Antidepressants Flashcards
Etiology of MDD
Changes in?
norepinephrine (NE)
serotonin (5-HT)
dopamine (DA)
Treatment Goals of MDD
Reduce symptoms of acute depression
Facilitate patient’s return to pre-morbid functioning
Prevent further episodes of depression
Hospitalization
Hospitalization should be based on what 4 factors?
Suicide risk
Physical state of health
Support system
Presence of psychotic features
Acute Phase of treatment for MDD
Lasting from 6-8 weeks
Goal: Remission of symptoms
Continuation phase of treatment for MDD
Lasting from 4-9 months(in addition to acute phase)
Goal: Eliminate residual symptoms and prevent relapse
Maintenance Phase of treatment for MDD
Lasting at least 12-36 months
Goal: Prevent recurrence
Choice of Agent is based on what for antidepressants?
Patient’s history of response Pharmacogenetics (hx of familial response) Subtype of depression Concurrent medical history Potential for drug-drug interactions Adverse events profile Drug cost
What is the response to antidepressants?
Approx. 65-70% of patients with varying types of depression improve with drug therapy
Well-documented placebo effect
Adverse effects may occur immediately
Resolution of symptoms may take 2-4 weeks (or longer!)
Adherence is essential to a successful outcome
What are the 5 classes of antidepressants
Tricyclic Antidepressants (TCAs) Monoamine oxidase inhibitors (MAOIs) Selective serotonin reuptake inhibitors (SSRIs) Mixed 5-HT and NE reuptake inhibitors Miscellaneous
What is the black box warning found on all antidepressants?
regarding ↑’d risk of suicidality in young adults
(18-24 years), during initial stages of treatment
TCA MOA
Block muscarinic (M1), adrenergic (α1), histamine (H1) receptors All potentiate activity of NE and 5-HT via reuptake blockade
TCA Pharmacokinetics
Well-absorbed; low bioavailability due to high 1st –pass metabolism in liver
T ½ about 24 hours (allows for QD dosing)
Highly lipophilic–> wide distribution throughout the body
Highly protein bound
hepatically metabolized
TCA Adverse Effects
Tachycardia Orthostatic hypotension Cardiac rhythm changes (i.e., QRS prolongation, ST depression, flattened or inverted T waves) Weight gain Sedation decrease seizure threshold sexual dysfunction****
What is really important to know about TCA’s?
narrow theraputic index
Fatal in overdose cardiac conduction abnormalities (i.e., torsades de pointes)
Tertiary amine TCAs
More pronounced anticholinergic, antihistaminergic, and hypotensive effects
Avoid in elderly due to postural hypotension risk of fall and other cardiovascular effects
TCA Contraindications? (6)
Patients with benign prostate hyperplasia
Patients with closed-angle glaucoma
Patients with cardiac disease
Baseline ECG (require for all)
Patients with hepatic impairment
Elderly patients
Particularly sensitive to antiACh effects
At ’d risk of TCA-induced cognitive toxicity (mild confusion to delirium)
TCA Drug interactions
Avoid use with other drugs that affect CYP450 system
May increase vasopressor response to direct-acting sympathomimetics (i.e., phenylephrine, epinephrine, NE)
Additive adverse effects with other agents with serotonergic, antiACh, sedative, or hypotensive properties
3 MAO-I medications
Phenelzine (Nardil®) (nonselective)
Tranylcypromine (Parnate®)
Selegiline transdermal patch (Emsam®)
Tranylcypromine (Parnate®)
Non-selective inhibition of MAO-A and MAO-B
Rare to see due to ADE
Selegiline transdermal patch (Emsam®)
Selective MAO-B inhibitor at 6 mg/24 hr patch (approx. 10 mg PO)
Non-selective inhibition at 9 mg- and 12 mg-per 24 hr patch
MAO-I MOA
Block metabolism of NE, 5-HT, and DA via inhibition of MAO enzyme
NE and 5-HT: metabolized by MAO-A
DA and Tyramine: metabolized by MAO-A and MAO-B
MAO-I pharmokinetics
Rapidly absorbed
Maximum MAO inhibition at 14 days
T ½ of 1-4 hrs
Clinical effects seen for up to 14 days after discontinuation
MAO-I Adverse Effects
Orthostatic hypotension - Dizziness Mydriasis - Edema Piloerection - Insomnia Tremor - Anorgasmia Excessive daytime sleepiness Weight gain hepatic dysfunction hypertensive crisis
Hypertensive Crisis that is an ADR in MAO-I
Occurs after ingestion of tyramine containing foods or drugs dietary restriction
Tyramine = pressure amine; metabolized in gut by MAO enzymes
Causes release of NE from presynaptic sites
Signs and symptoms: hypertension, occipital headache, neck stiffness, diaphoresis, heart palpitations, nausea, vomiting
Medical emergency
MAO-I drug interactions
Washout period of 14 days necessary when switching from an MAOI to another antidepressant or from another antidepressant to an MAOI (5 week washout when switching from fluoxetine to an MAOI)
Serotonin syndrome with other antidepressants
What are 6 SSRI medications used?
Fluoxetine (Prozac®) Sertraline (Zoloft®) Paroxetine (Paxil®) Citalopram (Celexa®) Escitalopram (Lexapro®) Fluvoxamine (Luvox®) – FDA approved for only OCD
SSRI’s
1st line therapy for MDD
Favorable safety profile
No evidence to suggest one SSRI more efficacious than another
Indicated for other psychiatric comorbidities
Anxiety disorders (i.e., OCD, PTSD, general anxiety
MOA of SSRI’s
Inhibit reuptake of 5-HT 5-HT activity in neuronal synapse
Low affinity for histaminergic, cholinergic, and α-adrenergic receptors
Pharmacokinetics of SSRI’s
T ½ = approx. 24 hrs for sertraline, paroxetine, citalopram, and escitalopram
T ½ = 7+ days for fluoxetine (and active metabolite norfluoxetine) 4-5wks to get to steady state
Hepatic impairment significantly interferes with metabolism
Measurement of serum concentrations does not correlate with clinical outcome
SSRI’s adverse effects
Nausea - Headache
Sleep disturbances - Agitation/anxiety
Sexual dysfunction - Tremor
Less sedating and cause less weight gain than TCAs or MAOIs
Serotonin syndrome with other serotonergic agents
Discontinuations Syndrome of SSRI’s
Potential for withdrawal symptoms with abrupt discontinuation of short-acting SSRIs
Symptoms: vivid dreams, nightmares, tremor, dizziness, crying spells, nausea, poor concentration
Occurs as early a 1-4 days or up to 25 days after discontinuation
Taper dose slowly over a period of 7-10 days
Fluoxetine Drug interactions
5-week washout after discontinuation before starting an MAOI (2-week washout for all other SSRIs)
Sertraline Drug interactions
Weak inhibitor of CYP2D6 at low doses; becomes more potent at higher doses (still weaker than fluoxetine and paroxetine)
No known clinically significant drug interactions
Citalopram and escitalopram Drug interactions
Possible dose dependent inhibition of CYP2D6
No known clinically significant drug interactions
Fluvoxamine Drug interactions
Potent inhibitor of CYP1A2
Weak inhibitor at CYP2C9
3 Mixed 5-HT/NE Reuptake Inhibitors
Venlafaxine (Effexor®)
Duloxetine (Cymbalta®)
Desvenlafaxine (Pristiq®) active metabolite of effexor
Venlafaxine
Extended-release (XR) formulation considered a 1st line agent for MDD
No significant adverse affects or cardiac affects
3 divided doses
Venlafaxine MOA
Potent 5-HT/NE reuptake inhibitor
5-HT reuptake inhibition 3-5 fold higher than NE reuptake inhibition at doses < 200 mg/day
Weak DA reuptake inhibitor
Venlafaxine Pharmacokinetics
Well-absorbed
Minimal plasma protein binding
T ½ = 5-11 hrs (longer with XR formulation)
Substantial 1st pass metabolism via CYP2D6
Venlafaxine Adverse effects
Side effect profile similar to SSRIs
Common side effects
Nausea, constipation, sedation, dry mouth, insomnia, dizziness, sweating, sexual dysfunction
Discontinuation syndrome
not for someone with uncontrolled HTN
Drug interactions for Venlafaxine
Weak inhibitor of CYP2D6
Little or no inhibition of other CYP enzymes
Can potentially accumulate when combined with CYP2D6 inhibitors; use cautiously
Serotonin syndrome
Duloxetine (5)
Balanced reuptake inhibitor if 5-HT and NE
FDA indicated for MDD, diabetic neuropathy and fibromyalgia
Adverse effect profile similar to venlafaxine (but no dose related in BP)
Metabolized at CYP2D6 and CYP1A2
T ½ = 12 hrs
Desvenlafaxine
Studies show no additional benefit above 50 mg/day with an increase in adverse effects at higher doses
Adverse effect profile similar to venlafaxine
No comparison studies with any other antidepressants
Buproprion/Wellbutrin
Most potent neurochemical action is DA reuptake inhibition (increase DA activity)
Very low reuptake inhibition of NE
No appreciable effect of reuptake of 5-HT
Buproprion/Wellbutrin indications
Depression: Wellbutrin® (immediate-release, SR, XL)
Smoking cessation: Zyban® (bupropion SR)
Buproprion/Wellbutrin Adverse effects
Use with caution with drugs known to seizure threshold
Use with an MAOI contraindicated
Very low inhibition of CYP 2D6
Use with agents metabolized via CYP2D6 should be used with caution
Nefazodone MOA
Both a 5-HT2 antagonist and 5-HT reuptake inhibitor
Negligible affinity for cholinergic, histaminergic, dopaminergic receptors
Nefazodone Adverse effects and black box warning
Black box warning related to cases of life-threatening hepatic failure
Common adverse events: light-headedness, dizziness, dry mouth, nausea, asthenia, orthostatic hypotension, sedation
Potent CYP3A4 inhibitor
Not a 1st line agent
Trazodone immediate release
Use as antidepressant has decreased due to adverse effects (i.e., orthostatic hypotension, dizziness, sedation)
Usual dosage range: 150-300 mg/day
Commonly used as a sedative at does of 50-100 mg HS
Rare cases of priapism, QTc prolongation
Trazodone extended release
Oleptro®
Starting dose: 150 mg once daily at bedtime
Increase by 75 mg/day every 3 days to a maximum of 375 mg/day.
Side-effect profile similar to immediate- release trazodone
Mirtazapine
Remeron®
Selective, presynaptic α2-receptor antagonist
Enhancement of NE transmission by α2-autoreceptor blockade stimulation of α2-adrenoreceptors ’d 5-HT firing
T ½ = 20-40 hrs
Mirtazapine adverse effect and drug interactions
Adverse Effects Sedation Dry mouth Constipation Increased appetite Weight gain
Drug interactions
Other sedating agents
MAOIs
Vilazodone
Viibryd®- dual 5-HT activity
maintenance dose of 40 mg once daily with food
Vilazodone Adverse effects
Adverse Effects:
Common: diarrhea, nausea, dizziness, dry mouth, insomnia, vomiting, and decreased libido, dry mouth
Rare: May cause new or worsening cataracts with long-term use
Levomilnacipran
Fetzima® - SNRI
Twofold greater potency for norepinephrine relative to serotonin reuptake inhibition
Higher selectivity for norepinephrine reuptake inhibition compared with venlafaxine and duloxetine
Levomilnacipran side effects
Side effects in clinical trials include nausea, constipation, and sweating
Primarily excreted by the kidneys
Role in treatment of depression unknown –only studied versus placebo
Vortioxetine
Brintellix® - Serotonin re-uptake inhibitor and agonist
Most common adverse reactions: nausea, constipation and vomiting
Vortioxetine drug interactions
Strong inhibitors of CYP2D6: Reduce dose by half
Strong CYP Inducers: Consider increasing dose
Role in treatment of depression unknown
St. John’s wort
Herbal product – not regulated by the FDA
Found to be safe and effective for treatment of mild-to-moderate depression
significant drug interactions
Potent CYP3A4 inducer
What is Electroconvulsive Therapy (ECT)
Small current used to induce a seizure
30 to 60 seconds in duration
Patients are sedated and neuromuscular blocking agents used to prevent muscle contractions
Course: 6-12 treatments (2-3 times/week)
ECT indications?
high suicide risk
rapid physical decline
drug non-response or intolerability
history of prior response to ECT
Contraindications and limitations of ECT
Contraindications: no absolute contraindications
Limitations/AEs: high relapse rate, impairments in memory and neurocognitive function, treatment- emergent mania, headache, nausea, muscle aches
Elderly Populations
Depression often mistaken for another disorder (i.e., dementia)
Depressed mood may be less prominent than other symptoms (i.e., loss of appetite, cognitive impairment, sleeplessness, anergia, anhedonia)
Somatic complaints frequent
Increased suicide attempts
SSRIs 1st line
Start LOW and go SLOW
Pregnancy Population
Risks and benefits must always be carefully weighed
New evidence for potential respiratory distress and withdrawal syndrome in neonates whose mothers took SSRIs during pregnancy
Risks of untreated depression?
ECT can be used safely during pregnancy
Sertraline and paroxetine appear in low concentrations in breast milk
3 ways to evaluate the response of treatment
Target signs and symptoms
Quality-of-life issues
Tolerability of the agent
Evaluation of target signs and symptoms (4)
Non-response: 50% ↓ in baseline symptoms
Remission: return to baseline functioning
Antidepressants: General Dosing Information (4)
Lag time before start of therapy and onset of clinical response can lead to noncompliance
Onset of activity usually takes 1-2 weeks
Improvement in energy, appetite, sleep disturbances
3-4 weeks usually required before mood- elevating response seen
Adequate trial: 6-8 weeks at a maximum dosage
Treatment Resistant Depression
Definition = remission not achieved after 2 optimal antidepressant trials (6-8 weeks)
2 approaches used for treatment of resistant depression
Switching
Augmentation with another antidepressant, lithium, T3 (triiodothyronine), atypical antipsychotic, ECT, psychotherapy
