MRCPsych Year 1 depression lecture sept 2013
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MRCPsych Year 1 depression lecture sept 2013



Lecture to year 1 East Midlands MRCPsych course on mood disorders at Leicestershire Partnership Trust

Lecture to year 1 East Midlands MRCPsych course on mood disorders at Leicestershire Partnership Trust



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    MRCPsych Year 1 depression lecture sept 2013 MRCPsych Year 1 depression lecture sept 2013 Presentation Transcript

    • MRCPsych Masterclass Dr Nick Stafford Consultant Psychiatrist Road with Cypress and Star . Vincent van Gogh
    •           Clinical Partners Ltd Nuffield Health Dr. Nick Stafford Ltd My Mind Books Ltd CB Films Ltd Channel 4 BBC Radio 4 BBC World Service BBC Radio Scotland Bipolar UK            Lilly Otsuka Pfizer Lundbeck AstraZeneca Bristol Myers Squibb GlaxoSmith Kline Servier Laboratories GW Pharma LOOK Psychologies
    • Epidemiology Aetiology Clinical Imaging Course Differential diagnoses
    • • Reactive • Endogenous • Melancholic • Neurotic Presumed aetiology Course • Unipolar • Recurrent • Bipolar Symptomatic picture International classifications • ICD-10 & 11 • DSM IV & V
    •      Lifetime risk of MDD = 15% MDD contributes significantly to 1.3-4.4% of all disability and premature deaths worldwide The lifetime risk of developing MDD in those born after WW2 is increasing For men and women the age of onset is getting younger Corresponds to the rise in psychiatric hospitalizations in adolescents
    • Bipolar Depression Lifetime risk About 1-5% 10-20% Sex ratio (M:F) 1:1 1:2 Lifetime risk for bipolar About 10% About 5% Lifetime risk for unipolar depression 20-30% 20-30% Average age of onset 21 yrs (?earlier) 27 yrs Suicide 15% 10% First-degree relatives:
    • = Genes + environment STRESS Major Theories of the causes of depression Stress and stress axis function Cognitive theory of depression Monoamine deficiency theory of depression UKCYM00844 Can we integrate these models based on cognitive and biological science?
    • Factor Family history High risk in families with history of depression (7%) or alcoholism (8%) Social class No relationship Life events Recent negative life events may precede episode Personality Insecure, worries, introverted, stress sensitive, obsessive, unassertive, dependant Childhood experience Early childhood trauma (e.g. significant loss, disruptive, hostile, negative environment) Postpartum Depressive episodes common Menopause No relationship Social network Relative lack of interpersonal relationships
    • Life events precede the onset of depression Losses precede 20% of cases Many suffer depression with no significant preceding life event Genetic, developmental, temperamental predispositions ?
    • Mood Anxiety symptoms Cognitions Biological symptoms Goaldirected behaviour Psychomotor changes
    • Description Symptoms Variants of moderate to severe depression Mild, moderate, severe Low mood Agitated Anhedonia Recurrent Change in appetite Retarded Psychotic symptoms Change in sleep Depressive stupor Change in body activity Somatic symptoms Loss of energy Atypical Anxiety Worthlessness / Guilt Brief recurrent Concentration / attention Self harm, suicide Ideas / acts of suicide Melancholic
    • Symptoms of depressed patients attending primary care physicians 31% Other 69% Physical symptoms A clinical study with 1146 depressed patients showed that 69% visited their primary care physician only because of physical symptoms.1 Headache Exhaustion Back pain Neck tension/hardening Palpitation Muscle pain Stomach troubles Abdominal disorders Weakness Neuralgia Dizziness Tightness in the chest Drowsiness A review of 14 studies found a mean of 65% of depressed patients experienced clinically significant painful symptoms. 2 1. 2. Simon GE et al. N Engl J Med. 1999;341:1329-1335. Bair MJ et al. Arch Intern Med 2003;163:2433-2445 UKCYM00844
    • Bipolar Unipolar Substance abuse +++ + Family history ++++ + Seasonality ++++ + Onset before age 25 +++ + Postpartum onset +++ + Psychotic depression <age 35 +++ -- Atypical features ++++ + Rapid on/off pattern ++ -- Recurrent MDE’s ++ + Antidepressants associated with hypomania / mania ++ -- ++++ -- Antidepressant wear-off ++ -- Mixed depression ++ -- Brief episodes of depression
    • Response2 • Remission3 • Recovery1 • Recurrence1 • (≥50% reduction in HAM-D17 (≤7 score on HAM-D17) (Remission for significant period of time) (A new episode) 1.Kupfer DJ. J Clin Psychiatry 1991;52 (5, Suppl): 28–34. 2.Fawcett J et al J Clin Psych 1997; 58(suppl 6):32–38. 3. Ballenger JC. J Clin Psych 1999; 60(suppl 22):29–34. UKCYM00844
    • Stress axis dysfunction1 endothelial dysfunction and platelet activation4,5 Pro inflammatory state2 Decreased neurotrophic factors6 Autonomic dysfunction3 Structural and functional brain changes7,8 1. Pariante C & Lightman S. Trends in Neuroscince 2008;31: 464-468 2. Miller AH et al. Biol Psychiatry 2009;65: 732-741 3. Brown AD et al. CNS Drugs 2009;23:583-602 4. Rajagopalan S et al. Am J Cardiol 2001; 88:196-198 5. Nemeroff CB and Mussleman D Am Heart J 2000;40:S57-62 6. Lee BH. J Affect Disord. 2007;101:239–244 7. Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156–1165 8. Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695 UKCYM00844
    • Emotional abuse Physical abuse Neglect Long lasting effects: Neuroendocrine Psycho-physiological Neurochemical
    • Newcastle Thousand Family Study 30 28.2 25 No multiple disadvantage group (n=223) 20 Multiple disadvantage group (n=39) 15 10 7.2 5 0 One year prevelance of MDD at 33 years of age (%) OR 5.1 (95%CI 2.1-12.0) p<0.001 Sadowski H et a. Br J Psychiatry 1999;174: 112-120 Children born in 1947 followed for 15 years. Family disadvantages measured such as loss of parent, parental ill health, social dependence, poor physical care, over crowding, poor mothering UKCYM00844
    • Monoamine hypothesis Subsensitivity of MA receptors Intracellular pathways
    •      Noradrenaline Serotonin Dopamine GABA Glutamine
    • TCAs / NARI MAOIs SSRIs SNRIs / dual actions Atypicals Mood stabilisers Antipsychotics EPA St John’s Wort
    • Lithium Valproate Lamotrigine Carbamazepine
    • Limbic System Raphe nuclei (5-HT source) Prefrontal cortex Locus coeruleus (NA source) Amygdala Descending 5-HT pathways Hippocampus Descending NA pathways Ascending pain pathways 5-HT=serotonin; NA=noradrenaline. Adapted from: 1. Bymaster FP, et al. Curr Pharm Des. 2005;11:1475–1493. 2. Fields H. Nat Rev Neurosci. 2004;5:565–575. 3. Fields HL, et al. Annu Rev Neurosci. 1991;14:219–245. UKCYM00844
    • • • • • Hormone & neurotransmitter Sympathetic neuron NT affecting heart Stress hormone Underlies fight-or-flight (increase HR, release of glucose, increase blood flow to skeletal muscle, increases brain’s oxygen supply) • Suppress neuro-inflammation (when released from the LC) • Attention, learning, unexpected uncertainty, decision making • Implication in the pathophysiology of depression mainly theoretical and by the known effects of antidepressants (SNRIs & TCAs)
    • Weber State University
    • Flower R et al. Rang and Dale’s Pharmacology 2007. Churchill Livingstone
    • Primarily found in gut (90%), platelets & CNS Presumed to be important contributor in feelings of wellbeing and happiness due to the assumed mode of action of antidepressants Gut enterochromaffin cells – function in motility. From gut finds its way into blood and then platelets. When platelets form around a clot serotonin serves as a vasoconstrictor
    •  5HIAA metabolized by liver  Increased levels in CSF of traumatic suicide sufferers  Two step oxidation and then excreted by the kidney  Carcinoid tumors release large amounts of serotonin  Carcinoid syndrome – flushing, diarrhoea, heart problems due to proliferation of myocytes
    • As a NT in the CNS, DA plays a major role in reward-motivated behaviour (every type of reward system studied seems to cause increases in levels of DA in the brain); Motor control; The release of several hormones (mainly via the HPA axis) Disorders associated with DA: • Parkinson’s disease • Mania • Schizophrenia/psychosis • ADHD • Restless legs Also involved in the immune system, kidneys & pancreas
    •  Reward  VTA, NA, PC  Seeking vs. Liking  Effect on behaviour in addictions  Cognition  PFC  Coordination of cognitive state with arousal state  Working memory function
    •  MAO-A & MAO-B are equally effective  Metabolites:  DOPAL  DOPAC  DOPET  MOPET  3-MT  HVA
    • The chief inhibitory NT in the CNS (but excitatory in the developing brain, as gradient of Cl- is reverse in immature neuron) Also directly responsible for muscle tone Predominantly in inter-neurones Receptors: • GABAA - ligand-gated ion channel • GABAB – metabotrobic receptors (G protein-coupled receptors that open or close ion channels via intermediaries)
    • Diffuse distribution in the cortex, neurons & glial cells The most abundant excitatory NT Long-term potentiation Learning & memory In its mono-sodium glutamate (MSG) form is used as a food additive NMDA receptor Glutamate needs to be removed rapidly from the interneuronal space as it is toxic and will lead to neuronal death
    • Manipulation of brain serotonin and noradrenaline levels via depletion and reuptake inhibition Tryptophan depletion Brain serotonin SSRI Brain noradrenaline AMPT = α-methylpara-tyrosine NARI *Note AMPT α-methylparatyrosine depletes noradrenaline and dopamine SSRI = selective serotonin reuptake inhibitor. NARI = noradrenaline reuptake inhibitor UKCYM00844
    • Mood1 lowered mood in family history + lowered mood in remitted drug free depression no effect - healthy subjects Cognition2,3,4,5 Trytophan depletion Mood AMPT Healthy subjects - Increased negative bias Remitted depressives – increased negative attentional bias healthy subjects decrease happiness6 and increase negative mood in combination with sleep derivation7 increased sleepiness, tiredness, anxiety, tensi on, anger,8 1. Ruhe HG et al. Molecular Psychiatry 2007;12:331-359 2. Klaassen T el al. Psychol Med 2002;32:167-172 UKCYM00844 3. Murphy FC et al. Psychopharmacology 2002;163:42-53 4. Roiser JP et al. Neuropsychopharmacology 2008;33:1992-2006 5. Hayward G et al. Biol Psychiatry 2005;57:517-524 6. Verhoeff NP et al. Pharmacol Biochem behav 2003;74:425-432 7. McCann UD et al. Neuropsychopharmacology 1993;8:345-356 8. McCann UD et al. Neuropsychopharmacology 1995;13:41-52
    • 60 p=0.0142 53.3 40 20 6.6 % or patients who relapse after AMPT *2 % patients % patients % or patients who relapse after acute tryptophan depletion*1 100 p<0.001 50 0 NARI (n=15) SSRI (n=15)  89 0 0 NARI (n=9) SSRI (n=10) The depressive symptoms experienced by the patients were the same as those experienced before antidepressant treatment. * relapse defined as > 50% increase in HDRS baseline score and HDRS score >17 *Note AMPT α-methylparatyrosine depletes noradrenaline and dopamine 1. Delgado PL et al. Biol Psychiatry 1999;46:212-220 2. Miller HL et al. Arch Gen Psychaitry 1996;53:117-128 SSRI = selective serotonin reuptake inhibitor NARI = noradrenaline reuptake inhibitor UKCYM00844
    • Recognition of happy emotional faces in depressed subjects Effects of depression 50 40 45.3 p<0.05 p<0.01 50 36.7 30 Effects of acute reboxetine 40 30 20 48.7 36.7 20 10 10 0 0 Healthy Comparison Subjects Placebo (n=15) Depressed Subjects Placebo (n=18) Depressed Subjects Placebo (n=18) Depressed Subjects Reboxetine (n=15) All patients medication free for > 3 months, given one dose of 4mg of reboxetine or placebo. Testing started 3 hours after medication administration Reboxetine also increased memory for positive information relative to placebo. Harmer CJ et al. Am J Psychiatry 2009;166:1178-1184 UKCYM00844
    • Dopamine Choline GABA cAMP Phenylethylamine Peptides (TRH, betaendorphin) Folic acid SAM Histamine
    • 24 hour cortisol profile in melancholic depression1 Lack of HPA axis normalisation in remitted patients with MDD may predict future relapse. 2 1. Wong ML et al. Proc Natl Acad Sci USA 2000;97:325-330 2. Aubry JM, et al. J Psychiatr Res. 2007;41:290–294 UKCYM00844
    • Chronic Stress Developmental history Changes in brain structure and function. Mental Illness2 Genetics HPA axis and autonomic nervous system Physical ill health e.g. metabolic syndrome heart disease osteoporosis Adapted from 1. Chrousos GP. Nat Rev Endocrinol. 2009;5:374-381 and 2. McEwen BS. Biol Psychiatry 2003;54:200-207 UKCYM00844
    • Maternal Stress Childhood stress changes in adult stress reactivity3 controls Parental stress 1. Entringer et al. Horm Behav 2009;55:292-98 2. Heim C et al. JAMA 2000;284:592-597 3. Nicolson NA. Psychoneuroendocrinol 2004;29:1012-1018 UKCYM00844
    • The human brain • Brain derived neurotrophic factor (BDNF) is associated with production of new neurons and their growth and development.1 • 5-HT and NA are believed to play roles in the modulation of BDNF.1 • Stress and glucocorticoids inhibit the actions of BDNF.2 UKCYM00844 Figure adapted from Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2008;3:page750. 1. Duman RS, et al. Arch Gen Psychiatry 1997;54(7):597-606. K 2. Duman RS. Biol Psychiatry 2004;56:140-145
    • Depression and cognitive decline in adult hypothyroidism T3 effects on antidepressant Dynamic reduction in plasma thyroxine in depressed patients using various somatic treatments Effect of thyroid hormones on mature brain functions Administering TRH induces a sense of wellbeing and relaxation Flattening of the diurnal TSH curve Blunted TSH response to administration of TRH Subclinical hypothyroidism / Positive antithyroid antibodies
    • Neocortical deactivation Limbic activation • Subgenual cingulate • Anterior insula • Amygdala • Right prefrontal cortex • Inferior parietal • Left prefrontal cortex Basal ganglia deactivation • Caudate • Putamen Depression
    • Patient symptoms      Dream brought on by a bee flying through a pomegranate, one second before waking up S. Dali Difficulty getting off to sleep Poor sleep EMW Increased waking Decreased total time
    • Non-REM  Increased stage 1  Decreased stages 3 & 4 REM  Decreased REM latency  Increased REM time in early hours  Decreased REM in late hours
    • Psychoanalytic Psychodynamic Karl Abrahams Sigmund Freud 1911 1920 Depression is unconsciously motivated Repressed sexual and aggressive drives against the self Precipitated by loss Behavioural models 1950 Inadequate positive reinforcement – Peter Lewinsohn Learned helplessness – Martin Seligman Regressions to anal or oral phases Cognitive behavioural model – Aaron Beck
    • Cognitive Distortions Arbitrary inference Negative selfview Selective abstraction Cognitive Triad Magnification Negative interpretation of experience Negative view of the future Minimisation
    • CORE BELIEFS SELF ESTEEM “No-one really likes me” “I will never be a success” “There's no point in going on” NEGATIVE AUTOMATIC THOUGHTS “Everything I do ends in failure” “My life is worthless” “I’m hopeless at everything” UKCYM00844
    • Nature / Nurture Inherited vulnerability to depression Hereditability 1.5 – 3x of MDD if first degree relative MDD Higher with recurrent depressive disorder Increased chance with further relative Increased risk of bipolar MZ twins raised together 76% MDD MZ twins raised apart 67% MDD DZ twins 19% MDD Adoption studies
    • Number of genes  Inconsistency of findings  Certain genes in certain families  Candidate genes   Monoaminergic  Gene / Environment interactions   Genetic linkage studies Chromoses involved in susceptibility 1,3,4,6,8,11,12,15,18
    • Author (numbers of families & cases) – Phenotype (s) Major Depressive Disorder • Zubenko 2003 (81; NA) – MDD–RE, MDD–R, MDD, all mood disorders, depressive spectrum • Holmans 2004 (297; 819) – MDD-RE • Utah 2003/5 (222; 1,800) – MDD, BD-I, BD-II, anxiety disorders Personality • Cloninger 1998 (105; 987) – Harm avoidance in alcoholism pedigrees • Fullerton 2003 (561; 1,122) - Neuroticism • Nash 2004 (283; 757) – Composite index of anxiety, depression, neuroticism • Neale 2005 (129; 343) - Neuroticism
    • Serotonin transport gene polymorphisms    1. 2. 3. The brain serotonin transporter (5HTT) is the principal site of action of many antidepressants.1 Transcriptional activity of the 5HTT gene is modulated by a gene linked polymorphic region (5HTTLPR).2 The short (s) allele is associated with lower transcriptional efficiency than the long (l) allele.2 Serretti A et al. Prog Neuro Psychopharmacol Biol Psychiatry 2005;29:1074-1084 Lesch KP et al. Science 1996 ;274:1527-1531 Diagram from Canli T & Lesch KP. Nat Neurosci 2007;10:1103-1109 UKCYM00844
    • Association of number of stressful life events aged 21-26yrs and depression outcome aged 26 as a function of 5HTT geneotype.1 Trier Social Stress Test in healthy subjects2 Meta analysis demonstrates greater amygdala activity in s allele carriers when shown pictures of fearful faces.3 S allele associated with poor response to SSRI antidepressants4 but not NARI antidepressants.5 UKCYM00844 1. Caspi A et al. Science 2003; 301:386-389 2. Way BM & Taylor SE. Biol Psychiatry 2010;67:487-492 3. Munafo MR et al. Biol Psychiatry 2008;63:852-857 4. Serretti A et al. Mol Psychiatry 2007;12:247-257 5. Huezo-Diaz P et al. Br J Psychiatry 2009;195:30-38
    • Hamilton Depression Scale MontgomeryAsberg Depression Scale Beck Depression Inventory Burns Depression Checklist Zung Self-Rated Depression Scale Center for Epidemiological Studies Depression Scale Hospital Depression and Anxiety Scale Depression Scale of Goldgerg Depression Outcomes Module Cornell Scale for Depression in Dementia Reynolds Adolescent Depression Scale Major Depression Inventory
    • Age of onset • Average age of onset mid teens to late 20s • Preceded by dysthymic disorder in 10-25% cases Duration of episode • Symptoms develop over days to weeks, with prodromals and comorbids • 18% last for >1 year Recovery • 50% will develop recurrent depressive disorder with variable outcome • 5-10% do not recover from first episode; 5% become bipolar Long term outcome • More benign in one third of patients • Length of cycle shortens with more frequent episodes Mortality and suicide • Up to 15% commit suicide • Need figures on DSH
    • Recovery Survival distribution function 1.0 Previous episodes Median N weeks well Asymptomatic 224.0 3+ 34 79.0 Residual SSD 1–3 57 34.0 Residual SSD 0.6 121 Asymptomatic 0.8 1–3 3+ 25 28.0 0.4 0.2 0 0 50 100 150 200 250 300 350 400 450 500 Weeks to first prospective relapse to any depressive episode MDD=major depressive disorder; SSD=subsyndromal symptoms of depression; Survival distribution function=cumulative proportion of cases surviving to given time interval. Judd LL, et al. J Affect Disord. 1998;50:97–108. UKCYM00844
    • Medical conditions (anything) Bereavement Other psychiatric disorders (anything) Adjustment disorder Acute stress
    • Medications Substance abuse Neurological disease Infectious disease Neoplasms Metabolic & endocrine disorders Collagen-vascular conditions Miscellaneous
    • Organic brain syndromes Normal sadness Schizophrenia Anxiety disorders
    • Watch and wait Counselling Exercise Stress management CBT / IPT … Mindfulness Medication ECT Psychosocial approaches Behavioural activation Self help Rare neurosurgery
    • Drugs causing depression CSF changes EEG studies Structural brain imaging DSM-V & ICD-11 Spiritual & Philosophical Evolutionary
    • Thank you