Depression Flashcards
What is neurology?
→ Branch of medicine, diagnosis & treatment of nervous system disorders
What is psychiatry?
→ Branch of medicine, diagnosis & treatment of disorders that affect the mind and psyche
What is human behaviour a product of?
→ Product of brain activity
What is the brain a product of?
→ Genetics and environment
→ Experience
What is depressive disorder?
→ A low state marked by significant levels of sadness
→ lack of energy
→ low self worth
→ Guilt
→ related syndromes
What is a major depressive disorder?
→ A severe pattern of depression that is disabling and not caused by factors such as drugs or a medical condition
What are characteristics of affective disorders?
→ Disorders of mood rather than thought/cognition
What is unipolar depression?
→ mood swings in one direction
→ most common depressive illness
How many unipolar depression cases are caused by the environment?
→ 75%
How many cases of unipolar depression are caused by genetics?
→ 25%
What is bipolar depression?
→ Oscillation between depression and mania
What is mania?
→ Excessive exuberance
→ enthusiasm
→ self confidence →impulsive actions → aggression → irritability → delusions of grandiose
What are the criteria used for depression diagnosis?
→ DSM-IV or ICD-10
What are the criteria for depression?
→ Five or more of the symptoms during the same 2 week period
What are the emotional symptoms of depression?
→ Apathy
→ pessimism
→ negativity → low self esteem → feeling guilty → loss of motivation → indecisiveness
What are the biological symptoms of depression?
→ Reduced activity
→ Loss of libido
→ Sleep disturbance
→ Loss of appetite
What are the animal models of depression?
→ Learned helplessness
→ mother infant separation is reversed by antidepressants
What is the gender bias in depression?
→ It affects twice as many females as males
What is the lifetime prevalence of depression in men and women?
→ 10-25% in women
→ 5-12% in men
When does the first depressive episode happen?
→ late adolescence
→ early adulthood
What is depression comorbid with?
→ terminal and chronic illness
→ thyroid dysfunction
→ neurological disease
→ stroke
→ drug abuse
How many depressed individuals will attempt suicide?
→ 20%
If one twin has depression what is the probability that the other will get it too?
→ 40-50%
What are environmental factors that may lead to depression?
→ loss
→ Environmental stressors
→ Social isolation
What is the monoamine theory for depression?
→ that there is a deficit of monoamines
→ 5-HT
→ dopamine
→ NA
What is the evidence for the monoamine theory?
→ Overall reduced activity of dopaminergic and serotonergic systems
→ Reserpine depletes the brain of NA and 5-HT and induces depression
→ main antidepressant drugs increase amines in the brain
What is the evidence against the monoamine theory?
→ It is difficult to show deficits in the brain of NA and 5-HT
→ most antidepressants take several weeks to work but increase in amines is acute
→ some antidepressants are weak and have no effect on amine uptake
→ cocaine blocks amine uptake but has no antidepressant effect
→ increase in 5-HT is linked to aggression and not depression
What is the neuroendocrine theory?
→ there is hypersensitivity to the HPA axis
What neurons input to the hypothalamus?
→ noradrenergic
→ 5-HT
Describe how cortisol is produced?
→ Hypothalamus releases CRH (corticotropin releasing hormone)
→ CRH acts on the pituitary - release of adrenocorticotropic hormone (ACTH)
→ Cortisol release from the adrenal cortex in response to increased ACTH in the blood
What does CRH do?
→ mimics depression like symptoms
What is cortisol and CRH like in depressed patients?
→ Cortisol is higher
→ increased CRH in CSF
What suppresses and increases the HPA axis?
→ hippocampus suppresses HPA
→ Amygdala increases HPA
What are glucocorticoid receptor gene expression regulated by?
→ Early experience
What causes glucocorticoid receptor expression in the brain?
→ tactile stimulation after birth activates 5-HT pathways to the hippocampus
→ it triggers a long lasting increase in the expression of glucocorticoid receptors in the hippocampus
How do SSRIs affect glucocorticoid receptor expression i the hippocampus?
→ they increase it
Lack of what receptor is associated with depression and why ?
→ Decreased glucocorticoid receptors in the hippocampus (cortisol)
→ more cortisol is needed to bind and negatively feedback to the hippocampus
→ hippocampus downregulates the HPA axis
What is the neurogenesis theory for depression?
→ Evidence of neuronal loss and decrease in neuronal activity in the hippocampus and prefrontal cortex
What promotes neurogenesis?
→ ECT
→ antidepressants
What promotes neurogenesis during development?
5-HT via BDNF (brain derived neurotrophic factor)
What increases BDNF?
→ SSRIs
What increases in the cortex of depressed people?
→ glutamate
Why does glutamate cause depression?
→ excessive glutamate leads to neurotoxicity which leads to neuronal death
Describe how excitotoxicity occurs
→ Chronic stress causes a big release of glutamate
→ Hyperactivation of NMDA receptors
→ Excitotoxicity occurs leading to neuronal loss
Describe how neurogenesis occurs mediated by NA and 5HT
→ Noradrenaline acts on alpha 2 receptors
→ 5-HT acts on 5-HT1A receptors
→ these cause beneficial gene transcription
→ increased neurogenesis and inhibition of neural apoptosis
What is an adverse effect of ECT?
→ Memory loss
What does psychotherapy help with?
→ overcoming negative views
What do tricyclic antidepressants do?
→ block reuptake of NA and 5-HT
What is an example of an SSRI?
→ Fluoxetine
What is an example of an NA selective reuptake inhibitor?
→ reboxetine
What do MAOI do?
→ block the degradation of 5-HT and NA →increases [NA/5-HT]cytoplasm and increases leakage of amine →Increases [NA/5-HT] in synaptic cleft →increases [5-HT] > [NA] > [DA]
What does lithium do?
→ Stabilises mood
→Li+ like Na+ gets into neurons but stays there=> depolarisation
What are psychological treatment?
→Cognitive behaviour therapy
→Interpersonal therapy.
Why are SSRI recommended first?
much safer and fewer side-effects
What are MAO-I associated with?
→food and drug interactions
→Tyramine (in cheese and wine) acts as indirect sympathomimetic and increases NA release
→Excess NA destroyed by MAO – if blocked NA will accumulate
→NA accumulation (Increases headache, intracranial haemorrhage => elevation in BP => severe hypertension)
→MAOIs not specific – reduce metabolism of opioid analgesics and alcohol
What are reversible MAOIs?
→RIMA
→Accumulation of NA displaces the RIMA allowing degradation of excess NA
→RIMAs safer and selective RIMAs (e.g moclobemide) better tolerated
What does chronic treatment of TCAs cause?
→downregulation of (β1) & 5-HT2
⍺2, 5-HT1A/1D (autoR)
→Also affect mACh, HR, 5HTR
What does chronic action of SSRIs cause?
→ increases [5-HT] down regulation of 5-HT1A/1D
autoreceptors, disinhibition of 5-HT
neuron, inc. 5-HT release
→increased 5-HT release down regulates
post synaptic 5-HT receptors
‘normalising’
Why are SSRIs safer and better tolerated?
Lack of anticholinergic effect and no cardiotoxicity – better compliance and recommended for long term use
Broader therapeutic profile
What are side effects of SSRIs?
Insomnia & sexual dysfunction (5-HT2)
→Nausea; GI distress; headache (5-HT3)
→Increased risk of suicidal behaviour under 18
→Not used in combination with
TCA, MAO-I
(inhibits TCA metabolism)
(serotonin syndrome/tremor, seizures, hyperthermia, CV collapse)
What are examples of future development of AD?
→Drugs affecting monoamine transmission
→Drugs affecting Ion channels
- nACh agonist, antagonist, partial agonist
- NMDA blockers (ketamine), could cause psychosis
→ Cortisol receptor antagonist, M1/M2 agonist, NK1/NK2 antagonists
What is lithium’s mode of action?
→inhibits enzymes involved in signal transduction (IP3, phosphorylation, GSK3, hormone induced cAMP inhibition)