stress and mood disorders

The stress response

• combination of things throughout the body in response to stimuli that is threatening to homeostasis Eg. Being attacked (scared), attacking someone (anger), hunger, cold and overheating

• Has effects throughout the body

• Stimulates the sympathetic and inhibits the parasympathetic nervous system causing less saliva, increased heart rate, constricting blood vessels → high blood pressure and increases sweating

• Post ganglionic neurons affect organs using noradrenaline

Systems stimulated during stress: adrenal hormones

• hypothalamus releases corticotropin releasing factor (CRF) which stimulates the anterior pituitary gland to release adrenocorticotrophic (ACTH) to the adrenal cortex which causes cortisol to be released which stimulates glucose/ energy to deal with stress

• Or adrenal medulla releases adrenaline into the bloodstream which stimulates pre ganglionic neurons

Activation of the stress response

• amygdala (central responds to homeostatic challenges e.g. too cold/ hot or medial which responds to psychogenic challenges e.g. anger/ scared)

• Subgenual anterior cingulate cortex (sgACC) has indirect activation

• Both activate the sympathetic nervous system and the HPA axis

Regulation of the HPA axis

• stress needs to go back down in order to not use too much energy

• Cortisol levels increase with stress and then gradually decrease with time due to clearing and stopped production

HPA axis: negative feedback

• direct negative feedback of cortisol on the PVN via glucocorticoid receptors (GR)

• Anterior hippocampus detects too much cortisol in blood using many MR and GR receptors that are sensitive to cortisol so signals to HPA axis to inhibit production (indirect inhibition)

• Dorsal anterior cingulate cortex influences how strong the cortisol response is and how long it lasts though indirect inhibition and used of GR receptors → early and intermediate term feedback

Major (unipolar) depression

• Symptoms: depressed mood, sleeping problems, fatigue, change in appetite, feelings of worthlessness and lethargy

• Has to be persistent and debilitating and not easily explained by outside factors

• Twice as common in women (could be skewed statistics as women are more likely to seek help)

Depression and the HPA axis

• dysregulated HPA axis is common in affective disorders

• Both pathological increases and decreases in cortisol can lead to depressive symptoms

Chronic stress: positive feedback

• amygdala stimulates the HPA axis

• Glucocorticoids activate the locus coerules which has noradrenergic projections which activate the amygdala → cortisol

• Becomes self stimulating due to overactivation

Chronic stress: reduced negative feedback

• repeated stimulation by glucocorticoids reduces sensitivity of receptors in the hippocampus

• Chronically high glucocorticoids also damage hippocampal neurons → reduction in negative feedback → less control when stressed

Reduction of stress in treatment from depression

• Decreased activation of the subgenual ACC (activates the stress response) after a variety of successful treatments for depression

• Shows depression treatment works on the stress response

Major depressive disorder and sleep

• fall asleep sooner

• Go into REM too soon

• More interruptions during sleep

• Reduction in SWS

Monoamine effects of chronic stress

• depletion of noradrenaline from locus coeruleus

• Depletion of serotonin from raphe nuclei

• Depletion of dopamine from VTA, n accumbens and prefrontal cortex

Major depressive disorder: pharmacological treatments

• Targeting mono-amines

• Ketamine

Role of mono-amines in depression

• reserpine (mono-amine antagonist) induces depression

• Lower levels of 5-HIAA in cerebrospinal fluid

• Tryptophan depletion experiments

SSRIs - targeting monoamines

• SSRI = selective serotonin reuptake inhibitor

• usually taken in pill form

• Lipophilic

• Different pharmacokinetics for different types:

  • fluoxetine (prozac): slow uptake, half life = 1-4 days

  • Fluvoxamine (faverin): bit faster, half life = 8-28h

  • Citalopram (cipramil): bit faster, half life = ~36h

• Only work after several weeks as the first two weeks is adaptation of auto receptors

Adaptation of auto receptors (how SSRIs work)

• initially, SSRIs increase 5HT levels in the synapse by blocking reuptake →Auto receptors reducing 5HT release through negative feedback → no change in 5HT levels as lower release and more in synapse for longer cancels out

• After roughly 2 weeks, the auto receptors adapt (tolerance) to the higher levels of 5HT → reduced negative feedback → gradual increase in release of 5HT

• Since 5HT reuptake is still blocked → 5HT levels in the synapse to be above original levels → more 5HT binding to post synaptic receptors

Adult hippocampal neurogenesis

• suppressed in animal models of depression

• Anti depressants increase neurogenesis

• More increase = more effective

• Destroying adult neurogenesis prevents antidepressants effects

• Exercise increases adult neurogenesis and improves depression symptoms

Ketamine

• dissociative anaesthetic and analgesic

• Can be snorted, taken in pills or injected

• Initial biological half life 10-15 minutes

Ketamine short term effects

• low doses = lightness/ euphoria, disconnection and strange perceptions

• Higher doses = mind body disconnectedness and k-holing (unresponsive and hallucinations)

Ketamine physiological action

• NMDA-R antagonist (Block receptors) responsible for:

  • anaesthesia

  • Dissociation and hallucinations

  • Amnesia

  • Analgesia