Getting the Most of Antidepressants RVU 05-03-2014 Larry O. Sanders, MD Diplomate of the American Board of Psychiatry and Neurology.

Getting the Most of Antidepressants

RVU 05-03-2014

Larry O. Sanders, MDDiplomate of the American Board of Psychiatry and Neurology

Goals

Screening the Primary Care population for Mental Disease.

First Line and Second Line Treatment of MDD.

Evidence that more than Major Depression is Involved.

When to Refer to Mental Health.

In US, Major Depression is aCommon Medical Illness

Why Treat Depression?

Disability

Morbidity- Depression makes existing somatic conditions worse. (Inflammatory Factors)

Mortality- Psychiatric patients die up to 20 years earlier than average. Most Common reason is Cardiovascular Disease!

Second is Suicide.

Inflammatory Factors, 1

Major Depression Increases

Inflammatory Factors, Worsening the Prognosis

ofSomatic Illness

Inflammatory Factors, 2

Somatic IllnessesIncrease

Inflammatory Factors,Worsening the Prognosis

ofMajor Depression

Depression and Atherosclerotic Disease.

• Major Depression carries 4X Risk of developing a Myocardial Infarction! Anda 1993, Barefot, et. Al. 1996, Pratt 1996

• MIs comorbid with MDD are 5X More likely to be Fatal. Anda 1993

• 16.5% Mortality Risk @ 6 months following Acute MI if also Depression vs 3% if not Depressed. Frasure-Smith 1993

• Major Depression carries same Risk Factor for developing an MI, as Cigarette Smoking!

Major Depression5 Symptoms, 2 Weeks, >50% each

day

Mood*

Sleep

Interest*

Guilt or Hopelessness

Energy

Concentration

Appetite

Psychomotor

Suicidal/Homocidal Ideation

* Depressed

Mood or Anhedonia must be present

(pneumonic “Sige Caps”)

10

Nature vs Nurture

• MDD is strongly genetic, with well over 100 genes involved.

• However, the largest risk for developing MDD as an adult is losing a parent before age 12.

• Many Environmental, Psychological and Sociological factors can effect it.

10

11

Medical Disease can appear as Major Depressive Disorder

• Many Medical Diseases can appear as MDD. R/O:–Hypothyroidism–Anemia, both Microcytic and Macrocytic–Any inflammatory Disease–Hyperparathyroidism (even slightly elevated Ca++

may be important)–Various Vitamin deficiencies, including: D, B12,

B6, Folate, etc.• Vitamin D deficiency seems more common since the use of high SPF Sunscreens. 11

Other (Free) Scales•PHQ 2 Screener

• ( Very brief. I don’t encourage its’ use).

•Zung Depression Rating Scale

•QIDS-SR

• Quick Inventory Depressive Symptomatology (Self Report)

•CUDOS

• Clinically Useful Depression Outcome Scale

Treat to Remission!

Sub-Syndromal Depression = Relapse

Months Well Judd 1998

7 months until Relapse!

One or more Symptoms

No Symptoms

Symptoms and Circuits

Advocated byStephen M. Stahl, MD

Circuit

When a Brain Circuit, when overstimulated or under-stimulated, it

will produce certain symptoms.

(adapted from Steven Stahl, MD)

Each Symptom, regardless of the disease,

comes from the Same Circuit Malfunction!


Symptoms & Circuits

By Knowing Which Symptom is related to which Circuit,

and by Knowing How Each Medication Effects Each Circuit

You can Logically Deduce Which Medication Will Best Treat Most Mental Conditions.


3 Major Circuits Contributing toMental Illness

Serotonin

Circuits

Serotonin

Norepinephrine

Circuits

Serotonin

Norepinephrine Dopamine

Circuits

SymptomsAssociated with

theseCircuits

Symptoms associated with Serotonin

•Serotonin helps us “Cope”.

•If Serotonin is too Low: Irritable, Anxious, Easily Overwhelmed, Hopeless, Suicidal, “poor sense of Well-being”

•If Serotonin is too High: Serotonin Syndrome; Agitation, Fasciulations, Hyperthermia, Vital Sign Disturbance, leading to stupor, come then death. [Although pharmacists warn of this, neither I nor any Psychiatric Colleagues have ever seen this condition. So it appears to be very rare.]

Symptoms associated with Norepinephrine

•Norepinephrine is like “Adrenaline”.

•If Norepinephrine too Low: Anergy, Immediate Memory Impaired, Psychomotor Retardation.

•If Norepinephrine too High: Irritable, Agitation, Insomnia. (Similar Symptoms to Low Serotonin).

Symptoms associated with Dopamine

•Dopamine provides Interests/Desire, mentally. (Dopamine has other physical functions as well).

•If Dopamine too Low: Apathy, Dementia, Muscle

•If Dopamine too High: Hedonism, Psychosis, Mania

Mood*Emotion

Cognitive Function

Serotonin

Norepinephrine

Dopamine

Symptoms & Circuits

Mood*Emotion

Cognitive Function

Suicidal/HomicidalFrustration, “Sense of Well Being”

Obsession, Sleep, Guilt or Hopelessness

Serotonin

Norepinephrine

Dopamine

Symptoms & Circuits

Mood*Emotion

Cognitive Function



Serotonin

Norepinephrine

Dopamine

Energy Alertness

Psychomotor Working Memory

Symptoms & Circuits

Mood*Emotion

Cognitive Function



Serotonin

Norepinephrine

Dopamine

DesireInterest*

Energy Alertness


Symptoms & Circuits

Mood*Emotion

Cognitive Function



Serotonin

Norepinephrine

Dopamine

IrritabilityAnxiety

DesireInterest*

Energy Alertness


Symptoms & Circuits

Mood*Emotion

Cognitive Function

ConcentrationMotivation



Serotonin

Norepinephrine

Dopamine

IrritabilityAnxiety

DesireInterest*

Energy Alertness


Symptoms & Circuits

Mood*Emotion

Cognitive Function




Serotonin

Norepinephrine

Dopamine

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


Symptoms & Circuits

Slaby and Tancradi 2002, Stahl 2004

Symptoms, Circuits & Medications

5HT1a5HT1a

Classes of Antidepressants

•SSRIs

•SNRIs, NaSSI

•SDRIs

•NDRIs (mechanism of Wellbutrin not fully understood)

•DRIs, DAgs

•NRIs – (not very effective).

• (MOAIs, not covered here, are powerful Antidepressants; but carry HTN risk with certain foods and/or meds and Serotonin Syndrome with SRIs.)

Suicidality vs Suicide

•An ironic fact about Antidepressant use is that Suicidality risk (thoughts, not death) increases transiently, BUT SUICIDE (DEATH) risk DECREASES in patients less than 24 y.o.! (expound)

Medications Effecting Primarily

Serotonin

SSRIs• “Multi Action” – ssri, 5HT1a, 1b, 3, & 7.

• Vortioxetine (Brintellix).

•“Dual Action” - SSRI & 5HT1a.

• Vilazadone (Viibryd).

• “Single Action” – SSRI.

• Escitalpram (Lexapro).

• Fluoxetine (Prozac). SSRI + bits of others.

• “Half Action” - Racemic mixture, half active.

• Cilatopram (Celexa).

“Multi Action”- Brintellix 5-20mg“Dual Action” - Viibryd 10-40mg“Single Action”- Lexapro 10-20mg Prozac 20mg“Half Action” - Celexa 40mg

SSRI

Mood*Emotion

Cognitive Function




Serotonin


IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


Larry O. Sanders, MDc 2002, 2014

Symptoms, Circuits & Medications-Trade Names

Medications effecting Both Serotonin and

Norepinephrine

SNRIs• Levomilnacipram (Fetzima) 1:2 S:N

• Duloxetine (Cymbalta) 9:1 S:N

• Desvenlafaxine (Pristiq) 15:1 S:N

• Venlafaxine(Effexor) 30:1 S:N

• At low dose is SSRI. At high dose SNRI. Strong W/D issues!

• {Paroxetine (Paxil) 20-40mg}

• Weight gain, Fatigue, Strong W/D issues!


SSRI

Mood*Emotion

Cognitive Function




Serotonin


IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SNRI

Fetzima 40-120mgCymbalta 60mgPristiq 50-100mgEffexor 75-375mg(Paxil) 20mg



NaSSAIndirectly elevates

Norepinephrine (Noradrenaline) and Serotonin

•Mirtazapine (Remeron)

•Sedating, increases appetite and weight gain.


SSRI

Mood*Emotion

Cognitive Function




Serotonin


IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SNRI




Remeron 30-45mg

(Indirect ^ S & N)

Medications Effecting

Norepinephrine and

Dopamine

NDRI

•Bupropion (Wellbutrin) 300-450mg

•IR. Not Well Tolerated.

•SR. Lasts 12 hours.

•XL. Lasts 24 hours.

Amphetamines

•Terminal Releasers

and

•Reuptake Inhibitors

of Norepinephrine and Dopamine


SSRI

Mood*Emotion

Cognitive Function




Serotonin


NRINDRI

Wellbutrin 300-450mg Amphetamines 10-

30mg b.i.d.

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SNRI




Remeron 30-45mg

(Indirect ^ S & N)

Medication Effecting

Serotonin and

Dopamine

SDRIs

•Sertraline (Zoloft)

•Usual Dose range 50-200 mg/d

•One of the best tolerated, most effective AD.


SSRI

Mood*Emotion

Cognitive Function




Serotonin


NRINDRI

Wellbutrin 300-450mg Amphetamines 10-

30mg b.i.d.

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SDRI

SNRI

Fetzima 40-120mgCymbalta 60mgPristiq 50-100mgEffexor 75-375mg(Paxil) 20mg Zoloft

50-200mg



Remeron 30-45mg

(Indirect ^ S & N)

Medications Effecting Primarily

Dopamine

DRI & DAgs

•Methylphenidate (Ritalin)

•Dopamine Agonists:

•Pramipexole (Mirapex).

•Evidence based treatment. Avg dose 0.95 mg.

•Ropinirole (Requip).


SSRI

Mood*Emotion

Cognitive Function




Serotonin


NRI

NDRI Wellbutrin 300-450mg Amphetamines 10-

30mg b.i.d.

DRI Ritalin 10-40mg bidMirapex 0.25-1.5

mg HS

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SDRI

SNRI


50-200mg



DAg

Remeron 30-45mg

(Indirect ^ S & N)

Medications Effecting PrimarilyNorepinephrine

NRIs•Desiparamine

•Atomoxetine (Strattera)

•(Atomoxetine is a failed antidepressant approved for use in AD/HD. No NRI, other than the TCA Desipramine, has beat placebo).


SSRI

Mood*Emotion

Cognitive Function




Serotonin


NRI DesipramineStrattera


30mg b.i.d.


mg HS

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SDRI

SNRI


50-200mg



DAg

Remeron 30-45mg

(Indirect ^ S & N)


SSRI

Mood*Emotion

Cognitive Function




Serotonin




30mg b.i.d.


mg HS

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SDRI

SNRI


50-200mg



DAg

Remeron 30-45mg

(Indirect ^ S & N)


SSRI

Mood*Emotion

Cognitive Function




Serotonin




30mg b.i.d.


mg HS

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SDRI

SNRI


50-200mg



DAg

Remeron 30-45mg

(Indirect ^ S & N)


SSRI

Mood*Emotion

Cognitive Function




Serotonin




30mg b.i.d.


mg HS

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SDRI

SNRI


50-200mg



DAg

Remeron 30-45mg

(Indirect ^ S & N)


SSRI

Mood*Emotion

Cognitive Function




Serotonin




30mg b.i.d.


mg HS

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SDRI

SNRI


50-200mg



DAg

Remeron 30-45mg

(Indirect ^ S & N)


SSRI

Mood*Emotion

Cognitive Function




Serotonin




30mg b.i.d.


mg HS

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SDRI

SNRI


50-200mg



DAg

Remeron 30-45mg

(Indirect ^ S & N)


SSRI

Mood*Emotion

Cognitive Function




Serotonin




30mg b.i.d.


mg HS

IrritabilityAnxiety

AppetiteAggression

Sex

DesireInterest*

Energy Alertness


SDRI

SNRI


50-200mg



DAg

Remeron 30-45mg

(Indirect ^ S & N)

Compliance“No Involvement, No

Commitment”

•Month 1 40% of Patients are off meds.

•Month 2 60% of Patients are off meds.

•S/E-Weight Gain, Sexual Dysfunction, Emotional Blunting, Cognitive Dysfunction.

•Don’t Realize the Condition is Genetic.

•Confusion with Treatment vs Cure.

When 1st Line Fails in MDD

•Refer to Venn Diagram to

•Increase Dose,

•Change Meds or

•Augment.

•5HT1a - Abilify, Seroquel, Viibryd.

•Lithium.

Don’t Underdose!

If dose 50-200, PCP often give 50mg, maybe 75 mg.

“You haven’t reached maximum dose until you have reached effect or intolerable side effects.”

Just When I Learned All of Life’s Answers,

They Changed the Questions!

The Most Common Causes of Treatment Failure

•Non-Compliance.

•Comorbid Anxiety.

•Bipolar Depression.

•Most experts believe that 20-30% of all Depressed Patients have a Bipolar Disorder

•Comorid Substance Abuse

•Depression with Psychosis (47% risk of manifesting BP1 or BP11 with in 10 years).

When is more than MDD Involved?

•Anxiety

•Psychosis

•Mania

•Substance Abuse

Anxiety• Anxiety Disorders are present in 20% PC Pts.

• Depression and Anxiety are HIGHLY Co-Morbid.

• If Depression present, 60% Chance of having Significant Anxiety Disorder AND vice versa.

• Untreated Anxiety consumes

• 6x more of your time &

• 6x more resources.

• Most Antidepressants Treat Anxiety Disorders, but it is Really Important to Know How to Select Proper Medication.

Types of Anxiety Disorders•Generalized Anxiety Disorder (GAD) -

Chronic Worry.

•Social Phobia (aka Social Anxiety) - Fear Social Judgement.

•Panic Disorder - Sudden, Intense Fear with Physical Symptoms.

•Post-traumatic Stress Disorder (PTSD) - symptoms delayed by > 1 month after trauma. Can be years. For every 1 soldier killed in action in Afganistan, 25 will die by suicide.

•Acute Stress Disorder - within 1 month of trauma.

•Obsessive-Compulsive Disorder (OCD) - Germs, Order, Counting, that they have Harmed to Others.

Anxiety Rating Scales

•GAD 7 - Rates GAD

•Zung Anxiety

•CUXOS

•YBOCS - for OCD

Treatment of Anxiety Disorders•Antidepressants

•Serotonin Agents treat all.

•NE helps GAD, but may make Panic Worse.

•BZs

•Gabapentin

Be Certain It’s NOT Bipolar

Depression!

Experts agree that 30-40% of ALL Depressive Disorders

have a component of Bipolar Disorder

Bipolar Mood States

53%32%

9%6%

50% 46%

1% 2%

Bipolar I Bipolar II

Adapted from Judd 2002 Judd 2003

(146 pts, 12.8 yrs) (86 pts, 13.4 yrs)

% of Weeks

46%46%50% 46%

MDQScoring

False Positives and False Negatives

with MDQ

Treating Bipolar Disorder

•Treating Bipolar Disorder is often a Complex Challenge, much more difficult than treating Depression or Anxiety.

•“Every Bipolar is an “n of 1.”

•Must treat Current State and

•Prevent both Mania and Depression.

If Psychotic Depression

•Treat BOTH Psychosis and Mood.

•Psychotic Depression is a High Risk for having an underlying Bipolar Disorder

Non-Medical Treatments

•Individual Psychotherapies

•CBT, Supportive, Psychodynamic.

•Exercise

•Family Therapy

•Group Therapy

When to Refer•Anytime you are uncomfortable.

•When Gravely Disabled, Imminently Suicidal or Homocidal (SEND TO ER!!!)

•Mania is present

•Psychosis present

•Anxiety doesn’t respond rapidly (Suicide Risk)

•When Substance Abuse present

•Therapy Needed or Helpful.

Epitaph of the Hypochondriac(or the Psych Patient)

Getting the Most of Antidepressants RVU 05-03-2014 Larry O. Sanders, MD Diplomate of the American Board of Psychiatry and Neurology.

Documents

circuit slide

md slide

neurology slide

depression vs

subsyndromal depression

mental disease

symptoms circuits

major depressive disorder