Lecture 3: Antidepressants and Mood Stabilizers Flashcards
Classes of Antidepressants (8)
- selective serotonin reuptake inhibitors (SSRIs)
- Serotonin norepinephrine reuptake inhibitors (SNRIs)
- Norepinephrine dopamines reuptake inhibitors (NDRI)
- Noradrenergic and Specific Serotonergic Antidepressants (NaSSa)
- Serotonin Antagaonist/Reuptake Inhibitors (SARIs/SPARI)
- Tricylclic Antidepressants (TCAs)
- Monoamine Oxidase Inhibitors (MOAIs)
- Misc.
Boxed warning
applies to any agent FDA=approved for depression (and some other)
- increased risk of suicidality
a. children, adolescents, young adults
b. use cautiously with psycholotherapy if possible, frequent follow-ups
c. suicide protective in patient > 65 years
d. educate patients
Serotonin syndrome
3 signs and their symptoms
rapid onset, combo of 2+ serotonin agonists
- mental status change: agitation and pressured speech
- autonomic instability: tachycardia, diarrhea, shivering, diaphoresis, mydriasis
- Neuromuscular abnormalities: clonus, hyperflexia, tremor, seizure
Antidepressant Withdrawal
- agents should be tapered over weeks if able
- EXCEP. fluoxetine self-tapers - Abrupt discontinuation can precipitate a withdrawal syndrome
Withdrawal Syndrome (FINISH)
Flu-like symptoms Insomnia Nauseau Iritability Sensory disturbance Headache
SSRIs method of action
-inhibition of reuptake of serotonin (5-HT) in the presynaptic neuron of the central nervous system
- 1st line tx of MDD
a. well tolerated
b. low rx toxicity in OD
SEE 12 if necessary.
slide 12
SSRIs adverse effects (11)
- nausea/vomiting/diarrhea
- MOST Sertraline - Insomnia
- MOST fluoxetine - Fatigue/Sedation
- MOST Paroxetine - Weight Gain
- Peroxetine - Diaphoresis-usual sweating
- Sexual Dysfunction
- Seizures
- Headache
- SIADH (syndrome of inappropriate anti-diuretic hormone secretion)
- anxiety/agitation during 1st few days-weeks of tx
- risk of bleeding
SSRI: adverse effect
QT interval prolongation
Drug name, allowable amounts
citalopram with most documented evidence of effect
- do not give > 40 mg a day or 20mg if 60 years or older
- may be more toxic in OD than other SSRIs
SSRI Adverse effect
Anticholnergic effects
paroxetine, recommend to avoid in elderly
SEE 16
slide 16
SNRI side effects
all SNRIS (10)
- nausea
- dizziness
- insomnia
- sedation
- constipation
- sexual dysfunction
- urinary retention
- SIADH
- narrow angle glaucoma
- dose related to increase in diastolic blood pressure (more common in venlafaxine/desvenlafaxine)
SSNRI adverse effects
Duloxetine (3)
- more anticholinergic effects
- urinary retention
- increases rx of hepatotoxicity esp. with ETOH
SSNRI adverse effects
Levomilnacipran
tachycardia
bupropion/Wellbutrin
method of action
dose
half life
SSNRI
1st line, augmenting agent
MOA: inhibits reuptake transporters of synaptic dopamine, norepinephrine- no serotonergic effects
dose: 150-450 mg daily
available in IR,SR,XL formulation
t1/2: 8-24 hours
Buproprion/wellbutrin
adverse effects
contraindication
SSNRI
AE: nausea, vomiting, weight loss, tremor, insomnia, xerostomia, hypertension, low rx sexual dysfunction
C: seizure disorder, high alcohol/benzodiazepine intake
- abrupt d/c of sedative can increase rx of seizure
- bullemia, anorexia nervosa
Mirtazapine/remeron
Method action
dose
SSNRI
1st line agent with compelling reason
MOA: antagonized presynaptic alpha-2 adrenergic receptors (increase NE, 5-HT) and protsynaptic 5-HT receptors
D: 15-60 mg daily
- 7.5 mg for insomnia
- doses 15 mg and above typically acitvating
Vortioxetine/ Trintellix
MOA
Dosage
Adverse effects
SSNRI
MOA: SSRI with 5-HT 1A agonism, mixed antagonist/partial agonist
Dose: 10 mg daily, max dose 20 mg daily
AE: nausea, constipation, vomiting, sexual dysfunction
*wait 21 days before starting MAOI (lone t1/2)
Nefazodone (Serzone)/Trazodone (desire)
MOA
Dose
Adverser effects
SSNRI
3rd line augmenting (d/t sedation)
MOA: antagonist at postsynaptic 5HT2, inhibits reuptake of serotonins
Dose: trazodone: 150-375 mg daily, 3 divided doses, XR form also available
nefazodone: 200-600 mg in 2 divided doses
AE: sedation, dizziness, orthostatic hypotension
trazodone-priapism (rare) prolonged erection of penis
nefazodone- hepatotoxicity (avoid in liver disease)
Vilazodone/Viibryd
Line of tx
MOA
Dosing
ADR
SSNRI
3rd line tx (new, less data)
MOA: serotonin reuptake inhibitor at 5-HT1A receptor-partial agonist (SPARI)
D: 10 mg x7 days -> 20 mg x 7 days -> 40 mg once daily
-take with food to increase absorption
ADR: gastrointestinal: diarrhea, nausea, vomtitin, xerostomia
neurologic: dizziness, isomnia
- CYP3A4 substrate
Tricyclic Antidepressant (TCAs)
MOA
SSNRI
MOA: inhibition of presynaptic reuptake of norepinephrine (NE) and serotonin (5-HT)
-antagonize histamine, alpha-adrenergic and muscarine receptors, cardiac sodium channels (adverse effects)
- use fallen out of favor: OD within 1 week supply
- poor tolerability
SEE slide 25 for TCAs
25 for TCAs
TCA adverse affects
SSNRI
- sedation
- decreased seizure threshold
- cardiovascular effects
- orthostatic hypotension/syncope, arythmies - sexual dysfunction
- tremor
- photosensitivity
- heat intolerance
TCA adverse effects
3 types and examples
- anticholinergic
- cholinergic rebound
- srying effects: SLUD - anti-histaminic
- weight gain
- sedation - Alpha-1 Adrenergic Antagonis
- orthostasis
- hypotension
- dizziness
Monoamine Oxidase Inhibitors
line of tx
MOA
3rd line agent for MDD
MOA: inhibition of monoamine oxidase enzymes, MAOa and MAOb causing increased concentrations of NE, 5-HT, and dopamine (DA) in neuronal synapse
infrequently used
- drug and food interactions, adverse effect
- used in treatment-resistant patients
MAOIS example
- Tranlcypromine
- isocarboxazid
- Phenelzine
- selegiline
MAOIS adverse effects
- hypotension, dizziness common
- Anticholinergic effects (MAOIs < TCAs)
- hepatotoxicity (rare)
- sexual dysfunction
- cautions in cardiac disease, hepatic impairment
Eketamine-Spravato
Indication
boxed warning
intranasal esketamine
I: augmentation for severe depression that failed 2 trials of antidepressants for adequate dose and duration
BW: sedation, dissociation, abuse, SI
REMS program
-must be administered by pt. in registered clinic and monitored for 2 hours after administration
Antipsychotics in Depression
FDA approved agents for augmentation
- Aripiprazole
- brexpiprazole
- olzanzapine (only in combo with fluoxetine/symbyax)
- quetiapine XR (seroquel XR)
*other antipsychotics may have bipolar depression indication
Mood Stabilizers: Goal of Therapy (5)
- rapid stabilization of symptoms
- patient safety and wellbeing
- Adherence and adverse effects
- prevent recurrence, switching
- improve functioning/return to baseline
Things to consider before rxing mood stabilizers
- are they currently taking therapy?
- what episode is the patient currently experiencing?
- What symptoms is the patient experiencing?
- what are patients specific factors for therapy selection?
- other medications?
- previous traits of success or failure?
- comorbitities? - is therapy optimized?
- is patient adherent?
- psychotic pts.
- use antipsychotics to treat
- can be used as mono therapy or in combination with a mood stabilizer - If immediate symptom relief require
- benzodiazepines short term
- need for sleep and significant agitation - Symptom improvement expectations
- 7-10 days with initial mood stabilizers
- may be less with additional therapy ~3-5 days
Guidelines- maintenance therapy
- after ~6 months stable
- maintaining adherence and optimal dosage very important
- non-adherence linked to episode frequency
- subtherapeutic dosages may increase medication d/c
Goals to guidelines and maintenance therapy
- relapse revention
2. early in course: restore cognitive impairment and preserve brain plasticity
Lithium
- Indiation
- MOA
- for bipolar disorder in acute manic episodes and maintenance
- data supports efficacy in preventing relapse and hospital admission
- suicide- protective properties - Inorganic cation that performs multiple functions within CNS ,true mechanism of action unclear
- alters cation transport across cellular membrane
- influences reuptake of serotonin, NE, GABA
- postsynpatic D2 receptor sensitivity decreased
- cAMP second messenger system
Lithium dosing
dosage forms
300 mg BID-TID
increase based on serum levels and response
typical dosing range: 900-1800mg/day
consolidate dose if able
- most commonly given BID
- may be given once daily
Dosage forms:
- IR capsule/tablet
- ER/SR tablet
- 8mgEG/5mL solution
Lithuim pharmacokinetics
- slow accumulation in CSF; two compartment model
- slow body distribution and delayed onset of action
- all cellulare membranes crossed slowly - Really eliminated by filtration-follows sodium no metabolism occurs
- Slow elimination from cells (t1/2 24 =/- 12 hrs)
- patient may present tocos with levels in therapeutic range - steady rate in 5 days
Lithium Monitoring
- CBC, TSH weight, metabolic profile with calcium
- 2x in first 6 months, then periodically - pregnancy tests; cardiac abnormalities in 1st trimester
- EKG
- baseline & annual if > 40 years old - serum levels: through, steady state
- acute mania: 0.8-1.2mEg/L
- maintenance and elderly: 0.6-1mEg/L
- Narrow therapeutic index: high risk drug**
Lithium management adverse effects
- GI: take with food, divide dose, ER
- Hypothyroidism: elavulate for severity and clinical correlation, levothyroxine supplement 25-50mcg daily
- Tremor: lower dose or give smaller amounts more frequently, monitor over time for resolution, administer propranalol
- weigh gain: encourage diet and exercise, monitor other causes
- Nephrogenic Diabeters Insipidue-like syndrome: lower dose if able, give total dose at bedtime, diuretics if severe (smiloride)
More lithium adverse effects
- memory impairment
- renal insufficiency
- typically mild GFR decrease - Hypercalcemia
- Cardiac Arrhythmias
- T wave or ST segment abnormalities - acne 33%, psoriasis 6%
Lithium Toxicity
- can be acute/chronic
- mild: <1.5mEg/L -> nausea, vomiting, hand tremor lethargy, diarrhea
- moderate: 1.5-1.5 -> course hand tremor, slurred speech, unsteady gait, confusion, muscle fasciculation
- severe (>2.5 mEg/L): seizures, stupor, coma, arrhythmia, death - when to dialyze
- >2.5 Meg,L if patient is symptomatic
- >4.0 mEm/L regardless of symptoms
*DO NOT GIVE ACTIVATED CHARCOAL
Lithium Drug Interactions (TALANS)
Thiazides Ace-inhibitors Loop diuretics ARBs NSAIDs Sodium
Valproic Adic/Divalproex: VPA
indication
MOA
dosing
FDA approved for bipolar disorder, acute, manic or mixed episodes
- mechanism in bipolar disorder unclear
- enhances GABA activity, inhibits reuptake
- normalizes sodium and calcium channels
dosing: 10-20 mg/mg/day adjusted by level
- max 60 mg/kg/day
VPA Monitoring
through serum levels after 3-5 days
-CBC, LFTs, Scr baseline, 3 months and annually
- Hepatotoxicity-greater incidence in 1st 6 months, contraindicated in acute liver disease
- pancreatitis
- severe nausea/abdominal pain/anorexia
- may be life threatening,, hemorrhagic complications
- teratogenic: neural tube defects, VPA syndrome
Carbamezepine (tegretol, equetro)
indication
MOA
Monitoring
FDA approved for bipolar disorder, actor manic or mixed episodes
MOA: blocks voltage-sensitive sodium channels, stimulated release of ADH, NMDA activity
Monitoring: CBZ serum levels at 10-14 days
- CBC baseline, 3 months, annually
- LFTS/electrolytes/scr/BUN baseline, 3 months, anually
- EKG
Carbamezepine adverse effects
MAJOR: **HLA-B*1502 positive risk of rash and systemic reactions
- anemia/agranulocytosis
- hepatotoxicity
- systemic hypersensitivity reactions
- fetal abnormalities in pregnancy
Minor: sedation, photosensitivity, alopecia, nystagmus, nausea/vomiting, constipation, vit D deficiency, SIAH
Lamotrigine (Lamictal)
indication
MOA
FDA approved for bipolar disorder maintenance
- used in depression as well
- not for acute mania
MOA: blocks voltage-gated sodium channels
-decrease glutamate release
Safer in pregnancy vs. other mood stabilizers
Lamotrigine
monitoring
Dosing
M: skin, CBC, LFTs, SCr baseline an annually
-dosing specific to decrease rash risk
no inducers/inhibitors: 25 mg daily x2 weeks, 100 mg daily x2 weeks, 200 mg daily x1 week, max 400 mg daily
Inudcers (phenytoin, CBZ): 50 mg daily x2 weeks, 100 mg daily x2 weeks, 200 mg daily x1 week max 400 mg daily
inhibitors: 25 mg every other day x2 weeks, 25 mg daily x2 weeks, 50 mg daily x1 week max 100 mg daily
Lamotrigine Adverse Effects
- skin rash and SJS/TEN***
- young age, fast titration, concomitant valproate
dizziness, ataxia, GI effects, diplopia, blurry vision, hematological rare, hepatitis, ascertain meningitis, HLH hemaphagocytic lymphohistiocytosis
Oxcarbazepine
*less common mood stabilizers
- more risk of SIADH vs. carbamezepine
- not FDA approved for bipolar disorder
- dosing 300 mg po bid up to 1200 mg daily
Topiramite (topamax)
less common mood stabilizer
- not FDA approved for bipolar disorder
- causes cognitive dulling (dopamax) and can increase nephrolithiasis
Dosing: 25 mg PO BID, max 400 mg daily
Antipsychotics
- SGAs have more clinical trial data supporting use, guideline recommended
- FGA have more hx data
- Monitoring & adverse effects smilier to treatment for other mental illnesses
- see antipsychotics lecutre
FDA indications for antipsychotics
- bipolar depression
- cariprazine
- lurasidone
- olanzapine/fluoxetine
- quetiapine - acute manic/mixed
- aripiprazole
- asenapine
- cariprazine
- olanzapine
- quetiapine
- risperidone
- ziprazidone
