Medical disorder in recurrent depression'

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Medical disorder in recurrent depression.

• possible shared genetic aetiology

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Depression and physical illness

• Many studies have examined the prevalence of
  depression in subjects with a range of physical
  disorders
• Epidemiological studies show high rates of
  co-morbidity between depression and anxiety
• Depression particularly noted to co-occur with
  hypothyroidism, epilepsy, migraine

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Depression and physical illness

• Few studies have examined physical health in
  subjects with depression
• Depression case control study (DeCC) has examined
  self reported medical illness in 1500 recurrently
  depressed subjects and over 800 controls selected
  for mental health

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Depression and physical illness

• Since many physical disorders are related to
  obesity BMI also examined
• BMI, gender and age controlled for when reporting
  effect size differences between cases and controls

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Method

• All subjects interviewed about lifetime ever
  occurrence of various physical health diagnoses
  as part of a genetic case control study
• Depressed subjects who had experienced 2 or more
  episodes of major depression of at least moderate
  severity recruited from psychiatric clinics (26)
  general practise (46) and through self help
  groups and media advertisement (28)

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Method

• from 3 UK sites Birmingham Cardiff and London
• Control subjects recruited via UK General
  Practise based Genetic-Environmental Nature of
  Emotional States in Siblings (GENESIS) and all
  were screened by telephone interview

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Diagnostic instruments

• Probands interviewed using Schedules for Clinical
  Assessment in Neuropsychiatry (SCAN) (DSMIV
  ICD10 diagnoses)
• Time frame for enquiry peak severity 4-6 weeks
  of worst and 2nd worst episodes of depression
• BMI derived from SCAN items

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Diagnostic instruments

• Controls screened by telephone using modified
  version of the Past History Schedule to ensure no
  present or past history of clinically significant
  psychiatric disorder
• Controls also asked present height and weight
  from which BMI calculated

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Diagnostic assessment

• A short structured interview established whether
  any case or control had ever been treated by
  their GP for various medical disorders
• Replies were simply scored as yes no or
  uncertain (recoded as no)

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Medical disorders

• Asthma
• Diabetes
• Epilepsy
• Hypercholesterol-
• aemia
• Hypertension
• Kidney disease
• Liver disease

• Myocardial
• infarction
• Osteoporosis
• Rheumatoid arthritis
• Hay fever
• Stroke
• Thyroid disease

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Whats the link??

• Elevated cortisol is a frequent finding in
  depression
• ? caused by acute /or protracted exposure to
  stress
• Acute exposure in form of severe threatening
  life events well recognised risk factor for
  depression

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Whats the link??

• Chronic stress at critical periods of brain
  development can reset HPA axis to higher levels
  of cortisol therefore predispose to depression
  in adult life (Charandari 03)
• Inappropriate responsiveness of HPA axis to
  stress can impair growth and development of CNS
• Impact on an individual will depend on genetic
  vulnerability as well as timing of exposure in
  terms of brain development (Seckl Meaney 04)

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• Say something about cortisol levels in childhood
  adversity
• Children of depressed mothers etc

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Cortisol and medical disorders

• Hypercortisolaemia in Cushings syndrome (?
  Picture??) associated with gastric ulcers and
  obesity
• HPA axis activation exerts hyperphagic and
  antithermogenic effects (Drapeau 03) and visceral
  obesity associated with increased cortisol
  clearance

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Cortisol and medical disorders

• Hypertension associated with enhanced
  cardiovascular stress reactivity
• Nyklicek (05)hypertensive subjects had enhanced
  HPA axis and immune system reactivity to stress
• Link with depression may be mediated by
  hyper-responsivity of sympathetic nervous system
  or genetic influences (Scalco 05)

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Cortisol and medical disorders

• Proinflammatory cytokines produced in excess in
  subjects with asthma and hay fever
• These cytokines associated with inflammatory
  activation of HPA axis (Hurwitz and Morgan 99)
• also suggested that inflammation may also play a
  part in osteoarthritis (Amin 95)

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Depression and thyroid dysfunction

• HPT axis abnormal in depression (Sullivan 97)
• (nb picture of HPT axis helpful here)
• Blunted TSH response to TRH differences in
  diurnal variation of thyroxine levels
  demonstrated in those with depression compared
  with controls

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Depression and thyroid dysfunction

• Points to central hypothalamic pituitary
  dysfunction associated with both thyroid
  abnormalities and glucocorticoid dysfunction

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Bottom up.

• evidence from genetic studies

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• Maternal behaviour in rats
• Arginine vasopressin its receptor (AVP AVPR1B)
• Glucocorticoid receptor gene (NRC1)

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Maternal behaviour in rats

• Maternal behaviour in rats epigenetically alters
  a NGF1-A transcription factor binding site in the
  promoter of the GR gene (Weaver 04)
• Provides a mechanism whereby environmental clues
  can regulate GR expression

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AVP AVPR1B

• AVP plays a major role in modulating HPA axis via
  a G-protein AVPR1B
• SNPs across both genes genotyped in large family
  based sample of childhood onset mood disorder
  (both UP BP)
• AVP SNPs showed no association with mood disorder
• 2 AVPR1B SNPs showed significance (Lys65Asn
  SNP5 )
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  (Dempster 06)

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NR3C1

• Polymorphisms in this gene may disrupt binding of
  transcription factors known to regulate GR
  expression
• SNPs examined across the coding regions of NR3C1
  in 394 families ascertained via a proband with
  childhood onset mood disorder
• Novel (rarer) polymorphisms identified results
  suggest a putative role in aetiology of COMD
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  (Mill 06)