Antidepressants - Bloom Flashcards
What does the monoamine theory of depression state?
What evidence supports (or fails to support) it?
What is the current status of this theory?
Depression results from deficient monoamine transmission in the CNS.
Drugs that facilitate monoaminergic transmission improve depression, while those that block it cause depression. Not all evidence supports, however (eg Cocaine does not treat depression, onset of effects is delayed, etc)
Depression is probably due to an imbalance of monoamine receptor & transmission. Potentiating this remains the best means to treat depression.
Norepinephrine Synthesis
Where is the main site of CNS synthesis?
Describe the biochemical pathway by which norepinephrine is synthesized.
Norepinephrine Synthesis
The Locus Ceruleus.
Tyrosine is converted to DOPA by tyrosine hydroxylase (rate-limiting), which is then decarboxylated by dopa-decarboxylase to dopamine. Once packaged by VMAT, dopamine is beta-hydroxylated into norepinephrine.
Norepinephrine Signaling
What stimulates release of norepinephrine?
Name 5 different possible fates of NE once secreted.
Norepinephrine Signaling
Nerve impulses which promote calcium influx (fusion of vesicles)
- Bind to post-junctional receptor, then…
- Uptake at the postsynaptic neuron or glia
- Presynaptic reuptake
- Diffusion away
- Binding to prejunctional receptor…
(6. Metabolism in cleft?)
Describe how blocking reuptake of a monoamine improves its transmission.
Describe the mechanism of tolerance to this.
When reuptake is blocked, the synaptic concentration of the neurotransmitter increases.
Eventually, the post-synaptic receptor will be downregulated due to the high level of activation.
Serotonin Synthesis
Where is the site of CNS synthesis of 5-HT?
Describe the biochemical pathway by which 5-HT is synthesized.
Serotonin Synthesis
The (two?) Raphe nuclei.
Tryptophan is 5-hydroxylated (by Tryptophan hydroxylase), then decarboxylated (by LAAD, like with dopamine). 5-HT is then packaged into vesicles by VMAT.
Serotonin Signaling
What is the primary means of termination of the serotonin signal?
What is the analogous protein seen in NE signaling?
Serotonin Signaling
Reuptake by SERT (followed by presynaptic metabolism by MAO).
Norepinephrine is reuptaken by NET.
Compare and contrast the roles of presynaptic receptors in NE and serotoninergic signaling.
In NE signaling, the alpha-2 autoreceptor functions in feedback inhibition.
In 5-HT signaling, feedback inhibition is handled by presynaptic 5-HT1A receptors. Note that there may also be alpha-2 heteroreceptors on serotoninergic presynaptic neurons.
How do SSRIs compare to TCAs?
What is their precise mechanism of action?
Most common side effects?
Same efficacy but less toxicity; SSRIs have thus replaced TCAs as first-line agents for depression.
They block SERT (it is unclear which are competitive and which are non-competitive inhibitors)
Nausea, insomnia, and sexual dysfunction.
Describe what occurs in the major SSRI side effect “serotonin storm”. How can this be avoided?
Why may SSRIs increase suicides?
Hyperthermia, muscle rigidity, and cardiovascular collapse occur secondary to excessive levels of serotonin. For this hreason, do not co-administer with MAOIs (or anything that can affect serotonin levels, eg Triptans)
SSRIs (and truly all antidepressants) can improve motivation before improving affect, giving severely depressed patients the werewithal to commit suicide.
There are about 15 symptoms of SSRI withdrawal, name some.
How quickly can this occur?
Dizziness, Light-headedness, vertigo/faintness, shock-lke sensations & paresthesia, anxiety, diarrhea, fatigue, gait instability, headache, insomnia, irritability, nausea/vomiting, tremor, visual disturbances
Symptoms begin within 1-7 days of stopping an SSRI.
(bolded are symptoms mentioned verbally during lecture)
Besides major depressive disorder, what conditions are SSRIs approved for?
OCD
Panic disorder
Social & Generalized anxiety disorders
PTSD
PMS/PDD
Vasomotor symptoms associated with menopause
Fluoxetine
How long-lived is its active metabolite?
What effect does it have on drug metabolism?
What is it mentioned for besides MDD?
Fluoxetine
(Norfluoxetine) - 7days or more.
It is a 2D6 inhibitor.
For PMS (as a sustained release product)
Sertraline
How long-lived is it?
What effects does it have on drug metabolism?
What is it mentioned for besides MDD?
Sertraline
Shorter than fluoxetine.
Fewer effects on drug metabolism than fluoxetine.
OCD, PTSD, and panic attacks.
What SSRI(s) is approved for OCD?
What SSRI is approved for hot flashes associated with menopause?
What is the relationship between citalopram and escitalopram?
Fluvoxamine (and sertraline)
Paroxetine
Escitalopram is an S-enantiomer, Citalopram is racemic.
Describe SNRIs in terms of their mechanism of action and side effect profile.
Duloxetine is the stereotypical SNRI. What is it approved for besides MDD?
SNRIs block both 5-HT and NE reuptake (like TCAs). Their side effect profile is more SSRI-like than TCA-like.
Duloxetine is approved for anxiety & various pain syndromes (neuropathic, back, osteoarthritic, fibromyalgia). Use with caution in patients with liver disease.
