[Show abstract][Hide abstract] ABSTRACT: Background: There is a robust empirical evidence base supporting the acute efficacy of electroconvulsive therapy (ECT) for severe and treatment resistant depression. However, a major limitation, probably contributing to its declining use, is that ECT is associated with impairment in cognition, notably in anterograde and retrograde memory and executive function. Preclinical and preliminary human data suggests that ketamine, used either as the sole anaesthetic agent or in addition to other anaesthetics, may reduce or prevent cognitive impairment following ECT. A putative hypothesis is that ketamine, through antagonising glutamate receptors, protects from excess excitatory neurotransmitter stimulation during ECT. The primary aim of the ketamine-ECT study is to investigate whether adjunctive ketamine can attenuate the cognitive impairment caused by ECT. Its secondary aim is to examine if ketamine increases the speed of clinical improvement with ECT.
[Show abstract][Hide abstract] ABSTRACT: Persistent major depression that does not respond to adequate first- or second-line treatment is a common problem in psychiatry. This article updates evidence on recommended treatment strategies and reviews the prospects of more experimental approaches. The main pharmacological development in recent years has been the demonstration that several atypical antipsychotic drugs are effective adjunctive agents in improving symptoms in depression unresponsive to selective serotonin reuptake inhibitors, although their adverse effect burden is high. There is optimism about novel pharmacological strategies based on glutamatergic and anti-inflammatory mechanisms. It is important to combine drug and psychological treatments whenever possible. With persistent therapeutic engagement, the majority of patients remit eventually, but subsequent relapse remains a problem. Clinicians should pursue an active and collaborative treatment plan that makes use of all effective therapeutic modalities and continues into the relapse-prevention phase.
[Show abstract][Hide abstract] ABSTRACT: Introduction or background:
Depression frequently fails to respond to initial treatment.
Sources of data:
Predominantly meta-analyses and RCTs but supplemented where necessary by additional data and the authors' clinical experience.
Areas of agreement:
A systematic assessment to identify remedial causes of poor response should be followed by planned sequential treatment trials. Joint decision making by the patient and clinician is essential. Strategies with the strongest support are antidepressant augmentation with lithium or second generation antipsychotics and adding cognitive behavioural treatment. Electroconvulsive therapy is highly effective in resistant depression but there is a high relapse rate when treatment ends.
Areas of controversy:
Some pharmacological strategies have inconsistent data (e.g. antidepressant combinations, T3 augmentation) or limited preliminary data (e.g. ketamine, antidepressant augmentation with pramipexole). The efficacy of vagus nerve stimulation, deep brain stimulation and repetitive transcranial magnetic stimulation is unclear.
A greater understanding of the causes of depression may assist the development of more effective treatments.
Areas timely for developing research:
Role of glutamate antagonists and psychological treatments, other than cognitive behavioural therapy, as adjunctive treatments.
British Medical Bulletin 08/2015; 115(1). DOI:10.1093/bmb/ldv034 · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Depressed patients who do not respond to second-line antidepressant drugs are characterised as suffering from treatment-refractory depression (TRD). Chronic psychosocial stress hypothalamic–pituitary–adrenal (HPA) axis dysfunction is associated with attenuated responses to antidepressants. Corticosteroid co-administration reduces the increase in forebrain 5-hydroxytryptamine with selective serotonin reuptake inhibitors, whereas antiglucocorticoids have the opposite effect. A Cochrane review suggesting that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD included a pilot study of the cortisol synthesis inhibitor, metyrapone. The
ntiglucocorticoid augmentation of anti
epression (ADD Study) was a multicentre randomised placebo-controlled trial of metyrapone augmentation of serotonergic antidepressants in patients with TRD.
To determine the efficacy and safety of augmentation of standard serotonergic antidepressants with metyrapone 500 mg twice a day for 3 weeks in patients with TRD.
A total of 165 patients with moderate to severe TRD aged 18–65 years were randomised to metyrapone 500 mg twice daily or placebo for 3 weeks, in addition to ongoing serotonergic antidepressants. The primary outcome was improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation estimated using analysis of covariance. Secondary outcomes included the degree of persistence of treatment effect for up to 6 months, and also safety and tolerability of metyrapone. ADD included substudies investigating the potential mechanism of action of metyrapone, and utilised a comparator group of healthy participants.
The estimated mean difference for each of our study outcomes between randomised groups, 5 weeks post randomisation (allowing for variation between centres and whether or not patients originate from primary or secondary care) was MADRS –0.51 [95% confidence interval (CI) –3.48 to 2.46]; Beck Depression Inventory (BDI) –2.65 (95% CI –6.41 to 1.10); Clinical Anxiety Scale 0.46 (95% CI –1.20 to 2.12); State–Trait Anxiety Inventory 1.2 (95% CI –0.6 to 3.0); European Quality of Life-5 Dimensions 0.015 (95% CI –0.069 to 0.099); EuroQol visual analogue scale 5.6 (95% CI –0.7 to 12.0); and Young Mania Rating Scale –0.04 (95% CI –0.52 to 0.45). The differences were not statistically significant and were small in relation to the change from baseline in both groups that was observed immediately after completion of therapy. Endocrinological data required for compliance assessment are not yet available. HPA function, similar in patients and control subjects, was not associated with differing clinical responses. Neuropsychological impairments were found, along with changes in brain structure and function, but no effect of metyrapone was seen on these measures.
The inclusion criteria led to the sample being broadly representative of patients with TRD, within the UK NHS, with high anxiety and BDI scores. Metyrapone augmentation of antidepressants is not efficacious for outpatients with TRD who are moderately depressed. There was no obvious benefit associated with the use of metyrapone, either on the primary outcome or over the period of follow-up, and this negative result extended to other secondary outcomes. Metyrapone was well tolerated. There were no serious adverse events attributable to it and adverse events were as common with the placebo. HPA axis function was not associated with differing clinical or neuropsychological outcomes.
The results of the study suggest that although metyrapone augmentation was well tolerated, it is ineffective in the treatment of refractory depression. This finding is contrary to a previous proof of principle study in more acutely unwell patients. Future research should consider whether or not antiglucocorticoid treatments, such as metyrapone, should be targeted at patients with confirmed hypercortisolaemia.
Current Controlled Trials ISRCTN45338259.
This study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.
[Show abstract][Hide abstract] ABSTRACT: Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.
In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.
The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals.
Our study is cross-sectional and applies self-report questionnaires.
Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.
PLoS ONE 03/2015; 10(3):e0116316. DOI:10.1371/journal.pone.0116316 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Prosocial emotions related to self-blame are important in guiding human altruistic decisions. These emotions are elevated in major depressive disorder (MDD), such that MDD has been associated with guilt-driven pathological hyper-altruism. However, the impact of such emotional impairments in MDD on different types of social decision-making is unknown.
In order to address this issue, we investigated different kinds of altruistic behaviour (interpersonal cooperation and fund allocation, altruistic punishment and charitable donation) in 33 healthy subjects, 35 patients in full remission (unmedicated) and 24 currently depressed patients (11 on medication) using behavioural-economical paradigms.
We show a significant main effect of clinical status on altruistic decisions (p = 0.04) and a significant interaction between clinical status and type of altruistic decisions (p = 0.03). More specifically, symptomatic patients defected significantly more in the Prisoner's Dilemma game (p < 0.05) and made significantly lower charitable donations, whether or not these incurred a personal cost (p < 0.05 and p < 0.01, respectively). Currently depressed patients also reported significantly higher guilt elicited by receiving unfair financial offers in the Ultimatum Game (p < 0.05).
Currently depressed individuals were less altruistic in both a charitable donation and an interpersonal cooperation task. Taken together, our results challenge the guilt-driven pathological hyper-altruism hypothesis in depression. There were also differences in both current and remitted patients in the relationship between altruistic behaviour and pathological self-blaming, suggesting an important role for these emotions in moral and social decision-making abnormalities in depression.
Psychological Medicine 10/2014; 45(06):1-13. DOI:10.1017/S0033291714002414 · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Psychological therapies can be effective in the treatment of depression and are valued by patients. Here, the authors provide an overview of the main psychological therapies available, their evidence base and their use in practice.
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
This study aimed to investigate the neural basis of working and episodic memory, including the encoding and retrieval of emotional memories, in patients with treatment resistant depression (TRD).
We demonstrated neural activity abnormalities in working & episodic memory in TRD. Decreased activity of the dlPFC in the n-back task could be a manifestation of the frontal hypoactivity found in depression; this is probably related to attentional and cognitive impairments. Posterior cingulate hypoactivity, shown during encoding, may represent the greater effort required for TRD patients due to attentional difficulties. Manifested by a greater need to switch off the default mode network. The anterior cingulate is associated with emotional processing and the emotion-specific under activity to positive image retrieval may contribute to memory/evaluation biases in TRD. Posterior insula activation has been associated with emotional significance during image recognition; increased activity in TRD may contribute to emotional bias.
69th Society of Biological Psychiatry Annual Meeting 2014; 07/2014
[Show abstract][Hide abstract] ABSTRACT: There is increasing evidence that genetic factors play a role in differential susceptibility to depression in response to severe or chronic adversity. Studies in animals suggest that nitric oxide (NO) signalling plays a key role in depression-like behavioural responses to stress. This study investigated whether genetic variation in the brain-expressed nitric oxide synthase gene NOS1 modifies the relationship between psychosocial stress and current depression score. We recruited a population sample of 1222 individuals who provided DNA and questionnaire data on symptoms and stress. Scores on the List of Life-Threatening Experiences (LTE) questionnaire for the last year and self-rated current financial hardship were used as measures of recent/ongoing psychosocial stress. Twenty SNPs were genotyped. Significant associations between 8 NOS1 SNPs, comprising two regional haplotypes, and current depression score were identified that survived correction for multiple testing when current financial hardship was used as the interaction term. A smaller 3 SNP haplotype (rs10507279, rs1004356, rs3782218) located in a regulatory region of NOS1 showed one of the strongest effects, with the A-C-T haplotype associating with higher depression scores at low adversity levels but lower depression scores at higher adversity levels (p=2.3E-05). These results suggest that NOS1 SNPs interact with exposure to economic and psychosocial stressors to alter individual's susceptibility to depression.Neuropsychopharmacology accepted article preview online, 11 June 2014; doi:10.1038/npp.2014.137.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; 39(12). DOI:10.1038/npp.2014.137 · 8.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Major depressive disorder (MDD) is associated with functional abnormalities in fronto-meso-limbic networks contributing to decision-making, affective and reward processing impairments. Such functional disturbances may underlie a tendency for enhanced altruism driven by empathy-based guilt observed in some patients. However, despite the relevance of altruistic decisions to understanding vulnerability, as well as everyday psychosocial functioning, in MDD, their functional neuroanatomy is unknown.
Using a charitable donations experiment with fMRI, we compared 14 medication-free participants with fully remitted MDD and 15 demographically-matched control participants without MDD.
Compared with the control group, the remitted MDD group exhibited enhanced BOLD response in a septal/subgenual cingulate cortex (sgACC) region for charitable donation relative to receiving simple rewards and higher striatum activation for both charitable donation and simple reward relative to a low level baseline. The groups did not differ in demographics, frequency of donations or response times, demonstrating only a difference in neural architecture.
We showed that altruistic decisions probe residual sgACC hypersensitivity in MDD even after symptoms are fully remitted. The sgACC has previously been shown to be associated with guilt which promotes altruistic decisions. In contrast, the striatum showed common activation to both simple and altruistic rewards and could be involved in the so-called “warm glow” of donation. Enhanced neural response in the depression group, in areas previously linked to altruistic decisions, supports the hypothesis of a possible association between hyper-altruism and depression vulnerability, as shown by recent epidemiological studies.
[Show abstract][Hide abstract] ABSTRACT: This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines management and formulary committees.
Journal of Psychopharmacology 04/2014; 28(5). DOI:10.1177/0269881114525674 · 3.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons with a possible role in stress-related disorders. Here we report that variants in genes for galanin (GAL) and its receptors (GALR1, GALR2, GALR3), despite their disparate genomic loci, conferred increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events in a European white population cohort totaling 2,361 from Manchester, United Kingdom and Budapest, Hungary. Bayesian multivariate analysis revealed a greater relevance of galanin system genes in highly stressed subjects compared with subjects with moderate or low life stress. Using the same method, the effect of the galanin system genes was stronger than the effect of the well-studied 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Conventional multivariate analysis using general linear models demonstrated that interaction of galanin system genes with life stressors explained more variance (1.7%, P = 0.005) than the life stress-only model. This effect replicated in independent analysis of the Manchester and Budapest subpopulations, and in males and females. The results suggest that the galanin pathway plays an important role in the pathogenesis of depression in humans by increasing the vulnerability to early and recent psychosocial stress. Correcting abnormal galanin function in depression could prove to be a novel target for drug development. The findings further emphasize the importance of modeling environmental interaction in finding new genes for depression.
Proceedings of the National Academy of Sciences 03/2014; 111(16). DOI:10.1073/pnas.1403649111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Evidence suggests that depression is a risk factor for dementia; however, the relationship between the two conditions is not fully understood. A novel gene (TOMM40) has been consistently associated with Alzheimer's disease (AD), but has received no attention in depression. We conducted a three-level cross-sectional study to investigate the association of the TOMM40 rs2075650 SNP with depression. We recruited a community sample of 1220 participants (571 controls, 649 lifetime depression) to complete a psychiatric background questionnaire, the Brief Symptom Inventory, and Big Five Inventory at Level-1, 243 (102 controls, 97 remitted, 44 currently depressed) to complete a face-to-face clinical interview and neuropsychological testing at Level-2 and 58 (33 controls, 25 remitted) to complete an emotional face-processing task during fMRI at Level-3. Our results indicated that the TOMM40 rs2075650 G allele was a significant risk factor for lifetime depression (p=0.00006) and, in depressed subjects, was a significant predictor of low extraversion (p=0.009). Currently depressed risk allele carriers showed subtle executive dysfunction (p=0.004) and decreased positive memory bias (p=0.021) together with reduced activity in the posterior (p(FWE)=0.045) and anterior (p(FWE)=0.041) cingulate during sad face emotion processing. Our results suggest that TOMM40 rs2075650 may be a risk factor for the development of depression characterized by reduced extraversion, impaired executive function, and decreased positive emotional recall, and reduced top-down cortical control during sad emotion processing.Neuropsychopharmacology advance online publication, 19 February 2014; doi:10.1038/npp.2014.22.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2014; 39(7). DOI:10.1038/npp.2014.22 · 7.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Major depressive disorder (MDD) is associated with abnormalities in financial reward processing. Previous research suggests that patients with MDD show reduced sensitivity to frequency of financial rewards. However, there is a lack of conclusive evidence from studies investigating the evaluation of financial rewards over time, an important aspect of reward processing that influences the way people plan long-term investments. Beck's cognitive model posits that patients with MDD hold a negative view of the future that may influence the amount of resources patients are willing to invest into their future selves.
We administered a delay discounting task to 82 participants: 29 healthy controls, 29 unmedicated participants with fully remitted MDD (rMDD) and 24 participants with current MDD (11 on medication).
Patients with current MDD, relative to remitted patients and healthy subjects, discounted large-sized future rewards at a significantly higher rate and were insensitive to changes in reward size from medium to large. There was a main effect of clinical group on discounting rates for large-sized rewards, and discounting rates for large-sized rewards correlated with severity of depressive symptoms, particularly hopelessness.
Higher discounting of delayed rewards in MDD seems to be state dependent and may be a reflection of depressive symptoms, specifically hopelessness. Discounting distant rewards at a higher rate means that patients are more likely to choose immediate financial options. Such impairments related to long-term investment planning may be important for understanding value-based decision making in MDD, and contribute to ongoing functional impairment.
Psychological Medicine 11/2013; 44(9):1-10. DOI:10.1017/S0033291713002584 · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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-Asberg 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.
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.