Pharmacotherapy of Depression Jerry Overman, Pharm.D., BCPP Clinical Pharmacy Specialist, Mental Health (NIMH) NIH Clinical Center Pharmacy Department

Pharmacotherapy of Depression

Jerry Overman, Pharm.D., BCPPClinical Pharmacy Specialist, Mental Health (NIMH)

NIH Clinical Center Pharmacy Department

WMSHP and DC-CCP Spring MeetingMay 10, 2014

9:00 AM

Jerry Overman, Pharm.D., BCPP

– has no financial interest or relationships to disclose

ObjectivesObjectives

Define major depressive disorder and list the core symptoms of the illness

Identify the various mechanisms and theories proposed for the pathogenesis of depression

List the medication classes used to treat depression

Discuss the pharmacology of the various classes of antidepressants and how these mechanisms relate to both efficacy and tolerability

Weissman MM, et al. JAMA. 2011;276:293-299.

Epidemiology of DepressionEpidemiology of Depression

Lifetime prevalence of a major depressive episode: 17%

– Male: 13%

– Female: 21%

Trends

– Age at onset: Younger

– Incidence: Increasing

Depression Guideline Panel. AHCPR publication 93-0550.

Depression and SuicideDepression and Suicide

Up to 15% of patients with major depressive disorder requiring hospitalization commit suicide

Depression Guideline Panel. AHCPR publication 93-0550.

Additional Risk Factors for SuicideAdditional Risk Factors for Suicide

Hopelessness

Male gender

White race

Advanced age

History of attempts

Medical illnesses

Substance abuse (self or family)

Psychotic symptoms

Living alone

Insomnia

Anxiety

Pharmacotherapy ReducesRisk of Suicide

Pharmacotherapy ReducesRisk of Suicide

0

50

100

150

200

250

300

Treated

Untreated

Isacsson G, et al. J Affect Disord. 1996;41:1-8.

Su

icid

es/1

00,0

00 p

erso

n-y

ears

141

259

DSM-5. Washington, DC: American Psychiatric Association. 2013.

DSM-5 Criteria for Major Depressive Episode

≥5 symptoms present during same 2–week period

Change from previous functioning

Functional impairment and/or distress

Symptoms not due to another cause

* Must include 1 of theseDSM-5. Washington, DC: American Psychiatric Association. 2013.

DSM-5 Criteria forMajor Depressive Episode

DSM-5 Criteria forMajor Depressive Episode

Sleep: Insomnia or hypersomnia

Interest: Anhedonia - loss of interest or pleasure

Guilt: Feelings of worthlessness

Energy: Fatigue

Concentration: Diminished ability

to think or make decisions

Appetite: Weight change

Psychomotor: Psychomotor retardation or agitation

Suicide: Recurrent thoughts

of death

5 Symptoms in the same 2-week period

DSM-5. Washington, DC: American Psychiatric Association. 2014.

Common Presenting Somatic ComplaintsCommon Presenting Somatic Complaints

“Tired all the time”, “blahs”

Headache, Pain

Malaise

Vague abdominal or joint pains

Disturbed sleep

Sexual or relationship problems

DSM-5. Washington, DC: American Psychiatric Association. 2013.Depression Guideline Panel. AHCPR publication 93-0550.

Psychological SymptomsPsychological Symptoms

Hopelessness

Low self esteem

Denial, discounting, or explaining away stigmatized feelings

Impaired memory, difficulty concentrating

Continuum of Depression and AnxietyContinuum of Depression and Anxiety

Anxietydisorders

Majordepressive

disorder

Comorbiddepression

and anxiety

Outcomes of Treatments of Major Depressive DisorderOutcomes of Treatments of Major Depressive Disorder

Dropout

Nonresponse/response w/residual symptoms

Response

– Incomplete remission

– Complete remission

Recovery

Rush AJ, et al. Psychiatr Ann. 1995;25:704.

Acute Recovery in Major DepressionAcute Recovery in Major Depression

HAM-D score 7

Patient asymptomatic

– No longer meets criteria for depression

– Minimal or no symptoms

Psychosocial and occupational functioning restored

Consequences of Failing to Achieve RecoveryConsequences of Failing to Achieve Recovery

Greater risk of relapse

Continued psychosocial limitations

Continued impairments at work

Worsens prognosis of other medical disorders

Increased utilization of medical services

Sustained elevation of suicide and substance abuse risks

Response and RemissionResponse and Remission

Euthymia

Symptoms

Syndrome

Treatment Phases

Progression

to disorder

Acute(6–12 wk)

Continuation(4–9 mo)

Maintenance(1 yr)

TimeTime

Incr

ea

sed

Incr

ea

sed

sev

eri

tys

eve

rity

RelapseRelapse

ResponseResponse

RemissionRemission

RecurrenceRecurrenceRelapseRelapse

Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.

+

+

Lost productivity—55%

Outpatient care—6%

Suicide—17%

Inpatient care—19%

Pharmaceuticals—3%

Economics of Depression—Total Annual Cost

Economics of Depression—Total Annual Cost

IdealAntidepressant

Rapid Onsetof Action

Once DailyDosing

Activity in a Range of Disorders

CostEffective

MinimalSide Effects

Safety inOverdose

No DrugInteraction

Profile of the Ideal AntidepressantProfile of the Ideal Antidepressant

New MechanismsNew Mechanisms Various effects on:

– Serotonin (5HT)

– Dopamine (DA)

– Norepinephrine (NE)

– Gamma amino butyric acid (GABA)

– NMDA Glutamate (N-Methyl-D Aspartate)

Tachykinins

– NK1, NK2, NK3

Corticotropin releasing factor

Glucocorticoid receptor antagonists

Neuropeptide Y

Brain Derived Neurotrophic Factor (BDNF)

Cannabinoid receptors

Ascending Aminergic SystemAscending Aminergic System

Brain Stem

Midbrain

Cortex

DA5-HT

NE

Selective manipulation of these aminergic transmitters has been the common denominator for all currently marketed antidepressants

These same systems are implicatedin anxiety

Mood, Emotion,Cognitive function

Motivation

SexAppetite

Aggression

AnxietyIrritability

Energy Interest

Impulse

Drive

Norepinephrine Serotonin

Dopamine

From Kaplan HI, Sadok BJ. In: Synopsis of Psychiatry, Behavioral Sciences, Clinical Psychiatry, 6th ed. Revised. 1991.

Thalamus

Striatum

Neocortex

Ventral striatum

Amygdaloid body

Hypothalamus

Olfactory and entorhinal cortices

Hippocampus Dorsal raphe nuclei

Cingulum

Cingulate gyrus

Hippocampus

Intracerebellar nuclei

Caudal raphe nuclei

To spinal cord

Cerebellar cortex

Serotonergic Innervation of the CNSSerotonergic Innervation of the CNS

Physiologic Distribution of SerotoninPhysiologic Distribution of Serotonin

5% CNS:

-regulates cognition, mood,

appetite, sleep, sexual behavior

95% GI tract:

-regulates intestinal movement

-90% cells of the lining of GI tract

-10% enteric neurons

*Also located in platelets to

facilitate aggregation for blood

clotting

Types of Receptors (5-HT1-7)Types of Receptors (5-HT1-7)

Receptor Function

1A, 1B , 1D, 1E, 1F Anxiety, aggression, sexual behavior, appetite, vasoconstriction

2A, 2B, 2C 2A: inhibits dopamine release; mediates anxiety, agitation, hallucinations, sexual behavior, weight gain/loss2B: Smooth muscle (GI tract), cardiovascular function2C: inhibits dopamine and norepinephrine release; mediates appetite, anxiety, mood, GI motility, sexual behavior, thermoregulation, weight gain/loss

3 Chemoreceptor trigger zone, emesis, GI/bowel motility, nausea, memory

4 Cardiac repolarization (seizure susceptibility), respiration, gastric emptying, oesophageal peristalsis, appetite, anxiety

5A, 5B Locomotion, anxiety, sleep, cognition, thermoregulation, respiration, mood, memory6

7

Norepinephrine Innervation of the CNSNorepinephrine Innervation of the CNSThalamus

Neocortex

Hypothalamus

Olfactory and entorhinal cortices

Hippocampus

Locus ceruleus

Cingulum

Cingulate gyrus

Hippocampus

To spinal cord

Cerebellar cortex

PituitaryAmygdala

Lateral tegmental NA cell system

From Kaplan HI, Sadok BJ. In: Synopsis of Psychiatry, Behavioral Sciences, Clinical Psychiatry, 6th ed. Revised. 1991.

Reuptake transporter

Autoreceptor

Neurotransmitter

Neurotransmitter receptor

POSTSYNAPTIC CELL

PRESYNAPTIC CELL SYNAPTIC CLEFT

Neurotransmitters—Mechanisms of Action

5-HT ReceptorsRegulatory Processes 5HT

1A

1D

3

5HT

5HT

Might food intakeRegulate vasculatureHeadache

Nausea? anxiety, insomnia, panic

5HT1D

synthesis 5HT storage release

5HT

5HT

5HT Transporter

Weight regulation ?

Sexual dysfunction, CNS stimulation

5HT1A

2C5HT

5HT2A

DA reuptake

inhibition

Reduce depressionReduce depression Psychomotor activationPsychomotor activation Antiparkinsonian effectsAntiparkinsonian effects

NEreuptake

inhibition

Reduce depressionReduce depression TremorsTremors TachycardiaTachycardia Erectile/ejaculatory dysfunctionErectile/ejaculatory dysfunction

5HT reuptakeinhibition

Reduce depressionReduce depression Antianxiety effectsAntianxiety effects GI disturbancesGI disturbances Sexual dysfunctionSexual dysfunction

Alpha1

block

Postural hypotensionPostural hypotension DizzinessDizziness Reflex tachycardiaReflex tachycardia Memory dysfunctionMemory dysfunction

AnxietyAnxiety

ACh block

Blurred visionBlurred vision Dry mouthDry mouth ConstipationConstipation Sinus tachyardia Sinus tachyardia Urinary retentionUrinary retention Cognitive dysfunction Cognitive dysfunction

H1

block

Sedation/drowsinessSedation/drowsiness HypotensionHypotension Weight gainWeight gain

Pharmacologic Effects of AntidepressantsPharmacologic Effects of Antidepressants

Antidepressant

Alpha2

block

The Evolution of AntidepressantsThe Evolution of Antidepressants

1950s1950s

1960s1960s

1970s1970s

1980s1980s

1990s1990s

MAOIsMAOIs

TricyclicsTricyclics

Older heterocyclicsOlder heterocyclics

SSRIsSSRIs

Newer dualNewer dualreuptake inhibitorsreuptake inhibitors

Selective dopamine Selective dopamine reuptake inhibitorsreuptake inhibitors

Mixed Receptor Mixed Receptor EffectsEffects

Brief history of MAOI’sBrief history of MAOI’s

Monoamine oxidase inhibitors first observed to have mood elevating properties (1950’s)

Limited prescribing

– Acute hypertension reported from ingestion of dietary tyramine - “cheese reaction”

– Interactions with other medications

– Introduction of the newer antidepressants

Continued efforts have been made to develop MAOI’s that do not require restriction of dietary tyramine

– One strategy has been to exploit the existence of multiple isoenzymes of MAO (MAOA and MAOB)

Monoamine Oxidase Inhibitor AntidepressantsMonoamine Oxidase Inhibitor AntidepressantsType Selectivity Agent Brand

Irreversible Nonselective Phenelzine

Tranylcypromine

Isocarboxazid

Nardil

Parnate

Marplan

MAO-A selective Clorgyline

MAO-B selective Selegiline Eldepryl

Reversible MAO-B selective Moclobemide

Brofaramine

Toloxatone

Befloxatone

Monoamine Oxidase InhibitorsMonoamine Oxidase Inhibitors

Drugs Brand Name Dosage Range (mg)

Isocarboxazid Marplan 20-60

Phenelzine Nardil 45-90

Tranylcypromine Parnate 20-60

Selegeline patch Emsam 6-12


1950s1950s

1960s1960s

1970s1970s

1980s1980s

1990s1990s

MAOIsMAOIs


SSRIsSSRIs





Tricyclic AntidepressantsTricyclic Antidepressants

Amitriptyline (Elavil)

Imipramine(Tofranil)

Clomipramine (Anafranil)

Amoxapine(Asendin)

Doxepin (Sinequan)

Nortriptyline (Pamelor )

Desipramine (Norpramin )

Maprotiline (Ludiomil)

Protriptyline (Vivactil)

Trimipramine (Surmontil)

NEreuptake

inhibition

Reduce depressionReduce depression TremorsTremors TachycardiaTachycardia Erectile/ejaculatory dysfunctionErectile/ejaculatory dysfunction

5HT reuptakeinhibition

Reduce depressionReduce depression Antianxiety effectsAntianxiety effects GI disturbancesGI disturbances Sexual dysfunctionSexual dysfunction

Alpha1

block

Postural hypotensionPostural hypotension DizzinessDizziness Reflex tachycardiaReflex tachycardia Memory dysfunctionMemory dysfunction

ACh block

Blurred visionBlurred vision Dry mouthDry mouth ConstipationConstipation Sinus tachyardia Sinus tachyardia Urinary retentionUrinary retention Cognitive dysfunction Cognitive dysfunction

H1

block

Sedation/drowsinessSedation/drowsiness HypotensionHypotension Weight gainWeight gain

Pharmacologic Effects of TCA’sPharmacologic Effects of TCA’s

Antidepressant


1950s1950s

1960s1960s

1970s1970s

1980s1980s

1990s1990s

MAOIsMAOIs



SSRIsSSRIs




Selective Serotonin Reuptake InhibitorsSelective Serotonin Reuptake Inhibitors

Drugs Starting Maximum Range

Fluoxetine 10 (QAM) 80 20-40

Paroxetine 10 (QHS) 50 20-40

Citalopram 10 40* 20-40

Escitalopram 5 20 10-20

Fluvoxamine 50 300 (BID) 100-300

Sertraline 25 200 50-200

* http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm297624.htm?source=govdelivery

1.) The antidepressant effects of the drugs are known to be limited to the s-isomer

2.) The difference between the effects of citalopram and escitalopram on the QT interval presumably means that the QT effects are not specific to the s-isomer

1.) The antidepressant effects of the drugs are known to be limited to the s-isomer

2.) The difference between the effects of citalopram and escitalopram on the QT interval presumably means that the QT effects are not specific to the s-isomer

http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm

FDA Recommendations re; Citalopram FDA Recommendations re; Citalopram Not recommended at doses greater than 40mg due to prolongation

of QTc interval

Not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute MI or uncompensated heart failure

Not recommended in patients who are taking other drugs that prolong QTc

The max recommended dose is 20mg per day for patients with hepatic impairment, patients > 60 years of age, patients who are CYP 2C19 poor metabolizers and patients who are taking another CYP219 inhibitor; these factors can lead to increased blood levels of citalopram, increasing the risk of QTc prolongation and Torsades de Pointes

http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm


1950s1950s

1960s1960s

1970s1970s

1980s1980s

1990s1990s

MAOIsMAOIs



SSRIsSSRIs




Serotonin and Norepinephrine Reuptake InhibitorsSerotonin and Norepinephrine Reuptake Inhibitors


Venlafaxine(Effexor)

25 375 150-375BID/TID

Venlafaxine(Effexor XR)

37.5 225 75-225QD

Duloxetine(Cymbalta)

10 60 20-60QD/BID

Desvenlafaxine (Pristiq)

50 100 50-100 QD

Levomilnacipran ER (Fetzima)

20 120 40 – 120 QD


1950s1950s

1960s1960s

1970s1970s

1980s1980s

1990s1990s

MAOIsMAOIs



SSRIsSSRIs




Dopamine and Norepinephrine Reuptake InhibitorsDopamine and Norepinephrine Reuptake Inhibitors


Bupropion

Wellbutrin

100mgBID 450mg(3-4 divided)

300-400

Bupropion

WellbutrinSR

150mgQD 200mgBID 300-400

Bupropion

WellbutrinXL

150mgQD 450mgQD 300-400

Bupropion

Zyban

150mgQD 300mg For 7-12wks


1950s1950s

1960s1960s

1970s1970s

1980s1980s

1990s1990s

MAOIsMAOIs



SSRIsSSRIs




Mixed Receptor EffectsMixed Receptor Effects

SRI, 5HT2 antagonist

– Trazodone (Desyrel, Oleptro)

– Nefazodone

Noradrenergic (alpha 2), 5HT2, 5HT3 antagonist

– Mirtazapine (Remeron)

SRI, 5HT1 partial agonist

– Vilazodone (Viibryd)

SRI, 5HT1a agonist, 5HT1b partial agonist, 5HT3/7 antagonist

– Vortioxetine (Brintellix)

Some Augmentation StrategiesSome Augmentation Strategies

Lithium

Thyroid Supplementation

Atypical Antipsychotics

Buspirone

Modafanil

Lamotrigine

Stimulants

………………………

Discontinuation SyndromeDiscontinuation Syndrome

Withdrawal Syndrome

– Can occur with most antidepressants

– Symptoms: dizziness, nausea, paresthesias, anxiety/insomnia

– Onset 36-72 hours

– Duration 3-7 days

SummarySummary

Depression is a biologically based illness that responds to antidepressant therapy in the majority of patients

Appropriate choice of antidepressant therapy should be based on past response, patient characteristics and adverse event profile

Appropriate trial length and dosage is important when evaluating response to antidepressants

Questions?

Documents

Pharmacotherapy of Depression Jerry Overman, Pharm.D., BCPP Clinical Pharmacy Specialist, Mental Health (NIMH) NIH Clinical Center Pharmacy Department