Pharmacology of Mood and Anxiety Disorders
Describe the characteristics of a depressive episode
- Sadness, indifference, apathy, irritability
- Δ in sleep, appetite, and weight
- Feeling shame/guilt
- Thoughts of death/dying
Describe the Amine hypothesis
- ↓ in aminie-dependent neurotransmission
- May result in upregulation of amine receptors
What drug is the amine hypothesis based on?
Inhibits VMAT (inducing depression)
T/F: An increase in amine function would relieve depression
Describe the neurotrophic hypothesis
- Low Brain Derived Neurotrophic Factor (BDNF) due to loss in dendritic spines and branches
- Antidepressants ↑ BDNF over time
What is the responsibility of BDNF?
Promote growth of neurons
In anxiety disorders, dysfxnl 5HT and NE NTMsn has been implicated, particularly in which systems?
- Basal Ganglia
Characterized by motor tension, autonomoic hyperactivity, vigilance
Generalized Anxiety Disorder (GAD)
Which NT is thought to be overactive in GAD?
Non-sedative non-bzd agent that can treat GAD w/ no anticonvulsant/ muscle relaxation effects
5HT1A partial agonist
T/F: Buspirone anxiolytic effects are typically seen immediately.
What is an advantage of buspirone?
No rebound anxiety / withdrawal signs w/ abrubt cessation
Recurring episodes involving sympathetic crisis (racing heart, dizziness, chest pain, flushes, chills)
T/F: Yohimbine precipitates panic attacks in pts and control subjects, potentially due to an abnormality in biogenic amines
Involves increased noradrenergic activity in the hippocampus and amygdala triggered by stimulus/stressor
T/F: Vietnam vets were shown to have high levels of circulating DA and exposure to combative stimuli causes increase in BP and HR.
Recurrent obsessions (i.e. germs) and compulsive behaviors (i.e. hand washing)
Disturbance of ___________ is thought to be involved in OCD
Before treatment, NT are released at pathologically low levels and exert ss levels of autoinhibitory feedback. What is the net effect of this?
Abnormally low baseline level of postsynaptic receptor activity (signaling)
T/F: Chronic use of antidepressants results in desensitization of the postsynaptic autoreceptors, causing inhibition of NT synthesis and reducing exocytosis = enhanced NTm
Fluoxetine brand name
Paroxetine brand name
Sertraline brand name
Citalopram brand name
Escitalopram brand name
Fluvoxamine brand name
Proposed adaptive presynaptic changes from chronic use of SSRIs
- 5HT1 desensitization and down-reg. = ↑ in presyn activity of 5HT
- SERT down-reg = ↓ clearance of 5HT
Proposed adaptive postsynaptic changes from chronic use of SSRIs
- 5HT2a desensitization and down-reg = Antidepressant effects
- ↑ cAMP --> ↑ CREB and ↑ BDNF (neurogenesis)
Which SSRIs produce active metabolites?
Fluoxetine and sertraline
T/F: Fluoxetine and it's metabolite, norfluoxetine, have long t1/2 (50 and 240 hrs)
Fluoxetine and paroxetine have been shown to inhibit which enzyme?
Fluvoxamine has been shown to inhibit which enzyme?
- GI upset, N
- Sex dysfxn
- Potential teratogen (paroxetine)
SSRI discontinuation syndrome characteristics
- GI disturbances
When does SSRI discontinuation syndrome occur?
After abrupt discontinuation of SSRI
Why is fluoxetine generally not associated w/ SSRI discontinuation syndrome ?
Long t1/2 and active metabolite w/ long t1/2
T/F: SSRIs have little or no affinity for various NT receptors such as M, α, and H1.
Serotonin syndrome can be caused by a combo of SSRIs and ______
Specific agents that can cause serotonin syndrome when combined w/ SSRIs:
- St. John's wort
Signs of Serotonin syndrome:
- Hyperactive bowel sounds
T/F: Serotonin syndrome is a pharmacokinetic drug-drug interaction because it refers to the MOA of the drug.
List examples of SNRIs
Venlafaxine brand name
Desvelnafaxine brand name
- Block SERT
- Block NET (weak)
Duloxetine brand name
- Block SERT
- Block NET
CYP1A2 and 2D6
T/F: SNRIs have strong affinity for M, α, and H1 receptors as well as SERT and NET
Levomilnacipran brand name
Levomilnacipran is the more active enantiomer of milacipran, an SNRI for what condition?
- Block SERT
- Block NET (slightly greater potency)
CYPs(3A4), then glucuronidation
List atypical SNRIs
Bupropion brand name
Blocks NET and DAT (weakly)
T/F: Bupropion has active metabolites and is also used for smoking cessation
Bupropion inhibits which enzyme?
Trazadone and nefazodone MOA
- Inhibit 5HT2
- Weak SERT inhibition
- H1 blockade (cause sleepiness)
- α1 blockade (cause ortho hypotn)
Mirtazapine brand name
- 5HT2 antagonist
- α2 antagonist
- H1 antagonist
Vilazodone brand name
- inhibit SERT
- 5HT1A partial agonist (this is thought to overcome acute presyn autoinhibition of 5HT neurons)
CYP3A4, 2C19, 2D6
Vortioxetine brand name
T/F: Vortioxetine is an antidepressant with a mixed MOA, including being a SERT inhibitor.
List examples of TCA tertiary amines
TCA Tertiary amines inhibit NET and SERT with a higher affinity for _______
Imipramine brand name
Clomipramine brand name
Doxepin brand name
TCA secondary amines inhibit NET and SERT w/ a higher affinity for _______
List examples of TCA secondary amines
Desipramine brand name
Nortriptyline brand name
Protriptyline brand name
TCA tetracyclic examples:
- Amoxapine (NE and DA)
- Maprotiline (NE)
Other pharmacodynamic actions of TCAs
- α1 blockade
- H1 blockade
- M blockade
What effects would α1 blockade cause?
Ortho hypotn, reflex tachycardia
What effects would H1 blockade cause?
Somnolence, weight gain
What effects would M blockade cause?
Dry mouth, constipation, blurred vision
Describe TCA absorption
Mostly well absorbed, first pass metabolism can affect bioavailability
T/F: TCAs are not widely distributed because they are ptn bound.
Where do TCAs accumulate in the body?
Cardiac tissue -- could cause toxic effects
CYP1A2, 2C19, 2D6, 3A4
Imipramine is active on its own and is metabolized to the active metabolite __________
Amitriptyline is active on its own and is metabolized to the active metabolite __________
- Confusion, delerium
- Dry mouth, blurred vision, constipation, urinary hesitancy
- Ortho hypotn, conduction defects, arrhythmias
- weight gain
- sexual disturbances
TCAs can cause hypertensive crisis when combined with ______
Describe symptoms of DC/withdrawal syndrome of TCAs
- Muscle aches
- Sleep disturbances
Acetylation and hydroxylation
Examples of MAOIs
Tranylcypromine brand name
Phenelzine brand name
Selegiline brand name
T/F: MAOIs are reversible inhibitors of MAO-A and MAO-B.
Selegiline is selective for which MAO (at low doses)
Hypertensive crisis can be caused if MAOIs are combined w/ what drugs/compounds?
- SSRIs (↑ catecholamines and inhibition of reuptake)
- Tyramine (fermented foods)
- OTC cold remedies containing sympathomimetics
St. John's wort MOA
Inhibit reuptake of 5HT, DA, NE
St. John's wort induces:
Esketamine brand name
Intranasal (↑ bioavailability than oral)
Brexanolone brand name
GABAa +allosteric mod.
Continuous IV over 60 hrs
- Formarly manic-depressive disorder
- Cycles of mania and depressed mood
Defined as gradiosity, paranoid thoughts, overactivity
- Hypomania (less severe than mania)
- No hospitalization/fxnl impairment
- No psychotic symptoms
Inhibits formation of inositol = depletes cell of PIP2
T/F: Before therapy, levels of PIP2 may be increased in a person experiencing mania.
Other effects of lithium:
- ↓ fxn of glycogen synthase kinase-3 (GSK-3)
- Can replace Na but does not maintain membrane potentials
What process is GSK-3 involved in
↓ GSK-3 fxn is seen with lithium and what other drug?
Time to lithium peak plasma levels
30 min-2 hrs
No metabolism; renal excretion
- CNS (tremor)
- Renal (polyuria and polydipsia due to ADH inhibition)
- Thyroid (benign goiter)
- CV effects
- Pregnancy affects (Ebstein's malformation)
Other drugs used for bipolar disorder
- Valproic acid