Anthony Cleare

King's College London | KCL · Department of Psychological Medicine

Classification of drug treatments for depression is described noting the ambiguities of current terminology and the move towards standardised nomenclature based on pharmacology and mode of action, such as that proposed by the Neuroscience-based Nomenclature group. Antidepressant drugs are described in terms of background, mechanism of action, pharm...

Background The poor detection of depression in primary healthcare (PHC) in low- and middle-income countries continues to threaten the plan to scale up mental healthcare coverage. AimsTo describe the process followed to develop an intervention package to improve detection of depression in PHC settings in rural Ethiopia. Method The study was conducte...

Introduction In psychedelic therapy, mystical as well as challenging experience may influence therapeutic outcome. However, predictors of such experience have not been sufficiently established. Determining predictors of their intensity is, therefore, potentially beneficial in targeting psilocybin therapy for depression. Methods In a post hoc data...

Experienced clinicians and academics from the International MAOI (monoamine oxidase inhibitor) Expert Group comment on questions of interest concerning MAOI pharmacotherapy for depression, especially as they pertain to the illustrative case summaries presented in this part one of the Expert Roundtable Discussion. These comments focus on practical t...

Aims Despite considerable preclinical evidence, clinical trials assessing the effects of probiotics on individuals with major depressive disorder (MDD) are scarce. This study aimed to provide further evidence of the acceptability, tolerability and putative efficacy of probiotics in this patient group and to improve our understanding of the underlyi...

The existing ‘gold standard’ assessments of depression suffer various issues, which include the evaluation of constructs extraneous to the core symptoms of the illness, and low sensitivity to change over time. Members of our team developed a new, simple visual analogue scale that aims to address these issues (M3VAS). Initial validation of the scale...

Importance: The microbiota-gut-brain axis is a promising target for novel treatments for mood disorders, such as probiotics. However, few clinical trials have been conducted, and further safety and efficacy data are needed to support this treatment approach. Objective: To provide acceptability and tolerability data and estimates of intervention...

Background 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. Aims The current study aimed to pilot a n...

Background and aims: We investigated kynurenine pathway (KP) metabolites levels and their association with suicidal ideation in patients with treatment-resistant depression (TRD) and elevated peripheral inflammation. The effect of antidepressant augmentation with minocycline on KP metabolites was tested. Methods: We analysed data from MINocyclin...

Background: 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 inconsi...

Background Immune-related mechanisms are increasingly recognised as important in the pathophysiology of depression, particularly treatment-resistant depression (TRD). Preliminary evidence suggests that people with TRD may benefit from anti-inflammatory interventions; however, the relative anti-inflammatory effects of therapies currently recommended...

Background Inflammation is a well-known risk factor for depression. Specifically, patients who do not respond to antidepressant treatment show higher levels of inflammatory biomarkers compared with responders. Thus, several studies have investigated the efficacy of anti-inflammatory add-on treatment in this population. However, major depressive dis...

Background Psychedelic therapy shows promise for Major Depressive Disorder, especially when treatment-resistant, as well as life-threatening illness distress. The objective of this systematic review, inclusive of meta-analysis, is to examine recent clinical research on the therapeutic effects of classic psychedelics on depressive symptoms. Methods...

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...

Background 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 pr...

Background Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current...

The mystical experience is a potential psychological mechanism to influence outcome in psychedelic therapy. It includes features such as oceanic boundlessness, ego dissolution, and universal interconnectedness, which have been closely linked to both symptom reduction and improved quality of life. In this review, 12 studies of psychedelic therapy ut...

Background: Treatment-resistant depression (TRD) has a profound cost to patients and healthcare services worldwide. Pharmacological augmentation is one therapeutic option for TRD, with lithium and quetiapine currently recommended as first-line agents. Patient opinions about pharmacological augmentation may affect treatment outcomes, yet these have...

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. Methods:...

Glucocorticoids mediate their actions, including feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis, through two distinct corticosteroid receptor subtypes: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Dexamethasone, specifically the dexamethasone suppression test (DST), was the first and most studied glucoco...

Background Depression is one of the commonest mental disorders in primary care but is poorly identified. The objective of this review was to determine the level of detection of depression by primary care clinicians and its determinants in studies from low- to middle-income countries (LMICs). Methods A systematic review and meta-analysis was conduc...

Objective: The increased prevalence and incidence of affective disorders among patients with gastrointestinal disease has been well established. However, few studies have investigated the inverse relationship. We aimed to identify all evidence of the prevalence and incidence of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) in...

Hormones have a crucial part in the progress and manifestation of a wide variety of different behaviors. Of all the neuroendocrine axes, the hypothalamus–pituitary–adrenal (HPA) axis has been the most extensively studied. There is evidence that disturbance in the HPA axis, the primary stress hormone system, could increase treatment resistance and r...

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 condu...

Background 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...

Introduction Clinical depression is usually treated in primary care with psychological therapies and antidepressant medication. However, when patients do not respond to at least two or more antidepressants within a depressive episode, they are considered to have treatment resistant depression (TRD). Previous small randomised controlled trials sugge...

Background 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...

Importance Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers. However, no attempts have been made to evaluate the specificity of these across the range of psychiatric conditions. Objective To conduct an umbrella and updated meta-analysis of gut m...

Background The Minocycline in Depression (MINDEP) study is a 4-weeks double-blind, placebo-controlled clinical trial, investigating the efficacy of minocycline in treatment resistant depressed (TRD) patients with major depressive disorder, and C-reactive protein (CRP) ≥ 1 mg/L. Methods We explored sex differences in the effects of study arms and C...

Evidence indicates that early life stress (ELS) may act as a risk factor for the development and maintenance of adulthood severe mental health disorders due to persistent dysregulation within the hypothalamic-pituitary-adrenal (HPA) axis. It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual...

(1) Background: Earwax might provide the long-term concentration of substances that are altered in chronic diseases. Standardised earwax extraction has to be exclusively performed by clinicians. We investigated the safety, reliability, and tolerance of a novel self-sampling earwax device in comparison with a clinical method; (2) Methods: We compare...

The bipolar disorder and major depression summaries of the 2020 Royal Australian and New Zealand College of Psychiatrists (RANZCP) clinical practice guidelines for mood disorders, published in the December 2020 issue of Bipolar Disorders, provide accessible and condensed overviews of current recommendations for diagnosis and management1,2. The 2020...

Background : Treatment resistant depression (TRD) poses a significant clinical challenge, despite a range of efficacious specialist treatments. Accurately predicting response a priori may help to alleviate the burden of TRD. This study sought to determine whether outcome prediction can be achieved in a specialist inpatient setting. Methods : Patie...

Background 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. Aims To explore the extent and nature of ‘treatment gaps’ (non-adherence to stepped care p...

Altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated in patients with treatment-resistant depression, although studies have often conflated patients with unipolar and bipolar depression. This is problematic given that the two groups often present with opposed neurovegetative symptom patterns. The aim of this st...

Background: Optimising treatments for patients with treatment-resistant depression (TRD) is key to reducing the burden of this severe illness. The anti-glucocorticoid medication metyrapone has mixed evidence supporting a role as a possible augmentation treatment in TRD. The degree of treatment resistance in depression has been associated prospecti...

Recent years have seen a rapid increase in the use of gut microbiota-targeting interventions, such as probiotics, for the treatment of psychiatric disorders. The objective of this update review was to evaluate all randomised controlled clinical trial evidence on the efficacy of probiotics for clinical depression. Cochrane guidelines for updated rev...

The biological bases of bipolar disorder include aspects related, among others, to neurohormonal pathways, neurotransmission, signal transduction, regulation of gene expression, oxidative stress, neuroplasticity, and changes in the immune system. There is still a gap in understanding its complex neurobiology and, consequently, developing new treatm...

This study aimed to investigate the role of baseline levels of peripheral inflammation when testing the efficacy of antidepressant augmentation with minocycline in patients with treatment-resistant depression. We conducted a 4-week, placebo-controlled, randomised clinical trial of minocycline (200 mg/day) added to antidepressant treatment in 39 pat...

In people with depression, immune dysfunctions have been linked with treatment non-response, but examinations of psychological therapy outcomes, particularly longitudinal biomarker studies, are rare. This study investigated relationships between inflammation, depressive subtypes and clinical outcomes to psychological therapy. Adults with depression...

This article outlines current guidelines for the pharmacological treatment of depression, with an update based on recently published information. For acute treatment of moderate to severe depression in the absence of specific factors, the recommendation is treatment with a selective serotonin reuptake inhibitor or mirtazapine. Recommendations for n...

Research has suggested a relationship between early life stress, and depression in particular longer episodes of depression with treatment resistant outcomes. However, the underlying mechanisms for this association remain poorly understood. Molecular studies indicate that, in general, the hereditary character of psychiatric disorders are polygenic,...

Aims Low mood and anhedonia are the core symptoms of major depressive disorder (MDD). However, there is no established visual analogue scale that measures pervasiveness of both symptoms. We aimed to validate the Maudsley 3-item Visual Analogue Scale (M3VAS) as a measure of core depressive symptoms and suicidality. Methods This is a cross-sectional...

Background “Short-term” samples are not the most appropriate for reflecting chronic cortisol concentration. Although hair is used for reflecting the systemic level of this hormone, its use as a “long-term” measure appears clinically problematic. Local and systemic stress and non-stress related factors may release cortisol that is accumulated in hai...

RationaleKetamine is the first widely used substance with rapid-onset antidepressant action. However, there are uncertainties regarding its potential urothelial toxicity, particularly after repeated application. In the context of rising recreational ketamine use, severe side effects affecting the human urinary tract have been reported. It is assume...

Online assessments allow cost-effective, large-scale screening for psychiatric vulnerability (e.g., university undergraduates or military recruits). However, conventional psychiatric questionnaires may worsen mental health outcomes due to overmedicalizing normal emotional reactions. Personality questionnaires designed for occupational applications...

Seminars in Clinical Psychopharmacology - edited by Peter M. Haddad June 2020

Most interventions for treatment-resistant depression (TRD) are added as augmenters. We aimed to determine the relative effectiveness of augmentation treatments for TRD. This systematic review and network meta-analysis (NMA) sought all randomized trials of pharmacological and psychological augmentation interventions for adults meeting the most comm...

Background: Pharmacological augmentation is a recommended strategy for patients with treatment-resistant depression (TRD). A range of guidelines provide advice on treatment selection, prescription, monitoring and discontinuation, but variation in the content and quality of guidelines may limit the provision of objective, evidence-based care. This...

Cambridge Core - Psychiatry and Clinical Psychology - Seminars in Clinical Psychopharmacology - edited by Peter M. Haddad

Background: "Short-term" samples are not the most appropriate for reflecting Chronic Cortisol Concentration (CCC). Although hair is used for reflecting the systemic cortisol level over "long-term", its use appears clinically problematic. Local stress and non-stress related factors may release a circumscribed cortisol secretion that is accumulated i...

Background: Earwax might provide the long-term concentration of substances that are altered in chronic diseases. Standardised earwax extraction needs to be exclusively performed by clinicians. We investigated the safety, reliability, and tolerance of a novel self-sampling earwax device in comparison with a clinical method. Methods: We compared the...

Background 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 concen...

Objective: Depression is the commonest mental disorder in primary care but is poor identified. The objective of this review was to determine the level of detection of depression by primary care clinicians and its determinants in studies from low-and middle-income countries (LMICs). Methods Design: Systematic review and meta-analysis. Review protoco...

Background: Differentiating between unipolar and bipolar depression can be clinically challenging, especially at first presentation. Patterns of cortisol secretion could aid diagnostic discrimination in affective disorders although there has been little comparative research to date. In this study, we investigated acute (saliva) and chronic (hair)...

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 therapi...

Substantial evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology. The most recent studies reviewed here suggest that early life stressors are associated with an increased risk for anxiety disorders in adulthood. Early life stress predisposes individuals to develop a number of p...

Aims and method 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 T...

Background: Anxiety disorders are highly comorbid with major depression but differ in their symptom profiles and pharmacological responses. Threat-sensitivity may explain such differences, yet research on its relationship to specific disorders is lacking. Methods: One-hundred patients (71 women) and 35 healthy controls (23 women) were recruited....

Hormones have a crucial part in the progress and manifestation of a wide variety of different behaviors. The main influence of the neuroendocrine system on behavior is its action on the neurobiology of neuropsychiatric disorders and its relationship with the pharmacodynamics of medicines. Of all the neuroendocrine axes, the hypothalamic-pituitary-a...

The hypothalamic-pituitary-adrenal axis has been implicated in the pathophysiology of depressive disorders. HSD11B1 encodes 11β-hydroxysteroid dehydrogenase type1 enzyme, responsible for converting cortisone to cortisol. Genetic polymorphisms in HSD11B1 may impact in depression outcome and risk of suicide. This study aimed to assess whether HSD11B1...

Background: Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors, but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or an...

Background Treatment-resistant depression is an important contributor to the global burden of depression. Antidepressant augmentation is a recommended treatment strategy for treatment-resistant patients, but outcomes remain poor. Identifying factors that are predictive of response to augmentation treatments may improve outcomes. Aims This review a...

Background: Overgeneralised self-blame and worthlessness are key symptoms of major depressive disorder (MDD) and were previously associated with self-blame-selective changes in connectivity between right superior anterior temporal lobe (rSATL) and subgenual frontal areas. In a previous study, remitted MDD patients successfully modulated guilt-selec...

Immune dysfunction has been posited as a key element in the aetiology of chronic fatigue syndrome (CFS) since the illness was first conceived. However, systematic reviews have yet to quantitatively synthesise inflammatory biomarkers across the literature. We undertook a systematic review and meta-analysis to quantify available data on circulating i...

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...

Background: Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or anxi...

Background Recently the gut microbiota has attracted significant interest in psychiatric research due to the observed bidirectional gut–brain communication. A growing body of evidence from preclinical work has suggested that probiotics may be effective in reducing stress and anxiety and alleviating low mood. It is unclear to what extent these effec...

Rationale The gut-brain axis includes bidirectional communication between intestinal microbiota and the central nervous system. Bifidobacterium and Lactobacillus spp. have been implicated in psychological health, such as depression, through various pathways (e.g. inflammation). Research needs a better understanding of direct and indirect effects th...

Background: Childhood trauma represents a risk factor for developing depression with increased rates of recurrence. Mechanisms involved include a disturbed regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Hair cortisol concentration (HCC) is a measure of long-term HPA axis activity with less interference from circadian and confounding...

Background: Two current theories regarding the neuroscientific bases of mood disorders involve alterations in glutamatergic neurotransmission and excessive activation of inflammatory pathways. We hypothesized that glutamate (Glu) levels and peripheral inflammatory markers would be associated with cognitive function, in patients with Bipolar Disorde...

Treatment-resistant and Multi-therapy resistant criteria for bipolar depression: A consensus definition – CORRIGENDUM - Diego Hidalgo-Mazzei, Michael Berk, Andrea Cipriani, Anthony J. Cleare, Arianna Di Florio, Daniel Dietch, John R. Geddes, Guy M. Goodwin, Heinz Grunze, Joseph F. Hayes, Ian Jones, Siegfried Kasper, Karine Macritchie, R. Hamish McA...

Neuropsychological dysfunction is a well-established finding in individuals with bipolar disorder type I (BP-I), even during euthymic periods; however, it is less clear whether this also pertains to bipolar disorder type II (BP-II) or those with subthreshold states (SBP; subthreshold bipolar disorder), such as bipolar not otherwise specified (BP-NO...

Background 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. Aims To determine the effects of childhood maltreatment on circulating levels of 41 inflammatory markers in healthy individuals and those...

Background Childhood maltreatment is widely reported across the world and the incidence of child cruelty and neglect offences is reportedly on the rise. Childhood maltreatment is strongly associated with a range of negative health outcomes in adulthood and represents the strongest environmental risk factor for Major Depressive Disorder (MDD). Immun...

Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis – CORRIGENDUM - Rebecca Strawbridge, Ben Carter, Lindsey Marwood, Borwin Bandelow, Dimosthenis Tsapekos, Viktoriya L. Nikolova, Rachael Taylor, Tim Mantingh, Valeria de Angel, Fiona Patrick, Anthony J. Cleare, Allan H. Young