Learning Pediatric Depressive Disorders Goals/Objectives Public - - PDF document

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Treatment Resistant Depression in Youth

John V. Campo, M.D.

Nationwide Children’s Hospital and The Ohio State University

Learning Goals/Objectives

• Familiarity with the prevalence and impact
• f depression in children and adolescents
• Familiarity with psychoeducation and

evidence based treatments for pediatric depressive disorders

• Develop a management approach for

pediatric depressive disorders that prove resistant to initial treatment

Pediatric Depressive Disorders Prevalence

• ~2% of children
• ~4 to 8% of adolescents
• Cumulative incidence 10-20% age 18
• Gender ratio

Equal before puberty Females predominate after puberty

Pediatric Depressive Disorders Public Health Relevance

• Often unrecognized

By patients and families By clinicians

• Functional impairment

Interpersonal and social impairment Poor school attendance/performance

• Risk of persistence/recurrence

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Pediatric Depressive Disorders Public Health Relevance (cont.)

• Psychiatric Comorbidity

~ 1/3 to 2/3 of patients Greater impairment and service use Associated with treatment resistance

• Physical Comorbidity

Functional somatic symptoms Minor physical illness Chronic physical illness

• Physical health risks

Suicide, violence, accidental injury Alcohol/drug/tobacco use Health risk behaviors/unhealthy lifestyle Exacerbation of existing physical disease

• Nonadherence
• Physiologic effects on disease process

Pediatric Depressive Disorders Public Health Relevance (cont.)

• Declining school performance
• Social withdrawal
• Temper outbursts/arguing
• Alcohol/substance abuse
• School absenteeism
• Functional somatic symptoms

Pediatric Depressive Disorders

Common Presentations – Signs

Major Depressive Disorder (MDD) Features in Youth

• Clinical picture similar to adults
• Median duration

7 - 9 months - clinical samples 1 - 2 months - community samples ~ 90% remit by 1 to 2 years

• Recurrence ~ 70% within 5 years

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• Bipolar disorder in 10 to 20%
• Predictors of bipolar disorder

Psychosis FH of bipolar disorder Rapid onset/offset Mania/hypomania with Rx

Major Depressive Disorder (MDD) Features in Youth (cont.)

• Greater initial severity
• Psychiatric comorbidity

Dysthymic disorder Other psychiatric disorder

• Anxiety, ADHD, Substance abuse
• Parental depression
• Parent-child conflict

Major Depressive Disorder (MDD) Risk for Prolonged Episode Major Depressive Disorder (MDD) Risk for Recurrence

• Greater initial severity
• Subsyndromal depression
• Parent-child conflict
• Abuse history
• Clear and frank diagnosis

Reassurance and education Address uncertainties

• Treatment as a partnership

Delineate responsibilities Facilitate communication Honest collaboration

• Instill hope and positive expectations

Building Foundation for Intervention Establishing Credibility

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Treatment of Pediatric Depression What is known?

• Psychotherapeutic treatment

Cognitive Behavioral Therapy Interpersonal Therapy

• Psychopharmacologic treatment

SSRIs

• Combination treatment

CBT + SSRI

Treatment

Self-Care

SSRIs Selective Serotonin Reuptake Inhibitors

Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac)

• FDA approved pediatric MDD, OCD

Fluvoxamine (Luvox)

• FDA approved pediatric OCD

Paroxetine (Paxil) Sertraline (Zoloft)

• FDA approved pediatric OCD
• Several positive RCTs

Best data for fluoxetine Less data for other individual SSRIs

• > 2 positive trials needed for FDA approval
• Often 4-5 trials needed for adult Rx approval
• High placebo response rates (33-59%)
• SSRI continuation may ↓ depression relapse
• Combination CBT + SSRI > SSRI alone

SSRI Efficacy Major Depressive Disorder (MDD)

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• 12-week multisite study of youth aged 12 to 17

years with MDD (N=439)

• Clinical Global Improvement

CBT + fluoxetine 71%* Fluoxetine 61%* CBT 43% Placebo 35%

• * significantly different from placebo
• CBT did not differentiate from placebo
• Suicidality ↓ from 29% to 10% by week 12

TADS Treatment for Adolescents w/ Depression Study SSRI Safety Practical Considerations

• Relatively HIGH therapeutic index (TI)

Low short term toxicity

• Risk of suicidality
• Risk of precipitating mania
• Pharmacodynamic interactions

Serotonin syndrome, bruising/bleeding

SSRI Safety Practical Considerations

• Pharmacokinetic drug-drug interactions

Cytochrome P-450 system

• Citalopram, escitalopram, sertraline least

problematic

• Lack of long-term safety data
• Usually mild and dose dependent

GI symptoms (e.g., nausea, diarrhea) Headache Anxiety, nervousness, panic Sleep disturbance Restlessness, irritability, and agitation Sedation, fatigue Dizziness or lightheadedness Sexual dysfunction Other (e.g., tremor, dry mouth, sweating)

• No well demonstrated long-term AEs in youth

SSRI Tolerability Common AEs (Side Effects)

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SSRI Safety FDA “Black Box” Warning

• To all antidepressant medications in U.S.

“increase the risk of suicidal thinking and behavior in children and adolescents…”

• Based on FDA review of 24 RCTs (N ~ 4400)

SSRIs (Citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) Non-SSRIs (Bupropion, mirtazipine, nefazodone, venlafaxine) 95 AEs reclassified from raw data

• “Suicidality” = attempt, SI, preparatory acts
• Suicidality in ~ 4% drug vs. 2% placebo

No completed suicides Only significant for venlafaxine alone

SSRI Safety A Public Health Perspective

• Coincident ↓ pediatric suicide rates with ↑

SSRI prescribing since late 1990s Similar findings in US and Europe Geographic trends for ↓ suicide with ↑ Rx

• Longer Rx may reduce suicide risk

Rx > 180 days vs. Rx < 55 days

• Studies of completed suicide

< 10% completed suicides who had been prescribed antidepressants + at autopsy

Reanalysis of FDA Data Antidepressant Efficacy for Youth

3 (2-5) <.001 37 (22-52)

69 vs. 39

1,162

6 Anxiety

6 (4-8) <.001 20 (13-27)

52 vs. 32

718

6 OCD

10 (7-15) <.001 11 (8-15)

61 vs. 50

3,430

15 MDD

NNT (95% CI) P- Value % Risk Difference (95% CI) % Response Drug vs. Placebo N = 5,310 # of RCTs

Dx

Bridge et al., JAMA 2007

CI= Confidence Interval RCTs = Randomized Controlled Trials

Reanalysis of FDA Data Rate of Emergent Suicidality

143 NS 0.7(-.4-2)

• 1vs. 0.2

1,162 6 Anxiety 200 NS 0.5(-1- 2) 1 vs. 0.5 718 6 OCD 125 NS 1(-0.1-2) 3 vs. 2 3,430 15 MDD

NNH P- Value % Risk Difference (95% CI) Emergent Suicidality (%) Drug vs. Placebo

N = 5,310

# of RCTs Dx

Bridge et al., JAMA 2007

CI= Confidence Interval NS = Not significant RCTs = Randomized Controlled Trials

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• “Start low and go slow”

Starting dose over first 3 to 7 days If tolerated, increase to target dose Reevaluate dose within 2 –3 weeks

SSRI Dosing

• Starting doses

Target Max 10 mg citalopram 20 mg 40 mg 5 mg escitalopram 10 mg 20 mg 10 mg fluoxetine 20 mg 40 mg 50 mg fluvoxamine 100 mg 300 mg 25 mg sertraline 50 mg 200 mg

SSRI Dosing

• 12-week multisite study of youth aged 12 to 18

years with MDD who failed to respond to SSRI (N=334)

• Clinical Response

SSRI 47.0 % Venlafaxine 48.2 % No CBT 40.5 % CBT 54.8 %

TORDIA Treatment of Resistant Depression in Adolescents

• Conclusion

CBT + Medication change > Medication change alone Switch to another SSRI just as efficacious as switch to Venlafaxine and with fewer adverse events

TORDIA Treatment of Resistant Depression in Adolescents

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SSRI Failure for Depression What to do with limited evidence?

• Encourage psychotherapy – especially CBT
• Medication option 1 – Switch to a different SSRI
• Medication option 2 – Switch to a different agent

Switch to different antidepressant class

• Novel agents (bupropion)
• SNRIs (venlafaxine, mirtazapine, duloxetine)
• Older agents (TCAs, MAOIs)

SSRI Failure for Depression What to do with limited evidence?

• Medication option 3 – Augmentation strategies

SSRI augmentation strategies

• Bupropion
• Busiprone
• Lithium
• Atypical antipsychotics (e.g., aripiprazole)

Ohio State University College of Medicine & Public Health

Treatment-Refractory Depression

Lessons from Sir Arthur Conan Doyle & Sherlock Holmes Stephen F. Pariser, M.D. Professor OSU Department of Psychiatry Director Mood Disorders Clinic Associate Chairman, CME

• Son of Charles Altamont Doyle, a civil servant

in the Edinburgh Office of Works, and Mary (Foley) Doyle. His father suffered from epilepsy and alcoholism and died in an asylum in 1893-mother kept a boarding house

• Educated in Jesuit schools; later studied at

Edinburgh University, qualifying as a doctor in

• 1885. After graduation practiced medicine until

1891, when he became a full time writer

• Based Sherlock Holmes* on Doctor Joseph

Bell, a surgeon and teacher**

*As far as Holmes' name, his last name may have been based on American jurist and fellow doctor Oliver Wendell Holmes and his first name may have come from Alfred Sherlock, a prominent violinist of his time. **Dr. Bell had the uncanny ability to reveal a patient's symptoms, diagnose patients and report on their origins before they would speak a word to him about their afflictions http://www.sherlock-holmes.org.uk/The_Society/Arthur_Conan_Doyle/Arthur_Conan_Doyle.htm

Sir Arthur Conan Doyle 1859-1930

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• "In teaching the treatment of disease and accident,“
• Dr. Bell stated, all careful teachers have first to show

the student how to recognize accurately the case.”

• “The recognition depends in great measure on the

accurate and rapid appreciation of small points in which the diseased differs from the healthy state…”

• Dr. Joseph Bell

http://www.sherlock-holmes.org.uk/The_Society/Arthur_Conan_Doyle/Joseph_Bell.htm *Conan Doyle met Dr. Bell in 1877 at the University of Edinburgh Medical School

• Dr. Joseph Bell (1837-1911)

The Inspiration for Sherlock Holmes*

Introduction/Definitions Epidemiology Medical comorbidity Psychiatric comorbidity Treatment issues Summary

Treatment-Resistant Depression

W: What do you imagine that it means? SH: I have no data yet. It is a capital mistake to theorize before

• ne has data. Insensibly one begins to twist facts to suit

theories, instead of theories to suit facts...’

• From a Scandal in Bohemia

Sir Arthur Conan Doyle

Sherlock Holmes

“…It Is a Capital Mistake to Theorize Before One Has Data…”

• 10%-30% have MDD episodes that last

longer than two years

• 20%-30% have MDD superimposed on

dysthymia (double depression)

• 60% of psychiatric hospitalizations
• Worsens morbidity and mortality of: CAD

and MI, Chronic Pain, Diabetes, Asthma

Trivedi, M. H., A. J. Rush, et al. (2004). "Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project." Arch Gen Psychiatry 61(7): 669-80.

Major Depressive Disorder

Typically Chronic Or Recurrent

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Increasing HAM-D17 Score

Depressed Response, but symptomati Remission (HAM-D17 ² 7) (Virtually symptom free)

Increasing HAM-D17 Score

Depressed Response, but symptomati Remission (HAM-D17 ² 7) (Virtually symptom free)

HAM-D17 Scores Efficacy – 50% Reduction/Remission ≤ 7

Questions are related to symptoms such as depressed mood, guilty feelings, suicide, sleep disturbances, anxiety levels and weight loss. Hamilton M. A rating scale fordepression. J Neurol NeurosurgPsychiatry 1960;23:56–62.

MDD: Earlier Age of Onset (STAR*D) Can Mean:

Zisook, S., I. Lesser, et al. (2007). "Effect of age at onset on the course of major depressive disorder." Am J Psychiatry 164(10): 1539-46.

• Never being married
• More impaired social and occupational

function

• Poorer quality of life
• Greater medical and psychiatric

comorbidity

• More negative view of life and the self
• More lifetime depressive episodes and

suicide attempts

• Greater symptom severity and suicidal

ideation in the index episode compared to those with later ages at onset of major depressive disorder

MDD: Earlier Age of Onset (STAR*D) Can Mean:

Zisook, S., I. Lesser, et al. (2007). "Effect of age at onset on the course of major depressive disorder." Am J Psychiatry 164(10): 1539-46.

• Bipolar depression is the predominant

abnormal affective pole and causes greater disability and economic burden than mania

• Bipolar patients spend 33% of their time in a

state of depression compared to 11% of time spent in a manic state.

• Duration of time depressed and severity of

depression are associated with increased risk for suicide, which occurs in 10% to 20% of bipolar patients

Bowden, C. L. and A. A. Krishnan (2004). "Pharmacotherapy for bipolar depression: an economic assessment." Expert Opin Pharmacother 5(5): 1101-7. Oral, E. T. and S. Vahip (2004). "Bipolar depression: an overview." IDrugs 7(9): 846-50. Post, R. M., C. F. Baldassano, et al. (2003). "Treatment of bipolar depression." CNS Spectr 8(12): 1-10; quiz 11. Ghaemi, S. N., K. J. Rosenquist, et al. (2004). "Antidepressant treatment in bipolar versus unipolar depression." Am J Psychiatry 161(1): 163-5.

Bipolar Depression

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Delayed Diagnosis of Bipolar Disorder Common

Perlis, R. H., E. Brown, et al. (2006). "Clinical features of bipolar depression versus major depressive disorder in large multicenter trials." Am J Psychiatry 163(2): 5-31.

• For misdiagnosed bipolar patients, when mood

stabilizer initiation is delayed, outcomes appear to be poorer

• Exposure to antidepressants, particularly in

the absence of mood stabilizers, can precipitate switching into manic or mixed states or cycle acceleration in a subset of bipolar patients

• Patients with MDD exposed to mood stabilizers

unnecessarily would be expected to suffer poorer outcomes because of side effects or lesser likelihood of treatment response

Risk for Bipolar Illness in Patients Initially Hospitalized for Unipolar Depression

• Cumulative proportion (45%)*

manifested signs of one or more manic or hypomanic periods at some point during these 15 years.

• May underestimate the magnitude of

polarity switches, since ratings were based on systematic assessments of affective syndromes for the 1 year preceding each follow-up assessment combined with data on course of illness, treatments, and narrative clinical material

Patients who were hospitalized for unipolar major depression (N=74; mean age=23.0 years, SD=3.8) were assessed prospectively as inpatients and then followed up five times over 15 years, at approximately 2, 5, 8, 11, and 15 years after discharge. *27% of the study group had developed

• ne or more distinct periods of

hypomania, while another 19% had at least one episode of full bipolar I mania.

Goldberg, Joseph F., Harrow, Martin, Whiteside, Joyce E. Risk for Bipolar Illness in Patients Initially Hospitalized for Unipolar Depression.Am J Psychiatry 2001 158: 1265-1270.

Depression: Bipolar/Unipolar

Depression Bipolar Unipolar Hx of Mania Yes No Sex Ratio Equal Women > Men Age At Onset Teens, 20s-30s 30s-50s Postpartum More common Less common Episode Onset Often abrupt More insidious Episodes Numerous Fewer Duration 3-6 months 3-12 months Psychomotor Retardation Agitation Sleep Hypersomnia Insomnia

Akiskal HS. Bipolar Depression: Phenomenology and Diagnosis. Program and abstracts of the 154th Annual Meeting of the American Psychiatric Association; May 5-10, 2001; New Orleans, Louisiana. Symposium 96A.

Introduction/Definitions Epidemiology Medical comorbidity Psychiatric comorbidity Treatment issues Summary

Treatment-Resistant Depression

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Kessler RC, McGonagle KA, Zhao S, et al. Arch Gen Psych 1994; 51:8-19. http://www.nimh.nih.gov/healthinformation/stard_qa_general.cfm

Mood Disorders Lifetime Prevalences

21% 13% 2% 2% 8% 5% 24% 15%

0.00% 6.25% 12.50% 18.75% 25.00% Women Men

Maj DepEp isod e Man icep isod e Dysth ym ia A n yA ffective Ep isod e 51.6 41.96 21.7 10 20 30 40 50 60 % Adequate Treatment of MDD 12-month cases who received health care treatment 12-month cases-treatment was adequate Summary: 12-month cases adequately treated

Kessler, R. C., P. Berglund, et al. (2003). "The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R)." JAMA 289(23): 3095-105.

Major Depression 12-month Cases Receiving Adequate Treatment

Most lifetime (72.1%) and 12-month (78.5%) cases had comorbid CIDI/DSM-IV disorders, with MDD only rarely primary.

• 30-45% of patients show partial

response or no response at all

• About 1/3 of patients achieve remission

(HAM-D17 ≤7) on single-drug therapies1-3

• 1. Fava M, Davidson KG. Psychiatr Clin North Am. 1996;19(2):179-200.
• 2. Fawcett J, Barkin RL. J Clin Psychiatry. 1997;58(suppl 6):32-39.
• 3. O'Reardon JP, Amsterdam JD. Psychiatr Ann. 1998;28(11):633-640.
• 4. Carvalho A. F., J. L. Cavalcante, et al. (2007). "Augmentation strategies for treatment-resistant depression: a literature review." J Clin Pharm Ther

32(5): 415-28.

Remission is Challenge

Introduction/Definitions Epidemiology Medical comorbidity Psychiatric comorbidity Treatment issues Summary

Treatment-Resistant Depression

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"Problems may be solved in the study which have baffled all those who have sought a solution by the aid of their senses." The Five Orange Pips

Thoughtful Consideration

• Prevalence of significant general medical

comorbidity in this population was 50.0% (95% CI = 48.1% to 52.0%)

• Concurrent significant medical comorbidity

was associated with older age, lower income, unemployment, limited education, and longer duration of index depressive episode

Yates, W. R., J. Mitchell, et al. (2007). "Clinical Features of Depression in Outpatients With and Without Co-Occurring General Medical Conditions in STAR*D: Confirmatory Analysis." Prim Care Companion J Clin Psychiatry 9(1): 7-15 Papakostas, G. I., T. Petersen, et al. (2003). "Axis III disorders in treatment-resistant major depressive disorder." Psychiatry Res 118(2): 183-8.

Clinical Features of Depression in Outpatients With and Without Co-Occurring General Medical Conditions

In STAR*D: Confirmatory Analysis (previously unanalyzed cohort; 2541 outpatients)

• Logistic regression analysis showed that CIRS

(Cumulative Illness Rating Scale) score was not associated with likelihood of remission or premature study discontinuation

• Medical comorbidity does not appear to be

associated with significantly poorer outcome among patients whose major depressive disorder failed initially to respond to an initial trial of 20 mg/day of fluoxetine

Perlis, R. H., D. V. Iosifescu, et al. (2004). "Effect of medical comorbidity on response to fluoxetine augmentation or dose increase in outpatients with treatment-resistant depression." Psychosomatics 45(3): 224-9. Papakostas, G. I., T. Petersen, et al. (2003). "Axis III disorders in treatment-resistant major depressive disorder." Psychiatry Res 118(2): 183-8.

Medical Comorbidity and Treatment Outcome

• The prevalence of pain in depressed

cohorts and depression in pain cohorts are higher than when these conditions are individually examined

• When pain is moderate to severe,

impairs function, and/or is refractory to treatment, it is associated with more depressive symptoms and worse depression outcomes

Bair, M. J., R. L. Robinson, et al. (2003). "Depression and pain comorbidity: a literature review." Arch Intern Med 163(20): 2433-45. http://www.pain.com/frameindex.cfm

Depression and Pain Comorbidity

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Musselman DL, et al. Arch Gen Psych 1998;55:580-592.

Major Depression and Cardiovascular Disease

• Evidence suggests stress and depression result in

impairment of the immune response and might promote initiation and progression of some types

• f cancer, mainly associated with a DNA tumour

virus, retrovirus insertion near a cellular oncogene and other viruses such as EBV

• Through HPA activation, the mediators released

during chronic stress suppress some non-specific and specific parts of the immune response* compromising the most important effectors of the immune response against tumours

*including NK-cell activity, phagocytosis, production of inflammatory cytokines (ie, interleukin 2, interferon , and TNF by Th1 cells), and cytotoxic T-cell activity,

Papilloma virus

Reiche, EMV, et al. Lancet Oncol 2004; 5: 617–25

Stress, Depression and Cancer

Introduction/Definitions Epidemiology Medical comorbidity Psychiatric comorbidity Treatment issues Summary

Treatment-Resistant Depression

The temptation to form premature theories upon insufficient data is the bane of our profession-

Part I: 2. Mr. Sherlock Holmes Discourses The Valley of Fear

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(255 depressed adult outpatients consecutively enrolled in MGH Depression Program)

Fava M, Rankin MA, Wright EC, et al. Anxiety disorders in major depression. Compr Psychiatry 2000;41:97-102. Kessler, R. C. (2003). "Epidemiology of women and depression." J Affect Disord 74(1): 5-13.*The World Health Organization’s Global Burden (Murray and Lopez, 1996). Kessler, R. C., P. Berglund, et al. (2003).

27 16.9 14.5 10.6 6.3 50.6 10 20 30 40 50 60 % Comorbid Psychiatric Diagnoses In Patients With Major Depression Social Phobia Simple Phobia Panic Disorder GAD OCD Total Patients With ADs

Comorbid Anxiety Disorders Present In Major Depression

• MDD (68.2%) and PTSD (50.0%) were

highly prevalent on a lifetime basis in female victims of IPV

• PTSD and MDD symptoms are frequently

seen in the aftermath of IPV, and often co-occur

Stein, M. B., Kennedy, C. Major depressive and post-traumatic stress disorder comorbidity in female victims of intimate partner violence. J Affect Disord 2001;66:133-8.

Major depressive and post-traumatic stress disorder comorbidity in female victims of intimate partner violence

Dansky BS, Brewerton TD, Kilpatrick DG, et al. Comorbidity of bulimia nervosa and alcohol use diesorders: results from the National Women’s Study. Int j EatDisord 2000;27:180-190.

Alcohol Abuse (AA) and Dependence (AD) By Psychiatric Group Status (3,006 women)

31 37 28 37 18 13 15 9 15 4

10 20 30 40 Bulimia PTSD Major Dep PTSD+Dep Controls

ETOH Abuse ETOH Dependence

Introduction/Definitions Epidemiology Medical comorbidity Psychiatric comorbidity Treatment issues Summary

Treatment-Resistant Depression

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• The dysregulation of 5-HT

and NE strongly associated with depression may amplify pain signals

• May help explain why dual

action antidepressants influence pain

Adapted from: Stahl SM. J Clin Psychiatry. 2002;63(5):382-383. Verma S, Gallagher RM. Int Rev Psychiatry. 2000;12(2):103-114.Blier P, Abbott FV. J Psychiatry Neurosci. 2001;26(1):37-43.

Ascending Pathway Descending Pathway

Dual Action Antidepressants and Pain

• Determine best “next-step” treatments for

depressed patients who fail to respond satisfactorily to earlier treatment attempts

• Compare relative efficacy and patients’

acceptance of different treatment strategies

• Determine longer term benefits of

successful strategies

• Compare their side effect burden and

economic costs

• Determine predictors of response to

specific treatments

Sequenced Treatment Alternatives to Relieve Depression

• Both psychiatric and primary care

settings

• Patients with non-psychotic major

depression (N=2876)

• Duration: 7 years (October 1999 -

September 2006)

• Stage I treatment Citalopram, 12-weeks

with mean final dose of 41.8 mg/day

Trivedi, M. H., A. J. Rush, et al. (2006). "Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice." Am J Psychiatry 163(1): 28-40.

Sequenced Treatment Alternatives to Relieve Depression

STAR*D Level 1

http://www.nimh.nih.gov/health/trials/practical/stard/questions-and-answers-about-the-nimh- sequenced-treatment-alternatives-to-relieve-depression-stard-study-all-medication-levels.shtml

• In level 1, participants were given the

antidepressant citalopram (Celexa) for 12 to 14 weeks

• Those who became symptom-free during this

time could move on to a 12-month follow-up period during which the citalopram was continued and patients were monitored

• Those who experienced intolerable side effects
• r did not become symptom-free during this

level could go on to level 2

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Evaluation of Outcomes With Citalopram for Depression Using Measurement-based Care in STAR*D: Implications for Clinical Practice

Trivedi, M. H., A. J. Rush, et al. (2006). "Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice." Am J Psychiatry 163(1): 28-40.

• QIDS-SR response rates: 47%;

QIDS-SR remission rates: 33%*

• Similar response/remission rates

in primary care and psychiatric settings

• Of participants who responded,

56.0% did so only at or after 8 weeks of treatment-of those who achieved QIDS-SR remission, 40.3% did so only at or after 8 weeks of citalopram

*Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR)

STAR*D Level 2

http://www.nimh.nih.gov/health/trials/practical/stard/questions-and-answers-about-the-nimh- sequenced-treatment-alternatives-to-relieve-depression-stard-study-all-medication-levels.shtml

• Participants had the option of switching to a

different medication or adding on to their existing citalopram

• Those who joined the “switch” group were

randomly assigned to either sertraline (Zoloft), bupropion-SR (Wellbutrin), or venlafaxine-XR (Effexor)

• Those who joined the “add-on” group were

prescribed either the non-SSRI antidepressant bupropion-SR (Wellbutrin), or buspirone (BuSpar)

• Participants could also switch to, or add on,

cognitive psychotherapy

Rush, A. J., M. H. Trivedi, et al. (2006). "Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression." N Engl J Med 354(12): 1231-42.

Randomly assigned 727 adult outpatients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram to receive one of the following drugs for up to 14 weeks: sustained-release bupropion (239 patients) at a maximal daily dose of 400 mg, sertraline (238 patients) at a maximal daily dose of 200 mg, or extended-release venlafaxine (250 patients) at a maximal daily dose of 375 mg.

Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression

%

21 26 18 27 25 25

0.0 7.5 15.0 22.5 30.0 HRSD-17 QIDS-SR-16 Sustained-release bupropion Sertraline Extended-release venlafaxine

After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another

• antidepressant. Any one of the medications in the study provided a

reasonable second-step choice for patients with depression.

STAR*D Remission Rates

by Steps Overall Remission Rates: 67%

Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M: Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163(11):1905-17

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STAR*D

Prognosis better at all levels for participants who entered follow-up in remission

• No differences in remission rates or

times to remission among medication switch or among medication augmentation strategies at any treatment level

• Participants who required increasing

numbers of treatment steps showed greater depressive illness burden and increasingly greater relapse rates in the naturalistic follow-up period (40%-71%)

Warden, D., A. J. Rush, et al. (2007). "The STAR*D Project results: a comprehensive review of findings." Curr Psychiatry Rep 9(6): 449-59.

55.5 24.7 9.3 26 19.7 11.7

10 20 30 40 50 60 % Probabilities

• f Onset of

Response* Onset of Response for Responders Onset of Response That Led to Final HAM-D Decrease of 50% 2-weeks 4-weeks 6-weeks

55.5 24.7 9.3 26 19.7 11.7

10 20 30 40 50 60 % Probabilities

• f Onset of

Response* Onset of Response for Responders Onset of Response That Led to Final HAM-D Decrease of 50% 2-weeks 4-weeks 6-weeks

Andrew A. Nierenberg, Amy H. Farabaugh, Jonathan E. Alpert, Johanna Gordon, John J. Worthington, Jerrold F. Rosenbaum, and Maurizio Fava Timing of Onset of Antidepressant Response With Fluoxetine Treatment Am. J. Psychiatry, Sep 2000; 157: 1423 - 1428.

*defined as 30% reduction in baseline HAM-D score

The lack of onset of response at 4-6 weeks was associated with about a 73%-88% chance that patients would not have an

• nset of response by

8 weeks.

Timing of Onset of Antidepressant Response With Fluoxetine Treatment

Antidepressant Tolerability

• Discontinuation rates due

to inability to tolerate medication range from approximately 10 to 25% (likely a conservative estimate- most clinical trials utilize generally healthy patient samples)

• Patients intolerant of one

medication may readily tolerate another one of the same class

Berman RM, et al. Treatment-refractory depression:Definitions and characteristics. DEPRESSION AND ANXIETY 5:154–164 (1997)Cassano, P. and M. Fava (2004). "Tolerability issues during long-term treatment with antidepressants." Ann Clin Psychiatry 16(1): 15-25.

• Prior history of depressive episodes
• Persistence of dysthymic symptoms after

recovery from an episode of depression

• Presence of an additional, nonaffective

psychiatric diagnosis

• History of severe and/or long-term depression
• Presence of a chronic general medical

disorder

• Consider symptom severity and longevity

Practice guideline for the treatment of patients with major depressive disorder. Am J. Psychiatry 2000; 157 (suppl):1-45.

Maintenance Phase Antidepressant Rx

Factors Contributing to Recurrence:

50%-85% Of Patients With Single Episode Of Major Depression Will Have Another

19

Introduction/Definitions Epidemiology Medical comorbidity Psychiatric comorbidity Treatment issues Summary

Treatment-Resistant Depression

The world is full of obvious things which nobody by any chance ever

• bserves-

Sherlock Holmes The Hounds of Baskerville 1901

• S: see the patient
• H: Hear the patient, listen, ask the patient what

they think is interfering with their recovery

• E: Evaluate the prior treatment approaches
• R: Recovery requires adherence, time and a plan
• L: Look for medical and psychosocial comorbidity
• O: Observe, examine when appropriate
• C: Consider interviewing the patient’s significant
• thers
• K: Knowledge-inspires confidence and hope

No !@%$#%@ SHERLOCK