Combining neuropsychology and genetics in the study of mood disorders

1
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_at_ed.ac.uk

2
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

3
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)

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

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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

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Cognitive deficits in depression and bipolar
disorder across mood states

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Brain regions implicated in mood disorders

• Prefrontal cortex
• Dorsolateral
• Verbal memory
• Attention
• Executive function
• Anterior cingulate
• Executive function
• Hippocampus
• Verbal memory

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Neuropsychological battery in this study

• Assessed for clinical recovery (euthymia) using
  HRSD (lt8)
• 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

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Patients and controls were well matched

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Results (1) MDD patients versus controls
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Results (2) MDD patients versus controls
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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

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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

• Rao et al., 1995, J. Am. Acad. Child Adol.
  Psych., 34, 566-578.
• Goldberg et al., 2001, Am. J. Psych., 158,
  1265-1270.
• Lisj et al., 1994, J. Aff. Disord., 31, 281-294.

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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
• gt 3 depressive episodes
• Brief major depressive episodes (lt 3 months)
• Atypical depressive symptoms
• Psychotic major depressive episodes
• Early age of onset (lt 25)
• Postpartum depression

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.
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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.
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pure unipolar patients versus BSD patients
CVLT, trials 1-5
Mean score CVLT trials 1-5
Controls gt DSM-IV MDD plt0.001 Controls gt BSD
plt0.001 Pure unipolar gt BSD plt0.06
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pure unipolar patients versus BSD patients
Trail-making Test
seconds
N.S.
BSD gt Controls plt0.001 BSD gt pure unipolar
plt0.03 pure unipolar gt Controls plt0.01
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pure unipolar patients versus BSD patients
Stroop Colour Word Test
errors
BSD gt Controls plt0.002 BSD gt pure unipolar
N.S. MDD gt Controls N.S.
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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

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

• Lu Gottschalk (2000) Progress in Brain
  Research, 128231-241
• Reid Stewart (2001) British Journal of
  Psychiatry, 178299-303
• Neves-Pereira et al. (2002) American Journal of
  Human Genetics, 71651-655
• Sklar et al. (2002) Molecular Psychiatry,
  7579-593

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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

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The BDNF val66met polymorphism affects
activity-dependant secretion of BDNF and human
memory and hippocampal function.Egan et al.,
(2003) Cell, 112257-269.

• 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

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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
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Is this polymorphism associated with cognitive
impairment in young adults with recurrent
depression?
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Genotype frequencies in this sample of MDD
patients (n40)

• 24 patients were val/val
• 15 were val/met
• 16 with at least one met allele
• 1 was met/met

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Comparison groups were well-matched
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Neuropsychological assessment
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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?

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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

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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