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What medications can cause depression?
Isotretinoin, anticonvulsants (Topiramate, Levetiracetam), BB, Clonidine, Methyldopa, OC, Corticosteroids, Tamoxifen
What is depression thought to be due to?
Depressed levels of monamines - 5HT, NE, DA
What antihypertensive drug depletes monoamines and causes depression in some patients?
Reserpine
What are the 3 phases of antidepressant treatment?
Acute (6-12 wks): sx remission
Continuation (4-9 mos): eliminate residual sx + prevent recurrence
Maintenance (12-36 mos): prevent recurrence
What patient is more likely to require lifetime antidepressant therapy?
Recurrent symptoms- ≥ 2-3 prior episodes
What are non pharmacological treatment options for depression?
Psychotherapy, ECT, rTMS
How long can it take antidepressants to work?
up to 6 weeks
T/F: TCAs & SSRIs don’t differ in efficacy, but differ in adverse effects (TCAs worse SEs).
True
List the antidepressant categories in order of most SEs to least SEs.
MAOIs > TCAs > SNRIs > SSRIs
What is the first MAOI used in TB that caused elevated moods in patients and lead to the development of other antidepressant medications?
Iproniazid
What drugs are monoamine oxidase inhibitors (MAOIs)?
Iproniazid (TB)
Phenelzine **
Tranylcypromine **
Isocarboxazid
Selegiline (Parkinson’s dz)
** main ones used for depression
What is the MOA of MAOIs?
Irreversible inhibitors of MAO-A & B → blocks breakdown of 5HT, NE & DA
What SEs are seen with MAOIs?
Postural hypotension (MC), wt gain, decreased libido, anorgasmia, hypertensive crisis (esp w/ tyramine foods or HTN meds)
What drug is associated with a hypertensive crisis?
HA, N/V, stiff neck, diaphoresis
can lead to CVA and death
can occur after stopping drugs (irreversible inhibitor; ~2 weeks)
MAOIs
How long does it take to regenerate enzymes after stopping an MAOI?
(*remember hypertensive crisis risk)
2 weeks
What is the treatment for a hypertensive crisis caused by an MAOI?
Anti-hypertensives
What foods should be avoided with MAOIs?
Tyramine containing foods - aged cheese, red wine, fave beans, sour cream, yogurt, cottage cheese, aged or processed meats, MSG, etc
What medications should be avoided with MAOIs because of their synergistic effects?
Amphetamines, appetite suppressants, asthma medications, cocaine, decongestants (pseudoephedrine), other antidepressants, etc
What is the MOA of TCAs?
Affect transporters & block reuptake of 5HT & NE → increased levels
Why were TCAs replaced by SSRIs as first line therapy for depression?
Bad ADR profile
What conditions besides depression can TCAs be used for?
Insomnia, pain conditions (block NE reuptake, good for MS or fibromyalgia)
What drugs are TCAs?
Amoxapine
Amitriptyline
Clomipramine
Desipramine
Doxepin
Imipramine
Nortriptyline
What drug is known to have the following adverse effects?
anticholinergic SEs (muscarinic blockade)
cardiac conduction delayed (Na channel blocker)
QRS prolong, vent arrhythmias, etc
Hypotension (alpha receptor blockade)
Sexual dysfunction, weight gain, sedation
**2 most dangerous → arrhythmias & seizures!
TCAs
What is the MOA of selective serotonin reuptake inhibitors (SSRIs)?
Inhibit SERT transporter → prevent 5HT reuptake & inc levels
What is the first line therapy for MDD?
SSRIs
What drugs are SSRIs?
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Sarafem)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
What SEs are seen with SSRIs?
GI upset, sexual disturbance, HA, insomnia, can improve or worsen anxiety sx, discontinuation / withdrawal phenomenon, QT prolongation (Citalopram, Escitalopram)
Which SSRIs can prolong the QT interval?
Citalopram & Escitalopram
Why do SSRIs need to be tapered slowly?
Withdrawal phenomenon with abrupt discontinuation → anxiety, sleep disturbance, inc risk of recurrence
Which SSRI is better for a patient with compliance concerns because of the lower risk of withdrawal phenomenons due to its longer half life?
Fluoxetine
What is BBW for SSRIs?
Suicide (can give depressed patient the energy to act on those thoughts or induce a manic episode in bipolar patients)
What patients have an increased risk of suicide on SSRIs?
Children, adolescents, and young adults
What SEs are seen with almost all antidepressant medications?
Sexual dysfunction & suicide risk
What is the MOA of SNRIs?
Block 5HT & NE reuptake → inc levels
TCAs and SNRIs have similar MOAs, but which has fewer side effects?
SNRIs
What other conditions can SNRIs be used for besides depression?
Fibromyalgia, peripheral neuropathies
What drugs are SNRIs?
Venlafaxine (Effexor)
Desvenlafaxine (Pristiq)
Duloxetine (Cymbalta)
Milnacipran (Savella)
Levomilnacipran (Fetzima)
What are SEs seen with SNRIs?
N, GI disturbances, sexual dysfunction
Which SNRI is associated with dose related increases in systolic BP?
Velafaxine
Which SNRI is associated with anticholinergic SEs (N, dry mouth, constipation, insomnia, diaphoresis)?
Duloxetine
What drugs are mixed serotonergic agents that are 5HT2 antagonists & 5HT reuptake inhibitors?
Trazodone (also blocks alpha 1 receptors)
Nefazodone (less use bc liver failure)
Vilazodone
What SEs are seen with Trazodone (Desyrel)?
Dizziness, hypotension, sedation, priapism (emergency)
What is an alternative agent to help with sleep if avoiding narcotics?
Mixed serotonergic agents (Trazodone, etc)
What is the MOA of Bupropion (Wellbutrin)?
inhibit reuptake & enhance release of NE & DA
(*NO 5HT effects)
What drug is used for depression as well as smoking cessation and has less sexual dysfunction than SSRIs?
Bupropion
What SEs are seen with Bupropion (Wellbutrin)?
N, V, tremor, insomnia, dry mouth, agitation, seizures & arrhythmias (dose related)
If a patient currently taking an SSRI is experiencing sexual dysfunction, what would you switch them to?
Bupropion (Wellbutrin)
What drug?
newer agent for depression
antagonist at presynaptic alpha 2 receptors → inc NE & 5HT release
also antagonizes 5HT2, 5HT3, & histamine receptors
SE: somnolence, wt gain, dry mouth, constipation
Mirtazapine (Remeron)
What drug?
newer agent for depression
acts as SSRI → 5HT agonist, partial agonist, & antagonist at various receptors
Vortioxetine (Trintellix)
What ADRs are seen with Vortioxetine (Trintellix)?
N, D, ejaculation & orgasm dysfunction
accumulation of drug if poor metabolizer/expresser of CYP2D6 enzyme
What is the MOA of NMDA receptor antagonists?
Regulate glutamate activity by blocking NMDA receptor
What drugs are NMDA receptor antagonists?
Ketamine (Ketalar)
Esketamine (Spravato)
What drug is given IV or oral and produces a mind out of body experience that can be used in the treatment of depression?
Ketamine
What drug is an intranasal NMDA receptor antagonist used for depression and must be used in a monitored setting?
Esketamine
What are there risks for with NMDA receptor antagonists?
Misuse / abuse (CIII), sedation, disassociation
What are the 4 major symptoms of serotonin syndrome?
Altered mental status (potential for seizures)
Hyperthermia (sweating)
Autonomic instability (Brady/tachycardia, hyper/hypotension)
Inc muscle tone (clonus, rhabdomyolysis - bad for kidneys)
What can cause serotonin syndrome?
Multiple serotonergic medications, tyramine interactions, MC seen with MAOIs
What is the treatment for serotonin syndrome?
Aggressive supportive care- cool IV fluids, evaporative cooling
Cyproheptadine (antihistamine w/ 5HT blocking effects)
What is important to remember when switching a patient from fluoxetine to another drug?
Long half life → give enough time to flush out
How does chronic therapy affect antidepressant half lives?
tissue accumulation → longer effects than apparent half life
How are antidepressant drug levels affected in cirrhotic patients?
Longer half lives
What antidepressant agents have fewer pharmacokinetic interactions?
Newer agents- Venlafaxine, duloxetine, bupropion
How are TCAs metabolized?
CYP enzymes (look for interactions!), also some are highly protein bound
What drugs besides antidepressants can cause serotonergic toxicity (milder than serotonin syndrome)?
Linezolid (MAOI like actions), Methylene blue (dye used in surgery), Triptans
**need antidepressant washout ~2-5 weeks
What herbal supplement has some efficacy in mild depression through some MAOI action & some inhibition of monoamine reuptake?
St. John’s Wort
What SEs are seen with St. john’s wort?
Dry mouth, dizzy, confusion, allergic rxn
CYP3A4 & P-glycoprotein inducer (lowers other drug levels)
Serotonergic toxicity when mixed w/ antidepressants
Wha tis the only antidepressant that has an indication for patients under 18 y/o?
Fluoxetine
What SEs can be seen with SSRIs in pregnancy?
Infant underweight, pulmonary issues, & can have withdrawal sx
What is the approach to treatment for depression?
Start with SSRI or SNRI, then TCAs, then MAOIs
What drug resembles Na (close on the periodic table) and there for the body treats it like Na?
Lithium
How is lithium excreted?
Not metabolized, excreted unchanged in urine
(*a drop in kidney function would increase levels)
What is first line for bipolar disorder / mood stabilization?
Lithium
What drug?
Mood stabilizer - can prevent manic episodes & reduce suicide risk
requires TDM
abrupt discontinuation can lead to relapse
Lithium
What acute SEs are seen with lithium at peak serum levels (~1-2 hours after dose)?
GI distress, osmotic diarrhea, muscle weakness / lethargy, polydipsia, nocturia
The following chronic adverse effects are seen with what drug?
Fine hand tremor
Nephrogenic DI & nephrotoxicity (glomerular sclerosis, interstitial nephritis)
Hypothyroidism (can look like depression),
Reversible cardiac effects (T inversion, AV block, etc)
Wt gain
Acne, pruritic dermatitis, worsen psoriasis
Slurred speech, ataxia
Lithium
How can a find hand tremor caused by lithium be corrected?
Switch to a long acting formula or treat w/ BB
What drug can cause nephrogenic diabetes insipidus (not enough ADH)?
Lithium
*must monitor lithium & K levels
What is the treatment for nephrogenic diabetes insipidus caused by lithium?
Loop or thiazide diuretics
(blocks Na + H2O absorption to inc urine volume & activate RAAS)
What is seen in a lithium overdose?
*acute- less CNS sx- not enough time for lithium to cross CNS
*chronic- levels accumulated over time (ex- dehydration, dec GFR)
Seizures, dysrhythmias, coma
What can lead to lithium accumulation and can cause a chronic overdose?
Dehydration, Na restriction, V, D, HF, cirrhosis
(any state that body holds on to Na)
What drugs can lead to lithium accumulation?
Thiazide diuretics, NSAIDs, ACEI, Salt restriction
What CYP enzyme interactions should be monitored for in lithium?
None- not metabolized by CYP enzymes
What anticonvulsant is the most prescribed mood stabilizer in the US that is good for acute mania and chronic therapy?
VPA
What SEs are seen with VPA?
GI distress, fine hand tremor, sedation, ataxia, lethargy, plt aggregation inhibition (bleeding risk), hyperammonemia, hepatotoxicity
*requires TDM + monitor liver & LFTs
Which anticonvulsant inhibits neuronal Na channels and is NOT a first line agent for bipolar but is useful in lithium refractory patients?
Carbamazepine (Tegretol)
What SEs are seen with Carbamazepine?
Gi disturbances, ataxia, lethargy, nystagmus, seizures, cardiac conduction changes, SIADH
*requires TDM
What drug interactions are seen with Carbamazepine?
CYP3A4 inducer- lowers levels of other drugs like anticonvulsants & oral contraceptives (use alternative BC)
What drug displaces carbamazepine from serum proteins (increasing free levels)?
VPA
What drug is a derivative of carbamazepine that blocks sodium channels & inhibits CYP2C19 and induces CYP3A4?
Oxcarbazepine (Trileptal)
Which is more likely to cause SIADH- Carbamazepine or Oxcarbazepine?
Oxcarbazepine
What SEs are seen with Oxcarbazepine?
Dizziness, sedation, HA, ataxia, GI disturbances, SIADH
What is the MOA of Lamotrigine (Lamictal)?
Block Na channels & inhibit glutamate release
*has both antidepressant & mood stabilizing effects
How does Valproate affect Lamotrigine?
decrease clearance → doubles half life
*need to decrease lamotrigine dose by half
What SEs are associated with lamotrigine?
Drowsiness, HA, tremor, rash & pruritus (common if combo w/ VPA), SJS
Which generation of antipsychotics blocks DA2 receptors only?
First generation
Which generation of antipsychotics blocks DA2 receptors and 5HT-2a receptors?
Second generation
What agent would be beneficial in a patient with acute mania presenting with agitation, aggression, and psychosis?
Antipsychotics + Benzos (restrain pt)
What drugs can be used in bipolar disorder and are thought to inhibit neurotransmitter release and synthesis?
CCBs - verapamil & nimodipine
What is the treatment algorithm for Bipolar disorder?
Start with mood stabilizer: Lithium, carbamazepine, VPA, or SGA
Consider adding benzos if insomnia, anxiety, agitation
2nd line: Oxcarbazepine
*if severe manic episodes → start w/ 2 agents
What is the next step for a bipolar patient who has an inadequate response to their current medication?
Lithium + anticonvulsant or SGA OR
Anticonvulsant + anticonvulsant or SGA
