john j. miller, m.d. october 2, 2015...• volunteer consultant to the insight meditation society...
TRANSCRIPT
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 1
Pharmacokinetic andPharmacokinetic and PharmacodynamicPharmacodynamicDifferences Among AntidepressantsDifferences Among Antidepressants
Pharmacokinetic andPharmacokinetic and PharmacodynamicPharmacodynamicDifferences Among AntidepressantsDifferences Among Antidepressants
John J. Miller, M.D.John J. Miller, M.D.
Medical Director, Brain HealthMedical Director, Brain Health
Staff Psychiatrist, Seacoast Mental Health CenterStaff Psychiatrist, Seacoast Mental Health Center
Consulting Psychiatrist, Exeter HospitalConsulting Psychiatrist, Exeter Hospital
Exeter, NHExeter, NH
John J. Miller, M.D.John J. Miller, M.D.
Medical Director, Brain HealthMedical Director, Brain Health
Staff Psychiatrist, Seacoast Mental Health CenterStaff Psychiatrist, Seacoast Mental Health Center
Consulting Psychiatrist, Exeter HospitalConsulting Psychiatrist, Exeter Hospital
Exeter, NHExeter, NH
October 2, 2015October 2, 2015
FinancialFinancial DisclosuresDisclosures
•• Medical Director, Brain HealthMedical Director, Brain Health
•• Staff Psychiatrist, Seacoast Mental Health Center,Staff Psychiatrist, Seacoast Mental Health Center,Exeter, NHExeter, NH
•• Consulting Psychiatrist, Exeter Hospital, Exeter, NHConsulting Psychiatrist, Exeter Hospital, Exeter, NH
•• Volunteer consultant to the Insight Meditation SocietyVolunteer consultant to the Insight Meditation SocietyBarreBarre, MA, MA
•• Speaker/consultant for Millennium HealthSpeaker/consultant for Millennium Health
•• Speaker/consultant for AstraZenecaSpeaker/consultant for AstraZeneca
•• Speaker/consultant forSpeaker/consultant for SunovionSunovion
•• Speaker for Forest (Speaker for Forest (ActavisActavis//AllerganAllergan))
•• Speaker/consultant for Takeda/Speaker/consultant for Takeda/LundbeckLundbeck
•• Speaker/consultant forSpeaker/consultant for OtsukaOtsuka//LundbeckLundbeck
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 2
The handout for this presentation isThe handout for this presentation isavailable in full color, two slides per pageavailable in full color, two slides per pagefor easy viewing, and downloadable at myfor easy viewing, and downloadable at my
websitewebsite’’s homepage:s homepage:
www.brainwww.brain--health.co/health.co/
Three pillars of knowledge forrational medication prescribing
Effective pharmacotherapy
Pharmaco-Kinetics
What thebody does to
the drug
Pharmaco-Dynamics
What thedrug does to
the body
Pharmaco-Genomics
How genesimpact adrug’s
effectiveness
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 3
The Wiring of the BrainThe Wiring of the Brain
• There are approximately 100 billion neurons in thehuman brain.
• There are on average 10,000 synapses/neuron
• Hence, there are approximately 1,000 trillion synapses.in the human brain = one quadrillion synapse/brain.
• There are approximately 100 billion neurons in thehuman brain.
• There are on average 10,000 synapses/neuron
• Hence, there are approximately 1,000 trillion synapses.in the human brain = one quadrillion synapse/brain.
Carey,Carey, NessaNessa; The; The EpigeneticsEpigenetics Revolution; New York;Revolution; New York;Columbia University Press; 2012Columbia University Press; 2012
Part 1
The history of psychiatric drugdiscovery and our earliestpsychiatric medications:
a case of serendipity
Part 1
The history of psychiatric drugdiscovery and our earliestpsychiatric medications:
a case of serendipity
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 4
A long, long time ago(about 14 billion years ago) . . .In our very own universe . . .An event occurred that lasted
one trillionth of one trillionth of one second . . .
And was named after a great TV show . . .
The Big Bang
Following the Big Bang, there were onlythree elements in the entire universe:
Hydrogen, Helium and Lithium
(over time, giant clouds of these 3 primordialelements accreted through gravitational forces tocreate stars and galaxies, and the additional 115
elements were created by strong forces within stars)
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 5
Mood Stabilizer - Lithium:our oldest psychiatric medication
Mood Stabilizer - Lithium:our oldest psychiatric medication
• Reportedly used in spring water to treatmania in the Roman and Greek eras.
• 19th century used to treat gout.
• 1870s used to treat mania in USA andDenmark.
• 1900 lithium abandoned as a medicationbecause pharmaceutical companies couldnot patent it.
• Reportedly used in spring water to treatmania in the Roman and Greek eras.
• 19th century used to treat gout.
• 1870s used to treat mania in USA andDenmark.
• 1900 lithium abandoned as a medicationbecause pharmaceutical companies couldnot patent it.
Mood Stabilizer - Lithium:our oldest psychiatric medication
Mood Stabilizer - Lithium:our oldest psychiatric medication
• 1949 Australian psychiatrist John Caderediscovered the effectiveness of Li salts inthe treatment of mania.
• 1970 FDA approved for mania.
• 1974 FDA approved for the prevention ofmanic-depressive disorder.
• 1949 Australian psychiatrist John Caderediscovered the effectiveness of Li salts inthe treatment of mania.
• 1970 FDA approved for mania.
• 1974 FDA approved for the prevention ofmanic-depressive disorder.
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 6
Clue about depression - Reserpine:an antihypertensive that lowers
blood pressure by depleting norepinephrine
Clue about depression - Reserpine:an antihypertensive that lowers
blood pressure by depleting norepinephrine
• 1952 Indian snakeroot (Rauwolfia serpentina)was found to contain reserpine.
• 1954 reserpine was introduced in the USA.
• Norepinephrine depletion was associated withincreased depression.
• Contributed significantly to the “monoaminedepletion hypothesis of depression”(norepinephrine, dopamine and serotonin).
• 1952 Indian snakeroot (Rauwolfia serpentina)was found to contain reserpine.
• 1954 reserpine was introduced in the USA.
• Norepinephrine depletion was associated withincreased depression.
• Contributed significantly to the “monoaminedepletion hypothesis of depression”(norepinephrine, dopamine and serotonin).
First Antidepressant - IproniazidFirst Antidepressant - Iproniazid
• 1952 researchers observed that patients treated withisoniazid for tuberculosis became “inappropriately happy”.
• Structure was modified, and in 1958 iproniazid was FDAapproved as the first antidepressant.
• 1961 withdrawn from the US market due to liver toxicity.
• Mechanism of action is that of a monoamine oxidaseinhibitor (MAOI). Raises levels of norepinephrine,dopamine and serotonin.
• Followed by the MAOIs Nardil and Parnate.
• 1952 researchers observed that patients treated withisoniazid for tuberculosis became “inappropriately happy”.
• Structure was modified, and in 1958 iproniazid was FDAapproved as the first antidepressant.
• 1961 withdrawn from the US market due to liver toxicity.
• Mechanism of action is that of a monoamine oxidaseinhibitor (MAOI). Raises levels of norepinephrine,dopamine and serotonin.
• Followed by the MAOIs Nardil and Parnate.
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 7
Monoamine Hypothesis of Depression
• All current FDA approvedantidepressants work by modulatingsome aspect of the three monoaminesserotonin, norepiniphrine and dopamine.
Monoamines are importantneurotransmitters
Monoamines are importantneurotransmitters
• Serotonin
• Dopamine
• Norepinephrine
• Epinephrine
• Melatonin
• Histamine
• Serotonin
• Dopamine
• Norepinephrine
• Epinephrine
• Melatonin
• Histamine
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 8
The fact that many psychiatricThe fact that many psychiatricmedications can bind to multiplemedications can bind to multiple
structurally similar receptorsstructurally similar receptorshelps us understand the etiology tohelps us understand the etiology to
the burden of side effects fromthe burden of side effects frompsychiatric medications.psychiatric medications.
Current Medications FDAApproved to Treat Major Depression:
Three important monoamineneurotramsmitters
Current Medications FDAApproved to Treat Major Depression:
Three important monoamineneurotramsmitters
• Serotonin
• Dopamine
• Norepinephrine
• Serotonin
• Dopamine
• Norepinephrine
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 9
Three Important NeurotransmittersThree Important Neurotransmitters
Dopamine Norepinephrine
Serotonin
Decreases anxiety
We All TreatDepression
AttentionMotivationPleasure
AlertnessAttention
Cognition
Part 2
An overview of the mechanism of actionof current psychiatric medications.
Neurotransmitters, medications, andhow they communicate with neurons to
create change in the way the brainfunctions.
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 10
Our evolving understanding ofhow psychiatric medications
work:
1) mechanism of action at thecellular level
2) mechanism of action at thelevel of circuits
Our evolving understanding ofhow psychiatric medications
work:
1) mechanism of action at thecellular level
2) mechanism of action at thelevel of circuits
Basic mechanism of action of someBasic mechanism of action of somepsychiatric medications.psychiatric medications.
•• Mechanism of action at the cellular level.Mechanism of action at the cellular level.
•• Research paradigm shift after the completionResearch paradigm shift after the completionof the sequencing of the human genome inof the sequencing of the human genome in2003.2003.
•• Effects on receptors at theEffects on receptors at the neuronal surfaceneuronal surface..
•• Effects in theEffects in the intracellular environmentintracellular environment..
•• Effects on theEffects on the informationinformation flow throughflow throughcircuitscircuits of different types of neuronsof different types of neurons
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 11
Receptor –EndogenousNeurotransmitter
Cell Membrane
Intra-cellular
Extra-cellular
Target receptor
Receptor Antagonist
Cell Membrane
Intra-cellular
Extra-cellular
Target receptorX
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 12
Receptor –Agonist
Cell Membrane
Intra-cellular
Extra-cellular
Target receptor
ReceptorAntagonist/Partial Agonist
Cell Membrane
Intra-cellular
Extra-cellular
Target receptor
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 13
Ionotropic ReceptorsIonotropic Receptors
• Receptors that open or close ionchannels, altering the influx or effluxof charged ions.
• Response occurs in milliseconds.
• Result is a change in the polarizationof a cell: depolarization orhyperpolarization.
• Receptors that open or close ionchannels, altering the influx or effluxof charged ions.
• Response occurs in milliseconds.
• Result is a change in the polarizationof a cell: depolarization orhyperpolarization.
Two significant ionotropicreceptor systems
Two significant ionotropicreceptor systems
• Glutamate
– The primary excitatory neurotransmitter
– NMDA-glutamate receptors manage influx ofpositive charge into neurons (Ca++, Na+) – thisis the receptor that ketamine antagonizes
• GABA (gamma-amino butyric acid)
– The primary inhibitory neurotransmitter
– GABA-A receptors manage the influx ofnegative charge into neurons (Cl-)
• Glutamate
– The primary excitatory neurotransmitter
– NMDA-glutamate receptors manage influx ofpositive charge into neurons (Ca++, Na+) – thisis the receptor that ketamine antagonizes
• GABA (gamma-amino butyric acid)
– The primary inhibitory neurotransmitter
– GABA-A receptors manage the influx ofnegative charge into neurons (Cl-)
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 14
Cell Membrane
Intra-cellular
Extra-cellular
NMDA-glutamateion channel
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ + + + + + + + + + + + + + + + +
MgMg
Mg= magnesium (2+)
Ca = calcium (2+)
Na = sodium (1+)
K = potassium (1+)
- Glutamate binding site
- Glycine binding site
Cl= chloride (1-)
K ClK K Cl Cl K Cl Cl K Cl K CL Cl K Cl K Cl K Cl Cl
Na Na Na Ca Na Ca NaNa Na Na Ca Na
Ca Ca CaNa Na
Influx of postitive chargewill depolarize the neuron -resulting in an action potential
Cell Membrane
Intra-cellular
Extra-cellular
NMDA-glutamateion channel
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ + + + + + + + + + + + + +
Ca Ca Ca
MgMg
AMPA-glutamateIon channel
Ca Ca Ca
Glycine Neuron
Ca CaCa Ca
MajorDepolarization
MinorDepolarization
MgMg
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 15
Cell Membrane
Intra-cellular
Extra-cellular
GABA-A chloride ion channel(heteropentameric glycoprotein)
aa
b
ge
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ ++ + + ++ + + ++ + + + ++ + + ++ + + + + ++
= GABA binding site
= benzo binding site
= ETOH binding site
= barbit binding site
Na = sodium (1+)
Cl= chloride (1-)
Cl Cl Cl Cl ClCl Cl ClCl Cl Cl Cl Cl Cl Cl Cl Cl
Na Na Na Na Na Na Na Na Na Na Na Na Na Na Na
Cl Cl ClCl Cl Cl
Influx of negative chargehyperpolarizes the neuron –
decreasing excitability
Metabotropic ReceptorsMetabotropic Receptors
• Receptors that mediate their response throughsecondary messenger systems.
• These receptors include the large population of“G-Protein Coupled Receptors”, which mayconstitute 80% of all human receptors.
• Initial response takes seconds, but the final resultmay take days, weeks or even months.
• G-Protein Coupled Receptors allow for anamplification of the original signal up to 10,000fold.
• Receptors that mediate their response throughsecondary messenger systems.
• These receptors include the large population of“G-Protein Coupled Receptors”, which mayconstitute 80% of all human receptors.
• Initial response takes seconds, but the final resultmay take days, weeks or even months.
• G-Protein Coupled Receptors allow for anamplification of the original signal up to 10,000fold.
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 16
G-Protein Coupled Receptor
a b g
G-protein
Cell Membrane
Effectors inactive
Intra-cellular
S = serotonin
Extra-cellular
Adenylyl cyclase
K+ ion channel
GDP
G-Protein Coupled Receptor
b gCell Membrane
Intra-cellular
S = serotonin
Extra-cellular
Adenylyl cyclase
aGTP
K+
K+
ATP cAMP
Activates Protein Kinase A
Activates CREB – a transcription factor
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 17
G-Protein Coupled Receptor
a b gCell Membrane
Effectors inactive
Intra-cellular
S = serotonin
Extra-cellular
Adenylyl cyclase
K+ ion channel
GDP
P
GTPase
A close up view of a
synapse
A close up view of a
synapse
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 18
SSSSSSSSSSSSSSSSSS
S SS S SS S SS S SS S
S S SS S
S S
SS SS S
Neuronal TransmissionInformation Flow
Neuronal TransmissionInformation Flow
Pre-synapticNeuron
Post-SynapticNeuron
X
5HT-1
S SS S SSSS S S
SS S S SS SS S SS S SS
S S
SSSSSSSSSSSSSSSSSS
SS SS S
Neuronal TransmissionInformation Flow
Neuronal TransmissionInformation Flow
Pre-synapticNeuron
Post-SynapticNeuron
XS SS S S
S S SSS S
S SS S SSSS S S
SS S S S
S SS S SS S SS S SS S
S S SS S
S S
X
X
Celada P, et al. J Psychiatry Neurosci 2004; 29 (4): 252-65.
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 19
SSSSSSSSSSSSSSSSSS
SS SS S
Neuronal TransmissionInformation Flow
Neuronal TransmissionInformation Flow
Pre-synapticNeuron
Post-SynapticNeuron
XS SS S S
S S SSS S
S SS S SSSS S S
SS S S S
S SS S SS S SS S SS S
S S SS S
S S
X
X
X
Celada P, et al. J Psychiatry Neurosci 2004; 29 (4): 252-65.
The Serotonin SystemThe Serotonin System
• Serotonin = 5-HT – needs to be synthesized– Folic acid does not cross the blood-brain-barrier
– Folic acid is metabolized by a multi-step process, with the criticalpoint involving the final methylation by MethyleneTetraHydroFolate Reductase (MTHFR) to form L-methyl-folate
– L-methyl-folate is a carbon donor that contributes to the synthesisof serotonin (and dopamine/norepinephrine)
• Serotonin transporter = 5-HTT– Two promoter sequences: short & long
– Two 5-HTT genes = 4 genotypes
– s,s; l,l; s,l; l,s
• Serotonin receptors– Seven families = 5-HT-1, 2, 3, 4, 5, 6 and 7
• Serotonin = 5-HT – needs to be synthesized– Folic acid does not cross the blood-brain-barrier
– Folic acid is metabolized by a multi-step process, with the criticalpoint involving the final methylation by MethyleneTetraHydroFolate Reductase (MTHFR) to form L-methyl-folate
– L-methyl-folate is a carbon donor that contributes to the synthesisof serotonin (and dopamine/norepinephrine)
• Serotonin transporter = 5-HTT– Two promoter sequences: short & long
– Two 5-HTT genes = 4 genotypes
– s,s; l,l; s,l; l,s
• Serotonin receptors– Seven families = 5-HT-1, 2, 3, 4, 5, 6 and 7
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 20
Serotonin Receptor FamiliesSerotonin Receptor Families• 5-HT 1A, B, D, E, F – these are inhibitory
• 5-HT 2A, B, C
• 5-HT 3A, B
• 5-HT 4A, B, C, D, E, F, H
• 5-HT 5A, B – these are inhibitory
• 5-HT 6
• 5-HT 7
• 5-HT 1A, B, D, E, F – these are inhibitory
• 5-HT 2A, B, C
• 5-HT 3A, B
• 5-HT 4A, B, C, D, E, F, H
• 5-HT 5A, B – these are inhibitory
• 5-HT 6
• 5-HT 7
Adayev T et al. Biosci Rep. 2005 Oct-Dec;25(5-6):363-85Pytliak M. 2011. Physiol Res. 60: 15-25.Stahl SM. Stahl’s Essential Psychopharmacology. 2008.Khan A. Expert Opin Investig Drugs. 2009; 18: 1753-1764.Barnes NM and Sharp T. Neuropharmacology. 1999: 38: 1083-1152.
Adayev T et al. Biosci Rep. 2005 Oct-Dec;25(5-6):363-85Pytliak M. 2011. Physiol Res. 60: 15-25.Stahl SM. Stahl’s Essential Psychopharmacology. 2008.Khan A. Expert Opin Investig Drugs. 2009; 18: 1753-1764.Barnes NM and Sharp T. Neuropharmacology. 1999: 38: 1083-1152.
Serotonin Receptor ClassesSerotonin Receptor Classes
• Metabotropic = GPCR
(G-Protein Coupled Receptors)
– All except 5-HT 3
• Ionotropic = 5-HT-Gated Ion-Channel
– Only 5-HT 3
– Permeable to monovalent cations
– Includes Na+, K+, Li+ and NH4+
• Metabotropic = GPCR
(G-Protein Coupled Receptors)
– All except 5-HT 3
• Ionotropic = 5-HT-Gated Ion-Channel
– Only 5-HT 3
– Permeable to monovalent cations
– Includes Na+, K+, Li+ and NH4+
Adayev T et al. Biosci Rep. 2005 Oct-Dec;25(5-6):363-85Adayev T et al. Biosci Rep. 2005 Oct-Dec;25(5-6):363-85
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 21
From receptors . . .
To . . .
Circuits
From receptors . . .
To . . .
Circuits
A serotonin neuron modulatinga dopamine neuron
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 22
SerotoninNeuron
DopamineNeuron
= Serotonin Neuron
= Dopamine Neuron
S = SerotoninD = Dopamine
D DD
D
V = 5HT-1A Serotonin Receptor
SerotoninNeuron
DopamineNeuron
= Serotonin Neuron
= Dopamine Neuron
S = SerotoninD = Dopamine
DD D DDD D D DD D D
DD D
V = 5HT-1A Serotonin Receptor
X
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 23
SerotoninNeuron
DopamineNeuron
= Serotonin Neuron
= Dopamine Neuron
S = SerotoninD = Dopamine
DD D DD D DD DD DD D
D D D DDDD D D
V = 5HT-1A Serotonin Receptor
A serotonin neuron modulating adomapine neuron
through a GABA(gamma-amino butyric acid) inter-neuron
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 24
DopamineNeuron
SerotoninNeuron
GABANeuron
= Serotonin Neuron
= GABA Neuron
= Dopamine Neuron
S = Serotonin
G = GABA
D = Dopamine
D DD DD D
V = 5HT-2A Serotonin Receptor
y = GABA Receptor
DopamineNeuron
SerotoninNeuron
GABANeuron
= Serotonin Neuron
= GABA Neuron
= Dopamine Neuron
S = Serotonin
G = GABA
D = Dopamine
DD D DD DDD D D
X
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 25
DopamineNeuron
SerotoninNeuron
GABANeuron
= Serotonin Neuron
= GABA Neuron
= Dopamine Neuron
S = Serotonin
G = GABA
D = Dopamine
DDD DD DDD DD D DDD D
DD DD D DD D DDD D DD D
Psychiatric Medications TodayPsychiatric Medications Today
From Serendipity:
To Molecular “fingerprinting”
From Serendipity:
To Molecular “fingerprinting”
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 26
*Roth BL, Sheffler DJ and Kroeze WK. Nat Rev Drug Discov. 2004 Apr;3(4):353-9
53receptors
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 27
Part 3
Our current medication portfolio for thepharmacological treatment of
Major Depressive Disorder:
Pharmacodynamics of Antidepressants
TargetingTargeting ““symptomssymptoms”” or treating aor treating a ““diagnosisdiagnosis””..
•• Patient withPatient with ““Major Depressive EpisodeMajor Depressive Episode””could present with:could present with:
–– Insomnia OR hypersomniaInsomnia OR hypersomnia
–– No appetite/weight loss OR hyperphagiaNo appetite/weight loss OR hyperphagia
–– Psychomotor retardation OR activationPsychomotor retardation OR activation
–– Severe worry/anxiety OR extreme apathySevere worry/anxiety OR extreme apathy
–– Choose treatment based on symptoms, notChoose treatment based on symptoms, notdiagnosis.diagnosis.
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 28
AntidepressantsAntidepressants
• Classes:
– Monoamine oxidase inhibitors (5)
– Tricyclic Antidepressants (10)
– Selective Serotonin Reuptake Inhibitors (6)
– Serotonin Norepinephrine ReuptakeInhibitors (4)
– Other (6)
• Classes:
– Monoamine oxidase inhibitors (5)
– Tricyclic Antidepressants (10)
– Selective Serotonin Reuptake Inhibitors (6)
– Serotonin Norepinephrine ReuptakeInhibitors (4)
– Other (6)
AntidepressantsAntidepressants
• Classes:
– Monoamine oxidase inhibitors
• Iproniazid = 1958 FDA approved as the firstantidepressant; 1961 removed due to hepatotoxicity
• Phenelzine (Nardil)
• Isocarboxazid (Marplan)
• Tranylcypromine (Parnate)
• Selegiline (EMSAM [transdermal patch])
• Classes:
– Monoamine oxidase inhibitors
• Iproniazid = 1958 FDA approved as the firstantidepressant; 1961 removed due to hepatotoxicity
• Phenelzine (Nardil)
• Isocarboxazid (Marplan)
• Tranylcypromine (Parnate)
• Selegiline (EMSAM [transdermal patch])
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 29
Monoamine oxidase inhibitors
• Oldest class of antidepressants
• Development related to the “monoaminehypothesis” of depression.
• Still occasionally used – underutilized.
• Raises brain levels of serotonin, dopamine andnorepinephrine.
• “Tyramine crisis” – caused by certain foods/drinks
• “Hypertensive crisis” – caused by many commonprescription and OTC drugs.
Schatzberg AF, Nemeroff CB, Eds. Essentials of Clinical Psychopharmacology, 3rded. Washington, DC: American Psychiatric Publishing; 2013.
AntidepressantsAntidepressants
• Classes:
– Tricyclic Antidepressants
• Classes:
– Tricyclic Antidepressants
• Doxepin
• Amoxapine
• Trimipramine
• Protriptyline
• Maprotiline• tetracyclic
• Doxepin
• Amoxapine
• Trimipramine
• Protriptyline
• Maprotiline• tetracyclic
• Amitriptyline
• Imipramine
• Nortriptyline
• Desipramine
• Clomipramine
• Amitriptyline
• Imipramine
• Nortriptyline
• Desipramine
• Clomipramine
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 30
SRI
NRIM1
H1
TCA
6-27 Stahl S M, Essential Psychopharmacology (2000)Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;
New York , NY; Cambridge University Press; 2008.Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;
New York , NY; Cambridge University Press; 2008.
Tricyclic Antidepressants: Many side effectsTricyclic Antidepressants: Many side effects
Sedation and weight gainSedation and weight gain
OrthostasisOrthostasis
Dry mouthConstipationBlurred visionUrinary retentionCognitive dysfunction
Dry mouthConstipationBlurred visionUrinary retentionCognitive dysfunction
Newer antidepressantdevelopment was
designed to preserveSRI or NRI
AntidepressantsAntidepressants
• Classes:
– Selective Serotonin Reuptake Inhibitors
• Prozac (fluoxetine)
• Zoloft (sertraline)
• Paxil (paroxetine)
• Luvox (fluvoxamine)
• Celexa (citalopram)
• Lexapro (es-citalopram)
• Classes:
– Selective Serotonin Reuptake Inhibitors
• Prozac (fluoxetine)
• Zoloft (sertraline)
• Paxil (paroxetine)
• Luvox (fluvoxamine)
• Celexa (citalopram)
• Lexapro (es-citalopram)
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 31
Fluoxetine (Prozac, Sarafem)Fluoxetine (Prozac, Sarafem)
SRI
NRI
CYP-2D6CYP-2D6
SSRI
CYP-3A4CYP-3A4
SSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor; CYP = cytochrome P-450 isoenzymeSSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor; CYP = cytochrome P-450 isoenzyme
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;New York , NY; Cambridge University Press; 2008.
Sertraline (Zoloft)Sertraline (Zoloft)
SSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitor;DRI = dopamine re-uptake inhibitorSSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitor;DRI = dopamine re-uptake inhibitor
Sigma 1
RI
SRISSRI
DRI
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;New York , NY; Cambridge University Press; 2008.
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 32
Paroxetine (Paxil)Paroxetine (Paxil)
SRI
NRI
CYP-2D6CYP-2D6
NOSInhibitorNOSInhibitor
m-ACh
SSRI
SSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor; m-ACh = muscarinic AntiCholinergic;CYP = cytochrome P-450 isoenzyme; NOS = nitric oxide synthase
SSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor; m-ACh = muscarinic AntiCholinergic;CYP = cytochrome P-450 isoenzyme; NOS = nitric oxide synthase
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;New York , NY; Cambridge University Press; 2008.
Fluvoxamine (Luvox)Fluvoxamine (Luvox)
SSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitor;CYP = Cytochrome P450.SSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitor;CYP = Cytochrome P450.
SRISSRI
CYP-3A4
CYP-1A2
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;New York , NY; Cambridge University Press; 2008.
John J. Miller, M.D. October 2, 2015
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Citalopram (Celexa)es-Citalopram (Lexapro)
Citalopram (Celexa)es-Citalopram (Lexapro)
SSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitorSSRI = serotonin selective re-uptake inhibitor; SRI = serotonin re-uptake inhibitor
SRISSRI
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;New York , NY; Cambridge University Press; 2008.
Inhibition of binding to human monoamineuptake transporters (Ki in nm) in vitro
Inhibition of binding to human monoamineuptake transporters (Ki in nm) in vitro
SRI NE 5-HT NE/5-HT
Duloxetine 7.5 0.8 9
Venlafaxine 2480 82 30
Clomipramine 38 0.28 136
Fluoxetine 240 0.81 296
Paroxetine 40 0.13 308
Fluvoxamine 1300 2.2 591
Sertraline 420 0.29 1448
Citalopram 4070 1.2 3392
Wong DT, Bymaster FP.; In: Jucker E, ed. Progress in Drug Research; 2002.Wong DT, Bymaster FP.; In: Jucker E, ed. Progress in Drug Research; 2002.
John J. Miller, M.D. October 2, 2015
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AntidepressantsAntidepressants
• Classes:
– Serotonin Norepinephrine ReuptakeInhibitors
• Effexor (venlafaxine)
• Cymbalta (duloxetine)
• Pristiq (desvenlafaxine)
• Fetzima (levomilnacipran)
• Classes:
– Serotonin Norepinephrine ReuptakeInhibitors
• Effexor (venlafaxine)
• Cymbalta (duloxetine)
• Pristiq (desvenlafaxine)
• Fetzima (levomilnacipran)
Venlafaxine (Effexor), duloxetine(Cymbalta) and desvenlafaxine (Pristiq)
Venlafaxine (Effexor), duloxetine(Cymbalta) and desvenlafaxine (Pristiq)
SRI
NRI
SNRI
SNRI = serotonin norepinephrine re-uptake inhibitor;SRI = serotonin re-uptake inhibitor;
NRI = norepinephrine re-uptake inhibitor.
SNRI = serotonin norepinephrine re-uptake inhibitor;SRI = serotonin re-uptake inhibitor;
NRI = norepinephrine re-uptake inhibitor.
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;New York , NY; Cambridge University Press; 2008.
John J. Miller, M.D. October 2, 2015
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levomilnacipran (Fetzima)levomilnacipran (Fetzima)
SRI
NRI
SSRI
NSRI = norepinephrine serotonin re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor;
SRI = serotonin re-uptake inhibitor.
NSRI = norepinephrine serotonin re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor;
SRI = serotonin re-uptake inhibitor.
AntidepressantsAntidepressants
• Classes:
– Other
• Desyrel (trazodone)
• Serzone (nefazodone)
• Remeron (mirtazapine)
• Wellbutrin (bupropion)
• Viibryd (vilazodone)
• Brintellix (vortioxetine)
• Classes:
– Other
• Desyrel (trazodone)
• Serzone (nefazodone)
• Remeron (mirtazapine)
• Wellbutrin (bupropion)
• Viibryd (vilazodone)
• Brintellix (vortioxetine)
John J. Miller, M.D. October 2, 2015
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Trazodone (Desyrel)Trazodone (Desyrel)
SARI = serotonin 2A antagonist/reuptake inhibitor; SRI = serotonin re-uptake inhibitor;H1 = anti-histamine.SARI = serotonin 2A antagonist/reuptake inhibitor; SRI = serotonin re-uptake inhibitor;H1 = anti-histamine.
SRI5HT-2A SARI
alpha 1 adrenergic antagonistalpha 1 adrenergic antagonist
Potent AntagonistPotent Antagonist
H1
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;New York , NY; Cambridge University Press; 2008.
Nefazodone (Serzone)Nefazodone (Serzone)
SARI = serotonin 2A antagonist/reuptake inhibitor; SRI = serotonin re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor; CYP = cytochrome P-450 isoenzymeSARI = serotonin 2A antagonist/reuptake inhibitor; SRI = serotonin re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor; CYP = cytochrome P-450 isoenzyme
NRI
SRI
CYP-3A4CYP-3A4
5HT-2A SARI
alpha 1 adrenergic antagonistalpha 1 adrenergic antagonist
Potent AntagonistPotent Antagonist
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition;New York , NY; Cambridge University Press; 2008.
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 37
Stahl S M, EssentialPsychopharmacology
(2000)
Primary mechanism is presynapticalpha 2 receptor antagonismat both serotonergic andnoradrenergic neurons
Primary mechanism is presynapticalpha 2 receptor antagonismat both serotonergic andnoradrenergic neurons
Mirtazapine (Remeron)Mirtazapine (Remeron)
7-10
SedationWeight gainSedationWeight gain
H1
5HT2C
5HT3
2
5HT2A
mirtazapine
Weight gainWeight gainDecreasedGI side effectsDecreasedGI side effects
Lower sexual dysfunction; antidepressantLower sexual dysfunction; antidepressant
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition; NewYork , NY; Cambridge University Press; 2008.
Bupropion (Wellbutrin) IR, SR and XLBupropion (Wellbutrin) IR, SR and XL
NRI
DRINDRI
NDRI = norepinephrine and dopamine re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor; DRI = dopamine re-uptake inhibitorNDRI = norepinephrine and dopamine re-uptake inhibitor;NRI = norepinephrine re-uptake inhibitor; DRI = dopamine re-uptake inhibitor
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology, 3rd Edition; NewYork , NY; Cambridge University Press; 2008.
John J. Miller, M.D. October 2, 2015
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5HT-1A
Vilazodone (Viibryd)Vilazodone (Viibryd)
SRI = serotonin re-uptake inhibitor; serotonin 5HT-1A receptor partial agonistSRI = serotonin re-uptake inhibitor; serotonin 5HT-1A receptor partial agonist
SRI
SRI+
receptor
Vortioxetine (Brintellix)Vortioxetine (Brintellix)
SRI = serotonin re-uptake inhibitor; serotonin 5HT-1A receptor full agonist;5HT-1B partial agonist; 5HT-1D antagonist; 5HT-3 antagonist; 5HT-7 antagonist.
SRI = serotonin re-uptake inhibitor; serotonin 5HT-1A receptor full agonist;5HT-1B partial agonist; 5HT-1D antagonist; 5HT-3 antagonist; 5HT-7 antagonist.
SRI
SRI+
receptors
John J. Miller, M.D. October 2, 2015
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Part 4
The incredible journey:
From the pill box to the toilet
Pharmacokinetics ofAntidepressants
Factors that impact how a drugenters and leaves the body
Factors that impact how a drugenters and leaves the body
• Absorption (gut, skin, sub-lingual, IM, IV)
• Bioavailibility
• Protein Binding
• P- Glycoproteins
• Phase I Metabolism = CYP450 Enzyme System
• Phase II Metabolism = Conjugation
– Glucuronidation, Sulfation and Methylation
• Half-life (T ½) of the medication
• Drug-Drug Interactions
• Excretion (urine, bile and gut)
• Absorption (gut, skin, sub-lingual, IM, IV)
• Bioavailibility
• Protein Binding
• P- Glycoproteins
• Phase I Metabolism = CYP450 Enzyme System
• Phase II Metabolism = Conjugation
– Glucuronidation, Sulfation and Methylation
• Half-life (T ½) of the medication
• Drug-Drug Interactions
• Excretion (urine, bile and gut)
John J. Miller, M.D. October 2, 2015
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From the medicine bottle to the toilet: theFrom the medicine bottle to the toilet: thelong and complex journey.long and complex journey.
Getting the medication into the body:Getting the medication into the body:
oral administrationoral administration
sublingual administrationsublingual administration
transdermal administrationtransdermal administration
nasal spraynasal spray
nebulizer inhalernebulizer inhaler
subcutaneous injectionsubcutaneous injection
intramuscular injectionintramuscular injection
intravenous injectionintravenous injection
From the medicine bottle to the toilet: theFrom the medicine bottle to the toilet: thelong and complex journey.long and complex journey.
Absorption from the gastroAbsorption from the gastro--intestinal tract:intestinal tract:
gastricgastric
small intestinesmall intestine
large intestinelarge intestine
PP--glycoprotein metabolismglycoprotein metabolism
Cytochrome PCytochrome P--450 metabolism450 metabolism
effects of irritable bowel syndromeeffects of irritable bowel syndrome
effects of gastric stapling/lap bandeffects of gastric stapling/lap band
John J. Miller, M.D. October 2, 2015
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Protein BindingProtein Binding
Not as clinically relevant as previously believed.
Properties of a drug that predict clinicallyrelevant displacement by protein binding:
low clearance drugslow therapeutic indexsmall volume of distribution
Examples: warfarin, tolbutamide, phenytoin
Not as clinically relevant as previously believed.
Properties of a drug that predict clinicallyrelevant displacement by protein binding:
low clearance drugslow therapeutic indexsmall volume of distribution
Examples: warfarin, tolbutamide, phenytoin
Protein Binding and Urinary Excretion of SRIsProtein Binding and Urinary Excretion of SRIs
Drug % ProteinBound
% UrinaryExcretion
Half-Life
fluoxetine 94 <2.5 14 days
S-sertraline 98 <1 26 hours
R-paroxetine 95 <2 21 hours
fluvoxamine 77 <5 15 hours
venlafaxine 27 4.6 5 hours
D-M-venlafaxine 30 29 11 hours
citalopram 80 10.5 35 hours
S-citalopram 56 18* 29 hours
The Pharmacological Basis of Therapeutics; Goodman & Gilman; 10th Edition; 2001*From Physician’s Desk Reference; 2004; page 1302.
The Pharmacological Basis of Therapeutics; Goodman & Gilman; 10th Edition; 2001*From Physician’s Desk Reference; 2004; page 1302.
John J. Miller, M.D. October 2, 2015
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Differing Metabolic PathwaysDiffering Metabolic Pathways
Uptake of an orally administered drug proceeds afterthe stomach passage via the small intestine.
In the gut and liver, a series of metabolictransformation occurs.
Uptake of an orally administered drug proceeds afterthe stomach passage via the small intestine.
In the gut and liver, a series of metabolictransformation occurs.
John J. Miller, M.D. October 2, 2015
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From the medicine bottle to the toilet: theFrom the medicine bottle to the toilet: thelong and complex journey.long and complex journey.
Hepatic metabolism (Hepatic metabolism (““first passfirst pass””):):
Cytochrome PCytochrome P--450 enzymes450 enzymes
substratesubstrate
inhibitorinhibitor
inducerinducer
ConjugationConjugation
GlucuronidationGlucuronidation
SulfonationSulfonation
MethylationMethylation
In Vivo inhibitory effects of SSRIs on theMajor Human Cytochrome P450 enzymes*
In Vivo inhibitory effects of SSRIs on theMajor Human Cytochrome P450 enzymes*
SSRI 1A2 2D6 2C9/10 2C19 3A3/4
Citalopram (40mg) - ++ - - -
Escitalopram (20mg) - ++ - - -
Fluoxetine (20mg) - +++ +++ ++ +
Fluvoxamine (150mg) +++ - +++ +++ ++
Paroxetine (20mg) - +++ - - -
Sertraline (100-200mg) - + - - -
* ( - = <20%; + = 20%-50%; ++ = 50%-150%; +++ = >150% )* ( - = <20%; + = 20%-50%; ++ = 50%-150%; +++ = >150% )
Preskorn, S; J Psych Practice; Vol. 9, No. 3; page 229; May 2003Preskorn, S; J Psych Practice; Vol. 9, No. 3; page 229; May 2003
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 44
From the medicine bottle to the toilet: theFrom the medicine bottle to the toilet: thelong and complex journey.long and complex journey.
Crossing the blood brain barrierCrossing the blood brain barrier
lipophilicitylipophilicity
PP--glycoproteinsglycoproteins
Polymorphisms of brain receptorsPolymorphisms of brain receptors
gene variantsgene variants
single nucleotide polymorphisms (SNPs)single nucleotide polymorphisms (SNPs)
promoter sequence variantspromoter sequence variants
processingprocessing intronsintrons//exonsexons
From the medicine bottle to the toilet: theFrom the medicine bottle to the toilet: thelong and complex journey.long and complex journey.
Getting out of the body:Getting out of the body:
renal excretionrenal excretion
biliary excretionbiliary excretion
sweating it outsweating it out
breathing it outbreathing it out
hemodialysishemodialysis
John J. Miller, M.D. October 2, 2015
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Reasons for treatment failure.Reasons for treatment failure.
•• Dose too lowDose too low
•• Time too shortTime too short
•• Absorption issuesAbsorption issues
•• NonNon--compliancecompliance
•• DrugDrug--Drug interactionDrug interaction
•• Wrong diagnosisWrong diagnosis
•• Substance abuseSubstance abuse
•• Ongoing psychosocial stressorsOngoing psychosocial stressors
•• Need to add/change psychotherapyNeed to add/change psychotherapy
•• Need to augment/combine medicationNeed to augment/combine medication
Reasons for treatment failure.Reasons for treatment failure.
•• Unacceptable side effectsUnacceptable side effectsleading to discontinuation:leading to discontinuation:
–– SedationSedation
–– OrthostasisOrthostasis
–– ConstipationConstipation
–– Dry mouthDry mouth
–– Bizarre dreamsBizarre dreams
–– ActivationActivation
–– Sexual dysfunctionSexual dysfunction
–– Weight gain/lossWeight gain/loss
–– RashRash
–– Cognitive effectsCognitive effects
–– HyperprolactinemiaHyperprolactinemia
John J. Miller, M.D. October 2, 2015
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Long-term Changes in Weight –Fluoxetine, Sertraline, and Paroxetine
Long-term Changes in Weight –Fluoxetine, Sertraline, and Paroxetine
Fava, M; Weight Gain and Antidepressants; J Clin Psychiatry 2000;61 (suppl 11):37-41Fava, M; Weight Gain and Antidepressants; J Clin Psychiatry 2000;61 (suppl 11):37-41
0
5
10
15
20
25
30
%of
Patients
With
Weig
htG
ain
>7%
Fluoxetine(n=44)
Sertraline(n=48)
Paroxetine(n=47)
6.84.2
25.5
§
Adapted from Table 2: “Incidence of Sexual DysfunctionWith Antidepressants Assessed by the Psychotropic-
Related Sexual Dysfunction Questionnaire” (N=1022)
Adapted from Table 2: “Incidence of Sexual DysfunctionWith Antidepressants Assessed by the Psychotropic-
Related Sexual Dysfunction Questionnaire” (N=1022)
Drug N Mg mean dose # with SD % with SD
Citalopram 66 28.7 48 72.7
Paroxetine 208 23.4 147 70.7
Venlafaxine 55 159.5 37 67.3
Sertraline 159 90.4 100 62.9
Fluvoxamine 77 115.7 48 62.3
Fluoxetine 279 24.5 161 57.7
Montejo, A., et. al.; J Clin Psychiatry; 62 (suppl 3), pages 10-21 (2001)Montejo, A., et. al.; J Clin Psychiatry; 62 (suppl 3), pages 10-21 (2001)
John J. Miller, M.D. October 2, 2015
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Polypharmacy.Polypharmacy.
•• Avoid if possibleAvoid if possible
•• After adequate dose/time on a medication,After adequate dose/time on a medication,consider cross titration to a different medication.consider cross titration to a different medication.
•• After failure of several monotherapy trials,After failure of several monotherapy trials,considerconsider ““rationalrational”” polypharmacy.polypharmacy.
•• Polypharmacy includes combination therapyPolypharmacy includes combination therapy(using two agents, each FDA approved as(using two agents, each FDA approved asmonotherapy) as well as augmentation therapymonotherapy) as well as augmentation therapy(the second agent is not FDA approved as(the second agent is not FDA approved asmonotherapy).monotherapy).
Thank you for your attention!
Questions??
Thank you for your attention!
Questions??
John J. Miller, M.D. October 2, 2015
www.brain-health.co/Brain Health – Exeter, NH 48
Additional ReferencesPreskorn SH; Clinically relevant pharmacology of selective serotonin reuptake inhibitors:an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism.Clin Pharmacokinet. 1997;32(Suppl 1):1-21.
Schatzberg AF, Nemeroff CB, Eds. Essentials of Clinical Psychopharmacology,3rd ed. Washington, DC: American Psychiatric Publishing; 2013.
Cozza KL, Armstrong SC, Oesterheld JR. Drug Interaction Principles For Medical Practice.Washington, DC: American Psychiatric Publishing; 2003.
Stahl SM. Essential Psychopharmacology of Depression and Bipolar Disorder.Cambridge, United Kingdom: Cambridge University Press: 2000.
Thase ME and Schwartz TL. Choosing Medications for Treatment-Resistant DepressionBased on Mechanism of Action. J Clin Psychiatry. 2015; 76:6, 720-727.
Goodman & Gilman. The Pharmacological Basis of Therapeutics: 10th Edition;New York: McGraw-Hill, Medical Publishing Division; 2001.
Fava M. Weight gain and antidepressants. J Clin Psychiatry. 2000;61 [suppl 11]:37-41.
Wong DT and Bymaster FP. In: Jucker E, editor. Progress in Drug Research; Series Volume 58; 2002.
Roth BL, Sheffler DJ and Kroeze WK. Magic shotguns versus magic bullets: selectively non-selectivedrugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004 Apr; 3(4):353-9.
Richelson E. Interactions of Antidepressants With Neurotransmitter Transporters and Receptorsand Their Clinical Relevance. J Clin Psychiatry. 2003; 64[suppl 13]:5-12.