Depressive Disorder

MRCPsych Masterclass

Dr Nick Stafford

Consultant Psychiatrist

Road with Cypress and Star . Vincent van Gogh

Declarations

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What you will learn today

Epidemiology

Aetiology

Clinical

Imaging

Course

Differential diagnoses

ICD 10 & DSM IV & now DSM-5

Classification

• ICD-10 & 11

• DSM IV & V

• Unipolar• Recurrent• Bipolar

• Melancholic

• Neurotic

• Reactive• Endogeno

us

Presumed aetiology

Symptomatic picture

International

classifications

Course

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

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%

Aetiology

Depressive disorderUnknown

Genetics

Biochemical

Psychodynamic

Socio-environment

al

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

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

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 ?

Central features of depression

Mood

Cognitions

Goal-directed

behaviour

Psychomotor changes

Biological symptoms

Anxiety symptoms

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

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 ++ --

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)

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

Early life stress

Long lasting effects:Neuroendocrine

Psycho-physiologicalNeurochemical

Neglect

Emotional abuse

Physical abuse

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

Neurotransmitters

Monoamine hypothesis

Subsensitivity of MA receptors

Intracellular pathways

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

Monoamine functions

Pathways involved in depression

Noradrenaline Serotonin Dopamine GABA Glutamine

Antidepressants

TCAs / NARI

MAOIs

SSRIs

SNRIs / dual actions

Atypicals

Mood stabilisers

Antipsychotics

EPA

St John’s Wort

Monoamine hypothesis

MA hypothesis - normal

MA hypothesis – NT depleted

MA hyp – receptor up regulation

NA reuptake transporters

Alpha-2 adrenergic receptor

Mechanism of action of an alpha-2 adrenergic receptor antagonist

Medications acting on second messenger system

Lithium Valproate

Lamotrigine Carbamazepine

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.

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)

NE production

Weber State University

NE degradation

Flower R et al. Rang and Dale’s Pharmacology 2007. Churchill Livingstone

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

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

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

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

DA degredation

MAO-A & MAO-B are equally effective

Metabolites: DOPAL DOPAC DOPET MOPET 3-MT HVA

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)

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

GABA function

Melatonin –regulatory systems

Parts of the brain affected by depression (everything?)

Distribution of 5HT1A receptors

5HT1A receptors in depression

Distribution of 5-HT2 receptors

Distribution of 5-HT2 receptors affected by depression

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

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

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

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

Other biochemical hypothses

Dopamine Choline GABA

cAMPPhenylethylami

nePeptides (TRH,

beta-endorphin)

Folic acid SAM Histamine

Neuroendocrine factors

Depressive

disorder

Emotional

trauma

HPA axisHPT axis

HPA axis

Antidepressants and HPA axis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

Differential diagnoses

Bereavement

Adjustment

disorder

Acute stress

Other psychiatric disorders (anything)

Medical conditions (anything)

Medical Conditions

Medications Substance abuse Neurological disease

Infectious disease Neoplasms

Metabolic & endocrine disorders

Collagen-vascular conditions

Miscellaneous

Psychiatric differentials (simplified)

Normal sadness

Anxiety disorders

Schizophrenia

Organic brain

syndromes

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

Other issues

Drugs causing depression

CSF changes

EEG studies

Structural brain imaging

DSM-V & ICD-11

Spiritual & Philosophical

Evolutionary

The End!

Thank you