Antidepressants

Question 1

How long do you wait for a response to an antidepressant before considering a switch to another agent, or an augmenting agent?

Answer 1

Typical response time to SSRIs is 3-6 weeks, if no response after 8 weeks, switch. If partial response, consider dose adjustment, adding augmenting agent, or switching.

Question 2

What are the major classes of antidepressants?

Answer 2

Tricyclic Antidepressants (TCAs)
Monoamine Oxidase Inhibitors (MAOIs)
Selective Serotonin Reuptake Inhibitors (SSRIs)
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)
Novel antidepressants (other)

Question 3

What are the major worrisome aspects of TCAs?

Answer 3

• Lethal at fairly low doses (a week’s supply can be lethal)
• can have QT prolongation even at blood levels within what’s considered therapeutic range
• Lots of side effects: antihistiminic, anticholinergic, antiadrenergic. Potentially lots of discomfort for patients.

Question 4

What’s a tertiary TCA and what are some examples?

Answer 4

• They have tertiary amine side chains. So what? Those side chains interact with a variety of receptors that cause the effects we’d rather not see patients experience (euphemistically known as side effects)
• Examples: imipramine, amitriptyline, doxepin, clomipramine
• These also have active metabolites: desipramine, nortriptyline

Question 5

Describe the undesired effects (side effects) by receptor type (i.e. antihistaminic SEs, anticholinergic, and antiadrenergic)

Answer 5

antihistamine: sedation and weight gain
anticholinergic: dry mouth, dry eyes, constipation, memory problems, possibly delirium)
antiadrenergic: orthostatic hypotension, sedation, sexual dysfunction

Question 6

What is the believed mechanism of the therapeutic action of TCAs?

Answer 6

They act on serotonin receptors

Question 7

What are the secondary TCAs? How are they believed to function?

Answer 7

• These are the active metabolites of some of the tertiary TCAs. Examples: desipramine, nortriptyline
• Primarily by blocking NE reuptake. Dopaminergic tone in the frontal cortex decreases as NE is uptaken (not sure if that’s a word) so blocking NE reuptake is thought to increase dopamine activity in this brain region.

Question 8

How are MAOIs believed to work?

Answer 8

They irreversibly bind to monoamine oxidase, an enzyme that metabolizes monoamines (NE, DA, 5HT) in the synaptic space, purportedly leading to higher levels of these biogenic amines.

Question 9

What are some of the undesired effects of MAOIs?

Answer 9

• Orthostatic hypotension, weight gain, dry mouth, sedation, sexual dysfunction, sleep disturbance.
• If combined with a serotonergic medication, can lead to serotonin syndrome
• Hypertensive crisis (usually if not adhereing to an MAOI diet)

Question 10

Explain the diet-related complication associated with MAOIs?

Answer 10

• Hypertensive crisis: earliest symptom is usually headache or visual disturbance.
• Eating tyramine-rich foods (aged cheeses, many alcoholic drinks–red wine, beer, aged/fermented foods (things that have been pickled) or things like salami and pepperoni

Question 11

What OTC medications do you need to warn pts about if they’re going on an MAOI?

Answer 11

• Sympathomimetics: dextromethorphan (found in cough medicine), epehdrine, pseudoephedrine, phenylpropanolamine (these last three are usually in cold medicine and sometimes diet pills)
• taking this with an MAOI can cause HTN crisis

Question 12

What is the usual wash-out period for starting an MAOI? Which SSRI is the exception (you have to wait longer than usual?)

Answer 12

• Usual washout period is two weeks–meaning you don’t start the MAOI until someone has been off of their serotonergic medication for at least two weeks.
• The exception is fluoxetine (which has a longer half-life) and the recommendation is to wait 5 weeks.

Question 13

Name some MAOIs.

Answer 13

tranylcypromine
isocarboxazid (Marplan)
phenelzine (Nardil)
tranylcypromine (Parnate)
selegiline transdermal (Emsam)*
linezolid (Zyvox)**
* often prescribed to patients with dementia or Parkinson’s
**this is an antibiotic often used when people have allergies to vancomycin
!!!! Take home point is that there are MAOIs that are not used for mental health reasons so be on the lookout for these anytime you’re thinking about prescribing a serotonergic agent to a patient

Question 14

Describe serotonin syndrome.

Answer 14

Symptoms include abdominal pain and diarrhea (there are lots of 5HT receptors in the GI tract), diaphoresis, hyperpyrexia (elevated temp not due to fever–not due to infection), tachycardia, HTN, myoclonus, delirium, irritability/agitation

Question 15

How are SSRIs believed to work?

Answer 15

They block presynaptic uptake of serotonin, thus increasing synaptic availability of this NT, not clear why/if this is how they work. If it were a direct effect, you wouldn’t see the 4-8 week lag before symptoms improve.

Question 16

What are SSRIs used for?

Answer 16

Most commonly depressive (unipolar depression, and cautiously in bipolar depression) and anxiety disorders (including GAD, panic, OCD, PTSD)

Question 17

What’s the major safety advantage to SSRIs versus older antidepressants?

Answer 17

They are far less cardiotoxic in overdose than TCAs or MAOIs.

Question 18

What are the most common undesired effects of SSRIs?

Answer 18

• GI upset like nausea and diarrhea, less common to see vomiting (lots of 5HT receptors in the gut, can usually mitigate this with slower up-titration and taking it with food)
• Sexual side effects (up to 30%, do not forget to talk with patients about this–part of informed consent); for some this means decreased libido, anorgasmia, or both
• Restlessness, nervousness, anxiety, possibly akathisia (more pronounced subjective sense of restlessness that is associated with increased risk for violent behavior and suicide)
• Insomnia (often depends on when it’s dosed, usually don’t give SSRIs in the PM or at HS)
• Fatigue/sedation
• Dizziness, tremors, headache

Question 19

What is the black box warning associated with SSRIs?

Answer 19

• There is an association with increase in suicidal thoughts in some subset of people who take SSRIs (mostly documented in adolescents).
• You need to warn patients of this and instruct them what to do if this occurs (are they going to call you? call the crisis line? go to the ED?)

Question 20

What should you tell patients about stopping SSRIs and when should you tell them this?

Answer 20

• Tell them before they start taking it (this is part of informed consent) that it is not recommended to stop these abruptly
• There are discontinuation syndromes associated with SSRIs; these vary in terms of severity. Some people don’t experience much, others develop pretty severe flu-like symptoms (nausea, aches, disequilibrium, dysphoria, agitation). For some people this can be pretty severe and may require lengthy tapers so warn people up-front.

Question 21

Name the most common SSRIs

Answer 21

paroxetine (Paxil)
fluoxetine (Prozac)
citalopram (Celexa)
sertraline (Zoloft)
escitalopram (Lexapro); s-enantiomer of citalopram
fluvoxamine (Luvox)
vilazodone (Viibryd); newer, not used much yet

Question 22

What is the dosing for paroxetine (Paxil)?

Answer 22

paroxetine: start 10-20/day, incr by 10mg increments weekly; max of 60mg daily
ER formulation: 25mg to start, can go up to 62.5mg/day by increasing 12.5mg/week

Question 23

What are things you should consider before usuing paroxetine specifically?

Answer 23

• Has a shorter half-life with some auto-inhibition of metabolism at higher doses so it’s believed to have the worst withdrawal syndrome of the SSRIs
• significant CYP2D6 inhibition which means more likely to have drug-drug interactions (I wouldn’t prescribe this for anyone with HIV or cancer as the drugs they may get to treat those conditions are likely to be affected by paroxetine)
• more anticholinergic than most SSRIs, so pt’s are more likely to gain weight and more likely to have sexual side effects
• more sedating than others so may be a good choice for someone with insomnia and you can consider dosing it at night; however, can cause insomnia in someone who didn’t have it before

Question 24

What is the typical dosing for fluoxetine?

Answer 24

-can start 10-20mg daily (usually in the AM as it can be activating for some people); can go up to 80mg daily; usually done ~10mg/week increments

Question 25

What are the pros and cons of fluoxetine?

Answer 25

PROS: has a long half-life so it’s a good choice for people who struggle with daily medications
- can be activating for some people which can be good for someone with neurovegetative symptoms of depression
-can also be used to mitigate withdrawal from other SSRIs (someone slowly tapering off another SSRI and having w/d sx’s you can prescribe 20mg of fluoxetine for a couple of days and stop it and it will auto-taper b/c of long half-life)
-generic
CONS: long-half life can cause build up in pts who don’t metabolize it quickly (shouldn’t use in pt’s with hepatic illness)
-lots of P450 interactions so not as good a choice for patients on a lot of meds
-activating property can be a bad thing in patients who are already anxious or having insomnia
-more likely to precipitate hypomania/mania than other SSRIs

Question 26

Pros and Cons of citalopram (Celexa)

Answer 26

Pros: low inhib of P450 so fewer drug-drug interactions; intermediate half-life, generic
Cons: dose dependent QT prolongation such that black box warning in place against doses higher than 40mg/daily; mild H1 antaganism so can be sedating (usually mild); GI side effects (less so than sertraline)

Question 27

How is escitalopram related to citalopram?

Answer 27

It is the s-enantiomer of citalopram and thus thought to be “more pure” with fewer side effects; debatable whether that’s true

Question 28

Pros and cons of escitalopram (Lexapro)

Answer 28

Pros: low P450 interaction so fewer drug-drug interactions; intermediate 1/2 life; purportedly more effective than citalopram in acute response and remission
Cons: also has dose dependent QT prolongation; can cause nausea and headaches

Question 29

What are the pros and cons of fluvoxamine (Luvox)?

Answer 29

Pros: shortest half-life; may have some analgesic properties
Cons: shortest half-life; GI distress, headaches, sedation, weakness?; strong inhibitor of CYP1A2 and CYP 2C19

Question 30

What do the SNRIs do?

Answer 30

Inhibit reuptake of both serotonin and norepinephrine. Conceptually, you can think of them as similar to TCAs but without as many of the antihistamine, antiadrenergic, anticholinergic effects of the TCAs.
Used to treat depression, anxiety, and in some cases, neuropathic pain.

Question 31

Pros and cons of venlafaxine (Effexor)?

Answer 31

Pros: very few drug-drug interactions (minimal P450 activity); short half-life and good renal clearance (doesn’t build up in pt’s system) so good for geriatric populations
Cons: 10-15 mmHg increase in DBP (dose dependent); can cause significant nausea (esp IR formulation); can cause severe discontinuation syndrome–recommended to taper over a couple of weeks minimum; QT prolongation; sexual side effects in >30%

Question 32

Pros and cons of desvenlafaxine (Pristiq):

Answer 32

Pros: minimal drug-drug interactions; short 1/2 life with good renal clearance (also good for geriatric populations)
Cons: GI distress in >20%, dose related increase in LDL, total cholesterol, and triglycerides

Question 33

Pros and cons of duloxetine (Cymbalta):

Answer 33

Pros: some evidence of efficacy for physical symptoms of depression; appears to have less effect on BP than venlafaxine, though jury is still out; FDA approved indication for neuropathic pain (often given to patients with fibromyalgia)
Cons: CYP2D6 and 1A2 inhibitor; can’t break the capsule as the active ingredient isn’t stable within the stomach; higher drop out rate in some studies

Question 34

What are the two main ‘novel’ antidepressants commonly used today?

Answer 34

mirtazapine (Remeron)

bupropion (Wellbutrin, also marketed under trade name Zyban for smoking cessation)

Question 35

Pros and cons of mirtazapine:

Answer 35

Pros: it’s serotonergic, but has different mechanism of action than SSRIs (it’s a 5HT2 and 5HT3 receptor antaganist) so it’s a useful augmenting agent; has antihistaminic property at low dose and can be used as a hypnotic if dosed at night; can also cause some appetite stimulation in people who are not eating well (e.g. geriatric populations, medically ill)
Cons: increases cholesterol in 15-20% of pts and triglycerides in about 6% of pts; sedating at lower doses, not as much at higher doses; weight gain

Question 36

Pros and cons of bupropion (Wellbutrin):

Answer 36

Pros: useful as an agumenting agent; mechanism believed to be due to inhibition of NE and DA reuptake; minimal weight gain and minimal sexual side effects, sedation, or cardiac toxicity; low risk of inducing mania; 2nd line agent for ADHD (consider using in pt’s with co-occuring substance use problems)
Cons: may increase seizure risk at higher dose (>450mg) thus avoid in pt’s with TBI, bulemia, anorexia; doesn’t treat anxiety and can exacerbate it in some cases; can contribute to insomnia; has abuse potential at higher doses (particularly the IR formulation)