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
The Evolution of AntidepressantsThe Evolution of Antidepressants
1950s1950s
1960s1960s
1970s1970s
1980s1980s
1990s1990s
MAOIsMAOIs
TricyclicsTricyclics
SSRIsSSRIs
Newer dualNewer dualreuptake inhibitorsreuptake inhibitors
Selective dopamine Selective dopamine reuptake inhibitorsreuptake inhibitors
Mixed Receptor Mixed Receptor EffectsEffects
Older heterocyclicsOlder heterocyclics
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
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
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
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
Serotonin and Norepinephrine Reuptake InhibitorsSerotonin and Norepinephrine Reuptake Inhibitors
Drugs Starting Maximum Range
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
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
Dopamine and Norepinephrine Reuptake InhibitorsDopamine and Norepinephrine Reuptake Inhibitors
Drugs Starting Maximum Range
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
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
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?