Tackling cognitive dysfunction in mood disorders: Outcome of the BAP sponsored Wellcome Masterclass

1. Tackling cognitive dysfunction in mood disorders: Outcome of the BAP sponsored Wellcome Masterclass Hamish McAllister-Williams Convenor, CADENCE Special Interest Group

2. Background - 1 • Wellcome Trust initiative: 'Masterclasses in Clinical Neuroscience‘ • To bring together basic researchers and clinicians to tackle key clinical problems and to promote translational research • Funding obtained in 2007 to run a Masterclass sponsored by the BAP and the Institute of Neuroscience, Newcastle University • “Tackling cognitive dysfunction in affective disorders: Focus on monoamines and corticosteroids”

3. Background - 2 • Masterclass phases: • Phase 1 - creation of web site • Phase 2 - two day residential meeting held on 5th to 7th March 2008 • Phase 3 - publication of consensus statement, development of collaborative groupings and formation of CADENCE • Four main topic areas: • defining and measuring the cognitive dysfunction in affective disorders; • modelling the relevant cognitive domains in the laboratory; • understanding the mechanisms underlying cognitive dysfunction in affective disorders; • examining cognitive dysfunction as a therapeutic target.

4. Masterclass – Residential Meeting • 52 delegates • Spanning pre-clinical and clinical research • University and industry based • PIs, post-docs and post-grads • Wellcome Trust involvement • UK, Europe, USA, Canada and Australia

5. Masterclass – Residential Meeting • A selective overview of topics discussed • Introduction • Why the particular focus was chosen • The nature of the cognitive dysfunction in affective disorders • The role of corticosteroids and monoamines in cognition • Methodology: Testing cognition in man and animal modelling • Lessons form MATRICS • The way forward

6. Why focus on cognitive dysfunction? • It forms an important clinical outcome • Patients complain of it • It predicts functional outcome of patients • It provides information about the underlying neuropathophysiology and psychopathology • It provides an important outcome measure for pharmaceutical studies

7. The nature of cognitive dysfunction in bipolar and unipolar disorders • Bipolar Disorder • Impairments in a range of domains. • Largest effect size for impairments: • Declarative memory, working memory, executive function, attention and speed of processing • Reasoning and IQ not affected • Mainly appears to be a trait rather than state effect • Number of episodes (esp. manic) predict degree of impairment • Unaffected relatives have smaller magnitude effects • Effects of co-morbidity and treatment poorly understood

8. The nature of cognitive dysfunction in bipolar and unipolar disorders • Unipolar Disorder • Declarative memory, executive function and speed of processing affected as in bipolar disorder • But greater variability and smaller effect sizes? • More correlation with severity of mood symptoms than in BD? • e.g. AVLT test results and diurnal variation • Differences between early and late onset depression, melancholic vs non-melancholic, psychotic and non-psychotic depression?

9. The nature of cognitive dysfunction in bipolar and unipolar disorders • Emotional processing abnormalities • Negative bias in effects of emotion on cognition • “seeing as”, memory and attention • NB cognitive control of emotion • Depressed bipolar - generally “anti” positive • Correlates with anhedonia • Depressed unipolar – also some “pro” negative effects? • Effects of comorbidity (esp. social phobia)? • Opposite effects not seen in mania

10. The role of monoamines and corticosteroids in cognition • Corticosteroids

11. Figure 1 Potential mechanisms by which the amygdala mediates the influence of emotional arousal on memory. LaBar KS and Cabeza R (2006) Cognitive neuroscience of emotional memory Nat. Rev. Neuro.7: 54–64 doi:10.1038/nrn1825

12. The role of monoamines and corticosteroids in cognition • Corticosteroids • Declarative memory - complex effects • Pre-learning cortisol or stress immediately post learning enhances memory, but cortisol or stress pre-testing impairs memory • ? enhanced consolidation of current events but decrease retrieval (decreases hippocampal activation) • Cortisol given in the p.m. enhances, while in the a.m. impairs, memory • Working memory • Cortisol impairs “difficult” working memory (but not for emotional material) • Autobiographical memory – impaired by cortisol • Executive function • Sex dependent effects of cortisol (♀ worse, ♂ better)

13. The role of monoamines and corticosteroids in cognition • Monoamines • Multiple differential roles in executive function

14. Differential regulation of the executive control processes (shown in italics) underlying the attentional set-shifting paradigm by DA, 5-HT, NA, and acetylcholine Support of set formation Support of set shifting Support of reversal learning Robbins, T. et al. Cereb. Cortex 2007 17:i151-160i; doi:10.1093/cercor/bhm066

15. The role of monoamines and corticosteroids in cognition • Monoamines • Multiple roles in executive function • Memory • Lowered 5-HT • Impairs consolidation of declarative memory • Increases negative attentional bias • Decreases memory for positive, and increases memory for negative, items • NA enhances emotional memory (interaction with cortisol) • DA enhances spatial working memory

16. Methodology: Testing cognition in man and animal modelling • Testing cognition in man • Morass of different tasks in the literature • Need to consider the “functional architecture” of various tasks • Consider: • Are tasks being done to understand which processes are affected? • The need for tasks with predictive validity

17. The multi-component working memory revision From: Working memory: looking back and looking forward Alan Baddeley, Nature Reviews Neuroscience 4, 829-839 (October 2003)

18. Object-location memory Position only memory particularly impaired in bipolar disorder (Gallagher et al.) Categorical and coordinate spatial representations within object-location memory van Asselen, M., Kessels, R.P.C., Kappelle, L.J., Postma, A. Cortex, 44 (3), p.249-256, Mar 2008

19. Methodology: Testing cognition in man and animal modelling • Most human cognitive tests can be modelled in animals • But which ones should we focus on? • Modelling allows pharmacological and anatomical dissection of processes • e.g. using specific ligands, neurotoxins, pathway lesions and KO mice

20. The Way Forward : Clinical Cohorts • Need to reduce data variance arising from heterogeneous patient cohorts – study well defined sub-populations • Explore using cognitive tasks to define sub-groups • Needs to involve unaffected relatives and at risk populations • Need to determine to what extent cognitive dysfunction and mood are separate or linked domains • Need to relate genetics to cognitive abnormalities (endophenotypes) • Need better/more comparisons of bipolar and unipolar disorder • Need better understanding of the effects of comorbidity

21. The Way Forward : Cognitive Testing • Agree on the best tests with the largest effect size, robustness, and test-retest and inter-rater reliability • Use more ecologically valid tests? • Strive for tests predictive of functional outcome? • Use tests to explore the components of cognitive processes • More work needed on the emotional valence of tests and emotional regulation • Standardise the tests and learn lessons from MATRICS / TURNS

22. The Way Forward : Animal Models • Need to map the appropriate animal tests onto the cognitive domains that show dysfunction • Modelling elements of the phenotype rather than the whole disease • Explore the potential for developing human cognitive tests that are based on reliable and well characterised animal tests • Need to consider issues around reward and motivation – frequently used in animal tests and influenced by illness Human Tests Animal Models

23. The Way Forward : HPA Dysfunction • Simple measures of plasma/salivary cortisol are probably inadequate • Need more detailed assessment of HPA function • Challenges to the HPA axis (e.g. DEX/CRH, waking cortisol or psychological challenges) may provide a better measure of adaptive ability • More accurate measures of GR activation need to be developed, including the balance between MR and GR and activation of receptor isoforms • Tests need to be applicable to large numbers of patients

24. The Way Forward : Monoamines • Build on basic neurobiology of the role of monoamines in cognition • Develop pharmacological tests (e.g. tryptophan depletion, antagonists) that target more specific monoamine systems • Apply tests to cognitive domains that display dysfunction in mood disorders • Measure monoamines in patients with (and without) cognitive impairment • Need to link various measurement strategies e.g. imaging and EEG

25. The Way Forward : CADENCE • Special Interest Group on ‘Cognition in Affective Disorder: Experimental Neurobiology and Clinical Evaluation (CADENCE) • Foster networking and collaboration (e.g. contact details on web, seek funding for follow on meetings) • Publication: a position statement • Develop sub-groups to address issues

26. Acknowledgements • Local PIs/Organising Committee • Nicol Ferrier • Colin Ingram (ION) • Sasha Gartside • Richard McQuade • John Gray • Peter Gallagher • Wellcome Trust - Kathryn Adcock • BAP - Susan Chandler • Admin support - Elaine Ord • All the chairs, presenters, discussants and delegates who attended the residential meeting