Depression - 2024 MPBD-1 PDF
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2024
Dr. Hylke Vervaeke
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Summary
This presentation explores the complex neurobiological underpinnings of depression, discussing the role of the HPA axis, brain circuits, and hippocampal volume. It also touches upon the brain-gut connection and the cytokine hypothesis. The presentation likely supports understanding and diagnosis of depression.
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Depression Dr. Hylke Vervaeke Depression What does it feel like? Depression & the brain: several hypotheses etiology depression What do genes have to do with it? – Heritability – Risk genes – Gene-environment interactions 2 What does it feel like?...
Depression Dr. Hylke Vervaeke Depression What does it feel like? Depression & the brain: several hypotheses etiology depression What do genes have to do with it? – Heritability – Risk genes – Gene-environment interactions 2 What does it feel like? ‘looking through grey glasses’ Antonie Kamerling (1966-2010) 3 What does it feel like? Fierce discussions on my facebook page after I put as status update ‘today the illness depression has claimed another victim’ 4 Diagnosis DSM 4; categorical DSM-5; not many changes 5 6 Diagnosis 10-20% will experience depression in their life Twice as much females According to WHO in top 10 causes mortality and morbidity Mood disorders are dominated by indirect costs, such as sick days, unemployment, long-term disability and suicide attempts Co-morbidity with anxiety, ADHD, addiction and other psychiatric disorders 7 Diagnosis Netherlands: 5% = 800 000 adults 160 000 chronic 8 Diagnosis Is depression a lifestyle disease? Lifestyle diseases (diseases of longevity or diseases of civilization) are diseases that appear to increase in frequency as countries become more industrialized and people live longer No lifestyle disease: 15 cities study WHO > includes cities in Africa & China > huge variation in depression prevalence, but not related to socio- demographic variables 9 Diagnosis Lack of objective diagnostic tests > depression is a compilation of symptoms Diagnosis quite variable + heterogeneity of the illness No clear line distinguishing people with mild clinical depression from those having tough time in course of normal life Diagnostic categories based solely on verbal information > biomarkers would be very useful 10 Depression and the brain Core deficit in depression? Past: monoamine hypothesis Because drugs that act on serotonin and / or noradrenalin pathways relieve symptoms of depression within few weeks Overly simplistic paradigm 11 Psychopathology and brain circuits Etiology of depression is moving beyond receptors, enzymes and other molecules as causes New paradigm: depressive symptoms are increasingly linked to malfunctioning specific brain circuits Genes + environmental risk factors conspire to produce inefficient information processing in neuronal circuitry Brain imaging > focus on brain circuits ‘Network hypotheses’ 12 Depression and the brain Core deficit in depression? Past: monoamine hypothesis Because drugs that act on serotonin and / or noradrenalin pathways relieve symptoms of depression within few weeks Overly simplistic paradigm 13 Neuroimaging findings 14 15 16 17 Neuroimaging Depression characterized by increased and sustained emotional reactivity Increased and sustained amygdala reactivity especially in response to emotional information > involuntary elaboration on negative topics Decreased DL-PFC activity in response to cognitive tasks (digit-sorting task) > but no performance deficits! Interaction between amygdala and DL-PFC: possible DL-PFC inhibition of amygdala? Insufficient communication between amygdala and DL-PFC 18 19 20 21 Neuroimaging Pharmacotherapy and behavioral therapy can normalize amygdala and PFC functioning 22 Current ideas etiology depression: Overactive amygdala Decreased activity PFC Decreased hippocampal volume: neurogenic hypothesis Overactive HPA-axis Decreased levels BDNF: BDNF hypothesis Brain-gut hypothesis Cytokine hypothesis Disturbed circadian regulation (chronobiological model) DMN (Default Mode Network) hypothesis All connected in complex interactions 23 Hippocampal volume Some studies found reduced hippocampal volume in patients with MDD, others did not Possible explanations contradictory results: 1. Dependent upon subtype of depression 2. Reduced hippocampal volume when depressed / normal hippocampal volume when successfully treated or non- depressed 3. Reduced hippocampal volume indicator for vulnerability depression in healthy people 24 25 26 Hippocampal volume study measured volume hippocampal subregions: head, body, tail decreased hippocampal tail and hippocampal head volumes could be trait changes (= vulnerability markers) hippocampal body changes may be dependent on actual mood state / treatment (current state: depressed vs. non-depressed) long-term antidepressant use may affect hippocampal volume in patients with MDD several different etiological pathways can contribute to decreased hippocampal volume 27 Reduction volume Reduction in volume PFC & hippocampus 1. Loss of volume neurons: dendritic atrophy and spine loss, decreased neuronal synapses 2. Loss of number neurons: inhibition neurogenesis (in hippocampus) 28 Current ideas etiology depression: Overactive amygdala Decreased activity PFC Decreased hippocampal volume: neurogenic hypothesis Overactive HPA-axis Decreased levels BDNF: BDNF hypothesis Brain-gut hypothesis Cytokine hypothesis Disturbed circadian regulation (chronobiological model) DMN (Default Mode Network) hypothesis All connected in complex interactions 29 Stress system Extra slides 30 Figure Kolb/Whishaw: Fundamentals of Human Neuropsychology, 27.2 The HPA Axis Sixth Edition Copyright © 2008 by Worth Publishers Extra slides 32 HPA-axis Overactive HPA-axis persistent finding in some subtypes of depression Increased peripheral plasma cortisol concentrations Elevated levels of CRH in brain Reduced glucocorticoid receptors (GC-R) = cortisol receptors in hippocampus and hypothalamus Negative feedback loop unable to shut down stress system A healthy stress system is a stress system with plenty of brain cortisol receptors! 33 HPA-axis Chronic stress via CRF / cortisol > decreased appetite, weight loss, loss of libido 34 Extra slides 35 HPA-axis Normalization of HPA-axis = necessary step for stable remission of symptoms Brain cortisol receptor = protein ; coded by brain GC-R-gene! Most AD and psychotherapy (and possibly other treatments) can restore efficient negative feedback by increasing gene/protein expression of GC- R in hypothalamus and hippocampus 36 Current ideas etiology depression: Overactive amygdala Decreased activity PFC Decreased hippocampal volume: neurogenic hypothesis Overactive HPA-axis Decreased levels BDNF: BDNF hypothesis Brain-gut hypothesis Cytokine hypothesis Disturbed circadian regulation (chronobiological model) DMN (Default Mode Network) hypothesis All connected in complex interactions 37 Decreased levels BDNF BDNF = Brain Derived Neurotrophic Factor BDNF required for neuronal development early in life BDNF in adult brain: neuronal survival, synaptic plasticity, synaptogenesis, dendrites, neurogenesis Levels of BDNF decreased in depressed patients in brain (PFC and hippocampus) and blood Chronic administration of antidepressants and other antidepressanrt treatments increase BDNF expression 38 39 Link HPA-axis, BDNF and hippocampal volume Reduced hippocampal volume: 1. Loss of volume neurons: dendritic atrophy and spine loss, decreased neuronal synapses 2. Loss of number neurons: inhibition neurogenesis (‘neurogenic hypothesis of depression’) High sustained levels of CORTISOL causes BOTH! 40 Link HPA-axis, BDNF and hippocampal volume High cortisol > toxic for hippocampal neurons: dendritic atrophy and spine loss, decreased neuronal synapses Inhibition of birth new granule cells in hippocampal dentate gyrus = decreased neurogenesis HOW: Cortisol inhibits gene expression of Brain Derived Neurotrophic Factor (BDNF) > effect reversed by chronic antidepressant treatment 41 Etiology depression WHY would in individual’s HPA-axis be overactive? Combination of genetic, epigenetic, and environmental factors may affect regulation of the HPA axis Genetic: variations in gene-variants for proteins that build HPA-axis Epigenetic & environmental: early experiences, stress during pregnancy, stress during post-natal life, poor parental care, childhood abuse, can affect the glucocorticoid system in the hippocampus and HPA-axis well into adulthood (altered gene regulation of brain cortisol receptor gene; via epigenetic OR other pathways) 42 Current ideas etiology depression: Overactive amygdala Decreased activity PFC Decreased hippocampal volume: neurogenic hypothesis Overactive HPA-axis Decreased levels BDNF: BDNF hypothesis Brain-gut hypothesis Cytokine hypothesis Disturbed circadian regulation (chronobiological model) DMN (Default Mode Network) hypothesis All connected in complex interactions 43 Brain – Gut Hypothesis Paradigm shift in biology In the gut also neurons and neurotransmitters are present ‘gut brain’ The ‘gut brain’ is also connected to the brain in a bidirectional way (‘gut-brain axis’) Furthermore, in your gut live zillions of micro-organsims (just as in your mouth, on your skin); this is called ‘microbiome’ The quality of the microbiome is found to be increasingly important for health in whole body and brain: paradigm shift Your brain-gut connections and your gut micribiome can influence probability of brain disorders! 44 45 ‘Psychobiotics’ Increasing evidence role of gut microbiome in health and disease May influence mood and depressive episodes Current: reseach into effects of food, antibiotics, probiotics (‘psychobiotics’) on mood 46 Current ideas etiology depression: Overactive amygdala Decreased activity PFC Decreased hippocampal volume: neurogenic hypothesis Overactive HPA-axis Decreased levels BDNF: BDNF hypothesis Brain-gut hypothesis Cytokine hypothesis Disturbed circadian regulation (chronobiological model) DMN (Default Mode Network) hypothesis All connected in complex interactions 47 48 49 Cytokine hypothesis Cytokines: pro-inflammatory mediators of immune system Interleukin-1β, interleukin-6, tumour necrosis factor–α (TNFα) Secretion + production of cytokines increased in subset of depression patients: interleukin-6, tumour necrosis factor–α (TNFα) Cytokines can modulate mood: sickness behaviour (social withdrawal, decreased exploratory and sexual behaviour) Similarity between sickness behaviour and depression is striking: withdrawal from physical and social environment that is accompanied by pain, malaise and decreased reactivity to reward (anhedonia) 50 Cytokine hypothesis patients who are treated with the recombinant human cytokines IL-2 and interferon-α (IFN-α) (such as in treatment Hepatitis C) > 1/3 develop depression relationship between inflammation and depression in physically ill patients prevalence of co-morbid depression in patients with coronary heart disease (a disease in which inflammation is now recognized as a major contributing factor) is three times higher than in the general population depression can actually be caused by inflammation in vulnerable patients 51 Cytokine hypothesis Research into antidepressant effect of anti inflammatory drugs such as NSAIDs may accelerate response SSRIs Other anti inflammatory agents such as omega 3 polyunsaturated fatty acids (PUFA) (in fat fish or as supplements) 52 Current ideas etiology depression: Overactive amygdala Decreased activity PFC Decreased hippocampal volume: neurogenic hypothesis Overactive HPA-axis Decreased levels BDNF: BDNF hypothesis Brain-gut hypothesis Cytokine hypothesis Disturbed circadian regulation (chronobiological model) DMN (Default Mode Network) hypothesis All connected in complex interactions 53 Circadian rhythm disruption Abnormalities in circadian rhythm and sleep: described in depression BUT huge heterogeneity (from non-disruption to severe disruption) 54 Circadian rhythm disruption central clock (50,000 pacemaker neurons) in the suprachiasmatic nucleus (SCN) in hypothalamus generation of circadian rhythms at the subcellular level is thought to depend on the activity of a key group of clock genes generating an automatic independent 24-hour periodicity SCN receives light and dark information directly from retina via the retinohypothalamic tract (RHT): synchronisation / resetting by environment SCN synchronizes peripheral clocks that are present in most cells of body 55 Circadian rhythm disruption Circadian timing disruption can cause depression Depression: Early morning awakening > phase shift in biological clock Sleep deprivation / exposure to light > correct phase shift, thereby ameliorating depressive symptoms Treatment of depression with light-therapy New antidepressant: agomelatine = synthetic melatonin receptor agonist + serotonin 2C receptor antagonist Animal research shows links between chronobiological and cytokine models and neurogenic hypothesis! 56 Extra slides 57 Linking chronobiological and cytokine models Animal research: inducing depression by long-term light deprivation in constant darkness (DD) After 4 weeks of DD > mice display depression-like behaviour Elevated levels of IL-6 Altered gene expression in hippocampus of clock genes per2 and npas2 Reduced neurogenesis in hippocampus Linking chronobiological and cytokine models and neurogenic hypothesis 58 New therapies Ketamine Psilocybin-assisted psychotherapy 59 New therapies New exciting line of research Dissociative anesthetic ketamine, an NMDA-antagonist, produces rapid (within hours!) antidepressant responses in treatment resistant patients Effect lasts 1-2 weeks Ketamine rapidly induces synaptogenesis, neurogenesis and reversal of atrophy caused by chronic stress 60 61 New therapies RCT: 64 patients treatment-resistant major depressive disorder between April and August 2022 Randomly assigned to two groups: intervention group: dose of 0.5 mg/kg of ketamine ; control group normal saline Rapid onset of action and sustained effect demonstrate the potential of ketamine to provide relief from depressive symptoms in a shorter timeframe compared to traditional treatment approaches These findings contribute to the growing body of evidence supporting the use of ketamine as a valuable therapeutic option for patients with treatment-resistant depression 62 63 64 New therapy 2010 – present: several clinical trials March 5 2019: ‘Janssen Announces U.S. FDA Approval of SPRAVATO™ (esketamine) CIII Nasal Spray for Adults with Treatment-Resistant Depression (TRD) Who Have Cycled Through Multiple Treatments Without Relief’ 65 New therapy The Nederlands: UMC Groningen pilot-study ketamine antidepressant Current research UMC Groningen + AMC Amsterdam: clinical trial oral ketamine in depression 67 New therapy In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity Implication: psilocybin’s antidepressant action may depend on a global increase in brain network integration Network cartography analyses: 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment 76 New therapy The antidepressant response to escitalopram was milder and no changes in brain network organization were observed Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration 77 Genetic factors Heritability: MDD: relatively low heritability Less severe depression: 25% Severe depression: 50% Bipolar depression (manic depression): 80% 80 Extra slides 81 Genes Gene-environment interactions 82 Extra slides 83 Life stress & depression Gene for serotonin transporter (5-HTT) Polymorphism: short allele (S) of long allele (L) Genotype SS, SL of LL Prospective study: – number stressful life events between age 21 – 26 + depression at age 26 – 5HTT genotype 84 Life stress & depression 85 Life stress & depression Genotype no (statistically significant) influence on chance depression if no stressful life events Increasing number stressful life events, increasing chance depression Gene-environment interaction: – increased chance depression genotype s/s en s/l but ONLY with increasing number life events – l\l relatively stable (resilient to life stress) 86 87 88 89 90 Gene-gene-environment interactions Having both the met allele of the BDNF polymorphism and two “s” alleles of 5-HTTLPR was associated with the highest depression scores, but only in the maltreated children. Children in the control group with these two genotypes did not have elevated depression scores. A significant four-way interaction also emerged, with the measure of the quality of the child’s relationship with his or her primary social support found to further moderate risk for depressive symptomatology in maltreated children with the most vulnerable genotypes. One of the first investigations to show that genetic risk can be ameliorated by positive environmental factors 91 What else… Regular aerobic exercise > induction of neurogenesis and normalization HPA-axis Deep Brain Stimulation Transcranial Magnetic Stimulation (TMS) Electro-Convulsive Therapy (ECT) … 92 Learning outcomes You are aware that the monoamine hypothesis is an outdated overly simplistic paradigm You can elaborate on the current ideas regarding the etiology of depression You can explain brain imaging findings, such as increased amygdala reactivity, decreased PFC activity, reduction volume hippocampus; their relation the symptoms of depression and the effects of treatment on these findings 93 Learning outcomes You can elaborate on the role of the HPA-axis in the etiology of depression You can integrate the current ideas and explain the relation between HPA-axis, BDNF and reduced volume hippocampus / PFC (Synaptogenic hypothesis of depression) You can explain (in general) how ketamine acts as a rapid antidepressant You can explain (in general) how psilocybin research for treatment resistant depression You can elaborate on the cytokines hypothesis and the chronobiological model 94 Learning outcomes You are aware of the recent paradigm shift regarding brain-gut micriobiome role in psychiatry (no details) You can elaborate on new therapies such as psilocybin and ketamine You can estimate the heritability of depression You can explain gene-environment interactions and give some examples You can elaborate on the study on gene-gene-environment-environment interactions, interpret the graphs and explain the effect of social support 95