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

Clinical characteristics

Genetic risk factors

‘endophenotypes’

environmental factors

Personality traits

Neurocognitive impairment

Drugs and alcohol

Life events

Early adversity

Bipolar-spectrum disorders

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 assessmentPersonality 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

  

Yes  

Yes

 

Yes  

No  ?

Executive function

Wisconsin Card Sort Test (WCST)

 Stroop test

 Trail-making Test,

part B (TMT-B)

 Yes

 Yes

  

Yes

 ? ?  

Yes

 Yes

 Yes

  ?

Verbal memory

California Verbal learning Test

(CVLT)

 

Yes  

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 MDD patients (n=63)

Mean (SD)

Controls  (n=33)

 Mean (SD)

Significance test and p-value

Age (years)

Gender ratio (F:M)

 21.7 (2.25) 

43:20

22.2 (2.29) 

19:14

t=-1.22, df=94, p<0.03 

X2=1.08, df=2, p<0.30

NART IQ Block design (WAIS) Education (years)

HRSD score

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

Current medications:Antidepressants only, n (%)Mood stabilisers only, n (%)Both, n (%)Neither, n (%)

48 (76.2)8 (12.7)6 (9.5)1 (1.4)

0000

------------

Results (1): MDD patients versus controls

Verbal learning and memory (CVLT)

MDD patients(n=63)

Mean (SD)

Controls(n=33)

Mean (SD)

Significance test

Trial 1 Trials 1 to 5 total Short delay recall Long delay recall

Delayed recognition minus false positives

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)

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

MDD patients(n=63)

Mean (SD)

Controls(n=33)

Mean (SD)

Significance test

Stroop colour trial correct Stroop colour word trial correct Brixton test Trail-making Part A (s) Trail-making Part B (s)

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)

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)

0

10

20

30

40

50

60

70

80

90

DSM-IV bipolar disorder DSM-IV MDD

% subjects

0

10

20

30

40

50

60

70

80

90

DSM-IV bipolar disorder DSM-IV MDD

% subjects

BSD

unipolars

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

46

48

50

52

54

56

58

60

62

Bipolar spectrum disorder(n=21)

'pure unipolar' (n=42)

Controls (n=33)

DSM-IV MDD (n=63)

Controls > DSM-IV MDD; p<0.001

Controls > BSD; p<0.001

Pure unipolar > BSD; p<0.06

Mean score

CVLT trials 1-5

‘pure unipolar’ patients versus BSD patients: Trail-making Test

0

10

20

30

40

50

60

70

TMA TMB

Bipolar spectrum disorder(n=21)

'pure unipolar' (n=42)

Controls (n=33)

BSD > Controls; p<0.001

BSD > ‘pure unipolar’; p<0.03

‘pure unipolar’ > Controls; p<0.01

N.S.

seconds

‘pure unipolar’ patients versus BSD patients: Stroop Colour Word Test

0

0.5

1

1.5

2

2.5

3

3.5

4

Stroop Colour Stroop Colour-Word

Bipolar spectrum disorder(n=21)

'pure unipolar' (n=42)

Controls (n=33)

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

Manji, H. (2003) American Journal of Psychiatry 160 (1) 24.

Intracellular signalling pathways mediating cellular resilience and neuroplasticity

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. Lu & Gottschalk (2000) Progress in Brain Research, 128:231-241

2. Reid & Stewart (2001) British Journal of Psychiatry, 178:299-303

3. Neves-Pereira et al. (2002) American Journal of Human Genetics, 71:651-655

4. Sklar et al. (2002) Molecular Psychiatry, 7:579-593

The Val66Met polymorphism of BDNF

– Single nucleotide polymorphism at nucleotide 196 (G/A; dbSNP number rs6265) produces an amino acid substitution at codon 66 (Val66Met)

– Approximate frequencies in human controls:• 68% val/val• 27% val/met• 5% met/met

The BDNF val66met 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 fMRI• 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)

Mean (SD)

Val/Met(n=9)

Mean (SD)

Significance test

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

Val/Val genotype

N=24

Mean (SD)

Val/Met or Met/MetgenotypeN=16

Mean (SD)

Significance test

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 full-time education

NART error scoreFull-scale IQ

Block design WAIS

16.8 (1.69)

10.5 (2.17)117.7 (2.71)

44.9 (6.87)

16.9 (1.50)

10.1 (2.60)118.1 (3.30)

46.9 (3.63)

N.S.

N.S.N.S.

N.S.

Comparison groups were well-matched:

Val/Val genotype

N=24

Mean (SD)

Val/Met or Met/Met genotypeN=16

Mean (SD)

Significance test

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 ATrailmaking BB-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 < 0.04P < 0.04

Stroop C errorsStroop CW errors

0.21 (0.41)2.17 (2.06)

0.50 (0.63)4.56 (3.54)

N.S.P < 0.02

Neuropsychological assessment:

Conclusions re: BDNF

• Neurocognitive abnormalities associated with this polymorphism of BDNF are not limited to hippocampal impairment

• In recurrent, early-onset major depression the val66met 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