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• Heterogeneous syndromes with heterogeneous etiology-> weakness of trying to construct a “unifying” theory of depression

• Observing pathological changes in the brain = difficult, limited techniques available (post mortem, neuroimaging, difficulties in transferring knowledge acquired from animal studies)

• Idiopathy of occuranceof depression (various risk factors, no consistent genetic risk modifiers). Interaction of genetic predispositions and environmental risk factors.

• Symptom based diagnostic approach poses obvious obstacles
  • To the interpretation of genome-wide association studies
  • To neuroimaging or post mortem investigation (with typical heterogeneity in data acquired from mood disorder samples, often consistent data only in subsets)

Etiological validity (=depression-like behaviour need to be caused by the same etiologiesthat trigger human depression. BUT: absence of definitive aetiologies for human depression!)

Pharmacological validity (= assays are sensitive to acutely administered known antidepressant compounds. BUT more than half of all depressed individuals do not respond fully to available antidepressants)

Face validity (= behavioralchanges brought about by stress or genetic manipulation superficially resemble depressive symptoms. E.g. animal’s decreased sucrose intake after chronic stress ≈ anhedonia)

Decreased monoamine function in the brain

• Serotonin hypothesis (for review: Power et al. 2004)

- reduced tryptophan production in MDD

- depletion -> increases depressive symptoms

- changes in serotonin metabolism: reduced 5-HT uptake / increased 5-HT receptors

- against: enduring character traits related to 5-HT function

• Noradrenergic theories

- many AD potent inhibitors of noradrenaline reuptake, little effect on 5-HT uptake

- challenge studies found reduced noradrenaline function

• Interaction of monoamines

- strong interaction between 5-HT and noradrenaline

- common receptors, projections-noradrenaline reuptake inhibition is potentiated of simultaneous 5-HT reuptake inhibition

- drugs that act on both like amitriptyline and venlafaxine have slightly enhanced efficacy (Smith et al. 2002)

• Whereas antidepressants increase synaptic neurotransmitter levelsin hours or days, it takes weeks or longer for clinical improvements to be fully evident (Stahl, 2005)

• Cocaine and other stimulant drugs rapidly enhance noradrenergic anddopaminergic neurotransmission, yet they do not have sustainedantidepressant effects (Stahl, 2005)

• Dietary depletion of tryptophan, precursor of serotonin, does not provoke depression in healthy individuals, nor does it worsenuntreated depressive episodes (Delgado et al. 1999)

Depression and dysfunctional changes in “limbic” regions

• Implication of several brain regions and circuits regulating emotion, reward and executive functions:Structural findings in post mortem studies & neuroimaging: ↓ grey matter & ↓ glial density in PFC & hippocampus-> cognitive impairments in depression

BUT: findings are not consistent, common problem: co-morbid diagnosis, medication history -> limited evidence for cause-effect relationFunctional: activity in amygdala and subgenualcingulate cortex correlated with dysphoric emotions!! Caution with simplistic “localization of function” approach to examine limbic structures

• HPA axis mediates response of the body to stress

• Dysregulated HPA axis plays a role in the pathology of depression

• Hyperactivity of the HPA indicated by higher daytime cortisol levels, higher corticotropin

• One of the mechanisms thought to be involved in HPA axis hyperactivity in depression is impaired feedback inhibition of the HPA axis by circulating glucocorticoids •Diurnal fluctuation in salivary cortisol in MDD. Extremely high morning cortisol in MDD also in patients with chronic stress or worrying, work overload