Depression
- "common cold of mental illness"=most widespread psychological disorder
- 1/10 chance of at least one depressive episode of clinical proportions
- All population groups are vulnerable
- 1/20 visits to doctor due to depression
- >100 depressed patients per doctor's list, but half unrecognised
- 20% develop mild depression
- patients may not mention depression due to embarrassment, stigma avoid lack of sympathy
- Unipolar:
- mixed anxiety and depression
- depressive episode (single)
- recurrent depressive (numerous)
- dysthymia persistent & mild (depressive personality)
- Bipolar:
- bipolar affective disorder with manic episodes
- cyclothymia persistent instability of mood
- associated with creativity:
- Akiskal-50% major depressive illness, 70% manic depressive illness
- Schildkraut & Hirshfeld (1990)->10% cyclothymia, 40% major depressive illness
>Brain areas involved in depression: prefrontal cortex, hippocampus, nucleus accumbens & amygdala
>Increased metabolic activity in amygdala and orbitofrontal cortex
Is depression inherited?
>Seligman(1975)-Learned Helplessness Theory
- Dogs were placed in a two-sided box. Dogs that had no prior experience with being unable to escape a shock would jump over the hurdle in the centre of the box to land on the safe side. Dogs that learned that escape was impossible would stay on the original side, not even try to go over the hurdle.
- Animals that learned helpless show biological features of depression: REM sleep alterations, loss of body weight, diminished sexual activity elevated corticosterone.
- Cognitive function is linked to biological function through this observation
- Is it cognitive product or stress induced inactivity?
- Recovery within 48 hours, which might be due to recovery of hypothalamic noradrenaline levels which is reduced in helpless animals
Chronic Antidepressant Treatment:
Up-regulation of second messenger pathway
Major Classes of antidepressants & some side effects
Effects of Chronic Antidepressant Treatment on Serotonin Neurons
Neurochemical Hypotheses of Depression
1. Monoamine Theory
>Depression is due to the depletion of monoamines e.g. Noradrenaline, serotonin, dopamine which originated as drugs that depleted such as reserpine neurotransmitters
>Limitations: too simplistic, delayed action of antidepressant drugs
>Modified to include down-regulation of NA receptors
2. Noradrenaline
>Noradregenic hypothesis-reserpine depression is due to reduced levels of NA
>supported by effects of antidepressants with increased NA metabolism
>problem: time delay of therapeutic effect
>hypothesis expanded to include receptor sensitivity
>by increased exposure of the receptor to NA eventually the sensitivity of the receptor is decreased.
3. Serotonin/5-HT
>Serotonin involved in pain sensitivity, emotionality and response to negative consequences
>Metabolite 5-HIAA (a marker for activity of serotonin) reduced in cerebrospinal fluid
>Low 5-HIAA associated with aggressive hostile and impulsive behaviour as in violent suicide attempts.
>Individuals with different alleles coding for the serotonin transporter have different reactivity to stress
The theory-Monoamine transporters
~Major mechanism controlling extracellular monoamine dynamics is re-uptake.
~This is achieved through presynaptic neurons via plasma membrane transporters
~Dopamine (DAT), Serotonin (SERT), Noradrenaline (NET)
~These remove neurotransmitters from outside cells and recycle back into releasing or neighbouring terminals.
~These transporters are targets of many psychostimulants and antidepressants, which interfere with transporter function.
~Normal function of these transporters can be studied using gene deletion technique.
~Mice lacking both SERT and DAT no place preference for cocaine suggesting SERT involvemnt in cocaine effects on reward.->SERT and DAT play a role in rewarding mechanism, lacking of them can lead to depression.
Drugs used to treat depression:
1. Tricyclics
- Inhibit re-uptake of noradrenaline and serotonin
- effective, cheap, but dose-related anticholinergic side-effects limit compliance
- often fatal in overdose
2. Serotonin selective reuptake inhibitors (SSRI's)
- inhibit reuptake of serotonin, e.g. inhibit reuptake of 5-HT and NA
- lack sedation, free of anticholinergic side effects
- narrow dose range but seem safe in overdose
- diffeent from tricyclics as little action on muscarinic cholinergics and histaminerfic receptors (will cause drowsy side-effect)
How they work
>Inhibiting the enzyme monoamine oxidase MAO that breaks down serotonin
>Blocking the transporter protein for serotonin re-uptake
The theory-Cortico-tropin-releasing factor
>CRF is a major neuropeptide mediator of stress responses in the CNS. It increases with stress level.
>It is expressed in the Paraventricular nucleus of the hypothalamus and coordinates the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary.
>CRF is high in CSF of depressed patients. (up to 6 times)
>HPA axis-Hypothalamic Pituitary Adrenocortical system
- CRF is released in response to environmental stressor (uncertainty arousal).
- ACTH is then released by the pituitary.
- Cortico-steroids are released
- When stressor terminated-negative feedback occurs, shut down of the HPA axis.
>Corticosteroids elevate in times of threat and at times of loss of control
>transcient (short-term) activation does not cause stress
>excessive long-term activation of HPA may induce long-term damage
>Depression is associated with increased activity of the HPA axis, results in enlargement of adrenal gland with elevated levels of cortisol.
>antidepressants lower activity in the HPA axis.
>Early experience (maternal separation) can bias towards later protracted activity of the HPA
>Corticosteroids are given for arthritis and cause depression
>Reuptake inhibitors boost the HPA system. Improvement in mental state associated with normalisation of HPA activity.
>Cushings Disease which involves excessive secretion of corticosteroids is commonly followed by depression.
Neurogenesis:
> Neurogenesis (new neurons generated) occurs throughout life in hippocampus & olfactory bulb.
>In rodent brain studies 9k new cells/day or 250000 new cells/month in adult, 50% became neurons
>Factors affecting neurogenesis:
- increase: exercise, environmental enrichment, antidepressants
- decrease: stress, sleep deprivation, age
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