DEPRESSION PREVALENCE OF CLINICAL DEPRESSION (1994) LIFETIME 17% (?) LIFETIME 17% (?) YEARLY 10%...

DEPRESSION

PREVALENCE OFCLINICAL DEPRESSION

(1994)

• LIFETIME 17% (?)LIFETIME 17% (?)• YEARLY 10%YEARLY 10%• Bipolar 5%Bipolar 5%

TREATMENT OF DEPRESSION IN PRIMARY CARE*

• Depression: 2Depression: 2ndnd. Most Common . Most Common Disorder in Primary CareDisorder in Primary Care• 40% Diagnostic Hit Rate40% Diagnostic Hit Rate• 87% Somatic Sx, 13% Mood Sx87% Somatic Sx, 13% Mood Sx (Greist, 2002)(Greist, 2002)

A RECURRING ILLNESS

• 20% SINGLE EPISODE20% SINGLE EPISODE• 80% RECURRENT or CHRONIC80% RECURRENT or CHRONIC

Depression: Fluctuating CourseDepression: Fluctuating Course

• N= 431 ( ¼ : 1st.episode, ½ recurrent, ¼ : double D.)

• 12 year Follow-up• Symptomatic: 58%, 42%: Sx-free• Time Symptomatic: > 15% MDD > 43% Sub-Syndromal ……

Depression: Fluctuating CourseDepression: Fluctuating Course

• N= 431 ( ¼ : 1st.episode, ½ recurrent, ¼ : double D.)

• 12 year Follow-up• Symptomatic: 58%, 42%: Sx-free• Time Symptomatic: > 15% MDD > 43% Sub-Syndromal ……

WORLD HEALTH ORGANIZATION STUDY

• Each day in Primary Care Medical Settings:Each day in Primary Care Medical Settings: > 25% of patients have Clinical Depression> 25% of patients have Clinical Depression > 10% have Anxiety Disorders> 10% have Anxiety Disorders > 10% have Substance Abuse Disorders> 10% have Substance Abuse Disorders cont.cont.

MOST COMMON DISORDERS SEEN IN PRIMARY CARE

• HypertensionHypertension• DepressionDepression

• Anxiety DisordersAnxiety Disorders

Most “Reactive Depressions”

If they reach the intensity level of If they reach the intensity level of Major Depression, will show Major Depression, will show

vegetative symptoms.vegetative symptoms.

BIOLOGIC SYMPTOMS

• ANHEDONIAANHEDONIA• SLEEP DISTRUBANCESSLEEP DISTRUBANCES• APPETITE DISTURBANCESAPPETITE DISTURBANCES• LOSS OF SEXUAL DRIVELOSS OF SEXUAL DRIVE• FATIGUEFATIGUE

Dysthymia“Ill-Humor”

• 5% Of the Population (lifetime 5% Of the Population (lifetime prevalence)prevalence)

• Most eventually also develop Most eventually also develop Major Depression Major Depression

Dysthymia

• Pharmacologic OutcomePharmacologic Outcome::

33% Excellent Response 33% Good Response 34% Poor Response (Akiskal, 1997)

Has the Has the Success ofSuccess of

AntidepressantsAntidepressantsBeen Over-Sold?Been Over-Sold?

15

Patients Recruited inPatients Recruited inAntidepressant Drug StudiesAntidepressant Drug Studies

Zimmerman, et al. (2002)Zimmerman, et al. (2002)

• N= 346 (MDD, outpatient practice)N= 346 (MDD, outpatient practice)• 86% would be excluded86% would be excluded

from drug studiesfrom drug studies

ITT: Intent to TreatITT: Intent to TreatResponse Rates: MDDResponse Rates: MDD

• Single Antidepressant trialSingle Antidepressant trial• Do not tolerate: 15%Do not tolerate: 15%• No response: 35%No response: 35%• ““Responders”: 50% Responders”: 50%

ITT RatesITT Rates• ““Responder” = 50% Responder” = 50% HAM-D, or HAM-D, or HAM-D Score of 7 or lessHAM-D Score of 7 or less• Responders:Responders: > Full Responders: HAM-D < 7> Full Responders: HAM-D < 7 50%50% > Partial Responders:> Partial Responders: HAM-D: 9-14: 50%HAM-D: 9-14: 50%

ITT: The Rest of the StoryITT: The Rest of the Story

• ““Full Responders”:Full Responders”: > 18% truly asymptomatic> 18% truly asymptomatic > 82% subtle residual > 82% subtle residual symptomssymptoms

Nierenberg, et al. (1999)Nierenberg, et al. (1999)

Partial Responders:Partial Responders:Is Symptomatic ImprovementIs Symptomatic Improvement

Good Enough?Good Enough?

Partial RespondersPartial Responders• Time to Next Episode:Time to Next Episode: * 3 times longer to next episode* 3 times longer to next episode remitters vs. partialremitters vs. partial respondersresponders• Quality of life Quality of life (espec. Social Functioning)(espec. Social Functioning)

Evidence-BasedEvidence-BasedMedicine andMedicine and

TreatmentTreatmentAlgorithmsAlgorithms

Depression

Implications forTreatment Success

1. Hopelessness and Drop-outs(long time to response)

2. Compliance: high risk patients3. Extreme response to side effects

4. Premature discontinuation(skepticism about meds : 62% ↑ in DC)

5. Patient preferences6. Inaccurate diagnosis

Rating Scales

First weeks of Treatment

• Aim to get some immediate relief• Medication strategies• Exercise• Bright light (details later)• Combat social withdrawal

26

On-Line AlgorithmsOn-Line Algorithms

• International Psychopharmacology Algorithm Project: endorsed by WHO www.IPAP.org

• www.MHC.com (also P 450: drug interactions)

Choosing a Choosing a First-lineFirst-line

AntidepressantAntidepressant

29

Targeting NeurotransmittersTargeting Neurotransmitters

NE: norepinephrine5-HT: serotoninDA: dopamine

33

NEWER GENERATIONANTIDEPRESSANTS

• SSRIsSSRIs: Serotonin (5-HT): Serotonin (5-HT)• NRIsNRIs: Norepinephrine (NE): Norepinephrine (NE)• Dual ActionDual Action:: Wellbutrin: NE and DopamineWellbutrin: NE and Dopamine Effexor: 5-HT and NE (SNRI)Effexor: 5-HT and NE (SNRI) Remeron: 5-HT and NE (SNRI)Remeron: 5-HT and NE (SNRI) Cymbalta (duloxetine): 5-HT and NE Cymbalta (duloxetine): 5-HT and NE Pristiq 5-HT and NEPristiq 5-HT and NE

Neurotransmitters and Behavior

• Serotonin: Anxiety, Rumination, Irritability, Aggression, Suicidality

Shelton and Tomarken (2001); Metzner, (2000)Shelton and Tomarken (2001); Metzner, (2000)

Neurotransmitters and Behavior

• Catecholamines: Dopamine and Norepinephrine: Anhedonia, Apathy, Impaired Attention

Shelton and Tomarken (2001); Metzner, (2000)Shelton and Tomarken (2001); Metzner, (2000)

Antidepressants Agorithm

Texas MedicationAlgorithm Project

TMAP

ANTIDEPRESSANT ALGORITHM

With Anxiety or Agitation: SSRIsAnergic:Atypical: PMDD:

38

Activation vs Switching• Activation: within hours; anxiety and/or initial insomnia• Switching: 3+ weeks; manic

symptoms

39

Benzodiazepine AugmentationStart up

(Ward Smith, et al.)

• Check for history of substance abuse• Antidepressant and tranquilizers• Early response…fewer drop outs

40

Benzodiazepine use: HMO Setting(Samari, 2007)

• N: 2440• Treated for 2 years with tranquilizers• Percent of those requesting increased doses: 1.6 %

41

ANTIDEPRESSANT ALGORITHM

With Anxiety or Agitation: Anergic: WellbutrinAtypicalPMDD

42

Stimulant augmentationwith anergic depressions

43

ANTIDEPRESSANT ALGORITHM

With Anxiety or Agitation: AnergicAtypical: watch for bipolarPMDD

44

ANTIDEPRESSANT ALGORITHM

Pre-Menstrual Dysphoria: SSRIs

45

ANTIDEPRESSANT ALGORITHM

Very Severe and/or Recurrent: Dual Action: Effexor, Pristiq, Cymbalta, Remeron, Wellbutrin

46

Metzner, 2000

Standard vs. Targeted Treatment% of Patients Improved

•Preliminary study of depressed patients sampled in outpatient private practice settingSTD: Standard Rx

•TTD: Targeted : selective antidepressants only

96%

65%

0%10%20%30%40%50%60%70%80%90%

100%

Standard Targeted

Imp

rove

d

47

GUIDELINES forMEDICAL TREATMENT of

DYSTHYMIA

• IRRITABILITY: IRRITABILITY: SSRIsSSRIs• LOW ENERGY, APATHY, LOW-GRADE LOW ENERGY, APATHY, LOW-GRADE

ANHEDONIA: ANHEDONIA: WellbutrinWellbutrin

not based on empirical studiesnot based on empirical studies

Additional Considerationsin Medication Choices

• Side EffectsSide Effects• Patient PreferencesPatient Preferences• PharmacokineticsPharmacokinetics

PHASES OF TREATMENT

• ACUTEACUTE: Until Asymptomatic: Until Asymptomatic• CONTINUATIONCONTINUATION: 6 months @ : 6 months @ Same Dose Same Dose →→• MAINTENANCEMAINTENANCE: Third Episode: : Third Episode: Lifetime TreatmentLifetime Treatment

Continuation Phaseof Treatment

• Minimum of six months…same dose• Patient-initiated discontinuation• High rates of acute relapse• Serotonin and emotional blunting• Dampens dopamine

Antidepressant Antidepressant Discontinuation SyndromesDiscontinuation Syndromes

• Symptoms: nausea, dizziness, Symptoms: nausea, dizziness, malaise, electric shock-like malaise, electric shock-like sensationssensations• Most likely:Most likely: Paxil, Effexor, Cymbalta, PristiqPaxil, Effexor, Cymbalta, Pristiq• Least likely: ProzacLeast likely: Prozac

MaintenancePhase

ADEQUATE TRIAL

• DOSEDOSE• COMPLIANCECOMPLIANCE• TIMETIME• BLOOD LEVELSBLOOD LEVELS

TIME TO RESPONSE

EARLY RESPONDERSEARLY RESPONDERS:: 2-4 WEEKS2-4 WEEKS LATE RESPONDERSLATE RESPONDERS:: SEVERE SYMPTOMSSEVERE SYMPTOMS FIRST EPISODE BEFORE 18FIRST EPISODE BEFORE 18 LONG DURATIONLONG DURATION (more than three months)(more than three months) 4-6 WEEKS4-6 WEEKS

Response• Remission• Partial• Poor

Overview: Options for Overview: Options for Inadequate ResponseInadequate Response

OptimizationOptimizationAugmentingAugmenting > Combination Treatments> Combination TreatmentsSwitching Drug ClassesSwitching Drug Classes

OptimizationOptimization

dose; dose; time time

Augmenting:Augmenting:CombinationCombination

SwitchingSwitching ClassesClasses

e.g serotonin e.g serotonin norepinephrine norepinephrinereuptake inhibitorreuptake inhibitor

Empirical StudiesEmpirical Studies

STAR-D: Sequenced Treatment Alternatives to Relieve Depression (NIMH)

STAR-D(2007)(2007)

• N= 4100• Ages 18-75• Average patient: 3 medical illnesses• 65%: psychiatric co-morbidity

62

STAR-D

• 80%: chronic or recurrent• 25%: have been depressed for 2+ years• 53%: anxious depressions

63

STAR-D Rating ScaleSTAR-D Rating Scalepagepage

Side effect scaleSide effect scalePage Page

Overview: Options for Overview: Options for Inadequate ResponseInadequate Response

OptimizationAugmenting > Combination TreatmentsSwitching Drug Classes

65

STAR-DSTAR-D(2006)(2006)

PHASE ONE:Celexa: average doses 40 mgResponse rates: 60%Remission rates: 30%Average time to remission: 7 weeksKEY: aggressive dosing

66

STAR-DSTAR-D(2006)(2006)

PHASE TWONon-remitters: randomized: > Switch > Augmentation

67

STAR-D: SwitchSTAR-D: Switch(2006)(2006)

Effexor: 25%Wellbutrin: 21%Zoloft: 17%

Average time to remission: six weeks

68

STAR-D: AugmentSTAR-D: Augment(2006)(2006)

Wellbutrin: 30%BuSpar: 30%

Augmenting: slightly higher yield than switching

69

New Study

70

STAR-D: After Phase 2

•55% reach remission

71

STAR-DSTAR-D(2006)(2006)

PHASE Three: > Switch: nortriptyline (tricyclic) or Remeron > Augment: lithium T3

72

STAR-DSTAR-D(2006)(2006)

PHASE Three: > Switch: nortriptyline or Remeron 13% > Augment: lithium 20% T3 20%

73

TT3 3 AugmentationAugmentation• 4 double bind studies: indicate efficacy• STAR-D study: very high yield• Few Side Effects• Dose: Cytomel 25-75 micrograms qd

74

STAR*D STAR*D Final OutcomesFinal Outcomes

67% 67% Complete remissionComplete remission

75

STAR-DCumulative Sustained

Recovery Rate

43%43%

76

STAR-D MonotherapySTAR-D Monotherapy

STAR-D MonotherapySTAR-D Monotherapy

STAR-D AugmentationSTAR-D AugmentationGuidelinesGuidelines

What Can Be Learned fromSTAR-D

• Use of rating scales• Aggressive dosing• Some suggestions: next steps• Testament to the difficulties in treating very severe depression

Head-to-Head Comparisons: SSRIs

• N= 26,000……….117 trials• Efficacy and tolerability• Among SSRIs: Sertraline (Zoloft) comes out on top• Lexapro #2 (not generic….no drug-drug interactions)

• Cochran Database Surveys (2009)

81

Head-to-Head Comparisons

• SSRIs: versus Effexor and Remeron better efficacy (dual action drugs)• SSRIs versus Wellbutrin: Wellbutrin: better tolerability• Best for headaches: Elavil

Cochran Database Surveys (2009)

82

PARTIAL RESPONSESTRATEGIES

• FIRSTFIRST: Check Compliance & : Check Compliance & Substance AbuseSubstance Abuse• INCREASE DOSEINCREASE DOSE• AUGMENTAUGMENT

Other augmentationOther augmentationStrategiesStrategies

Augmentation Strategies

• Lithium: 0.3-0.6 mEq/l > relapse x 3

> 7 fold suicides

THYROIDTHYROID• Adding TAdding T3 or 3 or TT4: augmentation4: augmentation

• TT4 4 for rapid cyclingfor rapid cycling• Hypothyroid in Lithium therapyHypothyroid in Lithium therapy

Thyroid AugmentationThyroid Augmentation• T4: levo-thyroxine:T4: levo-thyroxine: > Synthroid, Levothyroid, Levoxyl> Synthroid, Levothyroid, Levoxyl > 1 mcg per pound of weight qd> 1 mcg per pound of weight qd• T3: triiodothyronine:T3: triiodothyronine: > Cytomel> Cytomel > 25-75 mcg. qd> 25-75 mcg. qd

HypothalamusHypothalamus

TRHTRH

PituitaryPituitary

TSHTSH

ThyroidThyroidT3 T3 Gland Gland T4T4

TSHTSHThyroid StimulatingThyroid Stimulating

HormoneHormone

Depression andDepression and Hypo-ThyroidHypo-Thyroid

The most common medical cause of depression (10%)Grade I: T3 and T4: TSH Grade II: Normal T3/T4, but TSH

(Wolkowitz, 2003; Zweifel, 1997)

““Normal” TSH LevelsNormal” TSH LevelsHigh Normal Range 3.0| |Median 1.3||Low Normal Range 0.3

miliIU/Liter

““Normal” TSH LevelsNormal” TSH LevelsHigh Normal Range 3.0| 2.5| Median 1.3||Low Normal Range 0.3

miliIU/Liter

Stimulant Augmentation

MAOIsMAOIs

New MAOI:New MAOI:

EmsamEmsam

selegiline transdermal:selegiline transdermal:6-12 mg per day6-12 mg per day

Augmentation Strategies

• Atypical AntipsychoticsAtypical Antipsychotics: * Zyprexa *Abilify

*Geodon *Risperdal * Seroquel ?

Reducing Treatment-Resistant Unipolar Depression

MADRS Total: Acute Treatment

Mean modal dose during double-blind therapy: Flx = 52 mg/d, Olz = 12.5 mg/d, Olz + Flx = 13.5 mg/d + 52 mg/d.

Shelton RC et al. Am J Psychiatry 2001; 158:131-134.

Mea

n C

han

ge

fro

m B

asel

ine

(LO

CF

)

Weeks of Double-Blind Therapy

-20

-15

-10

-5

0

0 1 2 3 4 5 6 7 8

* * * * * * **

+ + +++ ++

Fluoxetine(n=10)

Olanzapine(n=8)

Olanzapine/Fluoxetine(n=10)

*p<0.05 vs Flx.+p<0.05 vs Olz.

Impr

ovem

ent

Folic AcidFolic Acid• Low serum levels in treatment-Low serum levels in treatment- resistant depression and earlyresistant depression and early relapserelapse• Co-factor: SerotoninCo-factor: Serotonin• 500 mcg 2 X per day500 mcg 2 X per day• With Depakote: 1-2 mg per dayWith Depakote: 1-2 mg per day

High Intensity Light Therapy

• Seasonal andSeasonal and non-seasonalnon-seasonal

• Caution with:Caution with: BipolarBipolar

POOR RESPONSESTRATEGIES

• CHECK COMPLIANCE andCHECK COMPLIANCE and SUBSTANCE ABUSESUBSTANCE ABUSE• INCREASE DOSEINCREASE DOSE• SWITCH CLASSES:SWITCH CLASSES: e.g. SSRI e.g. SSRI NE NE NE NE SSRI SSRI

Within Class Switches

• Reasons for switch: Reasons for switch: > Tolerability> Tolerability > Efficacy > Efficacy (espec. with partial Response)(espec. with partial Response)

• Two SSRI failures: switch classesTwo SSRI failures: switch classes

LATE EMERGING SEROTONINSIDE EFFECTS

• SEXUAL DYSFUNCTIONSEXUAL DYSFUNCTION > Inorgasmia > Inorgasmia • APATHY and EMOTIONAL BLUNTINGAPATHY and EMOTIONAL BLUNTING• WEIGHT GAIN (10% after one year)WEIGHT GAIN (10% after one year)

Prevalence SexualProblems / Complaints

• Reporting: 14%• Elicited on questionnaire 60%• N: 6300: only 29% had no other risk factors except antidepressant exposure……

Prevalence Sexual S.E.without other probable causes

• Celexa, Lexapro, Effexor 30%• Zoloft, Paxil 28%• Prozac, Remeron 24%• Serzone 14%• Wellbutrin 7% Clayton, et al. 2002

LATE EMERGING SEROTONIN SIDE EFFECTS

• SEXUAL DYSFUNCTIONSEXUAL DYSFUNCTION > Inorgasmia> Inorgasmia• APATHY and EMOTIONAL BLUNTING APATHY and EMOTIONAL BLUNTING • WEIGHT GAIN (10% after one year)WEIGHT GAIN (10% after one year)

GENDER DISTRIBUTIONDEPRESSION

Disorder Female : Male

• CHILDRENCHILDREN• TEENSTEENS• ADULTSADULTS

• BI-POLAR IBI-POLAR I• BI-POLAR IIBI-POLAR II

1 : 11 : 12 : 12 : 12 : 12 : 1

1 : 11 : 12 : 12 : 1

Premenstrual DysphoricPremenstrual DysphoricDisorder: PMDDDisorder: PMDD

Average female: 400 periodsAverage female: 400 periods 70 %: PMS at some point in time70 %: PMS at some point in time 30 %: significant PSM30 %: significant PSM 4 %: PMDD4 %: PMDD

Premenstrual DysphoricPremenstrual DysphoricDisorder: PMDDDisorder: PMDD

Premenstrual exacerbationPremenstrual exacerbation of Major Depression symptomsof Major Depression symptoms90% of women who successfully90% of women who successfully commit suicide: premenstrualcommit suicide: premenstrual

Premenstrual DysphoricPremenstrual DysphoricDisorder: PMDDDisorder: PMDD

TreatmentsTreatments:: > reduce caffeine, alcohol, salt,> reduce caffeine, alcohol, salt, sugar, and stop smokingsugar, and stop smoking > exercise> exercise > Serotonin antidepressants> Serotonin antidepressants > St. John’s Wort (case reports)> St. John’s Wort (case reports)

Premenstrual DysphoricPremenstrual DysphoricDisorder: PMDDDisorder: PMDD

Antidepressant treatmentsAntidepressant treatmentsMust target SerotoninMust target SerotoninIntermittent versusIntermittent versus continuouscontinuousQuick onset of actionsQuick onset of actions

PMDD and SEROTONIN

Fluctuating estrogen levels can have Fluctuating estrogen levels can have an impact onan impact on

Tryptophan hydroxylaseTryptophan hydroxylase(rate-limiting enzyme for production of 5-HT)(rate-limiting enzyme for production of 5-HT)

Allopregnenolone

• Neuro-steroid: synthesized in the brain• Potent GABA-A agonist• Low levels in MDD CSF (↑ with successful treatment)

Allopregnenolone

• PMDD: marked reduction• Rapid increase with SSRIs but not with non- serotonin antidepressants

Premenstrual DysphoricPremenstrual DysphoricDisorder: PMDDDisorder: PMDD

Calcium supplementationCalcium supplementation2 double blind, placebo controlled2 double blind, placebo controlled studiesstudies1200 mg per day (4 Tums)1200 mg per day (4 Tums)55% vs 36%55% vs 36%

Myths about Pregnancyand “Well Being”

• Risks of major depression: prenatal and postpartum: 21% (highest risk for women)

• Risks of discontinuing medications: Bipolar: 83% acute relapse Major depression: 68% relapse

116

Depression Depression and Pregnancyand Pregnancy

Depression and pregnancy: > Hypercortisolemia > Substance abuse > Suicide attempts > Post-partum exacerbation (bonding and attachment)

Depression and PregnancyDepression and Pregnancy

Depression and pregnancy: > Hypercortisolemia > Substance abuse > Suicide > Poor self care > Post-partum exacerbation (bonding and attachment)

FDA RATINGS: USE DURING PREGNANCY

A: No Risk. Well controlled studiesB: No Evidence of RiskC: Risk Cannot Be Ruled OutD: Positive Evidence of RiskX: Contraindicated in Pregnancy

120

Newer Antidepressants and Pregnancy

• FDA classifications: all “C” except:• Paxil: D > Discontinuation syndrome > 2nd and 3rd trimester exposure: risk of cardiac defects (2% vs 1%)

121

Antidepressants: Meta-analysis(Einarson and Erinarson, 2005)

• N: 1774 exposed fetuses• First trimester exposure• Major malformations: 2-3%• This equals the base rate in un-exposed fetuses

122

Antidepressants: Risks(Hauser, et al., JAMA 2009)

• Small but statistically non-significant increase in miscarriages• Not compared to non-depressed subjects• Premature birth: 20% greater: in both medicated and non-med mothers 123

Antidepressants: Risks

• No specific birth defects• ??? Cardiac defects in SSRIs ???

124

The Jury is Still Out

126

PSYCHOTIC DEPRESSIONS

• Antidepressants (AD) 35%Antidepressants (AD) 35%• Antipsychotics (AP) 45%Antipsychotics (AP) 45%• AD + AP 75%AD + AP 75%• ECT 90%ECT 90%

NoteNote: Continuation Phase: One Year: Continuation Phase: One YearAD and APAD and AP

ElectroconvulsiveElectroconvulsivetherapytherapy

ECT: Electro-convulsiveTherapy

Shock TreatmentsShock Treatments

V

DEPRESSION IN CHILDREN and ADOLESCENTS

MAJORMAJOR DEPRESSIONDEPRESSION

• Children 3%Children 3%• Teens: 10%Teens: 10% 35% recurrent35% recurrent 50% bipolar50% bipolar

Depression in Young Children

• Luby, et al. (2002)Luby, et al. (2002)• N=49N=49• Using DSM-IV criteria: 12 Dx as MDDUsing DSM-IV criteria: 12 Dx as MDD• Thus must use modified criteria…Thus must use modified criteria…

MDD Children: Modified Diagnostic Criteria

• Most of the day, more days than notMost of the day, more days than not• Play: themes of death, suicide, self-Play: themes of death, suicide, self- destruction (61%)destruction (61%)• Depressed or irritable mood orDepressed or irritable mood or Diminished interest plus 4 SxDiminished interest plus 4 Sx (vs 5 for adults)(vs 5 for adults)

SYMPTOMS IN CHILDREN

• ANHEDONIA / WITHDRAWAL (60%)ANHEDONIA / WITHDRAWAL (60%)• IRRITABILITY (81%)IRRITABILITY (81%)• LOW SELF-ESTEEM (78%)LOW SELF-ESTEEM (78%)• SCHOOL FAILURESCHOOL FAILURE• LONLINESSLONLINESS• VEGETATIVE Sx: Sleep andVEGETATIVE Sx: Sleep and Appetite Disturbance (80%)Appetite Disturbance (80%)• LOW ENERGY (58%) …..LOW ENERGY (58%) …..

Child and Adolescent Depression:Additional Signs

• Vague, non-specific physical complaintsVague, non-specific physical complaints• Running away from homeRunning away from home• Being boredBeing bored• Extreme sensitivity to rejection or failureExtreme sensitivity to rejection or failure• Reckless behavior; Acting OutReckless behavior; Acting Out• Difficulty with relationshipsDifficulty with relationships• Substance Use / AbuseSubstance Use / Abuse

Problems withthe studies

Meta analysis:Effect Size: 0.25

T A D STreatment for Adolescents with Depression Study

Effectiveness Outcomes

(2004)

Random Assignment• NIMH StudyNIMH Study• N: 432N: 432• PlaceboPlacebo• ProzacProzac• Cognitive Behavioral TherapyCognitive Behavioral Therapy• Combo: drug and CBTCombo: drug and CBT

Treatment Response: Week 12

7161

4335

0102030405060708090

100

Perc

ent

Responders

COMB FLX CBT PBO

T A D S

Effect Size

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

COMB FLX CBT

T A D S

Time to Onset of Effects

• Anxiety: 1-2 weeksAnxiety: 1-2 weeks• Depression: 4-6 weeksDepression: 4-6 weeks but responders in 10-12but responders in 10-12 week range !week range !

Paxil and Increased Suicidality

• UK study…N=1300 adolescentsUK study…N=1300 adolescents• Increased suicidality:Increased suicidality: Placebo: 1.2% Placebo: 1.2% Paxil: 3.4%Paxil: 3.4%• No actual SuicidesNo actual Suicides• 33 suicidal incidents …..33 suicidal incidents …..

Paxil and Increased Suicidality

• Acute Treatment dataAcute Treatment data• Discontinuation Discontinuation • State of Connecticut:State of Connecticut: Human ImplicationsHuman Implications

TADS(2004)

• At baseline: 29% suicidal ideasAt baseline: 29% suicidal ideas• Attempts: 1.6% Attempts: 1.6% • Actual Suicides: 0Actual Suicides: 0

Suicidality Is Reduced Overall

27

29.2

1314.6

2.7

11.6

0

5

10

15

20

25

30

Pe

rce

nt

Baseline Week 6 Week 12

CDRS13 > 1SIQ >= 31

T A D S

FDA DataN= 4400N= 300

http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4065s1.htm

All trials, all indications(Fixed effect model)

Emergence of SuicidalityRisk ratio

.01 .1 1 10 100

Study

% Weight Risk ratio (95% CI)

0.42 (0.15,1.15) CELE(MDD,18) 7.2 0.41 (0.16,1.04) CELE(MDD,94404) 8.9 1.82 (0.75,4.39) EFFEX(MDD,382) 4.2 0.84 (0.37,1.88) EFFEX(MDD,394) 7.1 2.00 (0.96,4.18) PAXIL(MDD,329) 5.8 0.70 (0.25,1.97) PAXIL(MDD,377) 4.9 3.92 (0.45,34.50) PAXIL(MDD,701) 0.6 4.73 (0.23,97.73) PAXIL(SAD, 676) 0.3 0.90 (0.26,3.12) PROZ(MDD,HCCJ) 2.6 0.78 (0.44,1.39) PROZ(MDD,HCJE) 13.7 0.71 (0.35,1.45) PROZ(MDD,X065) 8.7 0.90 (0.08,9.58) PROZ(OCD,HCJW) 0.9 0.81 (0.40,1.65) REMER(MDD,045) 9.0 0.80 (0.33,1.94) SERZ(MDD,141) 6.2 1.28 (0.58,2.79) SERZ(MDD,187) 6.6 1.04 (0.44,2.45) ZOLO(MDD,501001) 5.8 0.93 (0.43,1.99) ZOLO(MDD,501017) 7.4

0.93 (0.75,1.15) Overall (95% CI)

147 147

Discontinuation

All trials, all indications(Fixed effect model)

Worsening/Emergence of Suicidality/discontRisk ratio

.01 .1 1 10 100

Study

% Weight Risk ratio (95% CI)

0.82 (0.19,3.57) CELE(MDD,18) 5.1 0.60 (0.26,1.38) CELE(MDD,94404) 18.3 2.50 (0.52,11.93) EFFEX(MDD,382) 3.1 0.81 (0.21,3.19) EFFEX(MDD,394) 5.8 1.55 (0.49,4.94) PAXIL(MDD,329) 6.1 0.80 (0.21,3.10) PAXIL(MDD,377) 6.2 1.69 (0.36,7.98) PAXIL(MDD,701) 3.7 8.79 (0.47,165.62) PAXIL(SAD, 676) 0.7 0.67 (0.15,2.98) PROZ(MDD,HCCJ) 3.7 1.34 (0.66,2.71) PROZ(MDD,HCJE) 16.5 0.88 (0.31,2.48) PROZ(MDD,X065) 8.5 1.09 (0.11,10.83) PROZ(OCD,HCJW) 2.0 1.31 (0.39,4.46) REMER(MDD,045) 5.9 0.51 (0.11,2.30) SERZ(MDD,141) 7.3 1.29 (0.12,13.43) SERZ(MDD,187) 1.9 1.75 (0.21,14.28) ZOLO(MDD,501001) 2.1 1.50 (0.29,7.65) ZOLO(MDD,501017) 3.1

1.11 (0.81,1.50) Overall (95% CI)

149 149

Impact of Antidepressants on Suicide Rates

• 1957-1985: USA: suicide rates 1957-1985: USA: suicide rates 31% 31%• 1986-1999: USA: suicide rates 1986-1999: USA: suicide rates 13.5% 13.5%• 1986-1999: 4-fold 1986-1999: 4-fold Rx for Rx for antidepressantsantidepressants• Most people who die from suicideMost people who die from suicide were not receiving treatments forwere not receiving treatments for depressiondepression

Grunebaum, et al. (2004)Grunebaum, et al. (2004)

CDC Data: Ages 5-14CDC Data: Ages 5-14(Am. J. Psychiatry, 2006)(Am. J. Psychiatry, 2006)

1996-1998…Suicides: 9331996-1998…Suicides: 933Low rates of SSRI Rx:Low rates of SSRI Rx: 1.7 / 100,000 / year1.7 / 100,000 / yearHigh rates of SSRI Rx:High rates of SSRI Rx: 0.7 / 100,000 / year0.7 / 100,000 / year

Impact on PrescribingImpact on PrescribingCDC: Lubell, et al. 2007

• 1990-2003: suicides 1990-2003: suicides 29% 29% (ages: 10-24)(ages: 10-24)

• 30-40% decrease in prescriptions for30-40% decrease in prescriptions for antidepressants for kids and teens antidepressants for kids and teens • 2003-2004: teenage suicides2003-2004: teenage suicides increased by 18%increased by 18%

When antidepressantscan provoke suicide

V:OTC

Products Endorsed By:

• USP (US Pharmacopia)USP (US Pharmacopia)

ST. JOHN’S WORTST. JOHN’S WORT

157

Cochrane Data Base:Systematic Studies

• Meta analysis• St. John’s Wort; equal efficacy to prescription antidepressants• Linde, et al. (2008)

158

ST. JOHN’S WORTST. JOHN’S WORTTREATMENT

Reasons for use900-1800 mg per dayThree, divided dosesCost: $1.00 per day

159

ST. JOHN’S WORTST. JOHN’S WORT

Side effects: mild GI, sedation. No: weight gain or sexual dysfunctionWatch for Drug-Drug Interactions!Washout time before starting another antidepressant: 5 Days

160

S-Adenosylmethionine

SAM-eSAM-eComprehensive review of

literature (Papakostas, et al. , 2003)

76 studies world-wideComparable efficacy to ADsMuch better tolerated

162

SAM-eTreatment: Major Depression

400-1600 mg per day$3-5 per dayIV DosingMethyl donor: serotonin and norepinephrine

163

SAM-eSo Far lack of significant drug-drug

interactionsProblems: homocysteineTake: B vit. including FolateCan provoke maniaTreats osteoarthritis

164

Low Folic Acid: Associated withLow Folic Acid: Associated with

• Depression: > meta analysis: 10 epidemiologic studies: > significant relationship between low folate and depression (Gilbody, et al. 2007)

165

Low Folic Acid: Associated withLow Folic Acid: Associated with

• Decreased CSF metabolites: Serotonin (5-HIAA) Dopamine (HVA) Norepinephrine (MHPG)• Depression may lead to low folate

166

Folic AcidFolic AcidLow serum levels in treatment- resistant depression and early relapseLow folate: increased risk for dementia

167

Folic AcidFolic AcidDosing: 500 mcg per daySignificant augmenter vs placebo Prozac…took ten weeks (Coppen, 2000)

Deplin (L-methylfolate) > no advantage over folic acidWith Depakote: 1-2 mg per day

168

Omega-3Omega-3Fatty Acids:Fatty Acids:essential fatty acidsessential fatty acids

Families of Fatty AcidsFamilies of Fatty AcidsOmega-3 > LNA: seed and nut oils > EPA: fish oil > DHA: fish oil Omega-6 > LNA: seed and nut oils > Soy bean oil and corn oil > Arachidonic acid: Animal Tissue

170

Omega 3:6 ratios

• Typical USA diet: 1:20• Ideal: 1:3

Omega 3 Fatty Acids: Omega 3 Fatty Acids: Bipolar DisorderBipolar Disorder

Mixed findings (Stoll, et al. 1999; Peet and Horrobin, 2002; Nemets, et al., 2002)(Stoll, et al. 1999; Peet and Horrobin, 2002; Nemets, et al., 2002)

172

Omega-3 and Depression• Fish oil: Much better bio-availability• 1-2 grams a day (EPA + DHA)• 6 published studies: major depression > all: add-on studies > all significant better than placebo• ↑ omega 3, ↑ serotonin and dopamine transmission

173

Omega-3, Pregnancy and Major Depression

(Su, Chin, et al. 2008)

• N: 36• 8 weeks, double blind, placebo• EPA: 2.2 grams, DHA: 1.2 grams• Response: Omega-3: 62%...placebo: 27%• Remission: Omega-3: 38%...placebo: 18%• No side effects

Omega-3 Fatty AcidsOmega-3 Fatty Acids

Side effects: GI (diarrhea, nausea)Take with food…ginger root or ginger ale The mercury issue

175

176

5-HTP5-HTPTryptophan 5-HTP 5-HT (serotonin)

5-HTP5-HTP2 well controlled double-blind studies (total 108)300 mg per day (600 TRD)Main Side effect: Sedation (pm)Compounding pharmacyWatch for serotonin syndrome

Other OTC Options

CAUTION!

• MelatoninMelatonin• Kava KavaKava Kava• ValerianValerian

High-IntensityLight Therapy

High Intensity Light TherapyHigh Intensity Light Therapy

SAD and winter blues: 1:4Psychoanalytic views of seasonal mood changes (1945)

High Intensity Light TherapyHigh Intensity Light Therapy

Dosing: 2500 luxAverage time: 20 minutesMorning light is 2 x more effectiveEffects seen: 2-3 daysLost with placebo or discontinuation

High Intensity Light TherapyHigh Intensity Light Therapy

Use in non-seasonal depressionSide effects: nausea, jitteriness, eye strain, dizzinessBlue lights: forget it

High Intensity Light TherapyHigh Intensity Light Therapy

Contraindications: macular degeneration, retina diseases, post cataract surgeryUV effect on the skinBipolar disorder

Dawn Simulation

Sunlight Exposure(melanocytes…endorphins)

Exercise Dosing• 10,000 steps per day• Aerobic …in keeping with fitness• Two 10 minute sessions a day• 20 minutes: 3 times a week

St. Mom’s WortSt. Mom’s WortGiven to pre-schoolers:Given to pre-schoolers: renders themrenders them unconscious unconscious for 6 hoursfor 6 hours

Practice Case: 1

• 54 year old man. Profession: undertaker. No history of depression.

• 6 months ago funeral home was sold and he was not hired by the new owner. He had worked for the former funeral home for 25 years

• 3 months of unsuccessful job searching. Felt frustrated. Possibly low grade depression

Practice case: 1

• 3 months ago at family gathering, a relative made a comment about his “chronic unemployment”

• From that point there has been a downward spiral…increasing low self-esteem..

increasing depression

Clinical Symptoms

• Marked apathy and anhedonia• Early morning awakening• 11 pound weight gain• Suicidal ideas• Fatigue• Social withdrawal (impact on job search)• No sex drive (impact on marriage)

Other factors to consider

• Caffeine use: 4 – 12 oz. cups of coffee per day• Occasional alcohol use• Chronic headaches (takes OTC meds)• No significant medical illnesses• No use of prescription drugs• No drug abuse

Initial Questions

• What is the diagnosis?• Given the clinical picture, what class of

antidepressants should be considered as a first-line choice?....and why?

• He is started with an antidepressant (one that does not require initial titration)…the dose is considered to be in the therapeutic range

Three weeks

• He reports: no noticeable changes since starting medication treatment

• What do you do first? And why? (highest yield next step strategies)

You implement revised treatment plan

• Week 6 (since first dose): no improvement• What do you do?...and why

New Strategy Works

• 4 weeks into new treatment: 20% improvement on current medications…

• What do you do?• New scenario: 4 weeks: 50% improvement• 4 additional weeks: still at 50% improvement• What do you do?

New Scenario

• Week 3 into the initial treatment and you discover that the patient has cold intolerance.

• What might this suggest and how might it affect your treatment?

New Scenario:Different Presenting Clinical Symptoms

• Significant anxiety; lots of rumination• Early morning awakening• 11 pound weight loss• Suicidal ideas• Anger outbursts and marked irritability• Social withdrawal (impact on job search)• No sex drive (impact on marriage)

Questions

• Given the clinical picture, what class of antidepressants should be considered as a first-line choice?....and why?

• He reports that after the first day of treatment there is an increase in anxiety and agitation…what is going on and what might you do to address this situation?

Side Effect Problems:how might you address each?

• Significant nausea• Onset of initial insomnia• After he begins to respond positively, there is

some return of libido…he is relieved…• 4 weeks later he reports an inability to reach

an orgasm..what is likely to be happening?• What can you do?

Side Effect Problems:how might you address each?

• Different scenario: after 4 weeks, he starts to experience impotency…what is happening/

• What might you do?

New Scenario

• Treatment is successful… he has reached remission. • What do you do now?

New Scenario

• Treatment is successful… he has reached remission. • 2 months into continuation he

reports break-thru depressive Sx….what might be happening?....what can you do?