Download - MRCPsych Year 1 depression lecture sept 2013
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Depressive Disorder
MRCPsych Masterclass
Dr Nick Stafford
Consultant Psychiatrist
Road with Cypress and Star . Vincent van Gogh
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Declarations
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
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What you will learn today
Epidemiology
Aetiology
Clinical
Imaging
Course
Differential diagnoses
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ICD 10 & DSM IV & now DSM-5
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Classification
• ICD-10 & 11
• DSM IV & V
• Unipolar• Recurrent• Bipolar
• Melancholic
• Neurotic
• Reactive• Endogeno
us
Presumed aetiology
Symptomatic picture
International
classifications
Course
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Prevalence
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
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Epidemiology
Bipolar Depression
Lifetime risk About 1-5% 10-20%
Sex ratio (M:F) 1:1 1:2
First-degree relatives:
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%
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Aetiology
Depressive disorderUnknown
Genetics
Biochemical
Psychodynamic
Socio-environment
al
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What causes depression?
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Major Theories of the causes of depression
Stress and stress axis function
Cognitive theory of depression
Monoamine deficiency theory of depression
Can we integrate these models based on cognitive and biological science?
= Genes + environment
STRESS
Family history
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Risk factors
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
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Life events
Life events precede the onset of depression
Losses precede 20% of cases
Many suffer depression with no significant preceding life eventGenetic, developmental, temperamental predispositions ?
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Central features of depression
Mood
Cognitions
Goal-directed
behaviour
Psychomotor changes
Biological symptoms
Anxiety symptoms
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Clinical findings
Description
Mild, moderate, severe
Recurrent
Psychotic symptoms
Somatic symptoms
Anxiety
Self harm, suicide
Symptoms
Low mood
Anhedonia
Change in appetite
Change in sleepChange in body
activityLoss of energyWorthlessness /
GuiltConcentration /
attentionIdeas / acts of
suicide
Variants of moderate to
severe depression
Agitated
Retarded
Depressive stupor
Atypical
Brief recurrent
Melancholic
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1. Simon GE et al. N Engl J Med. 1999;341:1329-1335.2. Bair MJ et al. Arch Intern Med 2003;163:2433-2445
Symptoms of depressed patients attending primary care physicians
69%Physical symptoms
31%Other
Muscle pain
NeuralgiaTightness in the chest
Abdominal disorders
Exhaustion
Weakness
PalpitationBack pain
Headache
Neck tension/hardening
Stomach troubles
Drowsiness
Dizziness
A clinical study with 1146 depressed patients showed that 69% visited their primary care physician only because of physical symptoms.1
A review of 14 studies found a mean of 65% of depressed patients experienced clinically significant painful symptoms. 2
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Bipolar and unipolar differences
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
++ --
Brief episodes of depression ++++ --
Antidepressant wear-off ++ --
Mixed depression ++ --
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Treatment phases and course of depression
UKCYM00844 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.
• Response2 (≥50% reduction in HAM-D17
• Remission3 (≤7 score on HAM-D17)• Recovery1 (Remission for significant period of time)• Recurrence1 (A new episode)
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Major Depression – A biological disorder
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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;101:239–2447. Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156–1165 8. Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–
695
Structural and functional brain changes7,8
Pro inflammatory state2
Decreased neurotrophic factors6
Autonomic dysfunction3Stress axis dysfunction1
endothelial dysfunction and platelet activation4,5
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Early life stress
Long lasting effects:Neuroendocrine
Psycho-physiologicalNeurochemical
Neglect
Emotional abuse
Physical abuse
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Childhood Adversity and Major Depression
One year prevelance of MDD at 33 years of age (%)
0
5
10
15
20
25
30
7.2
28.2
No multiple disadvantage group (n=223)
Multiple dis-advantage group (n=39)
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Newcastle Thousand Family Study
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
Sadowski H et a. Br J Psychiatry 1999;174: 112-120
OR 5.1 (95%CI 2.1-12.0) p<0.001
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Neurotransmitters
Monoamine hypothesis
Subsensitivity of MA receptors
Intracellular pathways
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Neurotransmitters
Monoamines
• Noradrenaline
• Serotonin
• Dopamine
Subsensitivity of the
NA receptor
• Decrease density of beta-adrenoceptors
• Delayed onset
• Pre-synaptic upregulation
Abnormalities of
intracellular signal
transduction pathways
• Neurotansmitters
• Hormones
• Neuropeptides
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Monoamine functions
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Pathways involved in depression
Noradrenaline Serotonin Dopamine GABA Glutamine
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Antidepressants
TCAs / NARI
MAOIs
SSRIs
SNRIs / dual actions
Atypicals
Mood stabilisers
Antipsychotics
EPA
St John’s Wort
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Monoamine hypothesis
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MA hypothesis - normal
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MA hypothesis – NT depleted
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MA hyp – receptor up regulation
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NA reuptake transporters
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Alpha-2 adrenergic receptor
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Mechanism of action of an alpha-2 adrenergic receptor antagonist
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Medications acting on second messenger system
Lithium Valproate
Lamotrigine Carbamazepine
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Serotonin and noradrenaline pathways are widespread across the CNS
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Locuscoeruleus
(NA source)
Raphe nuclei(5-HT source)
Amygdala
Hippocampus
Descending NA pathways
Descending5-HT pathways
Ascendingpain pathways
Limbic SystemPrefrontal
cortex
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.
5-HT=serotonin; NA=noradrenaline.
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Norpinephrine pathways
• 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)
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NE production
Weber State University
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NE degradation
Flower R et al. Rang and Dale’s Pharmacology 2007. Churchill Livingstone
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Serotonin (5HT) pathways
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
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5HT biosynthesis
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
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Dopamine pathways
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
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DA biosynthesis & function
Reward VTA, NA, PC
Seeking vs. Liking Effect on behaviour in
addictions Cognition
PFC Coordination of
cognitive state with arousal state
Working memory function
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DA degredation
MAO-A & MAO-B are equally effective
Metabolites: DOPAL DOPAC DOPET MOPET 3-MT HVA
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GABA pathways
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)
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Glutamate pathways
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
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GABA function
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Melatonin –regulatory systems
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Parts of the brain affected by depression (everything?)
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Distribution of 5HT1A receptors
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5HT1A receptors in depression
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Distribution of 5-HT2 receptors
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Distribution of 5-HT2 receptors affected by depression
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Examining the role of serotonin and noradrenaline in human emotion and cognition
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Manipulation of brain serotonin and noradrenaline levels via depletion and reuptake inhibition
Brain serotonin Tryptophan depletion
SSRI
Brain noradrenaline
NARI
SSRI = selective serotonin reuptake inhibitor. NARI = noradrenaline reuptake inhibitor
AMPT = α-methyl-para-tyrosine
*Note AMPT α-methylparatyrosine depletes noradrenaline and dopamine
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Roles of serotonin and noradrenaline in mood and cognition
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Trytophan depletion
AMPT
lowered mood in family history + lowered mood in remitted drug free depressionno effect - healthy subjects
Mood1
Cognition2,3,4,5Healthy subjects - Increased negative biasRemitted depressives – increased negative attentional bias
Mood healthy subjects decrease happiness6 and increase negative mood in combination with sleep derivation7
increased sleepiness, tiredness, anxiety, tension, anger,8
1. Ruhe HG et al. Molecular Psychiatry 2007;12:331-359 2. Klaassen T el al. Psychol Med 2002;32:167-1723. Murphy FC et al. Psychopharmacology 2002;163:42-53 4. Roiser JP et al. Neuropsychopharmacology
2008;33:1992-20065. 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
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NARI (n=15)
SSRI (n=15)
0
20
40
60
6.6
53.3
Effects of monoamine depletion in patients who remit to treatment with serotonergic or noradrenergic antidepressants
The depressive symptoms experienced by the patients were the same as those experienced before antidepressant treatment.
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% or patients who relapse after acute tryptophan depletion*1
* relapse defined as > 50% increase in HDRS baseline score and HDRS score >17
1. Delgado PL et al. Biol Psychiatry 1999;46:212-2202. Miller HL et al. Arch Gen Psychaitry 1996;53:117-128
NARI (n=9)SSRI (n=10)
0
50
100 89
0
% or patients who relapse after AMPT *2
*Note AMPT α-methylparatyrosine depletes noradrenaline and dopamineSSRI = selective serotonin reuptake inhibitorNARI = noradrenaline reuptake inhibitor
p=0.0142
% p
ati
ents
% p
ati
ents
p<0.001
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Antidepressants reduce negative bias in depression.
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Recognition of happy emotional faces in depressed subjects
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.
Healthy Comparison Subjects Placebo
(n=15)
Depressed Subjects Placebo (n=18)
0
10
20
30
40
5045.3
36.7
Depressed Subjects Placebo (n=18)
Depressed Subjects Reboxetine (n=15)
0
10
20
30
40
50
36.7
48.7
Effects of depression Effects of acute reboxetine
p<0.05 p<0.01
Harmer CJ et al. Am J Psychiatry 2009;166:1178-1184
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Other biochemical hypothses
Dopamine Choline GABA
cAMPPhenylethylami
nePeptides (TRH,
beta-endorphin)
Folic acid SAM Histamine
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Neuroendocrine factors
Depressive
disorder
Emotional
trauma
HPA axisHPT axis
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HPA axis
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Antidepressants and HPA axis
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Stress axis function in major depression
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1. Wong ML et al. Proc Natl Acad Sci USA 2000;97:325-3302. Aubry JM, et al. J Psychiatr Res. 2007;41:290–294
24 hour cortisol profile in melancholic depression1
Lack of HPA axis normalisation in remitted patients with MDD may predict future relapse. 2
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The powerful effects of stress on brain and body
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HPA axis and autonomic nervous system
Changes in brain structure and function. Mental Illness2
Chronic Stress
Developmental history
Genetics
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
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Impact of stress across the lifecycle on stress axis function
changes in adult stress reactivity3
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Maternal Stress Childhood stress
1. Entringer et al. Horm Behav 2009;55:292-98 2. Heim C et al. JAMA 2000;284:592-5973. Nicolson NA. Psychoneuroendocrinol 2004;29:1012-1018
controls
Parental stress
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Stress may be acting via effects on brain neurotrophic factors
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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
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
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HPT axis (neuroendocrine)
Effect of thyroid hormones on mature brain functions
Depression and cognitive decline in adult hypothyroidism
T3 effects on antidepressant
Dynamic reduction in plasma thyroxine in depressed patients using various somatic
treatmentsAdministering 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
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Neuroimaging in depression
Depression
Limbic activation• Subgenual
cingulate• Anterior insula• Amygdala
Neocortical deactivation• Right prefrontal
cortex• Inferior parietal• Left prefrontal cortex
Basal ganglia deactivation• Caudate• Putamen
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Sleep
Patient symptoms
Difficulty getting off to sleep
Poor sleep EMW Increased waking Decreased total
time
Dream brought on by a bee flying through a pomegranate, one second before waking up S. Dali
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Sleep
Non-REM Increased stage 1 Decreased stages 3
& 4
REM Decreased REM
latency Increased REM time
in early hours Decreased REM in
late hours
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Psychosocial theories
PsychoanalyticKarl Abrahams
1911
Depression is unconsciously
motivated
Repressed sexual and aggressive
drives against the self
PsychodynamicSigmund Freud
1920
Precipitated by loss
Regressions to anal or oral
phases
Behavioural models1950
Inadequate positive reinforcement – Peter Lewinsohn
Learned helplessness –
Martin Seligman
Cognitive behavioural model
– Aaron Beck
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Cognitive Behavioural Model
Negative self-view
Negative interpretatio
n of experience
Cognitive Triad
Negative view of the future
Cognitive Distortions
Arbitrary inference
Selective abstraction
Magnification
Minimisation
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Negative Bias in Depression
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“No-one really likes me” “Everything I do ends in failure”
“I will never be a success”
“I’m hopeless at everything”
“My life is worthless”
“There's no point in going on”
CORE BELIEFS NEGATIVE AUTOMATIC THOUGHTSSELF ESTEEM
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Genetic epidemiology of depression
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
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Associati0n studies of candidate genes
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
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Candidate Genes
Serotonin transporter (SLC6A4)
Serotonin 2A receptor (5HTR2A)
Tryosine hydroxylase
(TH)
Tryptophan hydroxylase
1 (TPH1)
Catechol-o-methyltransferase (COMT)
5-HTTLRP long and short form
(regulates serotonin)
BDNF
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Genetic linkage studies
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
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Gene environment interactions in depression
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
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1. Serretti A et al. Prog Neuro Psychopharmacol Biol Psychiatry 2005;29:1074-1084 2. Lesch KP et al. Science 1996 ;274:1527-15313. Diagram from Canli T & Lesch KP. Nat Neurosci 2007;10:1103-1109
Serotonin transport gene polymorphisms
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Gene environment interactions
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Association of number of stressful life events aged 21-26yrs and depression outcome aged 26 as a function of 5HTT geneotype.1
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
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
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Rating scales for depression
Major Depression Inventory
Hamilton Depression
Scale
Montgomery-Asberg
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
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Course of depression
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
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Residual Symptoms and Number of Episodes in MDD May Influence the Course of Illness
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Weeks to first prospective relapse to any depressive episode
0.6
0.8
0.4
0.2
1.0
0
Su
rviv
al d
istr
ibu
tion
fu
ncti
on
0 50 100 150 200 250 300 350 400 450 500
Residual SSD 3+ 25 28.0
Medianweeks well
MDD=major depressive disorder; SSD=subsyndromal symptoms of depression; Survival distribution function=cumulative proportion of cases surviving to given time interval.
Previous episodes NRecovery
Asymptomatic 1–3 121 224.0
Asymptomatic 3+ 34 79.0
Residual SSD 1–3 57 34.0
Judd LL, et al. J Affect Disord. 1998;50:97–108.
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Differential diagnoses
Bereavement
Adjustment
disorder
Acute stress
Other psychiatric disorders (anything)
Medical conditions (anything)
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Medical Conditions
Medications Substance abuse Neurological disease
Infectious disease Neoplasms
Metabolic & endocrine disorders
Collagen-vascular conditions
Miscellaneous
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Psychiatric differentials (simplified)
Normal sadness
Anxiety disorders
Schizophrenia
Organic brain
syndromes
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Management options (some)
Watch and wait
Counselling
Exercise
Stress managemen
t
CBT / IPT …
Mindfulness
Medication ECT Psychosocial
approaches
Behavioural activation
Self help
Rare - neurosurger
y
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Other issues
Drugs causing depression
CSF changes
EEG studies
Structural brain imaging
DSM-V & ICD-11
Spiritual & Philosophical
Evolutionary
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The End!
Thank you