different strokes for differentdifferent strokes for different folks:...
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Different Strokes for DifferentDifferent Strokes for Different Folks: Treating Special
Populations with Depression
MDD Treatment Guidelines:Current Recommendations
Monotherapy (6–12 weeks)
partial response no response/not tolerated
Raise dose or augment Monotherapy (6–12 weeks)
no response/ not tolerated
Monotherapy (6–12 weeks)
no response/ not tolerated
Monotherapy (6–12 weeks)
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Different Strokes for Different Folks: Treating Special Populations with Depression
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MDD Treatment Guidelines:Are There Changes in Store?
Monotherapy (6–12 weeks)
partial response no response/not tolerated
Raise dose or augment Monotherapy (6–12 weeks)
no response/ not tolerated
Monotherapy (6–12 weeks)
no response/ not tolerated
Monotherapy (6–12 weeks)
Meta-Analysis: Majority of Improvement Occurs in First Two Weeks of Treatment
Week 6
14
D
Week 2
Week 2
Week 3
Week 3
Week 4
Week 4
Week 5
Week 5Week 6
4
6
8
10
12
kly
Red
uctio
n in
HA
M-D
Week 1Week 1
0
2
4
Active (N=5158) Placebo (N=3418)
Wee
k
Meta-analysis included 47 trials
Posternak, Zimmerman. J Clin Psychiatry 2005;66(2):148-58.
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Different Strokes for Different Folks: Treating Special Populations with Depression
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Under Investigation:Early Medication Change
• Early Medication Change (EMC) trial
Phase IV multi center multi step randomized• Phase IV, multi-center, multi-step, randomized, observer-blinded, actively controlled, parallel-group clinical trial
• First prospective investigation of whether non-improvers at 14 days of AD treatment with early medication change are more likely to achieve g yremission by 56 days than treatment as usual
Tadic et al. Trials 2010;11:21.
Evidence for the Increased Efficacy of Two Antidepressant Mechanisms Over One: SSRI + NRI
Remission
SSRI Treatment
Remission
NRI Treatment Combined Treatmen
Non-response
50%
Response36%
Remission7%
Non-response
33%
Partial response
50%
Response17%
Remission0%
Non-response
38%
Response8%
Remission54%
Adapted from Nelson JC et al. Biol Psychiatry 2004;55(3):296-300.
Partial response
7%
50% Partial response
0%
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Different Strokes for Different Folks: Treating Special Populations with Depression
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Review:Enhanced Remission With Early Combination
Nelson et al 2004 SSRI (fluoxetine) + NRI (desipramine)
Randomized trial Drug combination superior to monotherapy from initiation of treatment
Nelson et al., 2004 SSRI (fluoxetine) + NRI (desipramine)
Godfrey et al., 1990; Coppen and Bailey, 2000; Resler et al., 2008
SSRI (fluoxetine) + L-methylfolate
Fava et al., 2006 SSRI (fluoxetine) + eszopiclone
Blier et al., 2009 SSRI (paroxetine) + mirtazapine
SSRI (fluoxetine) + mirtazapine
Stahl SM. J Clin Psychiatry 2009;70.
Blier et al., 2010 SNRI (venlafaxine) + mirtazapine
NDRI (bupropion) + mirtazapine
Antidepressant Combinationsat Treatment Initiation
fluoxetine (N=28) fluoxetine + mirtazapine (N=25)
venlafaxine + mirtazapine (N=26) bupropion + mirtazapine (N=26)
10
15
20
25
m-D
Sco
re (
LOC
F)
0
5
Baseline 4 7 10 14 21 28 35 42
Statistically significant difference for fluoxetine monotherapy vs all combination treatment groups (F=3.87; df=3, 101, p=0.011)
Blier et al. Am J Psychiatry 2010;167:281-8.
Ha
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Different Strokes for Different Folks: Treating Special Populations with Depression
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• Three randomized controlled trials (fourth in progress)
Combination Therapy from the Start:L-methylfolate Plus Antidepressants
progress)
• Godfrey et al 1990– 24 depressed patients with low RBC folate
– 15 mg of d,l racemic methylfolate or placebo added to antidepressant treatment as usual
– Mood improved as did folate levels more than pantidepressants alone
Combination Therapy from the Start:Folic Acid and Fluoxetine
127 patients
62 patients: 500 μg 65 patients: placebo and62 patients: 500 μg folic acid and 20 mg
fluoxetine
65 patients: placebo and 20 mg fluoxetine
Greater improvement on Hamilton Rating Scale
% f
• only 61.1% of women were good responders
• 93.9% of women were good responders
• results mainly confined to women
This increase in plasma folate following treatment lead to a decrease in plasma
homocysteine, and also a lower depression score.
Coppen and Bailey. J Affect Disord 2000;60(2):121-30.
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Different Strokes for Different Folks: Treating Special Populations with Depression
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• Three randomized controlled trials
Resler et al 2008
Combination Therapy from the Start:Folic Acid and Fluoxetine
• Resler et al. 2008– 27 depressed patients on fluoxetine 20 mg
– 10 mg of folic acid or placebo added
– Mood improved and homocysteine levels decreased on folic acid
Resler et al, Neuroimmunomod 2008; 15(3):145-152
Combination Therapy From the Start:Eszopiclone and Fluoxetine
depression with insomnia Fluoxetine + eszopiclone
42% remission
Fluoxetine alone33% remission
treatment
Fava M et al. Biol Psychiatry 2006;59:1052-60;
Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.
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Different Strokes for Different Folks: Treating Special Populations with Depression
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Under Investigation:Early Combination
• Combining Oral Medications to End Depression (COMED) on the Depression Trials Network(COMED) on the Depression Trials Network
• Funded by NIMH
• Comparing potential benefits of combining any two antidepressants at initiation (bupropion, escitalopram, mirtazapine, venlafaxine)
Active support and monitoring (6–8 weeks every 1–2 weeks)
Mild depression
Guidelines for Treatment
Medication Cognitive behavioral therapy Interpersonal therapy
Moderate depression
Severe depression
Zuckenbrot RA et al. Pediatrics 2007;120:e1299-1312;Cheung A et al. J Fam Pract 2009;58(5):257-64; Cheung A et al. Pediatrics 2007;120:e1313-26.
Medication Medication + CBT
Severe depression
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Different Strokes for Different Folks: Treating Special Populations with Depression
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Medication
• Evidence-based treatments for adolescents include SSRIs
– Pooled AD trials: NNT=10, NNH=112,
– Fluoxetine and escitalopram are approved
• Warn patient and family about adverse effects
– Signs of switch to mania (excessive spending, risk taking, needing little sleep, promiscuous behavior, racing thoughts, pressured speech)
– Signs of behavioral activation (agitation, hostility, restlessness, suicidal ideation or behavior)suicidal ideation or behavior)
• Therapeutic dose is typically lower for adolescents than for adults
• Develop regular, frequent monitoring schedule
Cheung A et al. J Fam Pract 2009;58(5):257-64; Bridge JA et al. JAMA 2007;297(15):1683-96.
Treatment of Resistant Depression in Adolescents (TORDIA)
60
70Nonremitting
Remitting
Rat
ing
Sco
re
10
20
30
40
50
g
Chi
ldre
n’s
Dep
ress
ion
RS
cale
—R
evis
ed T
otal
S
0
0 6 12 24
C S
Week
N=334 adolescents with SSRI-resistant depression randomly assigned to alternate SSRI, venlafaxine, or medication switch + CBT.
Log time: p<0.001; remission: p=0.07; remission-by-log time: p<0.001.Emslie et al. Am J Psychiatry 2010;167(7):782-91.
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Different Strokes for Different Folks: Treating Special Populations with Depression
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Cognitive Behavioral Therapy (CBT):Goals and Benefits
• Typically weekly sessions for 12–16 weeks
Identify self defeating behaviors• Identify self-defeating behaviors
• Correct maladaptive thoughts
• Encourage participation in pleasurable activities
• Develop or reactivate social skills
• Develop problem solving strategies
Cheung A et al. J Fam Pract 2009;58(5):257-64.
Interpersonal Therapy (IPT)
• Typically 12–16 weeks
Addresses relationship difficulties arising from• Addresses relationship difficulties arising from– Grief (loss of someone significant)
– Interpersonal disputes (frequent fights with peers or family members)
– Role transition (change in school, break up)
– Interpersonal deficits (no significant relationship te pe so a de c ts ( o s g ca t e at o s poutside of family)
Cheung A et al. J Fam Pract 2009;58(5):257-64.
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Different Strokes for Different Folks: Treating Special Populations with Depression
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Risks of Antidepressants vs Depression
• No randomized controlled trials comparing effects of antidepressants vs depression during pregnancyantidepressants vs depression during pregnancy
Untreated depression Antidepressant effects
First trimester Third trimester
Impaired feto-placental functionMiscarriageLow fetal growth
Minor physical anomalyMiscarriage
Low birth weightSmall gestational agePulmonary hypertensionNeonatal withdrawal
Gentile S, Galbally M. J Aff Disord 2010, Epub ahead of print; Pedersen LH et al. Pediatrics 2010;125;e600-e608; Field. Int J Neurosci 2010;120:163-7.
Premature deliveryLow birth weightSmall gestational agePerinatal complications
Neuropsychological behavioral impairment
Antidepressant Use During Pregnancy and Lactation
Generic Pregnancy Risk Category
American Academy of Pediatrics (AAP) Rating
Lactation Risk Category
Amitripyline C Unknown, of concern L2
Bupropion C Unknown, of concern L3
Citalopram C Not available L3/L3 in older infants
Clomipramine C Unknown, of concern L2
Desipramine C Unknown, of concern L2
Doxepin C Unknown, of concern L5
Duloxetine C Not available Not availableDuloxetine C
Escitalopram C Not available L3/L3 in older infants
Fluoxetine C Unknown, of concern L2 in older infants, L3 if used in neonatal time
Adapted from ACOG Practice Bulletin. Obst & Gyn. 2008;111(4):1001-20.
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Different Strokes for Different Folks: Treating Special Populations with Depression
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Antidepressant Use During Pregnancy and Lactation (cont.)
Generic Pregnancy Risk Category
American Academy of Pediatrics (AAP) Rating
Lactation Risk Category
Fluvoxamine C Unknown of concern L2Fluvoxamine C Unknown, of concern L2
Imipramine D Unknown, of concern L2
Mirtazapine C Not available L3
Nefazodone C Not available L4
Nortriptyline D Unknown, of concern L2
Paroxetine D Unknown, of concern L2
S t li C Unknown of concern L2Sertraline C Unknown, of concern L2
Trazodone C Unknown, of concern L2
Venlafaxine C Not available L3
Adapted from ACOG Practice Bulletin. Obst & Gyn. 2008;111(4):1001-20.
Depression With or Without Dementia:Is it a Mood Disorder, a Cognitive Disorder, or Both?
DementiaGeriatricMDD
MDDDisorder
S t
Agitation
Apathy, Fatigue,Motivation
Cognition
++
++
+++
+
++
+++
++
+
+/-
++
++
+++Mood
MDDSymptom
Agitation /
+++ Most common++ Common
+ Average- None
Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.
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Treatment Recommendations
• Use of validated screening instrument
• Individual CBT and/or antidepressant treatment• Individual CBT and/or antidepressant treatment
• Patient education
• Insufficient evidence– Individual or group psychotherapy
• Not recommended for depression– Individual psychotherapy for overall mental health
– General education and/or skills training
– Geriatric health evaluation and management
– Exercise not targeting depression
– Rehabilitation and occupational therapy
Steinman LE et al. Am J Prev Med 2007:33(3):175-81.
Pharmacokinetics of Antidepressantsin the Elderly
• Absorption is generally complete, but slower
– Some medical conditions may reduce extent of absorptiony p
• Elderly have less fluid, so water-soluble medications can reach toxic levels more quickly
• Elderly have more adipose tissue, so fat-soluble medications (many psychotropics) are absorbed into less well-vascularized fat stores
– Take longer to reach therapeutic level
– Take longer to be excreted
Decreases in liver and kidney functions also cause longer time to• Decreases in liver and kidney functions also cause longer time to clearance and excretion
• Protein malnutrition is common, leaving more freely circulating protein-bound drugs (e.g., warfarin)
– Some psychotropics displace highly protein-bound drugs, increasing risk
Amella EJ. Am J Nursing 2006;83(2):372-89.
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Summary
• New research may soon lead to a revision of established treatment guidelinesg
• Treatment guidelines and risk/benefit ratios for antidepressants can vary for different subgroups
• For adolescents, don’t be afraid to use medication, but be sure to monitor and educate patients and their families about warning signs for mania and suicidality
• For pregnant women, discuss risks/benefits with the patient, the father, and coordinate with the pediatrician if treatment will occur postpartum
• For elderly, medication is often warranted but be aware of potential drug interactions and pharmacokinetic differences related to age
Copyright © 2010 Neuroscience Education Institute. All rights reserved.
Different Strokes for Different Folks: Treating Special Populations with Depression