Antidepressants I Flashcards
Affective Disorders (DSM-V) include:
- general anxiety disorders (GAD)
- post-traumatic stress disorders (PTSD)
- panic disorders, phobias
Types of Depression (DSM-V)
- major depressive disorder (MDD) or unipolar depression
- clinical depression (no manic episodes); recurring major depressive episodes
- treated by antidepressants - bipolar disorder (“manic depression”
- periods of depression alternating with periods of mania
- treated by mood-stabilizers - dysthymia (“persistent depressive disorder”)
- SAD
- postpartum depression
- adjustment disorder with depression/stress response syndrome
MDD facts (etiology, prevalence, comorbidity)
etiology: exact mechanisms unknown, 30-40% heritability, complex polygenic mechanism (genetics x env)
prevalence: 17% of US adults will be affected at least once, females affected twice as frequently as males, leading cause of disability, large economic cost, suicide is second leading cause of death in 15-29 year olds
comorbidity: chronic pain, stroke, CV disease, cancer
Broad range of symptoms DSM-V: Major Depression
- depressed mood (sad, empty, helpless, worried)
- anhedonia
- irritability
- low self-esteem
- feelings of hopelessness, worthlessness, and guilt
- decreased ability to concentrate and think
- decreased or increased appetite
- weight loss or weight gain
- insomnia or hypersomnia
- low energy, fatigue, or increased agitation
- decreased interest in pleasurable stimuli (food, sex, social int, etc)
- recurrent thoughts of death and suicide
must have at least 5 of these symptoms for longer than a 2 week period
currently available treatments for depression
- psychotherapy
- chemical antidepressants
- electroConvulsive therapy (ECT)
chemical antidepressants (overview)
all have similar efficacies and only work in 50-70% of patients with MDD
- therapeutic response is delayed (min 2-4 weeks before benefit)
- adverse side effects can limit usage
Monoamine Hypothesis of Depression
Abnormalities in serotonin (5HT), NE, and DA neurotransmission (deficiency)
(likely not mutually exclusive with neurotrophic hypoth)
Reserpine
BP med used in 1950s evoked depression by blocking VMAT
VMAT
vesicular monoamine transporter
- packages all monoamines
monoamines
DA, NE, 5-HT, melatonin, histamine
- all derived from amino acids in similar synthetic processes
- regulate: mood, sleep, appetite, peristalsis, arousal, sexual function, cognition, reward, motivation, aggression (sometimes with opposing effects)
monoamines act on what kinds of receptors
metabotropic GPCRS
location of production: DA, 5HT, NE
soma of producing neurons in:
- DA: VTA and substantia nigra
- 5HT: raphe nucleus
- NE: locus coerulus
Neurotrophic Hypothesis
Changes in nerve growth factors (BDNF) signalling play a role in cell survival and synaptic plasticity.
- loss of neurotrophic growth factors leads to neuronal atrophy and death
(BDNF activates TRK-B receptors leading to increased survival and growth) - possibly due to decrease in monoamine levels (NE and 5HT) and increased glucocorticoid levels (chronic stress)
- antidepressants increase BDNF in brain
(likely not mutually exclusive with monoamine hypoth)
Major antidepressant drugs
- monoamine oxidase inhibitors (MAOIs)
- Tricyclic (TCAs)
- selective serotonin re-uptake inhibitors (SSRIs)
- serotonin-norepinephrine re-uptake inhibitors (SNRIs)
- atypical antidepressants
Different mechanism of actions of antidepressants
- block enzymatic degradation by monoamine oxidase (MOA) - MAOIs
- block re-uptake into the presynaptic terminal by inhibition of transporters (SERT and NERT) - TCAs, SSRIs, SNRIs
- inhibition of presynaptic autoreceptors
- binding specific postsynaptic receptors (5HT2)
Other clinical uses for antidepressant drugs
- PTSD (SSRIs)
- Anxiety (SSRIs and SNRIs)
- Panic disorder (TCAs, MAOIs, SSRIs)
- OCD (SSRIs)
- enuresis (TCA)
- chronic pain (TCAs and SSRIs)
- eating disorder - bulimia (SSRIs)
- smoking cessation (Bupropion)
- Sedative (Trazodone)
Antidepressant side effects by the receptor they bind
(5HT, NE, DA, H1, Musc Ach, Alpha Adren)
Blockade of:
5HT - GI disturbances, anxiety (dose dependent), sexual dysfunction
NE - tremors, tachycardia
DA - psychomotor activation, anti parkinsonian effects, psychosis, increased attention and concentration
H1 - sedation, drowsiness, weight gain, hypotension
Muscarinic Ach - blurred vision, dry mouth, sinus tachycardia, constipation, urinary retention, memory dysfunction
alpha adrenergic - postural hypotension, reflex tachycardia, dizziness
Mechanism of action of MAOIs
increase synaptic availability of NE and 5HT by blocking their catabolism
- inhibit MAO enzymes (MAO-A and/or MAO-B)
Difference between MAO-A and -B
Monoamine oxidase A mainly breaks down tyramine, NE, 5HT and DA
MAO B mainly targets DA
Problems and most common side effects with MAOIs
- toxicity problems and potentially lethal food and drug interactions
- MAIN: Orthostatic hypotension and weight gain
- OTHER: headache, drowsiness, dry mouth, hypertension, sexual dysfunction (highest in irreversible MAOIs), increased tyramine can cause hypertension, increased circulation of bioamines (can’t combine with SSRI or SNRI) and NARROW therapeutic range
phenelzine and tranylcypromine
Antidepressants - MAO A and B inhibitor
- have worse side effect profile than other MAOIs
moclobemide
Antidepressant - MAO A inhibitor
MAOIs and Tyramine
If taking MAOIs avoid foods high in tyramine - could be lethal
Increase in tyramine and decrease in MAO (breaks down monoamines) you get increased NE:
- hypertensive crisis
- headaches, intracranial bleeding, stroke
Which foods have tyramine
- most cheese
- smoked/cured/dried/preserved meats and fish
- fava beans, overripe avocados, fruits
- chianti wines and beers with yeast
- chocolate and coffee
