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.
What is Venlafaxine, and what is it approved for?
What is Milnacipran approved for? What about its L-enantiomer?
Venlafaxine is an SNRI approved for MDD & Anxiety.
Milnacipran is approved for fibromyalgia, while levomilnacipran is approved for major depressive disorder (presumably, milnacipran is also approved for MDD).
Buproprion
What’s its mechanism?
What 3 conditions is it used to treat?
Side effect profile?
Weakly blocks NE and DA uptake.
Treats MDD, Seasonal Affective Disorder, & Nicotine Withdrawal
NO weight gain or sexual dysfunction!
Mirtazapine
Mechanism of action?
What is its most notable side effect?
What is it used to treat?
Blocks presynaptic alpha2 receptors in brain
Increases appetite
Besides MDD & mood disorders, used to stimulate appetite in AIDS patients
Trazodone
Mechanism of action?
Uses?
Notable side effects?
Weak SSRI-like effect.
Aside from MDD, also treats insomnia.
**Sedation, priapism, **and (rare) adverse CV effects
Vortioxetine
Mechanism of action?
Uses?
SSRI-like action, 5-HT1A agonist, and 5-HT3 antagonist
Newest drug approved for treating MDD.
What is the mechanism of action of tricyclic antidepressants?
When are trycyclics prescribed among antidepressants?
Block NE and 5-HT reuptake
Used secondarily to SSRIs
How long do tricyclic antidepressants need to be taken before an elevation of mood is noted?
~2-3 weeks
What are the common side effects of tricyclic antidepressants?
- Decreases REM, increases stage 4 sleep
- Prominent Anticholinergic effects
- Dry mouth
- Blurred vision
- Urinary retention
- Sedation
- Orthostatic hypotension
Rarely, what CV side effects can tricylclics cause?
What might be seen on EKG in this scenario?
- Effects:
- Palpitations
- Tachycardia
- Arrhythmias
- Due to anticholinergic effects + inceased NE
- EKG
- Lengthened QRS intervals
- Flattened or inverted T-waves
What are the symptoms of tricyclic antidepressant (TCA) overdose?
How is TCA overdose treated?
- Sxs:
- Hyperpyrexia (high fever)
- Blood pressure changes
- Seizures
- Coma
- Cardiac Conduction defects
- Treatment:
- Symptomatic treatment
- Observe for at least 3 days
- Long t1/2 of drugs
Name two drugs that TCAs have interactions with.
- Guanethidine - TCAs block guanethidine uptake
- Sympathomimetic drugs
Name a TCA that can also be used to treat:
- Enuresis in childhood
- Chronic pain
- OCD
- imipramine
- amitriptyline
- clomipramine (also SSRIs)
Name three MAOIs used to treat depression.
- Phenelzine (this looks like the one to know)
- Tranylcypromine
- Selegiline
How long does it take for a course of MAOIs to produce elevation of mood?
What may be seen in a non-depressed person who takes MAOIs?
~2wks
May produce stimulation, possibly even hypomania (esp. in bipolar patients)
Other than treating the depression itself, what else do MAOIs help with in depressed patients?
Helps correct sleep disorders in depressed pts
What adverse effects signify acute MAOI toxicity?
- Agitation
- Hallucinations
- Hyperpyrexia
- Convulsions
- Changes in BP
What substance must be avoided in the diet when taking an MAOI? Why?
Name 7 or so foods that contain substantial amounts of this substance.
Tyramine
Can have excessive sympathomimetic effects when MAO (which normally metabolizes tyramine) is inhibited
- Avocados
- Bean curd
- Soybean & soy products
- Figs & bananas
- Smoked, fermented, aged, or spoiled meats & fish
- Practically all cheeses
- Yeast extract (baked goods with yeast are fine)
- Protein supplements
What condition other than depression can MAOIs be used for?
Narcolepsy
If antidepressant drugs alone are not effective, what other drugs can be used to augment the effect?
- Augment with antipsychotic agents
-
Quetiapine, Aripiprazole, Olanzapine
- [“Quick Add-Ons”]
-
Quetiapine, Aripiprazole, Olanzapine
- also Ketamine - experimental
If antidepressant drugs alone are not effective, what three physiological treatments can be used?
- ECT (electroconvulsive therapy)
- TMS (transcranial magnetic stimulation)
- Deep brain stimulation (experimental)
What is the mechanism of action of the herb St John’s Wort, taken by some patients for depression?
What is the active compound in the herb?
MAOI activity
Contains hypericin (and others, but hypericin is best studied)
What are some risks of taking St. John’s Wort?
What drugs can it interact with?
-
Several Drug Interactions
- CYP3A4 inducer! Lowers effectiveness of:
- Birth control pills
- Protease inhibitors used in AIDS
- Cyclosporine
- CYP3A4 inducer! Lowers effectiveness of:
- Small risk of psychosis
