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




Copyright © 2010 Neuroscience Education Institute. All rights reserved.

Different Strokes for Different Folks: Treating Special Populations with Depression

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MDD Treatment Guidelines:Are There Changes in Store?


partial response no response/not tolerated

Raise dose or augment 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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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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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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• 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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• 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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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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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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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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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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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



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