Affective Disorders for MRCPsych

1. Andy Montgomery Consultant psychiatrist, Plymouth Affective Disorders for MRCPsych

2. 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.

3. Neuropathology of depression • Sources of data: • PM/lesion • Neuroendocrine • Monoamine depletion • Neuroimaging

4. 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

5. Depression: microstructure • Reduced neuronal size • Reduced dendritic spine density • ? reduced glial cell density

6. 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

7. 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

8. Neuroendocrine challenge tests: MDD • Cholinergic • Enhanced GH response to pyridostigmine (anti-cholinesterase) GABAergic • Reduced response to baclofen (GABA-B agonist) measure of GABAergic activity.

9. Monoamine manipulations • 5HT • Parachlorophenylalanine • Relapse in previously treated patients • Tryptophan depletion

10. Tryptophan depletion in MDD

11. 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

12. Tryp. depletion in MDD Bell 2001

13. 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

14. Endocrinology of psychiatric disorders

15. 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

16. Depression- HPA axis • Neuroendocrine function tests • Dexamethasone suppression test (Carroll 1982) • Cortisol suppression test • CRH test • dex/CRH test (Holsboer 2000)

17. Dex/CRH test

18. Causes of hypercortisolaemia • stress response • early life influences • genetic influences

19. 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

20. 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….

21. 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

22. 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)

23. 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)

24. Hypothesis: Stress Hypercortisolaemia 5-HT1A receptor expression Depression

25. Hypothesis: Stress Hypercortisolaemia 5-HT1A receptor expression Depression

26. 5-HT2A in depression • PM studies show increases • PET reductions or no difference • differential treatment effects: • SSRI increases • TCA reductions

27. 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

28. Receptor occupancy by SSRi Meyer et al 2001

29. Dopamine and depression • Dopamine: • reward • stress • psychomotor retardation • motivation • novelty • SSRi effects on nuc accumbens Hypothesis: reduced dopamine transmission in MD

30. Amphetamine induced DA release • Anand 2000 • 13 euthymic BPAD • No difference • Parsey 2001 • 9 depressed, 10 controls • No difference

31. D2 and depression • Striatum: • SPET studies: • ↓binding 3/4 • ↑binding 1/5 PET studies: • Psychotic patients no change binding • Reduced DS [11C]raclopride with SSRI Extra-striatal regions • No difference

32. D1, DAT and DA synthesis • D1 • reduced binding in frontal cortex DAT • increased binding in basal ganglia [18F]dopa • ?reduced uptake in left putamen

33. Future radioligand developments • displaceable 5-HT ligand • extra-striatal D2 • NA ligands • exotica: Sub P, CRH

34. Depression Blood flow studies: methods • Resting state • Activations psychological pharmacological • Mood induction

35. Blood flow studies (Drevets 2000)

36. 1. Subgenual anterior cingulate cortex

37. 1. Subgenual anterior cingulate cortex • Lesion studies: • Abnormal ANS response to emotion • inability to experience emotion • inability to use reward/punishing info ?DA involvement

38. 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

39. 2. Orbital cortex

40. 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

41. 3. Dorsolateral PFC

42. 3. Dorsolateral PFC • Areas not directly involved in emotion processing- • discriminative attention • selection for action • working memory increase flow

43. 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

44. 4. The Amygdalla

45. 4. The Amygdalla • Central role in organising emotional/stress responses • Electrical stimulation leads to • anxiety, • fear, • memories of dysphoric events, • increased cortisol release

46. 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