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 CRF which stimulates the anterior pituitary gland to release 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)

• 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 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

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

  • anaesthesia

  • Dissociation and hallucinations

  • Amnesia

  • Analgesia

Ketamine as an antidepressant

• sub-anaesthetic (low dose) can have a profound effect within hours of injection

• Typically a course of several doses per week for a few weeks

• Doesn’t last more than a few months

• Seems to work through new synapse formation in anterior cingulate cortex (structural changes)

Ketamine long term effects

• memory/ cognitive problems (possibly reversible) due to blockage of NMDA receptors

• Bladder and kidney damage (irreversible)

• Abdominal cramps (k-cramps)

Physical addictiveness of ketamine

• tolerance

• Withdrawal include psychotic features

Psychological addictiveness of ketamine

• less known about it

• NMDA-R antagonists can influence dopamine release in Mac

Anxiety disorders

• characterised by extreme worry, fear and chronic stress lasting more than 6 months, inappropriate to the situation and is debilitating

• Often comorbid with other disorders

• Twice as common in women than men

Treatments for anxiety

• talking therapies e.g. CBT

• Exposure therapy (if anxiety is to a specific situation)

• Drug treatments: SSRIs, Beta-blockers and Benzodiazepins

Benzodiazepines

• usually ingested (pills)

• Reach max blood concentration in about an hour

• Lipid solubility varies

• Half life can be 90minutes - 6 days

Benzodiazepines short term effects

• sleepiness (sedative) - used against insomnia

• Anxiolytic - reduces anxiety

• Anterograde amnesia - struggle to make new memories

• Muscle relaxation

• Mental confusion

• Recovery from alcohol withdrawal

Benzodiazepines physiological action

facilitation (agonist) of GABA-A receptors → Increases inhibitory processes (similar to alcohol)

GABA-A receptors in the brain

• cerebral cortex (amnesia and confusion)

• Hippocampus (amnesia and anti-epileptic)

• Spinal chord, brain stem (muscle relaxant)

• Amygdala, orbitofrontal cortex, insula (anxiolytic)

• Tuberomammillary nucleus (hypnotic)

Benzodiazepines long term effects

• mental confusion

• Dementia

• Learning problems

• Can improve after cessation of medication

Physical addictiveness (withdrawel) of benzodiazepine

• Anxiety (possibly higher than before so need to slowly build down dosage when stopping treatment)

• Insomnia

• Restlessness

• Agitation

• Irritability

Psychological addictiveness of benzodiazepine

• alcoholics can become addicted

• GABA-A receptors in the VTA and NAcc