The Neurobiology of Mood Disorders

Professor Keith MatthewsOctober 2013

Learning Outcomes• to gain an understanding of what may be altered

in the brain (and elsewhere) during disordered mood states

• to be aware of some of the key neurobiological findings in depression

• to appreciate the potential for such findings to inform prediction, prevention, and treatment

Core Clinical ProblemsAltered Mood

AnxietyArrested Intellectual Development

Behavioural Problems in AdultsDeliberate Self Harm

Eating DisordersMedically Unexplained Symptoms

Memory ProblemsMisusing Drugs or Alcohol

Psychological Responses to TraumaPsychosis

Synopsis

1. a brief review of the neural substrates for emotional behaviour.

2. how altered functioning might generate symptoms

3. a brief review of research identifying substrates differentiating the MDD brain from non-MDD brain.

4. overview of major neurobiological findings in patients with mood disorders

food warmth water

sexdefense / safety

to identify stimuli predicting appetitive or aversive consequences

What do I need to enable me to survive (& reproduce)?

to generate behavioural and other physiological responses to such stimuli (emotions!)

to integrate behavioural and other physiological responses to such stimuli

Functional Differentiation in the Brain

• Appetitive / Approach Systems• function to mediate seeking and approach

behaviours (incl. pleasure)

• ascending dopamine systems – mesolimbic/cortical projection

• ventral striatum• dorsal striatum (movement)• amygdala (conditioning / learning)• anterior cingulate (attention / conflict /

response selection)• orbitofrontal cortex (relative reward

preference / rule learning)

• Aversive / Defensive Systems• function to promote survival in event of

threat (fear / pain)

• ascending serotonin systems• NA / CRF / peptide transmitters

• central nucleus of amygdala• hippocampus• ventroanterior and medial

hypothalamus• periaqueductal gray matter

Functional Differentiation in the Brain

• Appetitive/ Approach Systems

• Aversive/ Defensive Systems

similar to many other syndromes…Disease/ condition Explanation

Asthma hypersensitive airways

Anaemia insufficient capacity to oxygenate organs (multiple causes)

Hypertension “a progressive cardiovascular syndrome arising from complex and interrelated aetiologies. Early markers of the syndrome are often present before blood pressure elevation is sustained; therefore, hypertension cannot be classified solely by discrete blood pressure thresholds.” ASH 2005

Osteoporosis Bone density slightly lower than other people the same age and gender

Depression altered sensitivity / accuracy of brain systems evaluating rewards and cues predicting reward within the environment?

Anxiety altered sensitivity / accuracy of brain systems evaluating threat and cues predicting threat within the environment?

Core symptoms of Major Depression

• Low mood• Anhedonia• Anergia

Other symptoms (ICD-10)

• reduced concentration and attention• reduced self esteem and self confidence• ideas of guilt and unworthiness• bleak and pessimistic views of the future• ideas or acts of self harm or suicide• disturbed sleep• diminished appetite

Disordered “Appetitive Functioning”

• difficulty identifying “rewarding” stimuli

• reduced contact with previously rewarding stimuli

• increased contact with aversive stimuli

• overall reduction of behaviour

• move less, eat less, lose weight(?), less sexual…

• dysphoric mood??

• attention / concentration ?

• loss of interest?

• avoidance?

• inactivity, anhedonia, weight change, loss of sexual drive

From Biology to Prediction of Symptoms - Depression

Disordered “Appetitive Functioning”

• previously neutral stimuli become “rewarding”

• increased exploration / overall activity

• increased “appetite” for food, activity, sex etc….

• intolerant of “aversion” / boredom

• intolerant of frustration• elevated / elated mood??

• increased interest / distractibility

• overactive / loss of need for sleep?

• disinhibition / risk taking / poor judgement

• irritability / dysphoria

From Biology to Prediction of Symptoms – Mania / Hypomania

Neurobiology of Depression: Overview

clinical observations

• epidemiology and genetics

• endocrinology

• post-mortem studies

• brain imaging

inference from therapeutic efficacy

• monoamine theories• antidepressant drug

actions – see Lecture CAS

• electroconvulsive therapy – see ‘Mx’ session

• neurosurgical therapies• - see ‘Horizons’ session

Epidemiology

• increased risk in 1st0 relatives where proband has MDD (3x) or BPD (2x)

• twin studies: MZ ‘v’ DZ = 27% ‘v’ 12%• heritability (proportion of variance) of Major

Depression around 70% (shared with anxiety)• onset of depression (first episode) associated

with excess of adverse life events• ‘exit events’ - separations, losses • adverse early experience (neglect) increases risk

of MDD

Childbirth…

• 7x increased risk of psychiatric admission in the 30 days following childbirth (risk for 24m)

• 75% of women experience ‘blues’ within 2 weeks• 10% of women develop MDD within 3-6 months • ‘puerperal psychosis’ - 1 in 500 deliveries with a risk of

recurrence of 1-3 with subsequent deliveries• despite intuitive appeal - no association with

hormonal changes has ever been demonstrated

Genetic EpidemiologyUnipolar Depression Bipolar Disorder

Lifetime prevalence 14-18% 1%

Sex Ratio (M:F) 1:2 1:1

Average age of onset 27 years 21 years

First degree relatives:

Lifetime risk for unipolar disorder 20-30% 20-30%

Lifetime risk for bipolar disorder Approx 2% Approx 10%

Relative risk 2-3

Gelder, M., Harrison, P. & Cowen, P. (eds) (2006) Shorter Oxford Textbook of Psychiatry. Oxford: Oxford University Press.

s/s = short allele homozygouss/l = heterozygousl/l = long allele homozygous

Caspi, A., Sugden, K., Moffitt, T. E., et al (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386-389.

Caspi, A., Sugden, K., Moffitt, T. E., et al (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386-389.

s/s = short allele homozygouss/l = heterozygousl/l = long allele homozygous

Endocrine changes in Major Depression

• HPA axis (cortisol)• increased secretion of ACTH• increased secretion of CORT• elevated CORT in urine, saliva• increased CRH in CSF• blunted ACTH to CRH• enlarged adrenal glands• 50-70% fail to suppress CORT

production following DEX• ? chronic hypersecretion of

CRF in hypothalamus

• HPT axis (thyroid T3 & T4 ) • 20-30% MD populations show

some dysfunction• increased TRH in CSF• TSH response to TRH blunted in

20-25% despite normal basal TSH, T3 and T4

• ? chronic hypersecretion of TRH in hypothalamus

The effects of stress…

Hippocampal Neurons

Cytoarchitectural Changes in MDD

Structural and Functional Neuroimaging

Key regions implicated in mood disorders

(a) Orbital prefrontal cortex and Ventromedial prefrontal cortex

(b) Dorsolateral prefrontal cortex

(c) Hippocampus and Amygdala

(d) Anterior cingulate cortex

Davidson et al, 2002, Annu. Rev. Psychol.

Structural imaging with MRI - the hippocampus

hippocampus

MRI: effects of MD on hippocampal volume

MRI: effects of duration of MD on hippocampal volume

Cognitive Function & MDD

Delay-dependent deficit in visual memory function for both depression and dementia of the Alzheimer-type. Recovered depressives were still impaired relative to controls.

Abas et al, Psychol Med, 1990

Anterior Insular Cortex• dense connectivity with Anterior Cingulate Cortex• long considered visceral sensory region• co-activation of AIC and ACC during almost all

studies of emotion• Parallel descending projections to sensory and

motor nuclei in brainstem• Proposed as limbic motor (ACC) and sensory (AIC)

cortices that engender the feeling (awareness) and motivation (agency) associated with emotion

implicated neural substrates

supporting diagnostic prediction

• orbitofrontal cortex• dorsolateral prefrontal

cortex• medial frontal cortex

(anterior cingulate)• insular cortex

supporting severity prediction

• medial temporal lobe – hippocampus and amygdala

• medial frontal cortex – anterior cingulate

• superior temporal gyrus• (language comprehension &

social cognition)

Bipolar Disorder• Structural imaging : reduced grey matter volume -

Brodmann Area 24 (Ant Cingulate)

• functional neuroimaging : increased metabolism in amygdala (L), correlates with outcome. Reduced metabolism OfC and Medial Ventral pfC, decreased FA of DTI in anterior cingulum.

• Post mortem studies : reduced glial cell numbers with NORMAL neuronal numbers Brodmann Area 24 and OfC

• NB- none are specific for BPD relative to MD

• Neurochemistry – signal transduction mechanisms, gene expression studies, PKA, PKC, cytoprotective protein bcl-2.

changes in reward sensitivitychanges in cognitive ‘attunement’changes in reward processingchanges in strength of functional connectivitychanges in micro & macroarchitecture

Learning Outcomes• to gain an understanding of what may be

altered in the brain (and elsewhere) during disordered mood states

• to be aware of some of the key neurobiological findings in depression

• to appreciate the potential for such findings to inform prediction, prevention, and treatment