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Transcript
Medications Used for Depression
in the Older Adult
Jena Ivey Burkhart, PharmD, BCPS, CPP
Clinical Assistant Professor, UNC Eshelman School of Pharmacy
Geriatric Clinical Pharmacist, UNC Division of Geriatric Medicine
[email protected]
September 2010
Objectives
1. Describe the mechanism of action of each
class of antidepressants
2. Compare and contrast antidepressants
with respect to efficacy, safety, and cost
3. Identify appropriate monitoring
parameters for antidepressant therapy
Treatment of Depression
1. Psychotherapy – cognitive and behavioral
2. Pharmacotherapy
–
–
–
–
–
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin/norepinephrine reuptake inhibitors
(SNRIs)
Atypical antidepressants
3. Electroconvulsive therapy (ECT)
Challenges of Treatment
• Reduced lean body mass, increased body
fat affect concentration of drugs
• Reduced hepatic and renal drug and
metabolite clearance
• Presence of medical illness may cause
pharmacodynamic changes (e.g. dementia)
• Drug-drug interactions
Biochemical Changes
in Older Adults
• Disregulation of CNS involving various
neurotransmitters (Limbic system dysfunction)
– Decrease in dopamine (DA) and/or 5hydroxytryptamine (5-HT or serotonin)
– Decrease in norepinephrine (NE)
– Increase in monoamine oxidase (MAO)
• Main targets of therapy: 5-HT and NE
Neurotransmitter Effects
Serotonin
Sex
Appetite
Aggression
Norepinephrine
Sadness
Anxiety
Aches and
Pain
Concentration
Attention
Motivation
Classes of Agents
• Tricyclic antidepressants (TCAs)
• Monoamine oxidase inhibitors (MAOIs)
• Selective serotonin reuptake inhibitors
(SSRIs)
• Serotonin/norepinephrine reuptake
inhibitors (SNRIs)
• Atypical antidepressants
• Other adjunctive agents
TCA – Mechanism of Action
www.csusm.edu/DandB/AD.html
TCAs
• Considered cornerstone of antidepressant
therapy for several decades
• Classified according to chemical structure
• Effectiveness:
– major depression
– masked depression
– pseudodementia
• Adverse effects limit use
Characteristics of TCAs
Drug
Mean
Dose
(mg/day)
Half-life
(hrs)
Anticholinergic
Effects
Sedation
Orthostasis
Weight
Gain
*Amitriptyline
30-100
10-22
+++
+++
+++
++
*Imipramine
30-100
10-25
++
++
+++
++
*Doxepin
75-150
12-23
++
+++
+++
++
*Nortriptyline
25-75
20-50
+
++
+
+
*Desipramine
30-125
12-24
+
+
++
+
*Tertiary Amines
*Secondary Amines
All available as generic
Characteristics of TCAs
Precautions/Contraindications
• Cardiac conduction disturbances
• Ischemic heart disease
• Existing cognitive dysfunction
• Low therapeutic index, potentially fatal
in overdose
TCAs – Place in Therapy
• Potentially severe adverse effects limit use
in older adults
• All equally effective
• May be ideal in certain patient populations
for certain indications
• Initiate at low dose and titrate to therapeutic
effect
MAOIs – Mechanism of Action
www.csusm.edu/DandB/AD.html
MAOIs
• Effectiveness:
– Depression refractory to TCAs
– Depressive phase of bipolar disorder
– Atypical depression/anxiety
• Adverse effects/potentially serious
interactions limit use
MAOIs
• Available agents
– Phenelzine (Nardil®)
• dose per day: 15-90 mg
– Tranylcypromine (Parnate®)
• dose per day: 10-60 mg
– Selegiline (Eldepryl®)
• dose per day: 5-10 mg
• Minimal anticholinergic effects and less sedating
as compared to TCAs
• Risk of hypertensive crisis when combined with
tyramine-containing foods or sympathomimetics
All agents available as generic
MAOIs
• Adverse Effects
– sexual dysfunction
– mild anticholinergic
effects
– orthostatic
hypotension
– sedation
(phenelzine)
– insomnia
(tranylcypromine)
• Drug Interactions
–
–
–
–
–
sympathomimetics
opiates
“tryptans”
SNRIs
SSRIs
MAOIs – Place in Therapy
• Not first-line, rarely used
• Used in more resistant forms of depression
• Adverse effects limit use
• Initiate at low dose and titrate to therapeutic
effect
SSRIs – Mechanism of Action
www.csusm.edu/DandB/AD.html
Selective Serotonin
Reuptake Inhibitors
• Equal efficacy when compared to TCAs and to each
other
• Considered first-line in older adults
– favorable adverse effect profiles
– once-daily dosing
– safety in cases of overdose
• Preferred agents for depression complicating
cardiovascular and cerebrovascular disease
Selective Serotonin
Reuptake Inhibitors
Drug
Starting Dose/Day Daily Dose Range
Fluoxetine (Prozac®)*
5-10 mg
5-20 mg
Fluvoxamine (Luvox®)
50 mg
100-300 mg
Paroxetine (Paxil®,
Paxil CR®)*
10-20 mg
20-60 mg
Sertraline (Zoloft®)*
25-50 mg
50-150 mg
Citalopram (Celexa®)*
10-20 mg
20-40 mg
Escitalopram
(Lexapro®)*
5-10 mg
10-20 mg
*Also available in solution or suspension
Available as generic
SSRI – Adverse Effects
• Gastrointestinal
– nausea, vomiting,
diarrhea
• Sexual dysfunction
• Headache
• SIADH/hyponatremia
•
•
•
•
Insomnia
Fatigue
Agitation
Akathesia and
dystonic reactions
SSRI – Adverse Effects
• Most likely to cause sedation
– paroxetine, fluvoxamine
• Most anticholinergic
– paroxetine
• Fluoxetine
– higher rates of anxiety/nervousness
– many drug interactions
– long t½
SSRI – Adverse Effects
• Fluvoxamine
– many drug interactions
– only approved for OCD
• Sertraline
– more diarrhea
– may be more activating (do not administer
at night)
• Citalopram, escitalopram
– may be more “neutral”
SSRI – Drug Interactions
Enzyme
Drugs metabolized Antidepressants
by enzyme
that inhibit enzyme
1A2
theophylline, TCAs,
caffeine, haloperidol
fluvoxamine
2C9
warfarin, phenytoin,
diazepam, TCAs
fluvoxamine,
fluoxetine, sertraline
2D6
Antipsychotics, TCAs,
β-blockers, 1C
antiarrhythmics
fluoxetine, sertraline,
paroxetine
3A4
TCAs, alprazolam,
triazolam,
cyclosporine,
erythromycin
fluvoxamine,
fluoxetine, sertraline
SSRI Withdrawal Syndromes
• More likely to occur with short t½ life agents
(paroxetine warning)
• May be due to sudden decrease in available
synaptic 5-HT in face of down-regulated
receptors
• Onset 24-72 hours and lasts up to 7-14 days
• Symptoms: dizziness, nausea, lethargy,
headache, parasthesia
Serotonin Syndrome
• Potentially life-threatening condition associated
with increased serotonergic activity in the CNS
• Seen with therapeutic medication use, inadvertent
interactions between drugs, and intentional selfpoisoning
• Anxiety, restlessness, tachycardia, vomiting,
diarrhea, tremor, muscle rigidity, hyperreflexia
• Need emergent medical care…call 911
SSRIs – Place in Therapy
• Considered first-line for depression in older adults
• Selection of agent depends on side effect profile
• Start at low doses and increase every 2-4 weeks
to achieve maximal therapeutic efficacy
• Citalopram, escitalopram, sertraline seem to be
best tolerated
Serotonin/Norepinephrine Reuptake
Inhibitors
Mechanism of Action
• Inhibit both 5-HT and NE reuptake
• Weak reuptake inhibition of DA
• Degree of neurotransmitter reuptake inhibition dependent on dosing of
agent
• Available agents
– Venlafaxine (Effexor®, Effexor XR®)**
– Duloxetine (Cymbalta®)
– Desvenlafaxine (Pristiq®)
**Venlafaxine immediate release (BID dosing) is only SNRI with generic
availability]
**Recently approved Venlafaxine ER but is not pharmaceutical equivalent to
Effexor XR, only costs about 20% less, 225 mg strength available
Serotonin/Norepinephrine Reuptake
Inhibitors
• Dosing
– Venlafaxine: 37.5 mg-75 mg up to 375 mg daily (no more than 225
mg/day extended release)
• enhanced response on NE with increasing doses
– Duloxetine: 20 mg up to 60 mg daily
• equal 5HT/NE reuptake inhibition at lower and higher doses
– Desvenlafaxine: 50 mg daily (doses higher than this have little
efficacy, more side effects)
• Prodrug of venlafaxine
• Use SNRIs for those who have not responded to
appropriate trials of other antidepressant agents
SNRI – Adverse Effects
•
•
•
•
•
Nausea
Constipation
Headache
Dizziness
Nervousness
•
•
•
•
Somnolence
Dry mouth
Sexual dysfunction
Increased seizure
risk
• Increased BP*
Atypical Antidepressants
• Mirtazapine* (Remeron®)
– 5-HT2/5-HT3 blockade, histamine-1 blockade
– little activity on alpha1, muscarinic, DA
• Trazodone* (Desyrel®)
– specific inhibitor of 5-HT reuptake
– α-adrenergic blockade
• Bupropion* (Wellbutrin®, Wellbutrin SR®,
Wellbutrin XL®)
– weak inhibitor of 5-HT, NE, and DA
*Available as generic
Mirtazapine (Remeron®)
• Dosing: 15 mg up to 45 mg daily, usually at bedtime
• More sedating at lower doses
• Side effects (decreased frequency reported at higher
doses)
–
–
–
–
sedation
appetite stimulation/weight gain
dry mouth
constipation
• May be optimal agent for depression accompanied by
insomnia, weight loss
Trazodone (Desyrel®)
• Dosing (depression): 100 mg up to 600 mg daily
– Used infrequently for depression due to side effects at higher
doses
• Dosing (insomnia): 25 mg up to 100 mg daily, dosed at
bedtime
• Side effects
– sedation (drug of choice for insomnia in the elderly)
– Orthostasis, bradycardia, hypotension
• Dose titration every 2-3 days may be necessary to
achieve adequate response
Bupropion (Wellbutrin®)
• Dosing: 75 mg up to
150 mg daily, XL forms
• Appears well tolerated
but limited data
available in older adults
• May be good agent for
apathetic depression,
augmenting agent
• Used in smoking
cessation (Zyban®)
• Side effects
–
–
–
–
–
–
insomnia
increases seizure risk
agitation
constipation
weight loss
NO sexual dysfunction
Other Adjunctive Agents
• May augment response to antidepressants for specific
target symptoms
• Stimulants
– Methylphenidate (Ritalin®)
– Modafinil (Provigil®)
• Mood stabilizers
– Carbamazepine
– Lithium
• Antipsychotics – approved for resistant depression (last
line option)
Choosing an Antidepressant
• All equally
effective
• Limited clinical
data in older
adults
• Patient
characteristics
• Prior response
•
•
•
•
Side effect profile
Drug interactions
Cost
Adherence
Monitoring Parameters
• Week 1
– anxiety
– insomnia
– appetite
• Week 2-3
– increase in energy
– increase suicide risk
– increase in libido
• Up to 4-8 weeks
– improvement in
dysphoria or
sadness
– improvement in
pessimism
– improvement in
anhedonia
*If response not adequate, may need to modify initial therapy
Summary of Antidepressant Therapy in
Older Adults
• Start low and go slow
• At least 6-8 weeks of treatment
recommended to achieve optimal effect
• Older patients may take longer to respond
• Achieving effective doses important
Summary of Antidepressant Therapy in
Older Adults
• Monitoring for response/adverse effects
key
• Continuation of therapy
– Treat initial episode at least 9-12 months
– If relapse when therapy discontinued, may
need treatment for life