Affective Disorders for MRCPsych

Affective Disorders for MRCPsych

Andy MontgomeryConsultant 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, shirt-sleeved 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 cingulatehippocampus

• subcortical white matter hyperintensities

Depression: microstructure

•Reduced neuronal size

•Reduced dendritic spine density

•? reduced glial cell density

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 challengeBlunted cortisol and PRL response in MDDCitalopram: 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 (anti-cholinesterase)

GABAergic•Reduced response to baclofen (GABA-B agonist) measure of GABAergic activity.

Neuroendocrine challenge tests: MDD

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 pulsesIncreased 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 CTNormalisation associated with recovery

Neuroendocrine function tests

•Dexamethasone suppression test (Carroll 1982)

•Cortisol suppression test

•CRH test

•dex/CRH test (Holsboer 2000)

Depression- HPA axis

Dex/CRH test

Causes of hypercortisolaemia

•stress response

•early life influences

•genetic influences

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- HPA axis

Thyroid axis30% reduced TSH response to TRHDifference between morning and evening TSH response Increased TRH in MDDPersistently blunted TRH responses associated with increased risk of relapseinteractions with 5-HT and NA systems

LeptinPeptide hormone produced by adipocytesRegulatory role in weight controlControlled by (amongst other factors) cortisol levelsHypothesis: increased cortisol in depression leads to increased leptin, but….

Depression

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)

Stress

Hypercortisolaemia

5-HT1A receptor expression

Depression

Hypothesis:

Stress

Hypercortisolaemia

5-HT1A receptor expression

Depression

Hypothesis:

5-HT2A in depression

• PM studies show increases

• PET reductions or no difference

• differential treatment effects:SSRI increasesTCA 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:rewardstresspsychomotor retardationmotivationnovelty

•SSRi effects on nuc accumbensHypothesis: reduced dopamine transmissionin MD

Amphetamine induced DA release

•Parsey 2001

9 depressed, 10 controlsNo difference

•Anand 2000

13 euthymic BPADNo difference

D2 and depression

Striatum:SPET studies: ↓binding 3/4 ↑binding 1/5

PET studies:Psychotic patients no change bindingReduced DS [11C]raclopride with SSRI

Extra-striatal regionsNo 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

•Resting state

•Activationspsychologicalpharmacological

•Mood induction

Blood flow studies: methods

Depression

Blood flow studies (Drevets 2000)

1. Subgenual anterior cingulate cortex

1. Subgenual anterior cingulate cortex

Lesion studies: Abnormal ANS response to emotioninability to experience emotioninability to use reward/punishing info

?DA involvement

•Decreased activity in depressives + reducedvolume

•?Increased activity (after correction forpartial volume effects)

•Returns to normal after effective AD Rx

1. Subgenual anterior cingulate cortex

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

increase flow

•Areas not directly involved in emotion processing-

discriminative attentionselection for actionworking memory

3. Dorsolateral PFC

Reduced flow in depression and inducedsadness

Loss of normal activation after acute TRP depletion

Related to impaired attention, memoryvisuospatial functions in MD

3. Dorsolateral PFC

4. The Amygdalla

•Central role in organising emotional/stressresponses

•Electrical stimulation leads to anxiety, fear, memories of dysphoric events, increased cortisol release

4. The Amygdalla

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