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

1. MRCPsych Masterclass
Dr Nick Stafford
Consultant Psychiatrist
Road with Cypress and Star . Vincent van Gogh

2. 
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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
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Lilly
Otsuka
Pfizer
Lundbeck
AstraZeneca
Bristol Myers Squibb
GlaxoSmith Kline
Servier Laboratories
GW Pharma
LOOK
Psychologies

3. Epidemiology
Aetiology
Clinical
Imaging
Course
Differential diagnoses

5. • Reactive
• Endogenous
• Melancholic
• Neurotic
Presumed
aetiology
Course
• Unipolar
• Recurrent
• Bipolar
Symptomatic
picture
International
classifications
• ICD-10 & 11
• DSM IV & V

6. 




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

7. 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:

9. = Genes +
environment
STRESS
Major Theories of the causes of depression
Stress and stress axis function
Cognitive theory of depression
Monoamine deficiency theory of depression
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Can we integrate these models based on cognitive and biological science?

10. 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

11. 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 ?

12. Mood
Anxiety
symptoms
Cognitions
Biological
symptoms
Goaldirected
behaviour
Psychomotor
changes

13. 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

14. 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
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15. 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

16. 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.
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17. 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
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18. Emotional
abuse
Physical
abuse
Neglect
Long lasting effects:
Neuroendocrine
Psycho-physiological
Neurochemical

19. 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
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20. Monoamine
hypothesis
Subsensitivity of MA
receptors
Intracellular
pathways

23. 




Noradrenaline
Serotonin
Dopamine
GABA
Glutamine

24. TCAs / NARI
MAOIs
SSRIs
SNRIs / dual actions
Atypicals
Mood stabilisers
Antipsychotics
EPA
St John’s Wort

32. Lithium
Valproate
Lamotrigine
Carbamazepine

33. 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.
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34. •
•
•
•
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)

35. Weber State University

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

37. 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

38. 
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

39. 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

40. 
Reward
 VTA, NA, PC

Seeking vs. Liking
 Effect on behaviour in
addictions

Cognition
 PFC
 Coordination of cognitive
state with arousal state
 Working memory function

41. 
MAO-A & MAO-B are
equally effective

Metabolites:
 DOPAL
 DOPAC
 DOPET
 MOPET
 3-MT
 HVA

42. 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)

43. 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

51. 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
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52. 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
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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

53. 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
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54. 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
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55. Dopamine
Choline
GABA
cAMP
Phenylethylamine
Peptides
(TRH, betaendorphin)
Folic acid
SAM
Histamine

59. 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
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60. 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
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61. 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
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62. 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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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

63. 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

64. Neocortical
deactivation
Limbic activation
• Subgenual cingulate
• Anterior insula
• Amygdala
• Right prefrontal cortex
• Inferior parietal
• Left prefrontal cortex
Basal ganglia
deactivation
• Caudate
• Putamen
Depression

65. 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

66. Non-REM
 Increased stage 1
 Decreased stages 3 & 4
REM
 Decreased REM
latency
 Increased REM time in
early hours
 Decreased REM in late
hours

67. 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

68. Cognitive
Distortions
Arbitrary
inference
Negative selfview
Selective
abstraction
Cognitive
Triad
Magnification
Negative
interpretation
of experience
Negative view
of the future
Minimisation

69. 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”
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70. 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

71. 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

73. 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

74. 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
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75. 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
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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

76. 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

77. 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

78. 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.
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79. Medical
conditions
(anything)
Bereavement
Other
psychiatric
disorders
(anything)
Adjustment
disorder
Acute stress

80. Medications
Substance abuse
Neurological
disease
Infectious disease
Neoplasms
Metabolic &
endocrine disorders
Collagen-vascular
conditions
Miscellaneous

81. Organic brain
syndromes
Normal
sadness
Schizophrenia
Anxiety
disorders

82. Watch and
wait
Counselling
Exercise
Stress
management
CBT / IPT …
Mindfulness
Medication
ECT
Psychosocial
approaches
Behavioural
activation
Self help
Rare neurosurgery

83. Drugs causing depression
CSF changes
EEG studies
Structural brain imaging
DSM-V & ICD-11
Spiritual & Philosophical
Evolutionary

84. Thank you