depression...to activity -- but moving from pain to pain. one does not abandon, even briefly,...

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DepressionDepression

J. H. Atkinson MDCourtesy of S. Zisook MD

J. H. Atkinson MDCourtesy of S. Zisook MD

Why Medical Students Need ToKnow How To Recognize And

Treat Depression (1)


Treat Depression (1) Common

• Each year, 10% US population (19 million Americanadults)• Coronary heart disease = 7 million• Cancer = 6 million• AIDS = 200,000

• 10% men and 25% women lifetime

Chronic and recurring Disabling

• 4th leading cause of disability worldwide; 2nd by 2020• Effects work, relationships and family more than almost

any other GMC• May be a risk for onset, persistence or severity of a variety

of GMCs

Common• Each year, 10% US population (19 million American

adults)• Coronary heart disease = 7 million• Cancer = 6 million• AIDS = 200,000

• 10% men and 25% women lifetime

Chronic and recurring Disabling

• 4th leading cause of disability worldwide; 2nd by 2020• Effects work, relationships and family more than almost

any other GMC• May be a risk for onset, persistence or severity of a variety

of GMCs


Treat Depression (2)


Treat Depression (2)Can be fatal

• Responsible for > 60% suicides• Increases mortality from co-occurring

GMCs

TreatableYet, diagnosis often missed and

treatment not provided orinadequately provided

Can be fatal• Responsible for > 60% suicides• Increases mortality from co-occurring

GMCs

TreatableYet, diagnosis often missed and

treatment not provided orinadequately provided

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5 Questions5 Questions

1. What is depression?2. Who gets it?3. Why?4. So what?5. How do you treat/manage it?

1. What is depression?2. Who gets it?3. Why?4. So what?5. How do you treat/manage it?

1. What Is Depression?1. What Is Depression?

Due to emotional weakness 71%

Caused by bad parenting 65%

Victim’s fault: can will it away 45%

Incurable 43%

Consequence of sinful behaviour 35%

Biological basis: involves thebrain

10%

Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder, 2000

Results of a general population study

Depressive Disorders...Depressive Disorders...

...must be distinguished fromthe “normal” fluctuating feelingsof joy, happiness, elation,sadness, “the blues,” andbereavement.

...must be distinguished fromthe “normal” fluctuating feelingsof joy, happiness, elation,sadness, “the blues,” andbereavement.

Pervasive

Persistent

Disabling

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Abraham LincolnAbraham Lincoln

“In this sad world of ours, sorrow comes toall,and it often comes with bitter agony.Perfect relief is not possible, except withtime. You cannot now believe that you willever feel better. But this is not true. Youare sure to be happy again. Knowing this,truly believing it, will make you lessmiserable now. I have had enoughexperience to make this statement.”

“In this sad world of ours, sorrow comes toall,and it often comes with bitter agony.Perfect relief is not possible, except withtime. You cannot now believe that you willever feel better. But this is not true. Youare sure to be happy again. Knowing this,truly believing it, will make you lessmiserable now. I have had enoughexperience to make this statement.”

“If what I feel were equally distributed to theentire human race, there would not be onecheerful face left on earth.”

Beyond DespairBeyond Despair

WILLIAM STYRON, DARKNESS VISIBLE, 1990

“The pain is unrelenting, and whatmakes the condition intolerable is theforeknowledge that no remedy willcome -- not in a day, an hour, amonth or a minute. It ishopelessness even more than painthat crushes the soul. So thedecision making of daily life involvesnot, as in normal affairs, shifting fromone annoying situation to anotherless annoying -- or from discomfortto relative comfort, or from boredomto activity -- but moving from pain topain. One does not abandon, evenbriefly, one’s bed of nails, but isattached to it wherever one goes”.

“The pain is unrelenting, and whatmakes the condition intolerable is theforeknowledge that no remedy willcome -- not in a day, an hour, amonth or a minute. It ishopelessness even more than painthat crushes the soul. So thedecision making of daily life involvesnot, as in normal affairs, shifting fromone annoying situation to anotherless annoying -- or from discomfortto relative comfort, or from boredomto activity -- but moving from pain topain. One does not abandon, evenbriefly, one’s bed of nails, but isattached to it wherever one goes”.

Major Depressive Episode (MDE)Major Depressive Episode (MDE) Five or more symptoms for > 2 weeks

• Depressed mood most of day every day• Diminished interest or pleasure

• Significant loss or gain in weight• Insomnia or hypersomnia nearly every night• Psychomotor retardation or agitation• Fatigue or loss of energy

• Feelings of worthlessness or excessive guilt• Diminished concentration or ability to make decisions• Recurrent thoughts of death , suicide, or a suicide

attempt

Five or more symptoms for > 2 weeks

• Depressed mood most of day every day• Diminished interest or pleasure

• Significant loss or gain in weight• Insomnia or hypersomnia nearly every night• Psychomotor retardation or agitation• Fatigue or loss of energy

• Feelings of worthlessness or excessive guilt• Diminished concentration or ability to make decisions• Recurrent thoughts of death , suicide, or a suicide

attempt

At least 1 of theseAt least 1 of these

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Over-View Of DepressiveDisorders

Over-View Of DepressiveDisorders

Bipolar Disorder (“Highs” and “Lows”)

Depressive Disorders (“Lows”)• Major Depressive Disorder (MDD)• Dysthymic Disorder• Double Depression (Dysthymic Disorder + MDD)• Depressive Disorder Not Otherwise Specified (NOS)

Depression due to Medical Conditions

Substance -Induced Depressive Disorder

Bipolar Disorder (“Highs” and “Lows”)

Depressive Disorders (“Lows”)• Major Depressive Disorder (MDD)• Dysthymic Disorder• Double Depression (Dysthymic Disorder + MDD)• Depressive Disorder Not Otherwise Specified (NOS)

Depression due to Medical Conditions

Substance -Induced Depressive Disorder

Single episode

Recurrent

Dysthymic DisorderDysthymic Disorder Depressed mood most of the day, more days than not, for

> 2 years• in children & adolescents, mood can be irritable for > 1

years

2 or more of the following symptoms• poor appetite or overeating• insomnia or hypersomnia• low energy or fatigue• low self-esteem• poor concentration or indecisiveness• feelings of hopelessness

During the period, never without symptoms for morethan 2 months at a time

Depressed mood most of the day, more days than not, for> 2 years• in children & adolescents, mood can be irritable for > 1

years

2 or more of the following symptoms• poor appetite or overeating• insomnia or hypersomnia• low energy or fatigue• low self-esteem• poor concentration or indecisiveness• feelings of hopelessness

During the period, never without symptoms for morethan 2 months at a time

Mood Disorders Due ToMedical Conditions

Mood Disorders Due ToMedical Conditions

Infectious Diseases: Hepatitis, HIV

Endocrinopathy: Thyroid, Diabetes, Cushing’s

Malignancy: Pancreatic, Lung

Hematologic: Pernicious Anemia

Neurologic: Parkinson’s, Huntington’s,Alzheimers, Stroke

Cardiovascular: Myocardial Infarction

Other: Chronic Pain, Chronic Fatigue,Fibromyalgia, High Utilizers

Infectious Diseases: Hepatitis, HIV

Endocrinopathy: Thyroid, Diabetes, Cushing’s

Malignancy: Pancreatic, Lung

Hematologic: Pernicious Anemia

Neurologic: Parkinson’s, Huntington’s,Alzheimers, Stroke

Cardiovascular: Myocardial Infarction

Other: Chronic Pain, Chronic Fatigue,Fibromyalgia, High Utilizers

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Substance -Induced MoodDisorder

Substance -Induced MoodDisorder

Alcohol Amphetamines Cocaine Opioids

HeavyMetals/Toxins

Interferon

Alcohol Amphetamines Cocaine Opioids

HeavyMetals/Toxins

Interferon

Sedatives/Hypnotics Reserpine Corticosteroids Anabolic Steroids Alpha-Methyldopa? Beta Blockers? Sex Hormones?

Polypharmacy

Sedatives/Hypnotics Reserpine Corticosteroids Anabolic Steroids Alpha-Methyldopa? Beta Blockers? Sex Hormones?

Polypharmacy

2. Who Gets Depressed?2. Who Gets Depressed?Risk factor Association

Past History Depression begets depression

Gender 10-25% women5-12% men

All ages Peak age onset 20-40

Family history 1.5-3 x risk

Marital status Separated and divorced; unmarriedmales; married females

Life events Postpartum, loss, childhoodtrauma/abuse

Health General medical illness, disability

Race/Ethnicity Native American > White> Black,Hispanic, Asian

Social supports Living alone, few friends or confidants

Substance use/abuse Alcohol, opiates, cocaine, stimulants,others

Anyone, including 5-25% medical students andphysicians, and their friends and families

Anyone, including 5-25% medical students andphysicians, and their friends and families

Risk Of Recurrence FollowingRecovery From An Index Episode

Of Major Depression

Risk Of Recurrence FollowingRecovery From An Index Episode

Of Major Depression

N=359 patients with MDD.Lavori PW, et al. Int J Meth Psychiatr Res. 1994;4:211-229.

Risk•Past history•Residual symptoms•Early or late onset•Severe, chronic, complicated•Women•Untreated

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3. Why? Etiologic TheoriesOf Depression

3. Why? Etiologic TheoriesOf Depression

• Biological factors(such as hormones,brain chemistry andfamily history/genetics)

• Psychological factors(learned helplessness,cognitive distortions,ambivalence - angerturned inward)

• Social factors (trauma,loss or stress)

• Biological factors(such as hormones,brain chemistry andfamily history/genetics)

• Psychological factors(learned helplessness,cognitive distortions,ambivalence - angerturned inward)

• Social factors (trauma,loss or stress)

Normal Brain Depressed Brain

More activity Less activity

A Bio-psycho-social Disorder Brain is Target Organ

Biological FactorsBiological Factors

GeneticsNeurotransmitterNeuroendocrineSleepAnatomic

GeneticsNeurotransmitterNeuroendocrineSleepAnatomic

Genetic Risk Factors ForMood Disorders

Genetic Risk Factors ForMood Disorders

Risk in first degree relatives• Major depressive probands:

Increased by about 2 fold• Bipolar probands: Increased

by about 7 fold (range 3.7-17.7)

Twin studies: Concordance ratesin MZ twins• Major depression: about 50%• Bipolars: about 70%

Risk in first degree relatives• Major depressive probands:

Increased by about 2 fold• Bipolar probands: Increased

by about 7 fold (range 3.7-17.7)

Twin studies: Concordance ratesin MZ twins• Major depression: about 50%• Bipolars: about 70%

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Neurotransmitter HypothesisNeurotransmitter Hypothesis

Mood disorders related toimbalances in catecholamineand/or serotonin levels

Mood disorders related todysregulation of neuro-receptors• Up-regulated beta-receptors

in depression• Up-regulated 5HT2

receptors in depression• Down-regulated alpha-1

presynaptic receptors indepression

Failure of neuroplasticity andsignal transduction

Mood disorders related toimbalances in catecholamineand/or serotonin levels

Mood disorders related todysregulation of neuro-receptors• Up-regulated beta-receptors

in depression• Up-regulated 5HT2

receptors in depression• Down-regulated alpha-1

presynaptic receptors indepression

Failure of neuroplasticity andsignal transduction

5 HT NEMDEMania

Neuroendocrine And SleepFindings In Depression

Neuroendocrine And SleepFindings In Depression

Neuroendocrine theories• Increased activity of the hypothalamic-pituitary-axis (HPA)

• increased CRH, ACTH and cortisol• “dexamethasone escape”• blunted CRH challenge response in depression

Sleep and circadian rhythms• Short latency from sleep onset to first REM period (“short

REM latency”)• Poor sleep continuity: reduced total sleep time and stages

3&4 (Delta) sleep; increased wakefulness during the night

Neuroendocrine theories• Increased activity of the hypothalamic-pituitary-axis (HPA)

• increased CRH, ACTH and cortisol• “dexamethasone escape”• blunted CRH challenge response in depression

Sleep and circadian rhythms• Short latency from sleep onset to first REM period (“short

REM latency”)• Poor sleep continuity: reduced total sleep time and stages

3&4 (Delta) sleep; increased wakefulness during the night

Brain Imaging And DepressionBrain Imaging And Depression

Magnetic Resonance Imaging• Increased ventricular volume (geriatric depression)• Increased white matter hyperintensities• Decreased cerebellar volume• Decreased temporal lobe, putamen, & caudate

volume• Increased pituitary gland volume

Functional Brain Imaging Measures(Positron Emission Tomography)• Increased glucose metabolic rate (GMR) in prefrontal

cortex, amygdala & cingulate gyrus during depression• Blunted decrease in local cortical GMR after

fenfluramine

Magnetic Resonance Imaging• Increased ventricular volume (geriatric depression)• Increased white matter hyperintensities• Decreased cerebellar volume• Decreased temporal lobe, putamen, & caudate

volume• Increased pituitary gland volume

Functional Brain Imaging Measures(Positron Emission Tomography)• Increased glucose metabolic rate (GMR) in prefrontal

cortex, amygdala & cingulate gyrus during depression• Blunted decrease in local cortical GMR after

fenfluramine

Drevets et al, 2002; Carlson et al, 2006Drevets et al, 2002; Carlson et al, 2006

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NegativeView ofFuture

NegativeView ofWorld

NegativeView of

Self

Loss of a parent at an early age or childhood abuse• Probably more important in MDD than BP

Psychoanalytic interpretations of depression• Real or imagined loss of an ambivalently held love object,

with resultant anger turned against self and loss of self-esteem

Interpersonal theory of depression• Problem areas: grief, interpersonal role disputes,role transitions, interpersonal deficits

Cognitive theories of depression• Learned Helplessness• Negative cognitive distortions

• E.g., “all or nothing”• Overgeneralization

• Cognitive triad (self, world, future)• Negative attribution style

Loss of a parent at an early age or childhood abuse• Probably more important in MDD than BP

Psychoanalytic interpretations of depression• Real or imagined loss of an ambivalently held love object,

with resultant anger turned against self and loss of self-esteem

Interpersonal theory of depression• Problem areas: grief, interpersonal role disputes,role transitions, interpersonal deficits

Cognitive theories of depression• Learned Helplessness• Negative cognitive distortions

• E.g., “all or nothing”• Overgeneralization

• Cognitive triad (self, world, future)• Negative attribution style

Psychological FactorsPsychological Factors

Cognitive TriadCognitive Triad

Negative view ofself• defective• inadequate• deprived• worthless• undesirable

Negative view ofworld• demanding• punitive• defeating

Negative view offuture• continued hardship• suffering• hopelessness• deprivation• failure

Stress

Mood Normal

Depression

R. Shelton 1999.

Social Factors

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Stressors

Depression

Stress and Depression

Stress Hypothesis of DepressionStress Hypothesis of Depression

1. Duman RS, et al. Biol Psychiatry. 2000;48:732-739.2. Sapolsky RM. Arch Gen Psychiatry. 2000;57:925-935.

Normal survivaland growth

BDNF

Increased survivaland growth

5-HT, NE and DA

Glucocorticoids

??

Pharmacotherapy, ECT,psychotherapy1

Dendriticbranching2

STRESS/DEPRESSION

Glucocorticoids

BDNF

1

Atrophy/deathof neurons

TREATMENT

Influence Of Life Stress OnDepression: Moderation By A

Polymorphism In The 5-HTT Gene



Individuals with one or two copies of theshort allele of the 5-HTT promoter geneexhibited more depressive symptoms,diagnosable depression, and suicidality inrelation to stressful life events and/orchildhood maltreatment than individualshomozygous for the long allele.

Caspi, A et al SCIENCE 301; 386 ff, JULY 18, 2003

Individuals with one or two copies of theshort allele of the 5-HTT promoter geneexhibited more depressive symptoms,diagnosable depression, and suicidality inrelation to stressful life events and/orchildhood maltreatment than individualshomozygous for the long allele.


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Patients with s/s allele may not respond to citalopram as well as other patients

Number stressful life events

Pro

babi

lity

of M

DE


Among the small group who experienced severe childhood abuse, s/s allele subjects rana 63% risk of MDE in young adulthood.

4. So What? MorbidityScorecard

4. So What? MorbidityScorecard

Physical Social Role Daysin bed

Currenthealth

Pain

Hypertension

Diabetes

Heart disease

Arthritis

Lung disease

None

Depressionequallydisabling

Depressionmoredisabling

Depressionnot asdisabling

Wells and Burnham, 1991

Major Causes Of DisabilityWorldwide

Major Causes Of DisabilityWorldwide

Rank 1990 2020(Estimated)

1 Lower respiratoryinfections

Ischemic heartdisease

2 Perinatal conditions

3 HIV/AIDS Road traffic accidents

4 Unipolar MajorDepression

Cerbrovasculardisease

5 Diarrheal diseases Chronic obstructivepulmonary disease

Murray and Lopez, eds. The Global Burden of Disease; 1996

Unipolar MajorDepression

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Suicide: Facts and FiguresSuicide: Facts and Figures

Approximately 32,000 people inthe United States die bysuicide each year. Aboutevery 16.6 minutes someonein this country intentionallyends his/her life.• 11th leading cause of death• 3rd leading cause of death for

people aged 10-24.• 2nd leading cause of death

among college students.• 2nd leading cause of death for

people aged 25-34.• 4th leading cause of death for

adults ages 18 - 65.

Approximately 32,000 people inthe United States die bysuicide each year. Aboutevery 16.6 minutes someonein this country intentionallyends his/her life.• 11th leading cause of death• 3rd leading cause of death for

people aged 10-24.• 2nd leading cause of death

among college students.• 2nd leading cause of death for

people aged 25-34.• 4th leading cause of death for

adults ages 18 - 65.

I feel certain that I'm going mad again. I feelwe can't go thru another of those terribletimes. And I shan't recover this time.Suicide note~~ Virginia Woolf, author, d. March 28, 1941

Suicide and Mood DisordersSuicide and Mood Disorders

20 - 40% persons with mood disordersexhibit non-fatal suicidal behavior, includingthoughts of suicide• 30% depressed inpatients attempt suicide

10-15% of persons with severe, recurrentmood disorders commit suicide

Elderly white males at greatest risk• >60% causally related to depression• 80% consult physician in month before death

Do antidepressants help or harm?

20 - 40% persons with mood disordersexhibit non-fatal suicidal behavior, includingthoughts of suicide• 30% depressed inpatients attempt suicide

10-15% of persons with severe, recurrentmood disorders commit suicide

Elderly white males at greatest risk• >60% causally related to depression• 80% consult physician in month before death

Do antidepressants help or harm?

Most effective prevention is early identificationand prompt treatment of depression

Depression and Suicidal Ideation inMedical Students and Residents

Depression and Suicidal Ideation inMedical Students and Residents

Demographic Characteristic Prevalence of ProbableMajorDepression (CES-D>21)

Prevalence ofsuicidal ideation

Trainee typeMedical Students (N>1200) 13.6* 6.6*

Residents (N>600) 7.2 3.9

Gender (N>1800)

Male 7.9 5.3

Female 15.2* 6.1

Ethnicity (N>1800)

African American 12.8 13.0*

Asian 13.9 6.3

Caucasian 13.0 4.5*

Latino 9.5 7.6

Total (N=1883) 12.0 (30.3% of those with past historymajor depression)

5.7 (68.5% of those with “probable majordepression”)

Goebert et al, Academic Medicine, 2009 * p<0.05

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Depression Risk Begins BeforeMedical School

Depression Risk Begins BeforeMedical School

% Premedical Studentswith MDD% Premedical Studentswith MDD UCSD Web Survey ofUCSD Web Survey of

2236 Undergraduates• 628 Premeds• 1,558 Non-Premeds

Increased severity ofdepressive symptomsand frequency MDDamong premeds• Woman > men• Hispanics> others• Asians also greater

intensity depressivesymptoms than non-Asians

2236 Undergraduates• 628 Premeds• 1,558 Non-Premeds

Increased severity ofdepressive symptomsand frequency MDDamong premeds• Woman > men• Hispanics> others• Asians also greater

intensity depressivesymptoms than non-Asians

Daniel Fang (MS-II) and Christina Young

3535

Access of Care and Barriers toCare

Access of Care and Barriers toCare

35 percent of physicians do not have a regular source of health care

Low rates of seeking help among medical students:• Only 22 percent of those screening positive for depression used

mental health services• Only 42 percent of those with suicidal ideation received treatment

Reasons:• lack of time (48%)• lack of confidentiality (37%)• stigma (30%)• cost (28%)• fear of documentation on academic record (24%)

Gross et al., Arch Intern Med, 2000

35 percent of physicians do not have a regular source of health care

Low rates of seeking help among medical students:• Only 22 percent of those screening positive for depression used

mental health services• Only 42 percent of those with suicidal ideation received treatment

Reasons:• lack of time (48%)• lack of confidentiality (37%)• stigma (30%)• cost (28%)• fear of documentation on academic record (24%)

Gross et al., Arch Intern Med, 2000

Suicide Risk FactorsSuicide Risk FactorsGeneral Mental illness

• Esp. Mood Disorder Past attempts Plan Means

• Esp. firearms

General Mental illness

• Esp. Mood Disorder Past attempts Plan Means

• Esp. firearms

Additional Risk for MDD Anxiety, agitation, or

enraged behavior Isolation Drug and/or alcohol

use or abuse History of physical or

emotional abuse Feelings of

hopelessness ordesperation

Additional Risk for MDD Anxiety, agitation, or

enraged behavior Isolation Drug and/or alcohol

use or abuse History of physical or

emotional abuse Feelings of

hopelessness ordesperation

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Depression And Chronic MedicalIllness

Depression And Chronic MedicalIllness

Increased prevalence of major depressionin the medically ill

Depression amplifies physical symptomsassociated with medical illness

Comorbidity increases impairment infunctioning

Depression decreases adherence toprescribed regimens

Depression increases mortality

Increased prevalence of major depressionin the medically ill

Depression amplifies physical symptomsassociated with medical illness

Comorbidity increases impairment infunctioning

Depression decreases adherence toprescribed regimens

Depression increases mortality

MDE AND MORTALITY AFTERAN MI (N=222)

MDE AND MORTALITY AFTERAN MI (N=222)

• 16% Met Criteriafor MDE

•Risk Independent ofMI Severity orMedications

Frasure-Smith et al 1993

5. How Do You Treat/ManageDepression?

5. How Do You Treat/ManageDepression?

Psychotherapy• Interpersonal• Cognitive behavioral• Psychodynamic

Medication Therapy• Antidepressants• Lithium• Some Anticonvulsants• Antipsychotics

Education• Patient• Family

Reduce/eliminatesymptoms

Restore “wellness” Prevent relapse

and recurrence

Goals of Treatment

APA Practice Guideline, 2000; Schulberg et al., 1998

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Psychodynamic PsychotherapyCognitive Behavioral TherapyInterpersonal Therapy

Psychotherapies

Dynamic PsychotherapyDynamic Psychotherapy

UnconsciousConflictsFree AssociationWorking Through

TransferenceNeurosis

UnconsciousConflictsFree AssociationWorking Through

TransferenceNeurosis

Cognitive Therapy

Depressed thoughts and behaviors lead todepressed mood and “depression”

Cognitive TriadNegative view of self (defective,

inadequate, deprived, worthless,and/or undesirable).

Negative view of world (demanding,punitive, defeating).

Negative view of future (continuedhardship, suffering, hopelessness,deprivation and failure).

Therapy involves correcting negativethoughts, beliefs, and distortions

Manualized

Brief

Here and now

Demonstrated effective formajor depression

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InterpersonalPsychotherapyInterpersonal

Psychotherapy Current interpersonal problems have roots in

early dysfunctional relationships Current interpersonal problems, grief, and/or

role transitions are likely to be involved inprecipitating or perpetuating currentdepressive symptoms

Therapist helps patient work throughinterpersonal conflicts, strengthens socialskills, grieve appropriately, and/or adapt tolife change

Current interpersonal problems have roots inearly dysfunctional relationships

Current interpersonal problems, grief, and/orrole transitions are likely to be involved inprecipitating or perpetuating currentdepressive symptoms

Therapist helps patient work throughinterpersonal conflicts, strengthens socialskills, grieve appropriately, and/or adapt tolife change

Manualized, brief, mostly here and now, demonstrated effectivefor Major Depression

1950s

1960s

1970s

1980s

1990s

MAOIs

TCAs

SARI

SSRIs

NaSSA

Isocarboxazid, phenelzine,tranylcypromine

Amitriptyline, clomipramine,desipramine, imipramine,nortriptyline, etc

Citalopram, fluoxetine,fluvoxamine, paroxetine,sertraline

SNRI

Mirtazapine

Duloxetine, venlafaxine,

Trazodone (nefazodone)

The Evolution ofAntidepressantsThe Evolution ofAntidepressants

NDRI Bupropion

2006 Transdermal MAOI-B Selegeline patch

Antidepressant OverviewAntidepressant OverviewAntidepressant Antianxiety

(anxietydisorders)*

Weight gain Sexual sideeffects

Lethal inoverdose

MAOIs + + + + +TCAs + +/- + + +SSRIs + + +/- + -NDRI + +/- - - -SNRIs + + - + -SARIs + +/- - +/- -NaSSA + +/- + - -

*All decrease anxiety associated with Major Depression; some more effective for anxiety disorders than others

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Initial Selection: APA PracticeGuidelines 2000

Initial Selection: APA PracticeGuidelines 2000

Chose psychotherapy only• Mild – if preferred and available• Moderate/severe

• Pregnancy, lactation or wish to become pregnant• Previous good response• Medications ineffective

Chose medication only• Mild – if preferred• Moderate/severe –treatment of choice

Chose psychotherapy plus medication• Clinically significant psychosocial issues, interpersonal

problems, or a comorbid personality disorder• History of only partial response to single treatment modality• Poor adherence to past medication trials• Chronic major depressions (e.g. chronic major depression,

double depression)

Chose psychotherapy only• Mild – if preferred and available• Moderate/severe

• Pregnancy, lactation or wish to become pregnant• Previous good response• Medications ineffective

Chose medication only• Mild – if preferred• Moderate/severe –treatment of choice

Chose psychotherapy plus medication• Clinically significant psychosocial issues, interpersonal

problems, or a comorbid personality disorder• History of only partial response to single treatment modality• Poor adherence to past medication trials• Chronic major depressions (e.g. chronic major depression,

double depression)

How Long Do You Keep Patients On TheirAntidepressants?

How Long Do You Keep Patients On TheirAntidepressants?

All patients treated at least 4-9 months after remission• Longer

• 2nd ‘close’ recurrence (within 2 yrs)• Chronic, severe or complicated depressions• Residual symptoms• Severe, ongoing stressors• Bipolar family history• Early or late onset

Consider long term maintenance treatment (years tolifetime) for clearly recurrent depression• > 3 episodes over past 5 years• When it makes good sense

All patients treated at least 4-9 months after remission• Longer


Consider long term maintenance treatment (years tolifetime) for clearly recurrent depression• > 3 episodes over past 5 years• When it makes good sense

APA Practice Guidelines 2000

Other TreatmentsOther Treatments

Electroconvulsive Therapy (ECT)Vagal nerve Stimulation VNS

Bright LightHormonesExercise

StimulantsHerbs

Sleep DeprivationrTMSDBS

Electroconvulsive Therapy (ECT)Vagal nerve Stimulation VNS

Bright LightHormonesExercise

StimulantsHerbs

Sleep DeprivationrTMSDBS

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5 Questions5 Questions

1. What is depression?A serious, chronic, recurring disorder of mood andassociated features

2. Who gets it?Anyone

3. Why?Biopsychosocial

4. So what?High morbidity and mortality

5. How do you treat/manage it?Education, psychotherapy and pharmacotherapy

1. What is depression?A serious, chronic, recurring disorder of mood andassociated features

2. Who gets it?Anyone

3. Why?Biopsychosocial

4. So what?High morbidity and mortality

5. How do you treat/manage it?Education, psychotherapy and pharmacotherapy

“In the depth of winter, I finally learned that withinme there lay within me an invincible summer”.

Albert Camus

ADDITIONAL SLIDESADDITIONAL SLIDESNot for use in 2010Not for use in 2010

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Depression andComorbid Medical Illness

Depression andComorbid Medical Illness

Prevalence Of Depressive DisordersIn Various Patient Populations*

% Prevalence

General PopulationChronically Ill

OutpatientsHospitalized Patients

Cancer outpatientsCancer Inpatients

StrokeMI

Diabetes 18.045.0

47.042.0

33.036.0

33.09.4

5.8

0 10 20 30 40 50

*There is a range of percentages depending on the study;Adapted from: WPA/PTD Educational Program on Depressive Disorders.Gavard JA, Lustman PJ, Clouse RE. Diabetes Care. 1993(Aug);16(8):1167-1178

Depression ComorbidityAdversely Affects Outcomes

Depression ComorbidityAdversely Affects Outcomes

Increases morbidity and mortality independent ofthe severity of myocardialdisease

Increases the need for pain medication and possiblymortality

Associated with poorrestoration of function and probably increasedmortality

Impaired quality of life, neurocognitive andfunctional impairment, poor adherance toantiretroviral therapy and accelerated diseaseprogression

Poorer glycemic control and greater prevalence ofcomplications (retinopathy, neuropathy, sexualdysfunction, etc)

Stroke

Cancer

CardiovascularDisease

HIV/AIDS

Diabetes

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Mechanisms By Which DepressionConfers Risk Of Medical ProblemsMechanisms By Which DepressionConfers Risk Of Medical Problems

Life-style and adherence issues Physiologic mechanisms

• Impaired sleep efficiency• Decreased heart rate variability• Platelet hyperactivity/hypercoagulability• HPA activation

• Increased CRF• Increased cortisol• Increased sympathetic nervous system activity• Impaired immune function

• Decreased BDNF• Increased inflammatory cytokines

• Tumor necrosis factor alpha (TNF-a)• Interleukin (IL-1 and IL-6)






Joynt et al Biol Psych, 2003; Rudisch and Nemeroff, BiolPsych, 2003; Mussellman et al AGP, 1998

Age of Onset Adult Patients withMDD (N>4000)

Age of Onset Adult Patients withMDD (N>4000)

Zisook et al 2006

•Mean age ofonset = 26(range = 2-71)

• > 1/3 beforeage 18

•Early onsetmore severe,recurring,disabling andsuicidality

•Earlier age ofonset forBipolarDisorder

12% 25%

50%

13%

Mechanisms By Which DepressionConfers Risk Of Medical ProblemsMechanisms By Which DepressionConfers Risk Of Medical Problems











Joynt et al Biol Psych, 2003; Rudisch and Nemeroff, BiolPsych, 2003; Mussellman et al AGP, 1998

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Nefazodone Vs CBT Vs Both ForChronic Major Depression (N=681)Nefazodone Vs CBT Vs Both For

Chronic Major Depression (N=681)

Duration current episodeMDD 8 yrs

43% double depression 30% history anxiety

disorder 60% personality disorder 33% history

alcohol/substance abusedisorder

20% no prior treatment Nefazodone worked faster Psychotherapy worked

better than Nefazodone insubset with childhoodabuse or trauma







Per

cent

Rem

issi

on

Keller, et al, NEJM, 2000Nemeroff, et al, PNAS, 2003

Antidepressants Among MostCommonly Prescribed Medications

Antidepressants Among MostCommonly Prescribed MedicationsRank US Sales ($ x millions)1. Codeine and combos 139.72. SSRI/ SNRI 117.43. HMG-CoA RI 101.34. ACEI 92.15. Beta Blocker 91.56. Oral Contraceptives 88.27. CCB 77.88. PPI 74.19. Antihistamine 70.2

10. Thyroid Synthetic 69.9

Rank US Sales ($ x millions)1. Codeine and combos 139.72. SSRI/ SNRI 117.43. HMG-CoA RI 101.34. ACEI 92.15. Beta Blocker 91.56. Oral Contraceptives 88.27. CCB 77.88. PPI 74.19. Antihistamine 70.2


IMS Health Data, 2002, PharmaTrends 2002, NDCHealth Corporation,http://www.ndchealth.com


Antidepressants: Wonder Drugs?Antidepressants: Wonder Drugs?

20 years ago the benzodiazepines were the mostwidely prescribed Psychotropic Agents.

With the advent of the “Prozac revolution” in 1989,SSRI’s have come to dominate the market, with 6agents now in this class.

Several other classes exist among the post-MAOI andTCA medications, including SARI’s, SNRI’s, NDRI’s,and NaSSI’s

Newer antidepressants (post-TCA) have restoredfunctioning to millions of people who were restrictedfrom this opportunity by older, high side effect agents.

But all are far from panaceas






http://www.ndchealth.com


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How Do AntidepressantsWork? Beyond Transmitters

and Receptors

How Do AntidepressantsWork? Beyond Transmitters

and Receptors Increase levels of noradrenalin, serotonin and/or

dopamine at the synapse Neurotransmitters stimulate or block receptors Activated receptors trigger “cascade” of events Second messengers activate transcription factors Transcription factors cause or block expression of

neuronal genes (eg gene for BDNF)

Increased cell survival and growth

Increase levels of noradrenalin, serotonin and/ordopamine at the synapse

Neurotransmitters stimulate or block receptors Activated receptors trigger “cascade” of events Second messengers activate transcription factors Transcription factors cause or block expression of

neuronal genes (eg gene for BDNF)

Increased cell survival and growth

Selecting The “Right”Antidepressant

All classes equally effective,sooooo…..Past and family historyClinical

features/ComorbiditiesSide effects and toxicities

Phases of Treatment Response inMDD

Phases of Treatment Response inMDD

Kupfer DJ. J Clin Psychiatry. 1991;52(suppl):28

RelapseReturn ofsymptoms

meeting thecriteria for MDDprior to recovery

Moo

d Im

prov

emen

t

Asymptomatic

Symptoms

Syndrome Response50% improvement

from baseline

RemissionMinimal symptoms,normal functioning

RecoveryLong-termremission

RecurrenceNew episode

of MDD

Treatment Phases: Acute12 wk

Continuation4–9 mo

Maintenance≥1 yr

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Major Depressive Episode(Continued)

Major Depressive Episode(Continued)

Significant distress or impairment ofsocial, occupational, or other areas offunctioning

Symptoms not a direct result of asubstance or medical condition

Not accounted for by bereavement

Significant distress or impairment ofsocial, occupational, or other areas offunctioning

Symptoms not a direct result of asubstance or medical condition

Not accounted for by bereavement

Depression: A Lifelong DisorderDepression: A Lifelong Disorder

Excerpts from: Betty, Sophia andGeorge

Excerpts from: Betty, Sophia andGeorge

4. So What? Course AndConsequences Of Depression

4. So What? Course AndConsequences Of Depression

Clinical Characteristic Community Sample* Treatment SeekingSample**

Mean age of onset 30 25.3

Mean age first treatment 33.5Mean number lifetime episodes 4.7 6

% last episode > 2 years 25

Mean duration depressiveepisode - weeks

24.3 100

% comorbid psychiatricdisorders

AlcoholDrugAnxiety Disorder

14.14.6

36.1

12.17.4

53.2

% attempted suicide 8.8 17.9% treated 60.6

*Hasin, D. S. et al. Arch Gen Psychiatry 2005;62:1097-1106**Trivedi et al, Am J Psychiatry 2006;163:28-40

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Suicidality Risk for Active Drug vs.Placebo (N= 10,000; 372 Placebo

Controlled Trials)

Suicidality Risk for Active Drug vs.Placebo (N= 10,000; 372 Placebo

Controlled Trials)Risk Factors

•All medications

•Nonresponse toTreatment

•Depression

• SubstanceDependence

•Under age 25

•Severe Depression

•AnxiousDepression

•Bipolar?

•Infrequent Contact?

Psychopharmacologic Advisory Committee, Dec, 2006(http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf)

Suicidality Odds Ratios for ActiveAntidepressant Drugs Relative to

Placebo

Suicidality Odds Ratios for ActiveAntidepressant Drugs Relative to

Placebo

Psychopharmacologic Advisory Committee, Dec, 2006(http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf)

Treatment For Adolescents WithDepression Study (TADS) Randomized

Controlled Trial (N=439)

Treatment For Adolescents WithDepression Study (TADS) Randomized

Controlled Trial (N=439)

Clinically significant suicidalthinking, which was presentin 29% of the sample atbaseline, improvedsignificantly in all 4treatment groups.Fluoxetine with CBTshowed the greatestreduction (P =.02).

Seven (1.6%) of 439patients attempted suicide;there were no completedsuicides.

The combination offluoxetine with CBT offeredthe most favorable tradeoffbetween benefit and risk foradolescents with majordepressive disorder.

Clinically significant suicidalthinking, which was presentin 29% of the sample atbaseline, improvedsignificantly in all 4treatment groups.Fluoxetine with CBTshowed the greatestreduction (P =.02).

Seven (1.6%) of 439patients attempted suicide;there were no completedsuicides.

The combination offluoxetine with CBT offeredthe most favorable tradeoffbetween benefit and risk foradolescents with majordepressive disorder.

Perc

enta

ge R

espo

nder

s

March et al, JAMA. 2004;292:807-820.

http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf

http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf

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Out of the SilenceOut of the Silence

SUMMARY: DepressiveDisorders

SUMMARY: DepressiveDisorders

CommonChronic and RecurrentHigh MorbidityHigh MortalityTreatable

CommonChronic and RecurrentHigh MorbidityHigh MortalityTreatable

Rx MDE: Psychotherapy (CBT Or IPT)Vs. Combined Psychotherapy -

Pharmacotherapy (N=595)

Rx MDE: Psychotherapy (CBT Or IPT)Vs. Combined Psychotherapy -

Pharmacotherapy (N=595)

0

10

20

30

40

50

60

4 8 12 16

Combination Therapy - Less Severe

Combination Therapy - More Severe

Psychotherapy Alone -Less Severe

Psychotherapy Alone- More Severe

Cum

ulat

ive

rem

issi

onra

tes,

%

Weeks of treatmentThase et al, 1997

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Nefazodone Vs CBT Vs Both ForChronic Major Depression (N=681)Nefazodone Vs CBT Vs Both For

Chronic Major Depression (N=681)













Per

cent

Rem

issi

on

Keller, et al, NEJM, 2000Nemeroff, et al, PNAS, 2003

Antidepressants Among MostCommonly Prescribed Medications

Antidepressants Among MostCommonly Prescribed MedicationsRank US Sales ($ x millions)1. Codeine and combos 139.72. SSRI/ SNRI 117.43. HMG-CoA RI 101.34. ACEI 92.15. Beta Blocker 91.56. Oral Contraceptives 88.27. CCB 77.88. PPI 74.19. Antihistamine 70.2


Rank US Sales ($ x millions)1. Codeine and combos 139.72. SSRI/ SNRI 117.43. HMG-CoA RI 101.34. ACEI 92.15. Beta Blocker 91.56. Oral Contraceptives 88.27. CCB 77.88. PPI 74.19. Antihistamine 70.2




Antidepressants: Wonder Drugs?Antidepressants: Wonder Drugs?













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How Long Do You Treat? APAPractice Guidelines 2000

How Long Do You Treat? APAPractice Guidelines 2000

Allow at least 3-4 weeks for initiation of response• Let the patient know this up front• Side effects Symptoms Function

If no or partial response at 3-4 weeks, increasedose

If partial response (and few side effects) by 6-8weeks, increase dose, augment ( e.g. lithium) orcombine (eg another antidepressant)

If no response (and/or troublesome side effects)by 6-8 weeks, it may be time change medications

Initial goal is remission by 12 weeks

Allow at least 3-4 weeks for initiation of response• Let the patient know this up front• Side effects Symptoms Function

If no or partial response at 3-4 weeks, increasedose

If partial response (and few side effects) by 6-8weeks, increase dose, augment ( e.g. lithium) orcombine (eg another antidepressant)

If no response (and/or troublesome side effects)by 6-8 weeks, it may be time change medications

Initial goal is remission by 12 weeks

Acute Treatment Phase

After Remission, How Long Do You Keep Patients OnTheir Antidepressants? APA Practice Guidelines 2000

After Remission, How Long Do You Keep Patients OnTheir Antidepressants? APA Practice Guidelines 2000

All patients treated thru the continuation phase for at least4-9 months after remission• Longer


Consider long term maintenance treatment for clearlyrecurrent depression• > 3 episodes over past 5 years• When it makes good sense

All patients treated thru the continuation phase for at least4-9 months after remission• Longer


Consider long term maintenance treatment for clearlyrecurrent depression• > 3 episodes over past 5 years• When it makes good sense

Continuation/Maintenance Treatment

Janice (Post-Treatment)Janice (Post-Treatment)

depression...to activity -- but moving from pain to pain. one does not abandon, even briefly,...

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