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
MAOIs are ____ line of treatment if ____
- last
- patient does not respond to SSRI and SNRI
Imipramine
first TCA from 1950s
- prototype
- anti-cholinergic used to treat bedwetting
- strong 5HT and NE reuptake inhib
besides depression, TCAs are also used to treat
chronic pain conditions
phobic and panic
OCD
TCAs summary
- second line treatment after SSRIs
- block 5-HT and NE reuptake
- immediate side effects, therapeutic effects in 2-3 weeks
- narrow therapeutic range, risk of suicide by overdose
- high protein binding and hepatic metabolism
TCAs: mechanism of action
- block reuptake of 5HT and NE by inhibiting SERT and NET
- densensitive presynaptic autoreceptors (promotes further release of 5HT and NE)
- reduce central beta adrenergic receptor responsiveness and density
- antagonizes cholinergic, histaminergic, and alpha-adrenergic receptors
Desipramine
More effective at treating neuropathic pain
- weaker anticholinaergic action
- stronger NE and 5HT properties
Amitriptyline
- highly anti-cholinergic
- high alpha-adrenergic blocking properties
- SEDATIVE
TCAs: side effects
ANTAGONISTIC ACTION: anti- histamine and anti-cholinergic
through antagonist action: dry mouth, constipation, blurred vision, urinary retention, confusion (from blocking cholinergic receptors)
- CNS toxicity, sexual dysfunction, cardiac toxicity (can cause lethal cardiac arrhythmias), overdose
TCA overdose three Cs
convulsions, coma, cardiac arrhythmias
Currently available SSRIs
fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine
SSRIs: used to treat
used in MDD, GAD, PTSD, OCD, Panic disorders, bulimia
SSRIs: mech of action
Selectively inhibit SERT and block reuptake of serotonin into presynaptic terminal
also downregulates autoreceptors
SSRIs: side effects
- safest AD
- in short-term can cause nausea, GI upset, diarrhea
- long-term can cause sexual dysfunction in 30-40% patients
Why is there a delayed onset of therapeutic action with SSRIs
Receptor desensitization, upregulation/downregulation, increase trophic factors, increased neuro- and synapto- genesis
Venlafaxine
- weak inhibitor of NET, greater affinity for SERT
- used for severe depression
Duloxetine
- balanced effect on 5HT and NE
- increasingly used for chronic pain over TCAs
SNRIs
block NET as well as SERT
- Trazodone
- Buproprion
- Mirtazapine
Atypical antidepressants
1. Blocks H1 receptor
2. blocks NE and DA reuptake (also used in smoking cessation)
3. blocks pre-synaptic alpha2 adrenergic receptors and increase synaptic 5HT and NE
Why should you NOT combine MAOIs, TCAs, SSRIs
side effects can be fatal:
- must have a waiting period between changing meds to allow body to return to naive state
Are SSRIs better at treating anxiety or depression? SNRIs?
SSRIs better for anxiety
SNRIs better for MDD
Pharmacological properties of antidepressants
- most had rapid oral absoprtion, peak plasma levels in 2-3 hours, and are tightly bound to plasma proteins, undergo hepatic metabolism and renal clearance
- most all inhibit CYP enzymes (2D6, 3A4, 1A2, 2C19)
- Never combine TCAs and SSRIs (long half lives)
