Antidepressant Drugs Flashcards
What is the difference between unipolar and bipolar depression?
Unipolar: most common, mood swings in 1 direction
75% cases REACTIVE (environmental factors)
25% cases ENDOGENOUS (genetic), strong hereditary tendency
Bipolar: moves between depression and mania
Type I: More mania episodes w or w/o depression
Type II: Hypomania + major depressive episodes
Describe the monoamine theory for depression
Depression is caused by less NA/ 5-HT system activity - e.g Reserpine depletes brain of NA + 5-HT which induces depression
Main antidepressants increase amine conc in brain
Give 5 evidences against the monoamine theory
lowered NA/Serotonin levels are hard to find in the plasma.
Although ADs increase amines, its therapeutic effects take several weeks!
Some ADs work despite having no effect on amine uptake (e.g trazodone)
Cocaine blocks amine uptake but has no AD. effect!
Decrease in 5HT in bipolar is linked to aggression, rather than depression
Outline the neuroendocrine theory for depression
NA & 5-HT neurons input to hypothalamus - Hyp. releases CRH–> ACTH release - increases cortisol release from adrenal cortex
Depression caused by hypersensitivity of this HPA axis
CRH becomes hyperactive, even without stressful stimuli!, increasing cortisol levels over time
4 reasons why neuroendocrine theory is strong?
Evidence of hyperactive HPA in depression
Increased [cortisol] in plasma of depressed patients
Increased [CRH] in the CSF
Genes + environment can contribute to this hyperactivity
Explain the neuroendocrine negative feedback loop for the HPA axis
HPA regulated by amygdala + hippocampus.
Amygdala activation induces HPA–> increases cortisol. - this acts on gcc receptors in hippocampus -> suppresses HPA axis.
however, there is Decreased hippocampal feedback in depression - leadingto inc. cortisol!
How is child neglection and tactile stimulation linked to the neuroendocrine depression theory?
child neglec: hippocampus had fewer gcc receptors; - thus cortisol can’t activate the hippocampus to suppress HPA axis.
More HPA activation= more cortisol release -> depression
whereas…
Tactile stimulation (cuddling) post birth increases 5HT in hippocampus, which increases gcc receptors. Cortisol can activate hippocampus suppress HPA axis -> overall reduces cortisol
describe 3 other theories of depression
Neuronal loss/ less activity in Hippocampus + PFC (decision making centres) –> ADs + ECT promote neurogenesis in hippocampus + PFC
there is Hippocampus atrophy in depressed patients.—> 5-HT & BDNF promotes neurogenesis in development
Increased glutamate in depressed –> therefore NMDA antagonists may treat depression eg ket
What are the psychological treatments for depression?
CBT: based on helping the depressed to recognise + change negative cognitive processes and thus improve mood/behaviour
Interpersonal Therapy: depression is multi-factorial - but interpersonal difficulties play a central role in maintaining depressive symptoms
What are MAOIs?
MAOIs rapidly increase [5-HT] > [NA] > [DA] - Increasing NA increases euphoria+motor activity
MAOIs downregulate a2, 5HT1A, b1, b2, 5HT2A, 5HT3
name 2 early MOAIs + problem of early MAOIs?
Early drugs e.g. phenelzine & isocarboxazid, are irreversible & nonselective
This can cause adverse interaction w dietary tyramine (cheese/wine etc), which displaces NA from vesicles -> major surge of NA–> symp. symptoms –> headache, hypertension etc. !
4 other side effects of MAOIs?
Accumulated DA displaces NA from vesicles, so less NA released w symp activity–> postural hypotension + dizziness
Central overstimulation–> serotonin syndrome symptoms
5HT autoreceptor downregulation increases appetite –> weight gain
Antimuscarinic effects (dry mouth, constipation, blurred vision, micturition issues)
So MOAIs only for severe depression if others don’t work!
What type of MAOIs solve the drug and food adverse effect problem? name this MOAI
Non specifc, old MAOIs reduce metabolism of opioid analgesics + alcohol–> cause adverse interactions due to NA surge. This is solved by REVERSIBLE MAOIs:
Reversible MAOIs (RIMA) e.g. moclobemide:
NA accumulation displaces the RIMA -> allowing degradation of excess NA
therefore RIMAs = safer + selective -> no major side effects:)
2 example of TCAs? + 4 effects? what do they initially do
Desipramine + Imipramine are NA & 5-HT reuptake inhibitors - but they initially increases [NA] & [5-HT] in synaptic cleft –> however there is No “cheese reaction” as excess NA is broken down by MAO
Downregulate autoreceptors: (β1), 5-HT2 ⍺2, 5-HT1A/1D
H1 antagonist
Also affect mACh, HR
3 groups of side effects of TCAs?
Anti-cholinergic & anti-muscarinic (M1) activity=
constipation, blurred vision, dry mouth, drowsiness (reversible)
Antihistamine, H1 antagonist= weight gain, sedation
⍺-adrenergic antagonist=decreases bp, postural hypotension; tachycardia; dizziness
3 things TCA metabolism inhibited by + How are TCAs associated w adverse drug interactions?
TCA metabolism inhibited by: antipsychotics, steroids, SSRIs.
TCAs potentiate alcohol & anaesthetic effects which can cause respiratory depression
Give 4 final disadvantages + limitations of TCAs, including patients who should not be using them
TCAs toxic in OD: heart attack, convulsions, delirium, coma, respiratory depression - therefore not used for suicide risk
TCAs not used in elderly or dementia – as cause confusion
TCAs not used in those w CVD ( as block K+ channels –> dysrhythmias)
Narrow therapeutic window - too little has no effect, too much can kill you
What are SSRIs? + 5 examples
what does chronic use of SSRIs cause?
3 other conditions they r used for?
5-HT reuptake inhibitor
fluoxetine; sertraline; paroxetine; citalopram; escitalopram
Chronic use of SSRIs will cause downregulation of both presynaptic and postsynaptic 5HT receptors (see below)
Also used for anxiety, GAD, OCD
SSRIs safer & better tolerated. 3 reasons Why?
Selective –> therefore Lack of anticholinergic effect – better compliance and recommended for long term use
Doesn’t induce NA increase (which causes the cardiotoxicity side effects)
Broader therapeutic profile
What are the 4 side effects + 1 limitations of SSRIs?
Side effects:
Insomnia & sexual dysfunction (5-HT2a)
Nausea; GI distress; headache, maybe also increased violence (5-HT3)
Increased risk of suicidal behaviour under 18
Shorter t½ –> risk of withdrawal effects
SSRIs generally not as effective as TCAs in severe depression (esp for suicide)
Explain why SSRIs are not used in combo w TCAs and MOAIs
Not used in combo w TCA, MAO-I as this inhibits TCA metabolism, causing serotonin syndrome= tremor, seizures, hyperthermia, CV collapse
Why do antidepressants take so long to have an effect?
We don’t know why for sure, however explain one of the main theories
Following SSRIs, serotonin is freely released at higher dose - however this isnt big enough to induce an instant AD effect
Changes in serotonin receptors don’t happen immediately - Takes ~2-3 weeks to induce downregulation of autoreceptors + hence have any positive effects!
Give the other ADs
compare Venlafaxine vs Trazodone VS Mianserin vs Mirtazipine
Venlafaxine: 5-HT & NA reuptake inhibitor (SNRIs). Side effects associated w adrenoreceptor activation.
Trazodone: 5-HT2, ⍺2, H1 antagonist & 5-HT reuptake inhibitor. Strong (sedative)
Mianserin: a2, 5HT2A, a1 antagonist. Can cause bone marrow depression
Mirtazapine: ⍺2 antagonist, increasing NA and 5-HT release
Potent 5-HT2, 5-HT3 & H1 antagonist
Lacks side effects linked to 5-HT2/3 receptors, sedative (H1)
Which other ADs are used to treat PPD and nicotine dependence?
Buproprion: inhibits NA, DA uptake but not 5HT uptake. Also treats nicotine dependence
Oestrogen: for treatment of postpartum depression
Acts on monoamine system, GABAergic, glutamatergic
What 3 things are in store for future AD development?
-Drugs affecting monoamine transmission
-Drugs affecting Ion channels - aka NMDA blockers (ketamine!!! but can cause psychosis + schizophrenia)
-Cortisol receptor, M1/2 + NK1/2 antagonists
Aside from OD and delayed therapeutic effect, what are 3 other general problems w AD?
Non responsive in certain people (30-40%).
Pharmacogenetics (P450, SERT polymorphisms associated w SSRI effectiveness)
Some respond to one AD type better than others, but ADs are more efficient than placebo
Explain how lithium can be used to treat BPD
acts as Mood stabilizer - used Prophylactically for depression, acute mania
Li+ like Na+ gets into neurons but stays there=> depolarisation
Inhibits enzymes involved in signal transduction
Narrow therapeutic window
Takes 3-4 weeks to get benefit
What are side effects of Li to treat BPD?
DCSCWgVImRPHyp
Side effect: drowsiness, confusion, seizures, coma, weight gain, vomiting, Na+ imbalance, retention due to increased aldosterone, polyurea, hypothyriodism
2 Other treatments of bipolar disorder?
Ion channel blockers: Valproate, carbamazepine, topiramate can suppress excitability + reduce mania. - however Valproate can cause liver damage so liver enzymes must be monitored!
Antipsychotics (mostly for mania): D2 antagonist, 5HT2A antagonists,
compare side effects of: MOAIs vs TCAs vs SSRIs
MOAIs:
Accumulated DA displaces NA from vesicles, so less NA released w symp activity–> postural hypotension + dizziness
Central overstimulation–> serotonin syndrome symptoms
5HT autoreceptor downregulation increases appetite –> weight gain
Antimuscarinic effects (dry mouth, constipation, blurred vision, micturition issues)
So MOAIs only for severe depression if others don’t work!
TCAs:
Anti-cholinergic & anti-muscarinic (M1) activity= constipation, blurred vision, dry mouth, drowsiness (reversible)
Antihistamine, H1 antagonist= weight gain, sedation
⍺-adrenergic antagonist=decreases bp, postural hypotension; tachycardia; dizziness
TCAs potentiate alcohol & anaesthetic effects which can cause respiratory depression
TCAs toxic in OD: heart attack, convulsions, delirium, coma, respiratory depression - therefore not used for suicide risk
TCAs not used in elderly or dementia – as cause confusion
TCAs not used in those w CVD ( as block K+ channels –> dysrhythmias)
Narrow therapeutic window - too little has no effect, too much can kill you
SSRIs:
Insomnia & sexual dysfunction (5-HT2a)
Nausea; GI distress; headache, maybe also increased violence (5-HT3)
Increased risk of suicidal behaviour under 18
Shorter t½ –> risk of withdrawal effects
SSRIs generally not as effective as TCAs in severe depression (esp for suicide)
