Overview of Treatment- Resistant Depression Charles DeBattista, MD Associate Professor of Psychiatry...

Overview of Treatment-Overview of Treatment-Resistant DepressionResistant Depression

Charles DeBattista, MDCharles DeBattista, MDAssociate Professor of Psychiatry and Associate Professor of Psychiatry and

Behavioral SciencesBehavioral Sciences

Stanford University School of MedicineStanford University School of Medicine©©Copyright by Charles DeBattista, Ph.D., 2008Copyright by Charles DeBattista, Ph.D., 2008

22

Teaching PointsTeaching Points

• Most depression does not respond Most depression does not respond adequately to single monotherapy adequately to single monotherapy trialstrials

• STAR*D provides some insights on STAR*D provides some insights on the utility of combination treatmentthe utility of combination treatment

• Devices may play an increasing role Devices may play an increasing role in TRDin TRD

33

OutlineOutline

• Definition of treatment resistanceDefinition of treatment resistance• Implications of failure to treat to remissionImplications of failure to treat to remission• Biological factors in treatment resistanceBiological factors in treatment resistanceSTAR*D Acute findingsSTAR*D Acute findings• Level 1Level 1• Level IILevel II• Level IIILevel III• Level IVLevel IVSTAR*D relapse findingsSTAR*D relapse findingsRole of Devices in treatment resistant depressionRole of Devices in treatment resistant depression• ECTECT• TMSTMS• VNSVNS• DBSDBS

44

Pre-Lecture ExamPre-Lecture ExamQuestion 1Question 1

Limitations of the STAR*D trial includeLimitations of the STAR*D trial include1.1. Lack of a placebo groupLack of a placebo group2.2. Patients had the option of not Patients had the option of not

participating in a randomizationparticipating in a randomization3.3. Lack of inclusion of common Lack of inclusion of common

augmenting agents such as augmenting agents such as antipsychoticsantipsychotics

4.4. All of the aboveAll of the above

55

Question 2Question 2

The chance of achieving acute The chance of achieving acute remission by one or more trials in remission by one or more trials in STAR*D wasSTAR*D was

1.1. 20%20%

2.2. 50%50%

3.3. 80%80%

4.4. 100%100%

66


Compared to medication augmentation Compared to medication augmentation in the STAR*D trial, the addition of in the STAR*D trial, the addition of cognitive therapy wascognitive therapy was

a.a. significantly less effectivesignificantly less effective

b.b. significantly more effectivesignificantly more effective

c.c. about equally effectiveabout equally effective

d.d. not studiednot studied

77


Transcranial magnetic stimulation has Transcranial magnetic stimulation has an effect size in clinical trials that isan effect size in clinical trials that is

1.1. About that of unilateral ECTAbout that of unilateral ECT

2.2. About that of bilateral ECTAbout that of bilateral ECT

3.3. Less than that of ECTLess than that of ECT

4.4. Greater than that of ECTGreater than that of ECT

88


The typical time to see effects from The typical time to see effects from vagus nerve stimulation arevagus nerve stimulation are

1.1. 4-8 weeks4-8 weeks

2.2. 12 weeks12 weeks

3.3. 16-24 weeks16-24 weeks

4.4. Greater than 24 weeksGreater than 24 weeks

99

Major Depressive Disorder Major Depressive Disorder (MDD)(MDD)• Affects 18 million US residents and 340 Affects 18 million US residents and 340

million worldwidemillion worldwide11 (16.2% lifetime risk) (16.2% lifetime risk)22; 2/3 ; 2/3 are femaleare female

• Depression is Depression is chronic or recurrentchronic or recurrent– 25% to 40% experience a recurrence within 2 25% to 40% experience a recurrence within 2

years of the index episodeyears of the index episode33

– 85% experience recurrence after 15 years85% experience recurrence after 15 years33

– 20% to 35% of patients who experience one 20% to 35% of patients who experience one episode of depression have chronic depressionepisode of depression have chronic depression4-64-6

1. Greden JF. J Clin Psychiatry. 2001;62(suppl 22):5-9. 2. Kessler RC, et al. JAMA. 2003;289:3095-3105. 3. Keller MB, et al. Biol Psychiatry. 1998;44:348-360. 4. Keller MB, et al. Am J Psychiatry. 1982;139:438-442. 5. Mueller TI, et al. Psychiatr Clin North Am. 1996;19:85-102. 6. Fava M, et al, for the STAR*D Investigators Group. Psychiatr Clin North Am. 2003;26:457-494.

1010

1. World Health Organization Web Site. Accessed July 7, 2005. 2. Greden JF. J Clin Psychiatry. 2001;62(suppl 22):5-9. 3. Fawcett J. Int Clin Psychopharmacol. 1993;8:217-220. 4. Rowan PJ, et al. Psychol Med. 2002;32:903-908. 5. Druss BG, et al. Am J Psychiatry. 2000;157:1274-1278. 6. Simon GE. Biol Psychiatry. 2003;54:208-215.

The Need for Long-Term The Need for Long-Term Treatment Options in Treatment Options in DepressionDepression• Fourth most disabling condition worldwideFourth most disabling condition worldwide11; most disabling ; most disabling

condition for females (US)condition for females (US)

• Increased morbidity of comorbid general medical Increased morbidity of comorbid general medical conditionsconditions22 and increased rate of suicide as percent of total and increased rate of suicide as percent of total mortalitymortality33

• Loss of productivity in workplaceLoss of productivity in workplace22

• Patients with depression use substantially more healthcare Patients with depression use substantially more healthcare services than do patients without depressionservices than do patients without depression4-64-6

• Depression is life shorteningDepression is life shortening– Increased risk of CV events, stroke, etc.Increased risk of CV events, stroke, etc.

1111

TRD Overview: Levels of TRD Overview: Levels of ResistanceResistance

Thase ME, Rush AJ. Treatment-resistant depression. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press, Ltd.; 1995:1082-1097.

Stage Treatment Response

0 No single adequate trial of medication

1 Failure to respond to an adequate trial of 1 medication

2 Failure to respond to 2 different monotherapy trials of medications with different pharmacologic profiles

3 Stage 2 plus failure to respond to augmentation of 1 of the monotherapies

4 Stage 3 plus failure of a second augmentation strategy

5 Stage 4 plus failure to respond to ECT

1212

TRD OutcomeTRD Outcome

50

25

15

35

15

0

10

20

30

40

50

60 Respond

Remit

Thus, over 20% of patients with MDD have TRDThus, over 20% of patients with MDD have TRD

1st Treatment1 2nd Treatment2 3rd Treatment (If Needed)2

1. Depression in Primary Care, Vol 2. Treatment of Major Depression. Rockville, Md: Agency for Healthcare Policy and Research, US Department of Health and Human Services; 1993. AHCPR Publication 93-0551.2. Fava M, et al. for the STAR*D Investigators Group. Psychiatr Clin North Am. 2003;26:457-494.

% o

f P

atie

nts

1313

Potential Causes of TRDPotential Causes of TRD

• MisdiagnosisMisdiagnosis

• Inadequate treatment, undertreatment, or Inadequate treatment, undertreatment, or starting treatment too latestarting treatment too late11

• Failure to achieve initial remissionFailure to achieve initial remission22

• NonadherenceNonadherence

• Failure to address concurrent disordersFailure to address concurrent disorders11

– Occult substance abuseOccult substance abuse– Occult general medical conditions (GMCs)Occult general medical conditions (GMCs)– Concurrent Axis I or II disordersConcurrent Axis I or II disorders

1. Thase ME, Rush JA. J Clin Psychiatry. 1997;58(suppl 13):23-29. 2. Judd LL, et al. J Affect Disord. 1998;50:97-108.

1414

Assessing Current Treatment andAssessing Current Treatment andChecking for Nonadherence (1)Checking for Nonadherence (1)

• Did the patient receive adequate treatment?Did the patient receive adequate treatment?– An inadequate dose or duration of treatment can prevent An inadequate dose or duration of treatment can prevent

remissionremission

• Experts recommend a minimum trial period between 6 Experts recommend a minimum trial period between 6 and 12 weeks in lengthand 12 weeks in length

• Pharmacokinetics can differ in elderly and pediatric Pharmacokinetics can differ in elderly and pediatric populationspopulations

• Is patient nonadherent?Is patient nonadherent?– Ask patient what they are taking and whenAsk patient what they are taking and when– ≥≥50% of patients fail to take antidepressants as prescribed 50% of patients fail to take antidepressants as prescribed

due to lack of understanding of instructions or unnatural due to lack of understanding of instructions or unnatural fears of side effects/drug dependencefears of side effects/drug dependence

– Ask about troubling and intolerable side effects, including Ask about troubling and intolerable side effects, including sexual dysfunction, nausea, akathisia, etc.sexual dysfunction, nausea, akathisia, etc.

Reus VI. Psychiatr Clin North Am 1996.Trivedi MH. Ann Clin Psychiatry 2003.

1515

Assessing Current Treatment andAssessing Current Treatment andChecking for Nonadherence (2)Checking for Nonadherence (2)

Patient has improved but has residual symptomsPatient has improved but has residual symptoms

Stahl SM. Psychopharmacology of antidepressants; 1997.

Optimize dose Augment/switch

Painful somatic symptoms: add pregabalin/switch to

dual-action agent

Fatigue: add bupropion or modafinil

1616

Assessing Current Treatment and Assessing Current Treatment and Checking for Nonadherence (3)Checking for Nonadherence (3)

If patient is nonadherent due to side effectsIf patient is nonadherent due to side effects

Stahl SM. Psychopharmacology of antidepressants; 1997.

Reduce dose/switch Utilize pharmacologic remedies

Insomnia: add trazodone or

zolpidem

Fatigue: add modafinil

Sexual dysfunction:

add sildenafil, vardenafil, tadalafil, or bupropion

Nausea: add mirtazapine

Activation/ jitteriness: add benzodiazepine

1717

Treatment-Resistant Treatment-Resistant Depression: PredictorsDepression: Predictors

• Higher baseline severity/longer Higher baseline severity/longer duration of illnessduration of illness

• Early onset of illnessEarly onset of illness

• Comorbid anxiety, panic symptoms, Comorbid anxiety, panic symptoms, substance abusesubstance abuse

• History of childhood abuseHistory of childhood abuse

• Lack of social supportLack of social support

1818

Biologic Treatment Biologic Treatment ResistanceResistance

• Morphologic brain changes and Morphologic brain changes and impaired neurogenesis with recurrent impaired neurogenesis with recurrent depression chronicitydepression chronicity1,21,2

• Genetic polymorphismsGenetic polymorphisms33

1. Henn FA, Vollmayr B. Biol Psychiatry. 2004;56:146-150. 2. Manji HK, et al. Nat Med. 2001;7:541-547.3. Neumeister A, et al. Psychopharmacology. 2004;174:512-524.

1919

Brain atrophy in Brain atrophy in depression?depression?

2020

Failure to Achieve Initial Failure to Achieve Initial Remission Produces Worse Remission Produces Worse Long-Term OutcomesLong-Term Outcomes

SSD=subsyndromal depression; subthreshold depressive symptoms.Reprinted from Judd LL, et al. J Affect Disord. 1998;50:97-108, with permission from Elsevier.

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

Weeks to First Relapse Into Major Depressive Episode (MDE)

0

0.2

0.4

0.6

0.8

1

Asymptomatic recovery (n=155) Residual SSD recovery (n=82)

MedianWeeks Well

23168

(95% ConfidenceInterval)

(169 – 332) (49 – 88)

2121

TRD MortalityTRD Mortality

• TRD is associated with TRD is associated with – Increased mortalityIncreased mortality– High risk of suicide (~15% of patients with TRD)High risk of suicide (~15% of patients with TRD)11

• Patients with well-characterized TRD are Patients with well-characterized TRD are likely to report hopelessness and likely to report hopelessness and prominent suicidal ideationprominent suicidal ideation – One third of patients studied reported significant suicidal ideas One third of patients studied reported significant suicidal ideas

or gesturesor gestures22

• Suicidal thoughts have a negative impact Suicidal thoughts have a negative impact on the course of depressionon the course of depression

1. American Pharmaceutical Association Web site. Accessed December 18, 2004. 2. Papakostas GI, et al. J Nerv Ment Dis. 2003;191:444.

2222

TRD MorbidityTRD Morbidity

• TRD is associated withTRD is associated with– Increased economic burdenIncreased economic burden– Greater healthcare utilization and costsGreater healthcare utilization and costs1-31-3

•Patients with depression made more than 3Patients with depression made more than 3 the number of doctor visits than those the number of doctor visits than those without depressionwithout depression22

•Hospitalized TRD group had 7Hospitalized TRD group had 7 the annual the annual health care costs of the outpatient TRD group health care costs of the outpatient TRD group and 19and 19 the costs of the comparison group the costs of the comparison group33

1. Russell JM, et al. J Clin Psychiatry. 2004;65:341-347. 2. Lépine J-P, et al, on behalf of the DEPRES Steering Committee. Int Clin Psychopharmacol. 1997;12:19-29. 3. Crown WH, et al. J Clin Psychiatry. 2002;63:963-971.

2323

Healthcare Utilization Increases With Healthcare Utilization Increases With Greater Degrees of Treatment Greater Degrees of Treatment ResistanceResistance

0

200

400

600

800

1,000

1,200

1,400

2 4 6 8Number of Depression Medication Regimen Changes

Hea

lth

care

Co

sts

per

Mo

nth

($)

Inpatient

Outpatient

PharmaceuticalTotal

Russell JM, et al. J Clin Psychiatry. 2004;65:341-347.

2424

Psychosocial Impact of TRDPsychosocial Impact of TRD

• The Longitudinal Interval Follow-up Evaluation (LIFE) scale The Longitudinal Interval Follow-up Evaluation (LIFE) scale was used to measure psychosocial functioning was used to measure psychosocial functioning in 92 patients with TRD in 92 patients with TRD

• Specific impairments notedSpecific impairments noted– Mild-to-moderate impairment in work-related activities Mild-to-moderate impairment in work-related activities – Good-to-fair interpersonal relations Good-to-fair interpersonal relations – Poor level of involvement in recreational activities Poor level of involvement in recreational activities – Mild impairment of ability to enjoy sexual activity Mild impairment of ability to enjoy sexual activity

• However, patients and clinicians rated global social However, patients and clinicians rated global social adjustment as pooradjustment as poor

Petersen T, et al. Eur Psychiatry. 2004;19:196-201.

2525

Clinical Management of TRDClinical Management of TRD

• Polypharmacy is common; which treatments or Polypharmacy is common; which treatments or combinations are best is not knowncombinations are best is not known1,21,2

• Preferred treatment steps are not definedPreferred treatment steps are not defined1,21,2

• ECT, which may be effective acutely, may be ECT, which may be effective acutely, may be declined, may not be sustained due to adverse declined, may not be sustained due to adverse events (AEs), and has poor long-term outcomesevents (AEs), and has poor long-term outcomes– Side effects and adherence limit treatment effectiveness Side effects and adherence limit treatment effectiveness – Greater treatment resistance is associated with lower Greater treatment resistance is associated with lower

ECT response and higher post-ECT relapse ratesECT response and higher post-ECT relapse rates3,43,4

1. Fava M, et al, for the STAR*D Investigators Group. Psychiatr Clin North Am. 2003;26:457-494. 2. Rush AJ, et al, for the STAR*D Investigators Group. Control Clin Trials. 2004;25:119-142. 3. Prudic J, et al. Am J Psychiatry. 1996;153:985-992. 4. Sackeim HA, et al. JAMA. 2001;285:1299-1307.

2626

““Treatment-Resistant” Depression:Treatment-Resistant” Depression:Other Contributing FactorsOther Contributing Factors

• Comorbid medical conditions, especially Comorbid medical conditions, especially endocrine/metabolic disorders and disturbances of endocrine/metabolic disorders and disturbances of thyroid/adrenal axesthyroid/adrenal axes– Disorders of this nature may affect drug efficacyDisorders of this nature may affect drug efficacy– Pharmacotherapies used to treat comorbid conditions Pharmacotherapies used to treat comorbid conditions

may also affect antidepressant efficacymay also affect antidepressant efficacy

• Nutritional deficienciesNutritional deficiencies– Folate, thiamine, B6, B12, copper, zincFolate, thiamine, B6, B12, copper, zinc

• Substance use/abuseSubstance use/abuse

• Sleep deprivationSleep deprivation

• Life (social/familial/financial) stressLife (social/familial/financial) stress

• Lack of exerciseLack of exercise

Reus VI. Psychiatr Clin North Am 1996.

2727

Treatment Algorithm Treatment Algorithm SnapshotSnapshot

Level2

Level1

Level2a

Level3

Level4

STAR*D Algorithm

Initial treatment: citalopram

Switch to: bupropion (sustained-release), cognitive therapy, sertraline,venlafaxine (extended-release); Or augment with: bupropion (sustained-release), buspirone, cognitive therapy

(Only for those receiving cognitive therapy in Level 2)switch to: bupropion (sustained-release) or venlafaxine (extended-release)

Switch to: mirtazapine or nortriptyline (Aventyl) or augment with: lithium (Eskalith, Lithobid) or triioclothyronine (only with bupropion [sustained-release], sertraline, venlafaxine [extended-release])

Switch to : tranylcypromine (Parnate) or mirtazapine combined withvenlafaxine (extended-release)

Rush AJ et al. (2003), Am J Psychiatry 160(2):237

2828

Two Thirds of STAR*D Two Thirds of STAR*D Citalopram Responders Citalopram Responders Improved by Week 6Improved by Week 6

Trivedi MH et al. (2006), Am J Psychiatry 163(1):28-40

N=2876Response = 50% QIDS-SR16

65.2%

17.8

24.522.9

11.5 11.0

4.97.6

0

5

10

15

20

25

30

2 4 6 8 10 12 >13

Weeks

Per

cen

t

2929

SER(238)

BUP(239)

VEN(250)

CT(62)

CIT +BUP(279)

CIT +BUS(286)

CIT +CT(85)

Switch Options Augmentation Options

Level 2Level 2

Randomize to Options Across All Acceptable Strategies*

*If strategy group is not acceptable to the patient, then he/she is randomized to treatment options within remaining acceptable treatment strategies. If all treatment strategies are rejected, then patient enters naturalistic follow-up; SER = sertraline; VEN = venlafaxine XR; CT = cognitive therapy; CIT = citalopram; BUS = buspirone; Rush AJ et al. (2004), Control Clin Trials 25(1):119-142

Level 2 Medication SwitchLevel 2 Medication Switch

3131

Primary Efficacy Outcome

HAM-D17 Remission

Level 2 Switch: Primary and Level 2 Switch: Primary and Secondary Efficacy OutcomesSecondary Efficacy Outcomes

Per

cen

t

QIDS-SR16

ResponseQIDS-SR16

RemissionHAM-D17

Remission

N=727; QIDS-SR = Quick Inventory of Depressive Symptomatology—Self-Rated; No significant differences among treatment groups; Rush AJ et al. (2006), N Engl J Med 354(12):1231-1242

17.621.3

24.8

0

5

10

15

20

25

30

35

40SERT BUP SR VEN XR

Level 2 Medication Level 2 Medication AugmentationAugmentation

3333

Level 2 Augment: Primary and Level 2 Augment: Primary and

Secondary Efficacy OutcomesSecondary Efficacy Outcomes P

erce

nt

QIDS-SR16

Response

Primary Efficacy Outcome

HAM-D17 Remission

QIDS-SR16

RemissionHAM-D17

Remission

N=565; No significant differences among treatment groups; Trivedi MH et al. (2006), N Engl J Med 354(12):1243-1252

29.7 30.1

0

10

20

30

40

50BUP SR BUS

Level 2 Cognitive Therapy Level 2 Cognitive Therapy StudiesStudies

3535

STAR*D Treatment Outcomes: STAR*D Treatment Outcomes: Remission Rates CT vs. Medication Remission Rates CT vs. Medication AugmentAugment

MED = medication augmentation; Thase ME et al. (2007), Am J Psychiatry 164(5):739-752

23.1

33.330.8

33.3

0

10

20

30

40

Per

cen

t

HRSD-17 QIDS-SR-16

CT(N=65)

MED(N=117)

3636

STAR*D Level 2 Treatment Outcomes: STAR*D Level 2 Treatment Outcomes: Remission Rates CT vs. Medication Remission Rates CT vs. Medication SwitchSwitch

Thase ME et al. In preparation

25.027.9

30.6

26.7

0

10

20

30

40

CT(N=36)

MED(N=86)

Per

cen

tHRSD-17 QIDS-SR-16

3737

Level 3Level 3

Randomize

Switch Options Augmentation Options

MRT NTPL-2 Tx

+ LiL-2 Tx+ THY

MIRT = mirtazapine; NTP = nortriptyline; Rush AJ et al. (2004), Control Clin Trials 25(1):119-142

3838

Treatment Outcomes Treatment Outcomes Remission: Level 3 SwitchRemission: Level 3 Switch

Fava M et al. (2006), Am J Psychiatry 163(7):1161-1172

HRSD-17 QIDS-SR-16

12.3

19.8

8.0

12.4

0

10

20

30

MIRT(N=114)

NTP(N=121)

Per

cen

t

3939

Treatment Outcomes Treatment Outcomes Remission: Level 3 Remission: Level 3 AugmentAugment

Nierenberg AA et al. (2006), Am J Psychiatry 163(9):1519-1530

HRSD-17 QIDS-SR-16

15.9

24.7

13.2

24.7

0

10

20

30

Lithium(N=69)

Triiodothyronine(N=73)

Per

cen

t

4040

Level 4Level 4

Randomize

Switch Options

TCPVEN-XR+ MRT

TCP = tranylcypromine; Rush AJ et al. (2004), Contol Clin Trials 25(1):119-142

4141

Treatment Outcomes Treatment Outcomes Remission: Level 4Remission: Level 4

McGrath PJ et al. (2006), Am J Psychiatry 163(9):1531-1541

HRSD-17 QIDS-SR-16

6.9

13.713.8

15.7

0

10

20

TCP(N=58)

VEN + MIRT(N=51)

Per

cen

t

4242

Mono = single medication regimen; Augm = combination medication treatment; 1Trivedi MH et al. (2006), Am J Psychiatry 163:28-40; 2Trivedi MH et al. (2006), N Engl J Med 354:1243-1252; 3Rush AJ et al. (2006), N Engl J Med 354:1231-1242; 4Nierenberg AA et al. (2006), Am J Psychiatry 163:1519-1530; 5Fava M et al. (2006), Am J Psychiatry 163:1161-1172; 6McGrath PJ et al. (2006), Am J Psychiatry 163(9):1531-1541

STAR-D Remission RatesSTAR-D Remission Rates Across All 4 Levels Across All 4 Levels

% R

emis

sio

n

10

20

30

40Level 11

Level 2 2, 3

Level 3 4, 5

Level 46

Mono

8-10 weeks

≤14 weeksAugm

Mono

Mono

HAMD-17 ≤7

Remission Definition:

Augm

Mono

Augm

Treatment ResistanceLow High0

11.9 weeks

≤14 weeks

4343

Level 1 Follow-Up: Relapse Level 1 Follow-Up: Relapse RatesRates

p<0.0001; Relapse = QIDS-IVR16 ≥11; Rush AJ et al. (2006), Am J Psychiatry 163(11):1905-1917

0

0.25

0.50

0.75

1.00

0 3 6 129

Cu

mu

lati

ve P

rob

abil

ity

of

Rel

apse

Months in Follow-Up

Remission Yes

No

4444

Level 2 Follow-UpLevel 2 Follow-Up


0

0.25

0.50

0.75

1.00

0 3 6 129

Cu

mu

lati

ve P

rob

abil

ity

Months in Follow-Up

Remission Yes

No

4545


P<0.0132; Relapse = QIDS-IVR16 ≥11; Rush AJ et al. (2006), Am J Psychiatry 163(11):1905-1917

0

0.25

0.50

0.75

1.00

0 3 6 129

Months in Follow-Up

Remission Yes

No

Cu

mu

lati

ve P

rob

abil

ity

4646


P<0.1387; Relapse = QIDS-IVR16 ≥11; Rush AJ et al. (2006), Am J Psychiatry 163(11):1905-1917

0

0.25

0.50

0.75

1.00

0 3 6 129

Months in Follow-Up

Remission Yes

No

Cu

mu

lati

ve P

rob

abil

ity

4747

Relapse in Follow-Up for Patients Relapse in Follow-Up for Patients Not Remitting to Different Not Remitting to Different Numbers of Acute Treatment Numbers of Acute Treatment StepsSteps


0

0.25

0.50

0.75

1.00

0 3 6 129Months in Follow-

Up

1 Step (N=388)

2 Steps (N=237)

3 Steps (N=66)

4 Steps (N=34)

Cu

mu

lati

ve P

rob

abil

ity

4848

Relapse in Follow-Up for Patients Relapse in Follow-Up for Patients Remitting With Different Numbers Remitting With Different Numbers of Acute Treatment Stepsof Acute Treatment Steps

p<0.0001; Relapse = QIDS-IVR16 > 11

0

0.25

0.50

0.75

1.00

0 3 6 129

Cu

mu

lati

ve P

rob

abil

ity

Months in Follow-Up

1 Step (N=1085)

2 Steps (N=383)

3 Steps (N=35)

4 Steps (N=15)

4949

Use of ECT in Patients With Use of ECT in Patients With MDDMDD• Patients with MDD most likely to benefit from ECTPatients with MDD most likely to benefit from ECT

– Patients with delusionsPatients with delusions11

– Elderly patientsElderly patients11

– Patients presenting with high suicide riskPatients presenting with high suicide risk11

– Patients with history of poor response to Patients with history of poor response to pharmacotherapypharmacotherapy22

– Patients with history of responsiveness to ECTPatients with history of responsiveness to ECT22

– Patients who choose itPatients who choose it22

– Patients with bipolar disorderPatients with bipolar disorder33

• ECT is a treatment used for MDD only after multiple ECT is a treatment used for MDD only after multiple treatments have been poorly tolerated or do not yield a treatments have been poorly tolerated or do not yield a therapeutic responsetherapeutic response

1. Fink M, Bailine S. Am J Managed Care. 1998;4:107-112. 2. Weiner RD, Krystal AD. In: Gabbard GO, ed. Treatments of Psychiatric Disorders. Washington, DC: American Psychiatric Press; 2001:1267-1293. 3. Kahn DA, et al. J Psychiatr Pract. 2000;6:197-211.

5050

Efficacy of ECT in MDD and Efficacy of ECT in MDD and TRDTRD• The acute effect of ECT in MDD is well establishedThe acute effect of ECT in MDD is well established

– Continuation therapy is required to prevent relapsesContinuation therapy is required to prevent relapses11

– In 1 recent study, within 24 weeks of achieving In 1 recent study, within 24 weeks of achieving remission (HAMD reduced by 60% and remission (HAMD reduced by 60% and ≤≤10), 64% of 10), 64% of patients had relapsedpatients had relapsed22

• TRD is predictive of post-ECT relapseTRD is predictive of post-ECT relapse– Patients with TRD are at high risk for relapse within 1 Patients with TRD are at high risk for relapse within 1

year following ECT responseyear following ECT response33

• Only 32% of patients with TRD maintained their Only 32% of patients with TRD maintained their response during the year after ECTresponse during the year after ECT treatmenttreatment44

1. Sackeim HA, et al. JAMA. 2001;285:1299-1307. 2. Prudic J, et al. Biol Psychiatry. 2004;55: 301-312. 3. Sackeim HA, et al. J Clin Psychopharmacol. 1990;10:96-104. 4. Sackeim HA, et al. Arch Gen Psychiatry. 2000;57:425-434.

5151

Medication Resistance Predicts Medication Resistance Predicts Relapse Following Successful ECTRelapse Following Successful ECT

• 94% of relapses 94% of relapses occurred in the first 6 occurred in the first 6 monthsmonths

• Patients with TRD were Patients with TRD were twice as likely to twice as likely to relapserelapse

• Significantly greater Significantly greater relapse in TRD relapse in TRD ((pp=0.01)=0.01)– TRD=68% relapseTRD=68% relapse– Non-TRD=36% relapseNon-TRD=36% relapse

• Higher HAMD at end of Higher HAMD at end of ECT predicted relapseECT predicted relapse

Sackeim HA, et al. Arch Gen Psychiatry. 2000;57:425-434.

010 20 30 40 50

Not Resistant

Medication Resistant

Weeks

0

0.2

0.4

0.6

0.8

1

Cu

mu

lati

ve P

rob

abili

ty o

f R

emai

nin

g W

ell

5252

Time-varying electrical current in a coil produces

focal 2 tesla magnetic fieldthat passes unimpeded through

skull and

induces current in neurons and

behavioral change

Modest to moderate effects in Sham Controlled studies

Transcranial Magnetic Transcranial Magnetic StimulationStimulation

5353

TMS Efficacy Yet to Be TMS Efficacy Yet to Be Established: Meta-analysis of Established: Meta-analysis of 14 Controlled Trials14 Controlled Trials

Martin JLR et al, Br J Psychiatry (2003), 182, 480-491.

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Vagus Nerve Stimulation Vagus Nerve Stimulation (VNS)(VNS)

LimitationsLimitations– Efficacy data from Efficacy data from

nonrandomized studynonrandomized study– Surgical procedureSurgical procedure– CosmesisCosmesis– Nonacute Nonacute

antidepressant effectantidepressant effect– MRI contraindicationMRI contraindication– Battery LifeBattery Life

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VNS Clinical Outcomes:VNS Clinical Outcomes:One Year Post-ImplantationOne Year Post-Implantation

40

50

40

17

4650

57

29

0

10

20

30

40

50

60

70

Response,HRSD

Response,MADRS

Response,CGI-I

Remission,HRSD

Evaluation Method

Patients

(%

)

3 months, n=30

6 months, n=29

9 months, n=27

12 months, n=28

HRSD=Hamilton Rating Scale for Depression, MADRS=Montgomery Asberg Depression Rating Scale, CGI-I=Clinical Global Impression-Improvement. HRSD≤10, for remission.

Patients received an additional 9 months of VNS after exiting a 3-month acute study.

Marangell LB et al. Biol Psychiatry 2002.

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Deep Brain Stimulation (DBS)Deep Brain Stimulation (DBS)

• FDA Approved for FDA Approved for Parkinson’s and TremorParkinson’s and Tremor

• Investigational for OCD, Investigational for OCD, TRDTRD

• Stereotactic Target from Stereotactic Target from MRI MRI

• Two chest-wall Internal Two chest-wall Internal Pulse GeneratorsPulse Generators

• Burr holes in skull for Burr holes in skull for electrode placementelectrode placement

• Stimulation parameters Stimulation parameters programmed by programmed by computer, through computer, through “wand”“wand”

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DBS: Subgenual Cingulate (Cg25) DBS: Subgenual Cingulate (Cg25) RegionRegion

Response in 4 of 6 patientsResponse associated with reduction in local and downstream limbic CBF on PET

Mayberg HS et al, Neuron, 2005

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ConclusionsConclusions

• TRD is common and associated with TRD is common and associated with significant morbidity and mortalitysignificant morbidity and mortality

• STAR*D highlights the difficulties of STAR*D highlights the difficulties of achieving and sustaining remissionachieving and sustaining remission

• Combinations of medications are Combinations of medications are often neededoften needed

• Devices may play an increasing role in Devices may play an increasing role in highly resistant depressionhighly resistant depression

1. American Pharmaceutical Association Web site. Accessed December 18, 2004. 2. Russell JM, et al. J Clin Psychiatry. 2004;65:341-347. 3. Crown WH, et al. J Clin Psychiatry. 2002;63:963-971. 4. Lépine J-P, et al, on behalf of the DEPRES Steering Committee. Int Clin Psychopharmacol. 1997;12:19-29.

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Post-Lecture ExamPost-Lecture ExamQuestion 1Question 1

Limitations of the STAR*D trial includeLimitations of the STAR*D trial include1.1. Lack of a placebo groupLack of a placebo group2.2. Patients had the option of not Patients had the option of not

participating in a randomizationparticipating in a randomization3.3. Lack of inclusion of common Lack of inclusion of common

augmenting agents such as augmenting agents such as antipsychoticsantipsychotics

4.4. All of the aboveAll of the above

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The chance of achieving acute The chance of achieving acute remission by one or more trials in remission by one or more trials in STAR*D wasSTAR*D was

1.1. 20%20%

2.2. 50%50%

3.3. 80%80%

4.4. 100%100%

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Compared to medication augmentation Compared to medication augmentation in the STAR*D trial, the addition of in the STAR*D trial, the addition of cognitive therapy wascognitive therapy was

a.a. significantly less effectivesignificantly less effective

b.b. significantly more effectivesignificantly more effective

c.c. about equally effectiveabout equally effective

d.d. not studiednot studied

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Transcranial magnetic stimulation has Transcranial magnetic stimulation has an effect size in clinical trials that isan effect size in clinical trials that is

1.1. About that of unilateral ECTAbout that of unilateral ECT

2.2. About that of bilateral ECTAbout that of bilateral ECT

3.3. Less than that of ECTLess than that of ECT

4.4. Greater than that of ECTGreater than that of ECT

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The typical time to see effects from The typical time to see effects from vagus nerve stimulation arevagus nerve stimulation are

1.1. 4-8 weeks4-8 weeks

2.2. 12 weeks12 weeks

3.3. 16-24 weeks16-24 weeks

4.4. Greater than 24 weeksGreater than 24 weeks

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Answers to Pre and Post Answers to Pre and Post Lecture ExamsLecture Exams

1.1. DD

2.2. CC

3.3. CC

4.4. CC

5.5. DD

Overview of Treatment- Resistant Depression Charles DeBattista, MD Associate Professor of Psychiatry...

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