version (experiment 2, n = 35) of the FIQT.
Behaviourally, those with MDD showed elevated negative self-comparison with others, higher self-dissatisfaction and lower perceived success on the task, compared with controls; however, FIQT scores were not related to existing self-report measures of self-reflection. In the functional magnetic resonance imaging version, greater activation in self-reflection versus control conditions was found bilaterally in the inferior frontal cortex, insula, dorsolateral prefrontal cortex, motor cortex and dorsal anterior cingulate cortex. No differences in neural activation were found between participants with MDD and controls, nor were there any associations between neural activity, FIQT scores or self-report measures of self-reflection.
Our results suggest the FIQT is sensitive to affective psychopathology, but a lack of association with other measures of self-reflection may indicate that the task is measuring a different construct. Alternatively, the FIQT may measure aspects of self-reflection inaccessible to current questionnaires. Future work should explore relationships with alternative measures of self-reflection likely to be involved in perception of task performance, such as perfectionism.
Enhanced post-awakening cortisol may serve as a biological marker for individuals with major depressive disorder. However, studies comparing post-awakening cortisol between patients with major depressive disorder (MDD) and healthy controls have produced conflicting findings. The aim of this study was to investigate whether this inconsistency could be due to the effects of childhood trauma.
A total of N = 112 patients with MDD and healthy controls were divided into four groups according to the presence of childhood trauma. Saliva samples were collected at awakening and 15, 30, 45, and 60 min later. The total cortisol output and the cortisol awakening response (CAR) were calculated.
The total post-awakening cortisol output was significantly higher in patients with MDD as compared to healthy controls, but only in those individuals reporting childhood trauma. The four groups did not differ regarding the CAR.
Elevated post-awakening cortisol in MDD may be confined to those with a history of early life stress. Tailoring and/or augmenting of currently available treatments may be required to meet the specific needs of this population.
Threat avoidance is a prominent symptom of affective disorders, yet its biological basis remains poorly understood. Here, we used a validated task, the Joystick Operated Runway Task (JORT), combined with fMRI, to explore whether abnormal function in neural circuits responsible for avoidance underlies these symptoms. Eighteen individuals with major depressive disorder (MDD) and 17 unaffected controls underwent the task, which involved using physical effort to avoid threatening stimuli, paired with mild electric shocks on certain trials. Activity during anticipation and avoidance of threats was explored and compared between groups. Anticipation of aversive stimuli was associated with significant activation in the dorsal anterior cingulate cortex, superior frontal gyrus, and striatum, while active avoidance of aversive stimuli was associated with activity in dorsal anterior cingulate cortex, insula, and prefrontal cortex. There were no significant group differences in neural activity or behavioral performance on the JORT; however, participants with depression reported more dread while being chased on the task. The JORT effectively identified neural systems involved in avoidance and anticipation of aversive stimuli. However, the absence of significant differences in behavioral performance and activation between depressed and non-depressed groups suggests that MDD is not associated with abnormal function in these networks. Future research should investigate the basis of passive avoidance in major depression. Further, the JORT should be explored in patients with anxiety disorders, where threat avoidance may be a more prominent characteristic of the disorder.
Improving Access to Psychological Therapies (IAPT) is a primary care therapy service commissioned by England's National Health Service (NHS) for people with unipolar depression and anxiety-related disorders. Its scope does not extend to ‘severe mental illness’, including bipolar disorders (BD), but evidence suggests there is a high BD prevalence in ostensibly unipolar major depressive disorder (uMDD) samples. This study aimed to indicate the prevalence and characteristics of people with BD in a naturalistic cohort of IAPT patients.
371 participants were assessed before initiating therapy. Participants were categorised by indicated diagnoses: BD type-I (BD-I) or type-II (BD-II) as defined using a DSM diagnostic interview, bipolar spectrum (BSp, not meeting diagnostic criteria but exceeding BD screening thresholds), lifetime uMDD or other. Information about psychiatric history and co-morbidities was examined, along with symptoms before and after therapy.
368 patients provided sufficient data to enable classification. 10% of participants were grouped as having BD-I, 20% BD-II, 40% BSp, 25% uMDD and 5% other. BD and uMDD participants had similar demographic characteristics, but patients meeting criteria for BD-I/BD-II had more complex psychiatric presentations. All three ‘bipolar’ groups had particularly high rates of anxiety disorders. IAPT therapy receipt was comparable between groups, as was therapy response (F9704 = 1.113, p = 0.351).
Notwithstanding the possibility that bipolar diathesis was overestimated, findings illustrate a high prevalence of BD in groups of people notionally with uMDD or anxiety. As well as improving the detection of BD, further substantive investigation is required to establish whether individuals affected by BD should be eligible for primary care psychological intervention.
Overgeneralised self-blame and worthlessness are key symptoms of major depressive disorder (MDD) and have previously been associated with self-blame-selective changes in connectivity between right superior anterior temporal lobe (rSATL) and subgenual frontal cortices. Another study showed that remitted MDD patients were able to modulate this neural signature using functional magnetic resonance imaging (fMRI) neurofeedback training, thereby increasing their self-esteem. The feasibility and potential of using this approach in symptomatic MDD were unknown.
This single-blind pre-registered randomised controlled pilot trial probed a novel self-guided psychological intervention with and without additional rSATL-posterior subgenual cortex (BA25) fMRI neurofeedback, targeting self-blaming emotions in people with insufficiently recovered MDD and early treatment-resistance (n = 43, n = 35 completers). Participants completed three weekly self-guided sessions to rebalance self-blaming biases.
As predicted, neurofeedback led to a training-induced reduction in rSATL-BA25 connectivity for self-blame v. other-blame. Both interventions were safe and resulted in a 46% reduction on the Beck Depression Inventory-II, our primary outcome, with no group differences. Secondary analyses, however, revealed that patients without DSM-5-defined anxious distress showed a superior response to neurofeedback compared with the psychological intervention, and the opposite pattern in anxious MDD. As predicted, symptom remission was associated with increases in self-esteem and this correlated with the frequency with which participants employed the psychological strategies in daily life.
These findings suggest that self-blame-rebalance neurofeedback may be superior over a solely psychological intervention in non-anxious MDD, although further confirmatory studies are needed. Simple self-guided strategies tackling self-blame were beneficial, but need to be compared against treatment-as-usual in further trials. https://doi.org/10.1186/ISRCTN10526888
Treatment-resistant depression (TRD) is classically defined according to the number of suboptimal antidepressant responses experienced, but multidimensional assessments of TRD are emerging and may confer some advantages. Patient characteristics have been identified as risk factors for TRD but may also be associated with TRD severity. The identification of individuals at risk of severe TRD would support appropriate prioritisation of intensive and specialist treatments.
To determine whether TRD risk factors are associated with TRD severity when assessed multidimensionally using the Maudsley Staging Method (MSM), and univariately as the number of antidepressant non-responses, across three cohorts of individuals with depression.
Three cohorts of individuals without significant TRD, with established TRD and with severe TRD, were assessed (n = 528). Preselected characteristics were included in linear regressions to determine their association with each outcome.
Participants with more severe TRD according to the MSM had a lower age at onset, fewer depressive episodes and more physical comorbidities. These associations were not consistent across cohorts. The number of episodes was associated with the number of antidepressant treatment failures, but the direction of association varied across the cohorts studied.
Several risk factors for TRD were associated with the severity of resistance according to the MSM. Fewer were associated with the raw number of inadequate antidepressant responses. Multidimensional definitions may be more useful for identifying patients at risk of severe TRD. The inconsistency of associations across cohorts has potential implications for the characterisation of TRD.
Individuals with treatment-resistant depression (TRD) experience a high burden of illness. Current guidelines recommend a stepped care approach for treating depression, but the extent to which best-practice care pathways are adhered to is unclear.
To explore the extent and nature of ‘treatment gaps’ (non-adherence to stepped care pathways) experienced by a sample of patients with established TRD (non-response to two or more adequate treatments in the current depressive episode) across three cities in the UK.
Five treatment gaps were considered and compared with guidelines, in a cross-sectional retrospective analysis: delay to receiving treatment, lack of access to psychological therapies, delays to medication changes, delays to adjunctive (pharmacological augmentation) treatment and lack of access to secondary care. We additionally explored participant characteristics associated with the extent of treatment gaps experienced.
Of 178 patients with TRD, 47% had been in the current depressive episode for >1 year before initiating antidepressants; 53% had received adequate psychological therapy. A total of 47 and 51% had remained on an unsuccessful first and second antidepressant trial respectively for >16 weeks, and 24 and 27% for >1 year before medication switch, respectively. Further, 54% had tried three or more antidepressant medications within their episode, and only 11% had received adjunctive treatment.
There appears to be a considerable difference between treatment guidelines for depression and the reality of care received by people with TRD. Future research examining representative samples of patients could determine recommendations for optimising care pathways, and ultimately outcomes, for individuals with this illness.
Major depressive episodes (MDEs) show diverse cortisol level alterations. Heterogeneity in symptom profiles, symptom severity and cortisol specimens may explain these heterogeneous results. Less severely ill out-patients with a non-melancholic MDE (NM-MDE) may have a variation in the rhythm of cortisol secretion rather than in its concentration.
Cortisol measures were taken (a) over a short-term period (12 h) by measuring daily salivary output using the area under the curve with respect to the ground (AUCg) and (b) over a long-term period (3 months) in hair. Additionally, cortisol reactivity measures in saliva – the cortisol awakening response and the 30 min delta cortisol secretion after awakening (DELTA) – were investigated in 19 patients with a melancholic MDE (M-MDE) and 52 with a NM-MDE, and in 40 matched controls who were recruited from the UK and Chile. Depression severity scores were correlated with different cortisol measures.
The NM-MDE group showed a decreased AUCg in comparison with controls (P = 0.02), but normal cortisol reactivity and long-term cortisol levels. The M-MDE group did not exhibit any significant cortisol alterations nor an association with depression severity scores. Higher Hamilton Rating Scale for Depression score was linked with decreased hair cortisol concentration (HCC, P = 0.05) and higher DELTA (P = 0.04) in NM-MDEs, whereas decreased HCC was the sole alteration associated with out-patients with severe M-MDEs.
The contrasting short- and long-term cortisol output results are compatible with an alteration in the rhythm of cortisol secretion in NM-MDEs. This alteration may consist of large and/or intense episodes of hypercortisolaemia in moderate NM-MDEs and frequent, but brief and sharp early-morning DELTAs in its severe form. These changes may reflect the effects of environmental factors or episodes of nocturnal hypercortisolaemia that were not measured by the short-term samples used in this study.
In a recent issue of BJPsych Open, McPherson & Hengartner (see https://doi.org/10.1192/bjo.2019.65) reviewed 11 trials examining psychological and pharmacological treatment outcomes for chronic or treatment-resistant depression. They concluded that when assessed in the long term, antidepressants become less effective whereas psychological therapies become more effective. We argue that the evidence does not support this; indeed, most of the studies reviewed do not directly compare antidepressant with psychological therapy treatments and there is little consistency between them in terms of populations and interventions examined. The issue of long-term outcomes is key for optimising clinical guidelines and deserves more intensive research and scrutiny to improve patient response in routine practice.
True Colours is an automated symptom monitoring programme used by National Health Service psychiatric services. This study explored whether patients with unipolar treatment-resistant depression (TRD) found this a useful addition to their treatment regimes. Semi-structured qualitative interviews were conducted with 21 patients with TRD, who had engaged in True Colours monitoring as part of the Lithium versus Quetiapine in Depression study. A thematic analysis was used to assess participant experiences of the system.
Six main themes emerged from the data, the most notable indicating that mood monitoring increased patients' insight into their disorder, but that subsequent behaviour change was absent.
Patients with TRD can benefit from mood monitoring via True Colours, making it a worthwhile addition to treatment. Further development of such systems and additional support may be required for patients with TRD to experience further benefits as reported by other patient groups.
As demonstrated by neuroimaging data, the human brain contains systems that control responses to threat. The revised Reinforcement Sensitivity Theory of personality predicts that individual differences in the reactivity of these brain systems produce anxiety and fear-related personality traits. Here we discuss some of the challenges in testing this theory and, as an example, present a pilot study that aimed to dissociate brain activity during pursuit by threat and goal conflict. We did this by translating the Mouse Defense Test Battery for human fMRI use. In this version, dubbed the Joystick Operated Runway Task (JORT), we repeatedly exposed 24 participants to pursuit and goal conflict, with and without threat of electric shock. The runway design of JORT allowed the effect of threat distance on brain activation to be evaluated independently of context. Goal conflict plus threat of electric shock caused deactivation in a network of brain areas that included the fusiform and middle temporal gyri, as well as the default mode network core, including medial frontal regions, precuneus and posterior cingulate gyrus, and laterally the inferior parietal and angular gyri. Consistent with earlier research, we also found that imminent threat activated the midbrain and that this effect was significantly stronger during the simple pursuit condition than during goal conflict. Also consistent with earlier research, we found significantly greater hippocampal activation during goal conflict than pursuit by imminent threat. In conclusion, our results contribute knowledge to theories linking anxiety disorders to altered functioning in defensive brain systems and also highlight challenges in this research domain.
Childhood maltreatment is one of the strongest predictors of adulthood depression and alterations to circulating levels of inflammatory markers is one putative mechanism mediating risk or resilience.
To determine the effects of childhood maltreatment on circulating levels of 41 inflammatory markers in healthy individuals and those with a major depressive disorder (MDD) diagnosis.
We investigated the association of childhood maltreatment with levels of 41 inflammatory markers in two groups, 164 patients with MDD and 301 controls, using multiplex electrochemiluminescence methods applied to blood serum.
Childhood maltreatment was not associated with altered inflammatory markers in either group after multiple testing correction. Body mass index (BMI) exerted strong effects on interleukin-6 and C-reactive protein levels in those with MDD.
Childhood maltreatment did not exert effects on inflammatory marker levels in either the participants with MDD or the control group in our study. Our results instead highlight the more pertinent influence of BMI.
Declaration of interest
D.A.C. and H.W. work for Eli Lilly Inc. R.N. has received speaker fees from Sunovion, Jansen and Lundbeck. G.B. has received consultancy fees and funding from Eli Lilly. R.H.M.-W. has received consultancy fees or has a financial relationship with AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Ferrer, Janssen-Cilag, Lundbeck, MyTomorrows, Otsuka, Pfizer, Pulse, Roche, Servier, SPIMACO and Sunovian. I.M.A. has received consultancy fees or has a financial relationship with Alkermes, Lundbeck, Lundbeck/Otsuka, and Servier. S.W. has sat on an advisory board for Sunovion, Allergan and has received speaker fees from Astra Zeneca. A.H.Y. has received honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. A.J.C. has received honoraria for speaking from Astra Zeneca, honoraria for consulting with Allergan, Livanova and Lundbeck and research grant support from Lundbeck.
Most people with bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of bipolar depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant bipolar depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant bipolar depression (MTRBD).
To reach consensus regarding threshold definitions criteria for TRBD and MTRBD.
Based on the evidence of standard treatments available in the latest bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of bipolar disorder experts using a modified Delphi method.
TRBD criteria in bipolar depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy.
The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.
Declaration of interest
In the past 3 years, M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. A.J.C. has in the past 3 years received honoraria for speaking from Astra Zeneca and Lundbeck, honoraria for consulting from Allergan, Janssen, Lundbeck and LivaNova and research grant support from Lundbeck. G.M.G. holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, MSD, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire and Sun Pharma. J.G. has received research funding from National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute and Wellcome. H.G. received grants/research support, consulting fees or honoraria from Gedeon Richter, Genericon, Janssen Cilag, Lundbeck, Otsuka, Pfizer and Servier. R.H.M.-W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. R.M. has received research support from Big White Wall, Electromedical Products, Johnson and Johnson, Magstim and P1Vital. S.N. received honoraria from Lundbeck, Jensen and Otsuka. J.C.S. has received funds for research from Alkermes, Pfizer, Allergan, J&J, BMS and been a speaker or consultant for Astellas, Abbott, Sunovion, Sanofi. S.W has, within the past 3 years, attended advisory boards for Sunovion and LivaNova and has undertaken paid lectures for Lundbeck. D.J.S. has received honoraria from Lundbeck. T.S. has reported grants from Pathway Genomics, Stanley Medical Research Institute and Palo Alto Health Sciences; consulting fees from Sunovion Pharamaceuticals Inc.; honoraria from Medscape Education, Global Medical Education and CMEology; and royalties from Jones and Bartlett, UpToDate and Hogrefe Publishing. S.P. has served as a consultant or speaker for Janssen, and Sunovion. P.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. E.V. received grants/ research support, consulting fees or honoraria from Abbott, AB-Biotics, Allergan, Angelini, Dainippon Sumitomo, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka and Sunovion. L.N.Y. has received grants/research support, consulting fees or honoraria from Allergan, Alkermes, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Servier, Sunovion, Teva and Valeant. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has also previously received funding for investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. P.R.A.S. has received research funding support from Corcept Therapeutics Inc. Corcept Therapeutics Inc fully funded attendance at their internal conference in California USA and all related expenses. He has received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing non-financial contributions to support this study. P.R.A.S. has received a presentation fee from Indivior and an advisory board fee from LivaNova.
Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.
We conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD.
Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions.
Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25–1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23–1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81–1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.08–1.30) and psychological (ES = 1.43, 95% CI 0.50–2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66–0.91) and psychological control (ES = 0.94, 95% CI 0.36–1.52).
Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.
Declaration of interest
In the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest.
Many patients with depressive disorders demonstrate resistance to psychological therapy. A frequent finding is hypothalamic–pituitary–adrenal (HPA) axis alterations. As cortisol is known to modulate cognitive processes, those patients may be less likely to profit from psychological therapy.
To conduct a systematic review and meta-analysis on cortisol as a predictor of psychological therapy response.
The Cochrane Library, EMBASE, MEDLINE and PsycINFO databases were searched. Records were included if they looked at patients with any depressive disorder engaging in psychological therapy, with a pre-treatment cortisol and a post-treatment symptom measure.
Eight articles satisfied our selection criteria. The higher the cortisol levels before starting psychological therapy, the more symptoms patients with depression experienced at the end of treatment and/or the smaller their symptom change.
Our findings suggest that patients with depression with elevated HPA functioning are less responsive to psychological therapy.
Evidence on mortality in severe mental illness (SMI) comes primarily from
clinical samples in high-income countries.
To describe mortality in people with SMI among a population cohort from a
We followed-up 919 adults (from 68 378 screened) with SMI over 10 years.
Standardised mortality ratios (SMR) and years of life lost (YLL) as a
result of premature mortality were calculated.
In total 121 patients (13.2%) died. The overall SMR was twice that of the
general population; higher for men and people with schizophrenia.
Patients died about three decades prematurely, mainly from infectious
causes (49.6%). Suicide, accidents and homicide were also common causes
Mortality is an important adverse outcome of SMI irrespective of setting.
Addressing common natural and unnatural causes of mortality are urgent
priorities. Premature death and mortality related to self-harm should be
considered in the estimation of the global burden of disease for SMI.
Changes in the hypothalamic–pituitary–adrenocortical (HPA) system are characteristic of depression, and in the majority of these patients these result in HPA axis hyperactivity. This is further supported by the reduced sensitivity to the inhibitory effects of the glucocorticoid, dexamethasone (DEX), on the production of adrenocorticotropic hormone (ACTH) and cortisol, during the DEX suppression test and the DEX-corticotropin-releasing hormone (DEX/CRH) test. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), several studies have examined the number and/or function of GRs in depressed patients. These studies have consistently demonstrated that GR function is impaired in major depression, resulting in reduced GR-mediated negative feedback on the HPA axis and increased production and secretion of CRH in various brain regions postulated to be involved in the causality of depression. This article summarizes the literature on GR in depression and on the impact of antidepressants on the GR in clinical and preclinical studies, and supports the concept that impaired GR signaling is a key mechanism in the pathogenesis of depression, in the absence of clear evidence of decreased GR expression. The data also indicate that antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Hypotheses regarding the mechanism of these receptor changes involve non-steroid compounds that regulate GR function via second messenger pathways, such as cytokines and neurotransmitters. Moreover, we present recent evidence suggesting that membrane steroid transporters such as the multidrug resistance (MDR) p-glycoprotein, which regulate access of glucocorticoids to the brain, could be a fundamental target of antidepressant treatment. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders.
Systematic studies on the outcome of treatment-resistant depression are
To describe the longer-term outcome and predictors of outcome in
Out of 150 patients approached, 118 participants with confirmed
treatment-resistant depression (unipolar, n= 7; bipolar,
n=27; secondary, n=14) treated in a
specialist in-patient centre were followed-up for between 8 and 84 months
The majority of participants attained full remission (60.2%), most of
whom (48.3% of total sample) showed sustained recovery (full remission
for at least 6 months). A substantial minority had persistent
subsyndromal depression (19.5%) or persistent depressive episode (20.3%).
Diagnosis of bipolar treatment-resistant depression and poorer social
support were associated with early relapse, whereas strong social
support, higher educational status and milder level of treatment
resistance measured with the Maudsley Staging Method were associated with
achieving quicker remission. Exploratory analysis of treatment found
positive associations between treatment with a monoamine oxidase
inhibitor (MAOl) in unipolar treatment-resistant depression and attaining
remission at discharge and at final follow-up, and duloxetine use
predicted attainment of remission at final follow-up.
Although many patients with treatment-resistant depression experience
persistent symptomatology even after intensive, specialist treatment,
most can achieve remission. The choice of treatment and presence of good
social support may affect remission rates, whereas those with low social
support and a bipolar diathesis should be considered at higher risk of
early relapse. We suggest that future work to improve the long-term
outcome in this disabling form of depression might focus on social
interventions to improve support, and the role of neglected
pharmacological interventions such as MAOIs.