Affective Disorders for
MRCPsych
Andy Montgomery
Consultant psychiatrist,
Plymouth
He [a psychiatrist] asked me if I was suicidal, and I
reluctantly told him yes. I did not particularize--since there
seemed no need to- did not tell him that in truth many of
the artifacts of my house had become potential devices for
my own destruction: the attic rafters (and an outside
maple or two) a means to hang myself, the garage a place
to inhale carbon monoxide, the bathtub a vessel to receive
the flow from my opened arteries. The kitchen knives in
their drawers had but one purpose for me. Death by heart
attack seemed particularly inviting, absolving me as it
would of active responsibility, and I had toyed with the
idea of self-induced pneumonia--a long frigid, shirtsleeved hike through the rainy woods. Nor had I
overlooked an ostensible accident, a la Randall Jarrell, by
walking in front of a truck on the highway nearby.... Such
hideous fantasies, which cause well people to shudder,
are to the deeply depressed mind what lascivious
daydreams are to persons of robust sexuality.
Neuropathology of depression
• Sources of data:
– PM/lesion
– Neuroendocrine
– Monoamine depletion
– Neuroimaging
Affective disorders: macrostructure
• lesion studies: left sided stroke-depression,
right sided-mania
• increased ventricular/brain ratio
• volume reductions:
 subgenual anterior cingulate
 hippocampus
• subcortical white matter hyperintensities
Depression: microstructure
•Reduced neuronal size
•Reduced dendritic spine density
•? reduced glial cell density
Neuroendocrine challenge tests: MDD
Serotonergic
•Fenfluramine (5-HT releaser) or L-Tryptophan
(precursor)



PRL and GH response to reduced.
Effective treatment (ECT or antidepressants)
normalises response.
? a measure of 5-HT1A receptor function (blocked by
pindolol, a 1A antagonist)
•Citalopram/clomipramine challenge


Blunted cortisol and PRL response in MDD
Citalopram: blunted PRL response in recovered
MDD
Neuroendocrine challenge tests: MDD
Adrenergic
•GH response to clonidine (α2 agonist) reduced
•? a trait marker- remains blunted when off medication
and depressed.
Dopaminergic
•Reduced GH response to apomorphine (DA agonist)inconsistent
Neuroendocrine challenge tests: MDD
Cholinergic
•Enhanced GH response to pyridostigmine (anticholinesterase)
GABAergic
•Reduced response to baclofen (GABA-B agonist)
measure of GABAergic activity.
Monoamine manipulations
• 5HT
– Parachlorophenylalanine
• Relapse in previously treated patients
– Tryptophan depletion
Tryptophan depletion in MDD
Tryptophan depletion results
•
•
•
•
Mild mood reduction in controls (♀>♂)
No mood change in MDD
Rapid relapse in some SSRI responders
Relapse in SAD light therapy
responders
• No effect in NARI responders
Tryp. depletion in MDD
Bell 2001
Dopaminergic manipulations
• Alphamethylparatyrosine
• recurrence of depressive symptoms
• Tyrosine depletion
– Similar mechanism to tryptophan depletion
– Reduces manic symptoms
– Reduces striatal DA release
– No effect in recovered depressed
Endocrinology of psychiatric disorders
Depression- HPA axis
HPA axis overdrive:
Increased ACTH and cortisol pulses
Increased CRH output in CSF (Nemeroff 1984)
Number of CRH neurones increased (Radsheer 1994)
CRH receptors reduced in frontal cortex (Nemeroff 1988)
Reduced ACTH response to cortisol. ACTH high or normal
Adrenal hyperplasia on CT
Normalisation associated with recovery

Depression- HPA axis
Neuroendocrine function tests
•Dexamethasone suppression test (Carroll 1982)
•Cortisol suppression test
•CRH test
•dex/CRH test (Holsboer 2000)
Dex/CRH test
Causes of hypercortisolaemia
•stress response
•early life influences
•genetic influences
Depression- HPA axis
Effects of hypercortisolaemia
-reduced 5-HT neurotransmission
Neurotoxic effects of corticosteroids
-increased cortisol associated hippocampal neuron changes.
-stressed rats have cortical damage
-depressed humans have reduced hippocampal volume
-Cushing’s patients may have reduced hippocampal volume
which correlates with cognitive deficits.
-”allostatic load” (McEwen)
•anti-glucocorticoid antidepressants
Depression
Thyroid axis
30% reduced TSH response to TRH
Difference between morning and evening TSH response
Increased TRH in MDD
Persistently blunted TRH responses associated with
increased risk of relapse
interactions with 5-HT and NA systems
Leptin
Peptide hormone produced by adipocytes
Regulatory role in weight control
Controlled by (amongst other factors) cortisol levels
Hypothesis: increased cortisol in depression leads to
increased leptin, but….

Radioligand studies in depression
•5-HT1A
•5-HT2
•5-HT transporter
•5-HT synthesis
•NK1 (sub P)
•D2 striatal/extra str
•D1
•DAT
•DA release
•DA synth
5-HT1A receptors
• Post-synaptic
– Limbic and cortical areas; hippocampus,
lateral septum, insula, cingulate and frontal
cortex
• Pre-synaptic (auto-receptor)
– Raphe nuclei
• Possible role in coping with aversive stimuli.
(Deakin and Graeff 1991)
5-HT1A receptors in depression
•Reduced 5HT1A in MDD (Sargent 2000, Drevets 1999)
•But not Parsey 2006
•Reduced in recovered depressed (Bhagwagar 2004)
•No change in euthymic BPAD (Sargent 2009)
Hypothesis:
Stress
Hypercortisolaemia
5-HT1A receptor expression
Depression
Hypothesis:
Stress
Hypercortisolaemia
5-HT1A receptor expression
Depression
5-HT2A in depression
• PM studies show increases
• PET reductions or no difference
• differential treatment effects:
 SSRI increases
 TCA reductions
5-HT transporters, and synthesis
• Reduced in brain-stem in MD
• Reduced in thalamus in SAD
• Potential for drug occupancy studies:
 ~80% occupancy of 5-HTT with 20mg
paroxetine
• Synthesis ([11C]alpha-methyltryptophan)
probably no change
Receptor occupancy by SSRi
Meyer et al 2001
Dopamine and depression
Dopamine:
 reward
 stress
 psychomotor retardation
 motivation
 novelty
•SSRi effects on nuc accumbens
Hypothesis: reduced dopamine transmission
in MD
Amphetamine induced DA release
•Anand 2000
13 euthymic BPAD
 No difference

•Parsey 2001
9 depressed, 10 controls
 No difference

D2 and depression
Striatum:
SPET studies:
 ↓binding 3/4
 ↑binding 1/5
PET studies:
 Psychotic patients no change binding
11C]raclopride with SSRI
 Reduced DS [
Extra-striatal regions

No difference
D1, DAT and DA synthesis
D1
• reduced binding in frontal cortex
DAT
• increased binding in basal ganglia
[18F]dopa
• ?reduced uptake in left putamen
Future radioligand developments
•displaceable 5-HT ligand
•extra-striatal D2
•NA ligands
•exotica: Sub P, CRH
Depression
Blood flow studies: methods
•Resting state
•Activations
psychological
pharmacological
•Mood induction
Blood flow studies (Drevets 2000)
1. Subgenual anterior cingulate cortex
1. Subgenual anterior cingulate cortex
Lesion studies:
 Abnormal ANS response to emotion
 inability to experience emotion
 inability to use reward/punishing info
?DA involvement
1. Subgenual anterior cingulate cortex
•Decreased activity in depressives + reduced
volume
•?Increased activity (after correction for
partial volume effects)
•Returns to normal after effective AD Rx
2. Orbital cortex
2. Orbital cortex
Increased activity in MD and induced sadness
•? Role in modulating behavioural, cognitive
and visceral responses to:
•Defensive, reward-directed, fear behaviours
•?An endogenous attempt to:
•attenuate emotional expression
•interrupt perseverative non-rewarding behaviours
3. Dorsolateral PFC
3. Dorsolateral PFC
•Areas not directly involved in emotion
processing discriminative attention
increase
 selection for action
flow
 working memory
3. Dorsolateral PFC
Reduced flow in depression and induced
sadness
Loss of normal activation after acute TRP
depletion
Related to impaired attention, memory
visuospatial functions in MD
4. The Amygdalla
4. The Amygdalla
•Central role in organising emotional/stress
responses
•Electrical stimulation leads to
 anxiety,
 fear,
 memories of dysphoric events,
 increased cortisol release
4. The Amygdalla
• Increased CBF in subtypes of
depressive disorder (FPDD, type I BPAD)
• CBF correlates with depression severity
• TRP depletion relapse associated with
increased flow