Combining neuropsychology and genetics in the study of

Combining neuropsychology and genetics in the study of mood disorders Daniel Smith MRCPsych Division of Psychiatry, University of Edinburgh Specialist Registrar in Psychiatry, Southern General Hospital, Glasgow. daniel. smith@ed. ac. uk

Overview – three reports: • Recurrent MDD patients versus controls • ‘pure unipolar’ patients versus bipolar-spectrum disorder (BSD) patients • MDD patients with BDNF gene abnormality versus patients without BDNF gene abnormality

Recurrent early-onset major depressive disorder (RE-MDD) • Defined as 2 or more episodes of MDD before age 22 • Is highly morbid (Zubenko et al, 2001) • Is probably a ‘more genetic’ sub-group of depression (Maher et al, 2002) • Carries a high risk of progression to bipolar disorder (Smith et al, in press)

Depression in young adults Bipolar-spectrum disorders Drugs and alcohol Life events Clinical characteristics environmental factors Early adversity ‘endophenotypes’ Personality traits Neurocognitive impairment Genetic risk factors BDNF

Outline of study 234 consecutive referrals in 12 month recruitment period 90 with current depression and at least one previous episode of depression 87 agreed to participate Initial assessment: SCID-1 diagnostic assessment; symptom severity; quality of life; family history; life events; drug and alcohol use; DSH and suicidal behaviour; blood sample for DNA After 3 months on treatment: Symptom severity; Quality of life Neuropsychology assessment Personality dimensions assessment

Neuropsychological impairment in mood disorders • Affected by clinical sub-type • Lack of study of homogeneous groups • Depends on stage of illness • ‘endophenotype’ theory versus ‘scarring’ effect • May reflect structural brain abnormalities

Cognitive deficits in depression and bipolar disorder across mood states Cognitive domain Cognitive task Euthymic state Depressed state Manic state Attention Continuous performance task (CPT) Trail-making Test, part A (TMT-A) Digit Symbol Substitution Test (DSST) No Yes Yes Yes No ? Executive function Wisconsin Card Sort Test (WCST) Stroop test Trail-making Test, part B (TMT-B) Yes Yes ? ? Yes ? Verbal memory California Verbal learning Test (CVLT) Yes Yes

Brain regions implicated in mood disorders • Prefrontal cortex • Dorsolateral: – Verbal memory – Attention – Executive function • Anterior cingulate: – Executive function • Hippocampus – Verbal memory

Neuropsychological battery in this study • Assessed for clinical recovery (euthymia) using HRSD (<8) • Estimate of intellectual functioning: • National Adult Reading Test (NART) • Number of years in full-time education • Block design sub-section score of the WAIS-R • Verbal memory: • California Verbal Learning Test (CVLT) • Executive function: • Stroop Colour Word Test • Brixton spatial anticipation test • Trail-making test A and B

Patients and controls were well matched Characteristic Gender ratio (F: M) NART IQ Block design (WAIS) Education (years) HRSD score Current medications: Antidepressants only, n (%) Mood stabilisers only, n (%) Both, n (%) Neither, n (%) Controls (n=33) Mean (SD) Significance test and pvalue Mean (SD) Age (years) MDD patients (n=63) 21. 7 (2. 25) 43: 20 22. 2 (2. 29) 19: 14 t=-1. 22, df=94, p<0. 03 2=1. 08, df=2, p<0. 30 X 117. 5 (3. 56) 44. 9 (5. 96) 16. 7 (1. 59) 2. 6 (1. 95) 115. 9 (3. 69) 45. 8 (3. 13) 17. 3 (1. 40) 1. 9 (0. 93) t=2. 02, df=94, p<0. 05 t=-0. 85, df=94, p<0. 40 t=-1. 93, df=94, p<0. 06 t=1. 71, df=94, p<0. 09 48 (76. 2) 8 (12. 7) 6 (9. 5) 1 (1. 4) 0 0 -----

Results (1): MDD patients versus controls Verbal learning and memory (CVLT) Delayed recognition minus false positives Controls (n=33) Mean (SD) Trial 1 Trials 1 to 5 total Short delay recall Long delay recall MDD patients (n=63) Mean (SD) 7. 0 (1. 85) 55. 2 (8. 42) 12. 5 (2. 69) 12. 6 (2. 64) 14. 7 (1. 49) 7. 7 (1. 79) 60. 7 (6. 57) 13. 5 (1. 91) 13. 9 (1. 98) 15. 2 (1. 00) Significance test t=-1. 85, df=94, p<0. 07 t=-3. 30, df=94, p<0. 001 t=-1. 77, df=94, p<0. 08 t=-2. 47, df=94, p<0. 01 t=-1. 4, df=94, p<0. 16

Results (2): MDD patients versus controls Attention and executive function Controls (n=33) Mean (SD) Stroop colour trial correct Stroop colour word trial correct Brixton test Trail-making Part A (s) Trail-making Part B (s) MDD patients (n=63) Mean (SD) 111. 6 (0. 63) 109. 1 (2. 58) 6. 8 (1. 67) 30. 3 (8. 0) 58. 6 (16. 4) 111. 7 (0. 47) 110. 4 (1. 17) 7. 4 (1. 62) 29. 0 (35. 3) 45. 3 (10. 9) Significance test t=-0. 50, df=94, p<0. 62 t=-2. 77, df=94, p<0. 01 t=-1. 78, df=94, p<0. 08 t=0. 28, df=94, p<0. 78 t=4. 27, df=94, p<0. 0001

Conclusion: MDD patients versus controls • Subtle impairments in: – Verbal memory – CVLT trials 1 to 5 total – Executive function – Stroop Colour Word errors – Trail-making Part B

Young people with recurrent depression are at high risk of progression to bipolar disorder • 19% of out-patient depressed adolescents develop bipolar disorder 1 • 47% of young adults hospitalised with depression develop bipolar disorder 2 • Bipolar illnesses tend begin with an episode of depression rather than mania 3 • Most people with bipolar disorder date the onset of their illness to adolescence 3 1. Rao et al. , 1995, J. Am. Acad. Child & Adol. Psych. , 34, 566 -578. 2. Goldberg et al. , 2001, Am. J. Psych. , 158, 1265 -1270. 3. Lisj et al. , 1994, J. Aff. Disord. , 31, 281 -294.

Diagnostic criteria for bipolar spectrum disorder (BSD) A at least one major depressive episode B no spontaneous DSM-IV hypomanic or manic episodes C either of the following plus two from D or both plus one from D: • First degree relative with bipolar disorder • Antidepressant-induced mania or hypomania D if none from C, at least six of the following: • • • Hyperthymic personality > 3 depressive episodes Brief major depressive episodes (< 3 months) Atypical depressive symptoms Psychotic major depressive episodes Early age of onset (< 25) Postpartum depression Antidepressant ‘wear-off’ (acute but not prophylactic response) Lack of response to > 2 antidepressant trials Ghaemi, S. N. , Ko, J. Y. , Goodwin, F. K. , Cade's Disease and beyond: misdiagnosis, antidepressant use and a proposed definition for bipolar spectrum disorder. Canadian Journal of Psychiatry, 2002. 47(2): p. 125 -134.

Diagnoses (using diagnostic criteria for bipolar spectrum disorder, BSD) Smith, D. J. , Harrison, N. , Muir, W. , Blackwood, D. H. R. , High prevalence of bipolar spectrum disorders in young adults with recurrent depression: toward a novel diagnostic framework. Journal of Affective Disorders. , in press.

‘pure unipolar’ patients versus BSD patients: CVLT, trials 1 -5 Mean score CVLT trials 1 -5 Controls > DSM-IV MDD; p<0. 001 Controls > BSD; p<0. 001 Pure unipolar > BSD; p<0. 06

‘pure unipolar’ patients versus BSD patients: Trail-making Test seconds N. S. BSD > Controls; p<0. 001 BSD > ‘pure unipolar’; p<0. 03 ‘pure unipolar’ > Controls; p<0. 01

‘pure unipolar’ patients versus BSD patients: Stroop Colour Word Test errors BSD > Controls; p<0. 002 BSD > ‘pure unipolar’; N. S. MDD > Controls; N. S.

Conclusion: ‘pure MDD’ patients versus BSD patients • BSD patients appear to have more impairment in: – Verbal memory (CVLT, trials 1 -5) – Executive function (Trail-making test, part B) • Indirect support for the validity of the proposed diagnostic criteria for BSD

Intracellular signalling pathways mediating cellular resilience and neuroplasticity Manji, H. (2003) American Journal of Psychiatry 160 (1) 24.

Brain-derived neurotrophic factor (BDNF) • Is a neurotrophin found in the neocortex, hippocampus and amygdala 1 • Modulates hippocampal plasticity and hippocampal-dependant memory 1 • Is upregulated by antidepressant therapy 2 • Is associated with bipolar affective disorder 3, 4 1. 2. 3. 4. Lu & Gottschalk (2000) Progress in Brain Research, 128: 231 -241 Reid & Stewart (2001) British Journal of Psychiatry, 178: 299 -303 Neves-Pereira et al. (2002) American Journal of Human Genetics, 71: 651 -655 Sklar et al. (2002) Molecular Psychiatry, 7: 579 -593

The Val 66 Met polymorphism of BDNF – Single nucleotide polymorphism at nucleotide 196 (G/A; db. SNP number rs 6265) produces an amino acid substitution at codon 66 (Val 66 Met) – Approximate frequencies in human controls: • 68% val/val • 27% val/met • 5% met/met

The BDNF val 66 met polymorphism affects activity-dependant secretion of BDNF and human memory and hippocampal function. Egan et al. , (2003) Cell, 112; 257 -269. – met allele associated with: • Poorer episodic memory • Abnormal hippocampal activation on f. MRI • Lower hippocampal intracellular N-acetyl aspartate – val/met exerts these effects through intracellular trafficking and activity-dependant secretion of BDNF

Bipolar patients carrying the Met allele of the BDNF polymorphism perform worse on the Wisconsin Card Sort Test Rybakowski et al (2003) Bipolar Disorders, 5(6): 468 -472 Val/Val (n=44) Val/Met (n=9) Significance test Mean (SD) Perseverative errors 10. 5 (5. 0) 17. 0 (15. 6) P < 0. 03 Non-perseverative errors 9. 8 (5. 5) 15. 9 (15. 2) P < 0. 04

Is this polymorphism associated with cognitive impairment in young adults with recurrent depression?

Genotype frequencies in this sample of MDD patients (n=40) • 24 patients were val/val • 15 were val/met = 16 with at least one met allele • 1 was met/met

Comparison groups were well-matched: Val/Val genotype N=24 Val/Met or Met/Met genotype N=16 Significance test Mean (SD) Age 21. 7 (2. 28) 22. 1 (1. 88) N. S. F: M ratio 2: 1 3: 1 N. S. MADRS score 2. 92 (2. 02) 3. 06 (1. 78) N. S. Premorbid IQ: Number of years of fulltime education 16. 8 (1. 69) 16. 9 (1. 50) N. S. NART error score Full-scale IQ 10. 5 (2. 17) 117. 7 (2. 71) 10. 1 (2. 60) 118. 1 (3. 30) N. S. Block design WAIS 44. 9 (6. 87) 46. 9 (3. 63) N. S.

Neuropsychological assessment: Val/Val genotype N=24 Val/Met or Met/Met genotype N=16 Significance test Mean (SD) CVLT (trials 1 -5) 55. 3 (8. 8) 55. 1 (8. 1) N. S. Brixton raw score 13. 0 (4. 15) 12. 5 (4. 00) N. S. Trailmaking A Trailmaking B B-A 28. 8 (6. 01) 53. 1 (9. 05) 24. 3 (8. 49) 29. 6 (7. 47) 65. 3 (21. 1) 37. 8 (19. 7) N. S. P < 0. 04 Stroop C errors Stroop CW errors 0. 21 (0. 41) 2. 17 (2. 06) 0. 50 (0. 63) 4. 56 (3. 54) N. S. P < 0. 02

Conclusions re: BDNF • Neurocognitive abnormalities associated with this polymorphism of BDNF are not limited to hippocampal impairment • In recurrent, early-onset major depression the val 66 met BDNF polymorphism is associated with impaired frontal executive function but not with hippocampal impairment • Is this a reflection of a bipolar diathesis in these young recurrently depressed patients?

Final Summary • Subtle frontal and hippocampal impairments in euthymic young adults with recurrent depression compared to controls – Is this an endophenotypic characteristic? • Neuropsychological support for the proposed diagnostic criteria for bipolar-spectrum disorder (BSD) • Possible to demonstrate that abnormalities of genes implicated in cognitive function and risk for mood disorder are associated with cognitive deficits in recovered patients

Acknowledgments • Funded by the Kate Hodgson Memorial Fellowship, University of Edinburgh and by the Health Foundation UK • Psychiatric genetics research group in Edinburgh: – Douglas Blackwood – Walter Muir – David Porteous – Maura Walker – Margaret van Beck • Genotypying lab at the University of Dundee: – Murray Wilkie – Gillian Smith – Roland Wolf • Thanks to general practitioners at the University Health Service in Bristo Square, Edinburgh and community mental health team at Ballendon House, Edinburgh