44
PRECISION DOSING AND TOLERABILITY OF ANTIDEPRESSANTS
PRECISION DOSING AND TOLERABILITY OF ANTIDEPRESSANTS
Learning Objectives
• List clinical factors that guide antidepressant medication selection and dosing
• Describe the effect of pharmacokinetic genes on antidepressant blood levels and describe the implications for dosing
• Describe predictors of antidepressant side effects and strategies to manage antidepressant-related sexual dysfunction and activation
What Is Precision Dosing?
Gonzalez et al. Precision Dosing: Public Health Need, Proposed Framework, and Anticipated Impact. Clin Transl Sci 2017;10:443-54.
• Individualization of drug treatment regimens based on patient factors that alter
• drug metabolism, disposition and/or
• response and/or• tolerability
Impr
ovem
ent
Plasma concentration
0
20
40
60
80
100Efficacy
Toxicity
What Is Precision Dosing?
Organ dysfunction
Genetics
Age
Body size
Concomitant medications
Interactions
55
Sex
Patient-Specific Pharmacologic Factors
Time
Con
cent
ratio
n
Drug class
Disease state
Pharmacokinetic data
Disease and Medication Factors Targeted Dosing
Precision DosingAntidepressant Blood Levels
Antidepressant Plasma Levels
<50 50-79 80-109 110-139 >140
0
2
4
6
8
-2
M1
5HT2C
SRI
H1
1
sodium channelblocker
NA+
5HT2A
NRI
nortriptyline (minimal SRI)
Nonresponse Intolerability
Åsberg et al. British Medical Journal 1971;3:331-4.
Antidepressant Plasma Concentration Monitoring
Medication + Metabolite Recommended therapeutic range (consensus), ng/mL
amitriptyline + nortriptyline 80–200 clomipramine + norclomipramine 175–450imipramine + desipramine 175–300nortriptyline 70–170citalopram 30–130escitalopram 15–80fluoxetine + norfluoxetine 120–300 fluvoxamine 150–300mirtazapine 40–80
Paroxetine Plasma Concentrations by Dose
0
100
200
300
400
500
600
0 10 20 30 40
Paro
xetin
e C
once
ntra
tion
(ng/
mL)
Paroxetine Dose (mg/day)
Ueda M et al. The impact of CYP2D6 genotypes on the plasma concentrations of paroxetine in Japanese psychiatric patients. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2006;30:486-91.
Precision DosingPharmacogenetics
Precision Dosing and Metabolism
Fast Metabolizer Low Blood Levels
History of Treatment Resistance
May require very high oral dosing+ + =
Slow Metabolizer High Blood Levels
History of Side Effects
May require low oral dosing to tolerate and
respond to medications that are
substrates of the affected enzyme
+ + =
Precision Dosing and Pharmacogenetics
Ramsey et al. Gene-Based Dose Optimization in Children. Annu Rev Pharmacol Toxicol 2020;60:4.1–4.21.
Citalopram & Escitalopram Metabolism and Relevance to Precision Dosing
citalopramN-oxide
2C193A42D6
r-desmethyl-citalopram
s-desmethyl-citalopram
2C193A42D6
s-didesmethyl-citalopram
r-didesmethyl-citalopram
2D6
2D6
2D6Amine
oxidase
Amineoxidase
S-Citalopram
R-Citalopram
Effect of 2C19 Polymorphism on Escitalopram Concentrations
Jukic et al. Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure: a retrospective study based on 2,087 patients. Am J Psychiatry 2018; Tulisiak et al. Annual Meeting of the American Academy of Child & Adolescent Psychiatry, Chicago Illinois, October 2019.
Precision Escitalopram Dosing CYP2C19
Strawn et al. J Child Adol Psychop 2019;29(5):340-7.
Intermediate metabolizerPoor metabolizer
Normal metabolizerRapid metabolizerUltrarapid metabolizer
Phenotype Equivalent dose
Poor metabolizer
10 mg
Intermediatemetabolizer
15 mg
Normalmetabolizer
20 mg
Rapid metabolizer
25 mg
Ultrarapidmetabolizer
30 mg
Precision Dosing and Antidepressant Kinetics and Long Half-Lives Mean That…
• Initial dose titration may not be necessary
–Fluoxetine may not require titration• Takes longer to reach steady state
–Side effects can manifest late–Dose adjustments require patience
• A few missed doses may not be as detrimental in terms of risk of relapse
• Washout can take longer• Residual dose may remain for
several days (weeks in some cases) after discontinuing
Serotonin Transporter (5-HTT) Occupancy andPlasma Fluoxetine Concentrations
0
20
40
60
80
100
0 10 20 30 40 50 60 70
Stria
tal 5
-HTT
Occ
upan
cy (%
)
Dose (mg/day)
Serotonin Transporter (5-HTT) Occupancy andDose or Plasma Concentration of Citalopram
0
20
40
60
80
100
0 10 20 30 40 50 60 70
Stria
tal 5
-HTT
Occ
upan
cy (%
)
Dose (mg/day)
Serotonin Transporter (5-HTT) Occupancy andDose or Plasma Concentration of Sertraline
0
20
40
60
80
100
0 20 40 60 80 100 120 140 160 180 200 220
Stria
tal 5
-HTT
Occ
upan
cy (%
)
Dose (mg/day)
Precision Approaches & Pharmacodynamics• Meta-analysis of the association between 5-HTTTR polymorphism and SSRI efficacy
for depression (15 studies, N=1435) (Horstmann et al, 2009)• s/s variant lower remission rates (p<0.0001)• s/s and s/l variants had lower response rates
SSRI
α2
SSRI
long/longshort/longshort/short
Does plasma paroxetine concentration predict response?
PLoS One 2014;9(5):e98099.
0
20
40
60
80
100
120
0 50 100 150 200
MAD
RS
impr
ovem
ent (
%)
Paroxetine plasma concentration (ng/mL)
PLoS One 2014;9(5):e98099.
0
20
40
60
80
100
120
0 50 100 150 200
MAD
RS
impr
ovem
ent (
%)
Paroxetine plasma concentration (ng/mL)
s/ss/l
0
20
40
60
80
100
120
0 50 100 150 200
MAD
RS
impr
ovem
ent (
%)
Paroxetine plasma concentration (9ng/mL)
l/l
Does plasma paroxetine concentration predict response?
Precision DosingOlder Adults
Precision Citalopram Dosing in Older Adults
0
5
10
15
20
25
30
40 50 60 70 80 90
R-c
italo
pram
Cle
aran
ce (L
/m)
Age (years)
Male0
5
10
15
20
25
30
40 50 60 70 80 90
R-c
italo
pram
Cle
aran
ce (L
/m)
Age (years)
Female
Precision DosingSex Effects
Precision SSRI Dosing in Older Adults: Citalopram Clearance Differs By Sex
Antidepressant TolerabilityWeight gain, Sweating and Sexual Dysfunction
Serotonergic Side Effects & Tolerability
Fundal tone
De Ponti F. Pharmacology of serotonin: what a clinician should know. Gut 2004;53:1520-35
Antral motility5-HT4
Gastric emptying
Lower esophageal tone
Visceral sensitivity5-HT3/4/7
Emesis5-HT3
clotting
Sexual function gluconeogenesis
temperature
TolerabilityAntidepressant-Related Weight Gain
Beyer et al. Meta-analysis: risk of hyperhidrosis with second-generation antidepressants. Depression & Anxiety. 2017;34:1134-1146.
Antidepressant-Related Hyperhidrosis
sertraline
duloxetine
vortioxetine
paroxetine desvenlafaxine
bupropionfluoxetine
Dopamine transporter Kifluvoxamine
0 3 6 9
citalopram/escitalopram
Log
risk
ratio
vilazodone
Escitalopram-Related Weight Gain
p=0.018
Aldrich et al. Frontiers in Pharmacology 2019(10):99.
TolerabilityAntidepressant-Related Activation
SSRI-Related Activation
• Emerges early in treatment or following an increase in dose (Reinblatt et al. 2009)
• Resolves when the dose is decreased or medication is discontinued.
• Rate of resolution is related to the rate of activation onset.
• Related to medication exposure for fluoxetine, escitalopram, and fluvoxamine, and metabolizer phenotype for escitalopram
Activation
Impulsivity
Insomnia
Restlessness
Hyperactivity
Irritability
Disinhibition
Luft et al. Antidepressant-induced activation in children and adolescents: risk, recognition and management. Curr Prob Pediatr Ad 2018.
TolerabilityAntidepressant-Related Hyperhidrosis
Antidepressant-Related Hyperhidrosis
sertraline
duloxetine
vortioxetine
paroxetine desvenlafaxine
bupropionfluoxetine
Dopamine transporter Kifluvoxamine
0 3 6 9
citalopram/escitalopram
Log
risk
ratio
Beyer et al. Meta-analysis: risk of hyperhidrosis with second-generation antidepressants. Depress Anxiety 2017;34:1134-46.
Antidepressant-Related Hyperhidrosis
Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide 6th ed 2016.Nicholas et al. Treatment of Primary Craniofacial Hyperhidrosis: A Systematic Review. Am J Clin Dermatol 2015;16(5):361-70.Lee et al. Efficacy of Glycopyrrolate in Primary Hyperhidrosis Patients. Korean J Pain 2012;25(1):28-32.
• Anticholinergics• Glycopyrolate
• 1 mg BID, then titrate by 2 mg/day
• Max dose = 8 mg/day.
• Oxybutinin (ER)• 5 mg daily
• Alpha-1 antagonists
BupropionFluvoxamineVortioxetine
VenlafaxineDesvenlafaxine
SertralineFluoxetineDuloxetine
Citalopram/Escitalopram
TREATMENT
TolerabilityAntidepressant-Related Sexual Dysfunction
Options for Intolerable Sexual Dysfunction
• Dosing at night (or larger dose at night)
• Daytime exercise• Adjunct options
• Bupropion• Buspirone (60 mg/d)• Cyproheptadine• Estrogen cream (women)• Mirtazapine• Phosphodiesterase 5 (PDE-5) inhibitor• Pimavanserin
Rizvi SJ et al. J Psychosom Res 2011;70:99-109; Serretti A, Chiesa A. Clin Pharmacol Ther 2011;89(1):142-7.
Adjunctive Sildenafil for SSRI-Associated Sexual Dysfunction
• Sildenafil 50–100 mg/day • Significant improvements in:
• Erectile dysfunction (p=0.004)• Arousal (p=0.01)• Ejaculation (p<0.001)• Orgasm (p=0.007)• Overall satisfaction (p=0.02)
54.4%
0
20
40
60
Sildenafil Placebo
% Im
prov
ed
4.4%
p<0.001
Nurnberg et al. JAMA 2003;289:56-64.Nurnberg et al. JAMA 2008;300:395-404.
Women, N=98• Sildenafil 50–100 mg/day • Significant improvements in
• achieving orgasm (p=0.01) • quality of orgasm (p=0.03)
• Does not improve desire, arousal-sensation or arousal-lubrication
Men, N=90
00.5
11.5
2
SildenafilPlacebo
CG
I Sex
ual
Func
tioni
ng S
cale
Pimavanserin and Sexual Function in SSRI-Treated Adults
Interest in sexAbility to get
arousedAbility to orgasm
Overall sexual satisfaction
Cha
nge
from
Bas
elin
e (L
S M
ean
+/-S
E)
Freeman et al. Improvement of sexual functioning during treatment of MDD with adjunctive pimavanserin: A secondary analysis. Depress Anxiety 2020;1-11.
pimavanserin
Summary
• Precision antidepressant dosing requires consideration of pharmacokinetics, medication class, age, sex, race, pharmacogenomic characteristics
• Antidepressant side effects are related to pharmacokinetic and pharmacodynamic factors
• Decreased metabolism—more concentration-related side effects (e.g., sedation, weight gain)
• Antidepressant-related sexual side effects can be addressed with pimavanserin, PDE-5 inhibitors, potentially bupropion, and, in one study, buspirone
Posttest 1A 70-year-old retired physician with generalized anxiety disorder has been treated with escitalopram 20 mg qAM for 15 years. She has noted increased weight gain, tiredness, and dry mouth over the past 5–6 years. Her anxiety has been stable. Her concomitant medications are aspirin 81 mg daily and atorvastatin 40 mg daily. Physical examination and thyroid panel, as well as complete blood counts and a comprehensive metabolic panel, do not suggest an etiology for her symptoms. Which is the potential cause of her symptoms?
1. She has become more sensitive to escitalopram related antihistaminergic effects as she’s aged
2. She has become an ultrarapid metabolizer for CYP2C193. As she has aged, her CYP2C19 activity has decreased4. She has developed a new onset somatization disorder
Posttest 2
A 50-year-old preschool teacher with generalized anxiety disorder has a past medical history remarkable for diabetes mellitus, which is controlled with metformin 1000 mg BID. She has been treated with paroxetine 40 mg daily and has experienced significant hyperhidrosis. Which of the following is associated with a lower risk of hyperhidrosis compared to paroxetine?
1. Sertraline2. Duloxetine3. Vortioxetine4. Escitalopram
Posttest 3
A patient is a CYP2C19 poor metabolizer. Treatment with which of the following SSRIs requires dose adjustment?
1. Sertraline and escitalopram2. Fluvoxamine3. Vilazodone4. Fluoxetine and paroxetine
