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Deciphering Treatment Advances in

Neuropsychopharmacology: A Case-based ApproachKelly C. Lee, Pharm.D., MAS, BCPP, FCCP

Associate Professor of Clinical Pharmacy

Associate Dean for Assessment and Accreditation

Director, PGY2 Residency in Psychiatric Pharmacy

UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences

Kimberly B. Tallian, Pharm.D., BCPP, FASHP, FCCP, FCSHP

Psychiatry Pharmacy Specialist

Scripps Mercy Hospital, San Diego

Adjunct Clinical Professor UCSD, UCSF, & KGI Schools of Pharmacy

Benjamin Malcolm, Pharm.D., MPH

Assistant Professor of Pharmacy Practice

Western University of Health Sciences, College of Pharmacy

Disclosures

• Dr. Kelly Lee is a consultant for Otsuka America Pharmaceutical, Inc.

• Drs. Kimberly Tallian & Benjamin Malcolm have no potential conflicts of interest (including funding sources or ties to funding sources)

• Drs. Lee, Tallian, & Malcolm have no proprietary information or results of ongoing research that may be subject to different interpretations

• This program abides by the non-commercialism guidelines for continuing education

Learning ObjectivesPharmacists

• Compare and contrast advances in neuropsychotropic drug treatment with current practice guidelines and drug/patient specific parameters for depression, schizophrenia, and epilepsy

• Describe current and future applications of pharmacogenomic markers to be used to tailor medication therapy for patients with depression, schizophrenia, and epilepsy

• Evaluate and develop neuropsychotropic drug regimens for patients with depression, schizophrenia, and epilepsy using a case-based approach

Technicians

• Compare and contrast advances in neuropsychotropic drug treatment with current practice guidelines and drug/patient specific parameters for depression, schizophrenia, and epilepsy

• Describe current and future applications of pharmacogenomic markers in depression, schizophrenia, and epilepsy

• Discuss special handling and side-effects of new neuropsychotropic drug treatments for depression, schizophrenia, and epilepsy

Pre-Test Questions

A 45 year old patient comes to the clinic after recently starting an SSRI a week ago. Which of the following adverse effects would you least likely expect to see?

A) Anxiety

B) Bone loss

C) Insomnia

D) Nausea

Pre-Test Questions

A 50 year old Caucasian woman with depression needs to start an antidepressant. Which gene has the most evidence for predicting antidepressant response?

A) Catechol-o-methyltransferase

B) Monoamine oxidase enzyme

C) Serotonin transporter

D) Tryptophan hydroxylase

Pre-Test Questions

Which of the following epilepsy medications is appropriate in a patient that is HLA-B*1502 positive?

A) Phenytoin (Dilantin)

B) Brivaracetam (Briviact)

C) Oxcarbazepine (Trileptal)

D) Eslicarbazepine (Aptiom)

E) Zonisamide (Zonegran)

Pre-Test Questions

In CYP2D6 poor metabolizers, which of the following is an appropriate choice that may be initiated at a normal starting dose?

A) Risperidone (Risperdal)

B) Brexpiprazole (Rexulti)

C) Iloperidone (Fanapt)

D) Lurasidone (Latuda)

Pre-Test Questions

Which of the following is considered a partial dopamine agonist?

A) Iloperidone (Fanapt)

B) Asenapine (Saphris)

C) Lurasidone (Latuda)

D) Cariprazine (Vraylar)

•Case Introduction•Pharmacogentics in Mental Health•New Drugs and Pharmacogenetic Considerations•Depression

•Epilepsy

•Schizophrenia

Presentation Outline

CC: “I’m down and anxious”

JS is a 47 year old male with a history of schizophrenia, depression, and complex partial seizures who presents to the outpatient MTM clinic complaining of severe anxiety and nausea over the past week. Notably he has recently undergone some changes to his medication regimen.

Current Meds: • Duloxetine 60mg PO daily (started 1 week ago)

• Risperidone 3mg PO QHS (titrated up over past month)

• Depakote ER 1500mg PO at bedtime

Case Presentation

Past Medical History:• Obesity, GERD

Past Psychiatric History:• Hospitalized 2 times in the last 5 years due to antipsychotic nonadherence;

no hospitalizations in the past year

Past Medication History:• Severe anxiety and nausea after trial of fluoxetine, paroxetine, & sertraline

• Weight gain with olanzapine, dystonia with haloperidol

Case Presentation Cont.

•You contact JS’s outpatient psychiatrist to gather further information. The psychiatrist mentions JS has been a tough case due to past medication intolerance, leading them to order a pharmacogenetic testing for JS.

•They just received the results and agrees to fax them to you. They are open to your assistance in helping to redesign JS’s medication regimen and wonder if “one of the new ones” would be a good choice.

•You agree to review the results as well as newer pharmacotherapies available and discuss potential change in therapy.

Outpatient Collateral

Pharmacogenetic Testing Results for JSGene Protein/Receptor Phenotype

CYP2D6 CYP2D6 Poor metabolizer

CYP2C19 CYP2C19 Extensive metabolizer


CYP1A2 CYP1A2 Intermediate metabolizer

SLC6A4 Serotonin Transporter (SERT) Normal activity

HTR2A 5HT2A Receptor Normal activity

HTR2C 5HT2C Receptor Normal activity

DRD2 D2 Receptor Normal activity

HLAB*1502 Human Leukocyte Antigen Positive

CPIC Guidelines for Neuropsychiatric Drugs

Antidepressants

Burden of Depressive Disorders by Country, Sex, Age and year. Findings from the Global Burden of Disease Study 2010. PLOS Medicine Nov 2013 and WHO 2012

~ 1 million lives are lost yearly due to suicide (3000 suicide deaths daily)

Major Depression: Affective disorder characterized by feelings of sadness and/or hopelessness that significantly affect social/occupational function

DSM-5 Diagnostic Criteria•Five of the following on most days within 2 weeks: • depressed or irritable mood nearly all day occurring most days

• anhedonia

• substantial weight loss or gain (≥5% of body weight)

• insomnia or hypersomnia

• fatigue or low energy

• poor concentration or ability to think or indecisiveness

• feelings of worthlessness or inappropriate guilt

• psychomotor agitation or retardation

• recurrent thoughts of death or suicide with or without plan

•Functional impairment

18

Treatment19

•Psychotherapy

•Antidepressants• Monoamine oxidase inhibitors (MAOIs)

• Tricyclic antidepressants (TCAs)

• Selective serotonin reuptake inhibitors (SSRIs)

• Serotonin norepinephrine reuptake inhibitors (SNRIs)

• Dopamine reuptake inhibitors

• Phenylpiperazines

• Miscellaneous (Ketamine, L-methylfolate, antipsychotics, augmenting agents)

•Electroconvulsive therapy & repetitive transcranial magnetic stimulation (rTMS)

Depression Treatment Algorithm

*adequate trial is 4-6 weeks of therapeutic dose

American Psychiatric Association Practice Guidelines (2010)•Level I Recommendations

• Following antidepressants are comparable in effectiveness

• SSRIs

• SNRIs

• Bupropion

• Tricyclic antidepressants (TCAs)

• Monoamine oxidase inhibitors (MAOIs)

• SSRI, SNRIs, mirtazapine and bupropion are optimal for most patients

•MAOIs reserved for treatment-resistance

21

CANMAT Guidelines (2016)

FIRST LINE (LEVEL I EVIDENCE)

•SSRI• Citalopram (Celexa)

• Escitalopram (Lexapro)

• Fluoxetine (Prozac)

• Fluvoxamine (Luvox)

• Paroxetine (Paxil)

• Sertraline (Zoloft)

FIRST LINE (LEVEL I EVIDENCE)

•SNRI• Desvenlafaxine (Pristiq) • Duloxetine (Cymbalta) • Venlafaxine (Effexor)

•Others• Bupropion (Wellbutrin) • Mirtazapine (Remeron)• Vortioxetine (Trintellix)

CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. Can J Psychiatry. 2016 Aug 2. pii: 0706743716659417. [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/pubmed/27486148


CANMAT Guidelines (2016)SECOND LINE (LEVEL I EVIDENCE)

•Tricyclic antidepressants

•Levomilnacipran (Fetzima)

•Quetiapine (Seroquel)

•Selegiline transdermal (Emsam)

•Trazodone (Desyrel)

•Vilazodone (Viibryd)

THIRD LINE (LEVEL I EVIDENCE)

•Phenelzine (Nardil)

•Tranylcypromine (Parnate)




•Antidepressants• Levomilnacipran (Fetzima)• Vilazodone (Viibryd)• Vortioxetine (Trintellix)

•Antipsychotics• Aripiprazole (Abilify)• Quetiapine XR (Seroquel XR)• Brexpiprazole (Rexulti)

Advances in Depression Treatment

•FDA Indication◦ Major Depression

•Mechanism of Action◦ Block presynaptic 5HT and NE reuptake

•Greater NE reuptake at lower doses, 5HT at high doses

•No blockade of alpha 1, muscarinic or histamine receptor

Levomilnacipran (Fetzima)

•Adverse Effects: Hypertension, tachycardia, mydriasis, urinary retention, seizures

•Common for class: GI effects (nausea, constipation, diarrhea), insomnia/somnolence, sexual dysfunction, dizziness, dry mouth, sweating, suicide risk

•No significant inhibition of P450 enzymes; not recommended for ESRD

•All SNRIs not recommended with MAOI, triptans and other serotonergic agents due to serotonin syndrome risk*

Levomilnacipran (Fetzima)

•Indication• Major Depression

•Mechanism o f Action: Block presynaptic 5HT

•Adverse Effects: Nausea, vomiting, diarrhea, insomnia• Common for class: GI effects (nausea,

constipation, diarrhea), insomnia/somnolence, sexual dysfunction, dizziness, dry mouth, sweating, suicide risk

•Contraindications: MAOIs, CYP3A4 inhibitors (20mg recommended), CYP3A4 inducers

Vilazodone (Viibryd)

Vortioxetine (Trintellix)28

•FDA Indication• Major Depression

•Mechanism of Action• 5-HT reuptake inhibitor via SERT (antidepressant effect)

• 5-HT1D receptor antagonist (antidepressant effect)

• 5-HT3 receptor antagonist (antidepressant effect)

• 5-HT7 receptor antagonist (antidepressant, sleep/wake modulation)

• 5-HT1A receptor agonist (anxiolytic effect)

• 5-HT1B receptor partial agonist (antidepressant effect)

•Potential Future Indications: ADHD (?)

Vortioxetine (Trintellix)30

•Adverse Effects◦ Nausea, vomiting, constipation, other serotonergic side effects

•Drug Interactions◦ Strong inhibitors of CYP2D6 can increase vortioxetine (e.g. bupropion)

◦ Strong inducers of CYP enzymes can decrease vortioxetine (e.g. carbamazepine, phenytoin)

◦ Contraindicated with concurrent use of MAOI as well as for 3 weeks after stopping vortioxetine

◦ No significant protein binding interactions noted (e.g. aspirin, warfarin)

Why do we need pharmacogenomics for antidepressants?•Only 30% of patients with major depressive disorder achieve symptomatic remission with the first antidepressant treatment

•Early studies showed that antidepressant response had a familial pattern and between ethnicgroups

•42% of variance in antidepressant response associated with genetic variations

•Pharmacogenomics may be useful in drug selection and prevention of adverse effects

•Pharmacokinetic and pharmacodynamic factors important

Antidepressant Clinical Response•Serotonin Transporter (SLC6A4, 5HTTLPR, 17q11.1-q12)• Presence of 44 base pair insertion results in

long (L) allele (twice transporter expression vs. S allele)

• Absence of 44 base pair insertion results in short (S) allele

•The L allele is present in about 50-60% of Caucasian population, and 30-40% in Asian populations

Kato et al 2010, Serretti et al 2007Copyright ©2010 Regents of the University of California. All rights reserved.

Outcome in Entire Sample

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patientsA Serretti, M Kato, D De Ronchi and T Kinoshita

Outcome in Caucasians

Outcome in Asians

Antidepressant Toxicity•Most antidepressants are metabolized by cytochrome P450 (CYP450) enzymes

•CYP2D6 gene is polymorphic resulting in different abilities to metabolize drugs that are substrates for this enzyme

•Variants of CYP2D6 enzyme can predispose individuals• Ultra-rapid metabolizers (UMs)• Extensive metabolizers (EMs)• Intermediate metabolizers (IMs)• Poor metabolizers (PMs)

•Patients identified as PMs who received medications influenced by CYP2D6 isoenzyme had significantly more moderate or marked side effects compared to individuals identified as UMs

•Patients who were PMs of CYP2D6 had significantly longer hospitalization stays due to greater side effect burden from antidepressants than patients with other metabolizer status

Copyright ©2010 Regents of the University of California. All rights reserved.Bertilsson 2007; De Leon et al 2006

Metabolic Pathway: Amitriptyline, Nortriptyline and Paroxetine

Hicks JK et al. Clinical Pharmacology & Therapeutics 2013:93(5):402.

• 5-10% of Caucasians lack CYP2D6 enzyme

• Most PM phenotypes in Asians due to CYP2D6*10 allele

CPIC: Paroxetine Recommendations (CYP2D6)Genotype Implications Recommendations Classification

Ultrarapid metabolizer Increased metabolism to less active compounds; lower/undetectable concentration may therapy failure

Select alternative drug not predominantly metabolized by CYP2D6

Strong

Extensive metabolizer Normal metabolism Initiate therapy with recommended starting dose

Strong

Intermediate metabolizer

Reduced metabolism compared to extensivemetabolizers

Initiate therapy with recommended starting dose

Moderate

Poor metabolizer Greatly reduced metabolism; higher plasma concentrations may side effects

Select alternative drug not predominantly metabolized by CYP2D6 or if paroxetine warranted, reduce dose by 50%

Strong

Hicks JK et al. Clin Pharmacol Ther 2015;98(2):127-134.

CPIC: Citalopram and Escitalopram Recommendations (CYP2C19)

Genotype Implications Recommendations Classification

Ultrarapid metabolizer Increased metabolism; lower plasma concentration may therapy failure

Select alternative drug not predominantly metabolized by CYP2C19

Moderate

Extensive metabolizer Normal metabolism Initiate therapy with recommended starting dose

Strong

Intermediate metabolizer

Reduced metabolism compared with extensive metabolizer

Initiate therapy with recommended starting dose

Strong

Poor Metabolizer Greatly reduced metabolism as compared with extensive metabolizer; higher plasma concentrations may side effects

Consider 50% reduction of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19

Moderate

Hicks JK et al. Clinical Pharmacology & Therapeutics 2015;98(2):127-134.

Pharmacogenetics and Genomics 2013;23:535-548

• Open-label study of 113 (unguided) and 114 (guided) groups

• Patients who received antidepressants based on genetically-guided interpretive reports provided to prescribers had greater response rates and remission after 8 weeks

Pharmacogenomic Test for Antidepressants•Pharmacogenomic tests available for serotonin transporter genes

•Several FDA-approved pharmacogenomic tests for CYP2D6 and CYP2C19• Despite the availability, tests often do not get used clinically

• Problems include cost and provider familiarity with test and results

• Reimbursement may be obtained but coverage is not consistent

•Genotyping for CYP2D6 and CYP2C19 may predict probability for efficacy and toxicity of many antidepressants

•Genotyping prior to initiation of antidepressants not common practice

•Genotyping results may not be necessary for antidepressants used at low doses

Copyright ©2010 Regents of the University of California. All rights reserved.De Leon et al 2006 41

Antidepressant Choice for Patient JS*

Gene Protein/Receptor Phenotype Drugs Affected




SLC6A4 SERT Normal activity


The World Journal of Biological Psychiatry, 2015; 16: 142–170

Antidepressant Choice for Patient JS*Gene Protein/Receptor Phenotype Drugs Affected

CYP2D6 CYP2D6 Poor metabolizer Paroxetine, fluoxetine, venlafaxine,vortioxetine, sertraline, duloxetine, bupropion, many TCAs

CYP2C19 CYP2C19 Extensive metabolizer --

CYP2C9 CYP2C9 Extensive metabolizer --

SLC6A4 SERT Normal activity --

HTR2A 5HT2A Receptor Normal activity --• First line choices without CYP2D6 dependent metabolism (CANMAT 2016): Citalopram, escitalopram,

mirtazapine• Second lines choices without CYP2D6 dependent metabolism (CANMAT 2016): Vilazodone, levomilnacipran

*Little evidence exists for the use of antidepressants in depression comorbid with schizophrenia and should be limited to use when schizophrenic symptoms are controlled and depressive symptoms are present

The World Journal of Biological Psychiatry, 2015; 16: 142–170

Anticonvulsants (AEDs)

JS’s depression has improved after a month but complains that he is tired and noticeably unsteady on his feet. You run stat labs and abnormal laboratory findings are reported as follows:

Ammonia: 52 [reference range: 9-30 umol/L]

Valproic Acid: 113.7 [reference range: 50-100 mcg/mL]

JS is diagnosed with valproic acid-induced hyperammonemia and valproic acid is discontinued. What anticonvulsant would you recommend?

Case Presentation [Cont.]

Epilepsy: Age-Related Incidence

46

Modified from WA Hauser et al. Epilepsia 34:453, 1993

0

50

100

150

200

0 20 40 60 80

Incid

ence/1

00,0

00

Age (yrs)

SeniorNeoplasms

cerebrovascular accidentsneurodegenerative disorders

Pediatricperinatal & neonatal insults

genetic susceptibility

Adulttrauma

complex febrile seizuresstatus epilepticus

47

SeizuresTypes Generalized Partial

Simple Complex SecondarilyGeneralized

Absence Myoclonic Tonic - Tonic AtonicClonic

Common Seizure Types

Complex partial

36%

Simple partial

14%

Generalized

tonic-clonic

23%

Other generalized

8%Myoclonic

3%

Unclassified

3%

Partial unknown

7%

Absence

6%Hauser A. Epilepsia. 1992;33(suppl 4):S6-S14.

1840 1860 1880 1900 1920 1940 1960 1980 2000

0

5

10

15

20

Bromide

PhenobarbitalPhenytoin Primidone

Ethosuximide

Sodium Valproate

Benzodiazepines

Carbamazepine

Zonisamide

Felbamate

Gabapentin

TopiramateFosphenytoin

OxcarbazepineTiagabine

Levetiracetam

Rufinamide

Lacosamide

Pregabalin

Eslicarbazepine

Perampanel

Clobazam

Ezogabine

Calendar Year

Nu

mb

er o

f L

icen

sed

An

tico

nv

uls

an

t D

rug

s

Lamotrigine25

Common Anticonvulsants (AEDs)Brivaracetam

Epilepsy – Treatment GuidelinesComplex Partial Seizures

Glauser T et al. Epilepsia. 2013;54(3):551-63; NICE Clinical Guideline: 137;Nov, 2013.

Treatment Guideline

First-line Second-line Third-line Later Interventions

ILAE (2013) CarbamazepineLevetiracetamPhenytoinZonisamide

Valproate GabapentinLamotrigineOxcarbazepinePhenobarbitalTopiramateVigabatrin

ClonazepamPrimidone

NICE (2012) CarbamazepineLamotrigineLevetiracetamOxcarbazepineValproate

ClobazamGabapentinTopiramate

LacosamidePhenobarbitalPhenytoinPregabalinTiagabineVigabatrinZonisamide

Not Applicable

Why Do We Need New Agents?Problems with current AEDs

◦ Seizure control◦ Newly diagnosed well treated◦ Still 40% with therapy resistance◦ New AEDs over last 20 years have not changed this equation!

◦ Safety/tolerability◦ Some new (and old) AEDs still have important safety and

tolerability problems

How do we make progress?Revolutionary Drugs◦ Drugs that work with new mechanisms never tried

before◦ Expectation: They will control seizures that

existing drugs can’t control

Evolutionary Drugs◦ Improve on existing drugs◦ Expectation: We can eliminate some of the

problems/side effects of good drugs, without reducing their effect on seizures

What do we know about AEDs at time of approval?

• How the drug works in difficult to control seizures (proof that drug is better than placebo)

• Side effects when used at titration rates and doses employed in trials, over short term

• Safety in 1500-15,000 subjects

• Some drug interactions

What don’t we know about AEDs at time of approval?

• How the drug works in other types of seizures

• How the drug works in newly diagnosed patients

• Comparative data vs. new or old AEDs

• Impact at different ages• Pediatric• Elderly

• Best dose, titration schedule

• Some safety issues (including long-term)

• How well the drug works by itself

• Pregnancy & Breastfeeding effects

•FDA Indication – Schedule V•Adjunctive therapy for adults with partial seizures age 17 years

•MOA• Selective enhancement of sodium channel slow inactivation• Binds to collapsin response mediator protein 2 (CRMP-2)

•Available Formulation•Oral, IV

•Administration Considerations•Not affected by food•Dose adjustment in renal & hepatic dysfunction

Lacosamide (Vimpat) - Revolutionary

•Metabolism•Strong CYP3A4 or CYP2C9 inhibitors

•Adverse Effects•Dizziness, headache, diplopia, fatigue, abnormal coordination,

blurred vision, tremor, nystagmus, nausea, weight neutral

•Caution in cardiac conduction problems & severe cardiac disease

Lacosamide (Vimpat) - Revolutionary

•FDA Indication – Schedule V **To be discontinued June 2017**•Adjunctive treatment of partial-onset seizures in adults ≥ 18 years

•MOA•Neuronal KCNQ/Kv7 potassium channel opener

•Available Formulation•Oral

•Administration Considerations•Not affected by food•Dose adjustment required for moderate to severe renal & hepatic

dysfunction

Ezogabine (Potiga) - Revolutionary

•Metabolism• Predominately metabolized via glucuronidation & acetylation• Reduced levels by inducing AEDs • Inhibits P-glycoprotein medications

• Adverse Effects• Dose-related: drowsiness (23%), somnolence (22%), dizziness (15%), vertigo (8%),

confusion (9%)• Other: tremor, memory loss, gait disturbances, double vision, red/orange/brown

urine• Urinary Retention: occurs w/in first 6 months (e.g., inability to urinate, weak urine

stream, pain with urination)• Blue skin discoloration• BBW: Retinal abnormalities in 1/3 of patients treated for 4 yrs & vision loss

Ezogabine (Potiga) - Revolutionary

•FDA Indication • Adjunctive therapy in the treatment of partial-onset seizures with or without

generalized seizures in patients aged 12 years and older

•MOA•Non-competitive, selective antagonist of AMPA glutamate receptor to

block chemical release


•Administration Considerations•Not affected by food•Dose adjustment required for mild to moderate hepatic dysfunction;

avoid in severe renal or hepatic dysfunction

Perampanel (Fycompa) - Revolutionary

•Metabolism• Reduced levels by inducing AEDs [Major CYP3A4 substrate]

• Reduces effectiveness of oral contraceptives [Minor CYP3A4 Inducer]

• Adverse Effects• Dose-related: Dizziness, somnolence, headache, fatigue, irritability, falls,

ataxia, balance disorder, vertigo

• GI: Nausea, weight gain

• BBW: Dose-related serious &/or life-threatening neuropsychiatric events including aggression, anger, homicidal thoughts, hostility within first 6 weeks of therapy +/- previous history

Perampanel (Fycompa) - Revolutionary

•Old Mechanism of Action BUT Safer & More Powerful

•Prodrug activated to eslicarbazepine [major metabolite of oxcarbazepine]

•Adverse Effects• Dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo,

hyponatremia [5.1%], blurred vision, rash

Eslicarbazepine (Aptiom) - Evolutionary

Carbamazepine (Tegretol) Eslicarbazepine (Aptiom)

•FDA Indication – Schedule V• Adjunctive treatment of drug-resistant, partial-onset seizures in patients ≥ 16

years

•MOA•N-propyl analog of levetiracetam• Selective high affinity for synaptic vesicle protein 2A (SV2A) in the brain

and shows sodium channel blockade

•Available Formulation•Oral, IV

•Administration Considerations•Not affected by food•Dose adjustment required for hepatic dysfunction; no dose adjustment

required for mild to moderate renal dysfunction

Brivaracetam (Briviact) - Revolutionary

•Metabolism• Inhibits epoxide hydrolase & lesser degree CYP3A4 and CYP2C19

• Weakly induces CYP3A4

• Adverse Effects• Common: Headache, somnolence, dizziness, fatigue, irritability,

nausea/vomiting

Brivaracetam (Briviact) - Revolutionary

AED Hypersensitivity Syndrome (AHS)

Internal Organs

Fever Rash

Occurs within first 2 to 8 weeks at start of therapy

AHS Outcomes: SJS & TENs

Stevens Johnson Syndrome (SJSs)

Toxic Epidermal Necrolysis (TENs)

• Estimated Frequency• 1/10,000 to 6/10,000

• Arene Oxide Intermediate• Aromatic ring

• Black Box Warning• Screen genetically for HLA-B*1502 allele prior to initiating carbamazepine

Initiating carbamazepine or like derivatives

• Patients with the positive allele should not be

treated with carbamazepine or like derivatives unless

the benefit clearly outweighs the risk


Alldredge B. Ped Neurol. 1994;10:169-71.


•HLA-B*1502 Cross-reactivity• Up to 80%

• Relative contraindications in JS:

◦ Carbamazepine

◦ Eslicarbazepine

◦ Felbamate

◦ Lamotrigine

◦ Oxcarbazepine

◦ Phenobarbital

◦ Phenytoin

◦ Zonisamide

Phenobarbital Amitriptyline Eslicarbazepine

Phenytoin Carbamazepine Oxcarbazepine

Chung WH et al. Expert Opin Drug Saf. 2010;9(1):15-21; Shear et al. J Clin Invest. 1988;82:1826-32.

68

Lamotrigine ± Inducer & AHS Connection

Other

UGT1A4

CYP

Glucuronide Product

Arene Oxide Intermediate

Rash

Anderson GD. Epilepsia 2002;43(suppl 3):53-9;Anderson M et al. BMJ. 2015;5(6):e008298.

Lamotrigine + Valproic Acid & AHS Connection

69

Other

UGT1A4

CYP

Glucuronide Product

Arene Oxide Intermediate

Rash

Anderson GD. Epilepsia 2002;43(suppl 3):53-9;Anderson M et al. BMJ. 2015;5(6):e008298.

AED Hypersensitivity Syndrome (AHS)Pharmacogenomics Correlation

Major Population/Country HLA-B*1502 & *3101 Allele Frequency Correlation with Carbamazepine - SJS/TENs

Han Chinese (Taiwan) 4.3%/ 2% Strong/Low - *1502/ *3101

Han Chinese (Hong Kong) 7.2%/ 2% Strong/Low - *1502/ *3101

Thai (Thailand) 6.1% Strong - *1502

Malay (Malaysia) 8.4% Strong - *1502

South Han (China) 7.1% Unknown - *1502

North Han (China) 1.9% Unknown - *1502

Indian (India) 1 – 6% Unknown - *1502

Japanese (Japan) 0.1%/ 9% No Association/Strong - *1502/ *3101

Korean (Korea) 0.4%/ 5% No Association/Strong - *1502/ *3101

Northern Europe 0%/ 2 – 5% No Association/Strong - *1502/ *3101

Chung WH et al. Expert Opin Drug Saf. 2010;9(1):45-21;McCormack M et al. N Engl J Med. 2011;364(12):1134-43;Song JS et al. Ann Lab Med. 2014;34:372-75.

CPIC: Phenytoin/FosphenytoinRecommendations (CYP2C9 & HLA-B 1502 Carrier vs. Non-Carrier)

Genotype Implications Recommendations Classification

CYP2C9 – HLA-B 1502 CarrierExtensive, intermediate, & poor metabolizer

Increased risk of phenytoin-induced SJS/TENs

If naïve to phenytoin/ fosphenytoin, do not use

STRONG

CYP2C9 – HLA-B 1502 Non-CarrierExtensive metabolizer

Normal metabolism Initiate standard maintenance dosage

STRONG

CYP2C9 – HLA-B 1502 Non-CarrierIntermediate metabolizer

Reduced phenytoin metabolism increased phenytoin plasma concentration

Consider 25% dose reduction of standard maintenance dosage

MODERATE

CYP2C9 – HLA-B 1502 Non-CarrierPoor metabolizer

Reduced phenytoin metabolism increased phenytoin plasma concentration

Consider 50% dose reduction of standard maintenance dosage

STRONG

Caudle KE et al. Nature. 2014;96(5):542-58.

Epilepsy – Treatment GuidelinesComplex Partial Seizures

Glauser T et al. Epilepsia. 2013;54(3):551-63; NICE Clinical Guideline: 137;Nov, 2013.

Treatment Guideline

First-line Second-line Third-line Later Interventions

ILAE (2013) CarbamazepineLevetiracetamPhenytoinZonisamide

Valproate GabapentinLamotrigineOxcarbazepinePhenobarbitalTopiramateVigabatrin

ClonazepamPrimidone

NICE (2012) CarbamazepineLamotrigineLevetiracetamOxcarbazepineValproate

ClobazamGabapentinTopiramate

LacosamidePhenobarbitalPhenytoinPregabalinTiagabineVigabatrinZonisamide

Not Applicable

Pharmacogenetic Testing Results for JSGene Protein/Receptor Phenotype





SLC6A4 Serotonin Transporter (SERT) Normal activity


HTR2C 5HT2C Receptor Normal activity

DRD2 D2 Receptor Normal activity

HLAB*1502 Human Leukocyte Antigen Positive

JS is diagnosed with valproic acid-induced hyperammonemia and valproic acid is discontinued. What anticonvulsant would you recommend?



OPTIONS

• Brivaracetam (Briviact)

• Gabapentin (Neurontin)

• Levetiracetam (Keppra)

• Pregabalin (Lyrica)

• Ezogabine (Potiga)

• Lacosamide (Vimpat)

• Perampanel (Fycompa)

Antipsychotics

JS returns to clinic complaining of increasing auditory hallucinations despite being further titrated up to risperidone 6mg PO QHS. You suspect that he’s not able to metabolize his risperidone and would like to make an alternative recommendation. What do you recommend?

Case Presentation

Schizophrenia•EpidemiologyoPrevalence approximately 1% worldwide

oOnset in late adolescence to early 30’s

oNo gender or racial differences

•Pathophysiology• Characterized by positive and negative symptoms of at least 6 months

duration

• Course is variable although typically characterized by episodes or exacerbations of symptoms and decline in functioning

Symptoms

•Anhedonia

•Avolition

•Alogia

•Restricted Affect

•Social isolation

•Psychomotor retardation

◦ Paranoia

◦ Hallucinations

◦ Delusions

◦ Disorganization

◦ Agitation

◦ Bizarre behavior

Mood and cognitive symptoms are also typical

Treatment & Side Effects

•Antipsychotics• Efficacy related to D2 blockade as well as modulation of other

neurotransmitter circuits (5HT, glutamate)

•First generation•High D2 blockade •Extrapyramidal side effects (EPS)

•Second generation•Typically exhibit 5HT2A antagonism• Lower EPS and higher metabolic side effects

Treatment GuidelinesWorld Federation of Societies in Biological Psychiatry (WFSBP) 2012

American Psychiatric Association (APA) 2004/2009

Patient Outcomes Research Team (PORT) 2009

Texas Medication Algorithm Project (TMAP) 2006

1st Line 1st episode: olanzapine, quetiapine, risperidone, haloperidolOther: Any SGA (except lurasidone) or Haldol

SGA SGA SGA (except olanzapine, clozapine), FGA

2nd Line SGA, FGA, clozapine SGA, FGA, clozapine SGA, FGA SGA, FGA

3rd Line Clozapine Clozapine Clozapine Clozapine

Salvage Clozapine augmentation, antipsychotic + ECT

Clozapine augmentation

Clozapine augmentation, SGA,FGA, combinations

Table adapted from Goldstone LW. BCPP Pharmacotherapy Review Course. Ch 11, pg 594

Medication Non-adherence Associated with Exacerbation

•Non-adherence •Most common reason for disease relapse

•Multi-faceted phenomenon•Medication tolerability

•Medication efficacy

Genetic Factors

•Genetic factors influence drug metabolism and efficacy•Affects adherence and treatment outcomes

•Affects propensity for side effects

•Affects target receptor sites

Personalization of medication optimal

Newer Antipsychotic Approvals in Schizophrenia

• Iloperidone (Fanapt) – 2009

•Asenapine (Saphris) – 2009

• Lurasidone (Latuda) - 2010

•Brexpiprazole (Rexulti) - 2015

•Cariprazine (Vraylar) - 2015

Iloperidone (Fanapt)

•FDA Indication•Schizophrenia

•MOA•D2 and 5HT2A antagonist

•Available Formulation•Oral tablet

•Administration Considerations•With or without food

Iloperidone (Fanapt)

•Metabolism•Hepatic adjustment (not recommended w/severe impairment)

•Decrease dose by 50% for CYP2D6 poor metabolizers or strong CYP2D6 inhibitors

•Half life doubled with CYP2D6 poor metabolizers•P88 and P95 active metabolites

•Adverse Effects•Common: Orthostatic hypotension, hyperprolactinemia, weight

gain, somnolence, xerostomia, QTc prolongation

Brenner MD. Pharmacogenomics. 2014 Apr;15(6):869-84

Iloperidone Genome Wide Association Studies (GWAS)

•>300,000 SNP’s examined from phase III trial data (n=218)

•Six SNP’s correlated with response: Most hypothetically associated with disease etiology

•Six SNP’s with putative roles in cardiac function and QTcprolongation

•None associated with PK or PD parameters identified in pharmacogenetic studies

Volpi et al. Mol. Psychiatry 14(11), 1024–1031 (2009)Lavendan et al. Mol. Psychiatry 14(8), 804–819 (2009)

Asenapine (Saphris)

•FDA Indication •Schizophrenia•Acute treatment of manic or mixed episodes adjunctively or as

monotherapy

•Pharmacology•5HT1A/B/C, 5HT2A/B/C, 5HT5A, 5HT6, 5HT7 antagonism; D1, D2A/2B, D3, D4 antagonism; α1A/2A/2C anatognism, H1 antagonism

•Available Formulation•Sublingual tablet

Asenapine (Saphris)

•Administration Considerations•Avoid food or drink within 10 minutes of administration

•Doubling dose results in non-linear increases in exposure

•Metabolism•CYP1A2 and Glucuronidation (UGT1A4)

•Adverse Effects• Common: Oral paresthesia/hypoesthesia, EPS, somnolence, weight

gain, dyslipidemia

Lurasidone (Latuda)

•FDA Indication •Schizophrenia

•Depression associated with bipolar I as monotherapy or adjunctively

•Pharmacology•MOA: D2 and 5HT2A antagonist

•α-2A/2C antagonism, partial 5HT1A agonism


Lurasidone (Latuda)

•Administration Considerations•Take with food (350 calorie minimum)

•Metabolism•Dose reduction w/strong CYP3A4 inhibition; may require higher

dosage with CYP3A4 inducers

•Hepatic and renal adjustment

•Adverse Effects•Common: Nausea, vomiting diarrhea; EPS; increasing anxiety

Brexpiprazole (Rexulti)•FDA Indication •Schizophrenia

•Adjunctive therapy to antidepressants for major depression

•MOA•Partial agonist at 5HT1A and D2 receptors; antagonist at 5HT2Areceptors


Brexpiprazole (Rexulti)


•Metabolism•CYP3A4 and CYP2D6 dose adjustments

•Renal and hepatic dose adjustments

•Adverse Effects•Common: Hyperglycemia, dyslipidemia, weight gain, akathisia,

EPS, headache

Brexpiprazole Dose Adjustments

Metabolic Parameter Dose Adjustment in Schizophrenia

CrCl <60ml/min Max 3mg daily

Child Pugh ≥7 Max 3mg daily

Strong CYP2D6 or CYP3A4 inhibition Reduce dose by 50%

Strong CYP2D6 AND CYP3A4 inhibition Administer 25% of usual dose

CYP2D6 poor metabolizers Reduce dose by 50%

Brexpiprazole vs. Aripiprazole

• Brexpiprazole and aripiprazole:• Partial agonist activity for 5-HT1A and D2 receptors• Antagonist activity for 5-HT2A receptors

• Brexpiprazole has less intrinsic dopaminergic activity and reduced affinity for 5HT1A, 5HT2A, α-1B

• Single head to head exploratory study found similar efficacy with lower incidence of akathisia with brexpiprazole

Citrome et al.Psychopharmacol. 2016 Jul;31(4):192-201Stahl SM. CNS Spectr. 2016 Feb;21(1):1-6

Cariprazine (Vraylar)

•FDA Indication •Schizophrenia

•Acute treatment of manic or mixed episodes in Bipolar I

•MOA•Partial agonist at 5HT1A, D2 and D3 receptors; antagonist at 5HT2A receptors


Citrome L.Clin Schizophr Relat Psychoses. 2016 Summer;10(2):109-19

Cariprazine (Vraylar)


•Metabolism•CYP3A4: reduce dose by 50% with strong inhibitors, not

recommended with strong inducers

•Equipotent active metabolites desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR)

•Adverse Effects•Common: akathisia, EPS, restlessness, insomnia, somnolence, GI

upset

Citrome L. Clin Schizophr Relat Psychoses. 2016 Summer;10(2):109-19

Pharmacogenetics in Newer Antipsychotics

•Pharmacokinetic variants •CYP2D6: iloperidone, brexpiprazole

•CYP1A2: asenapine?

•CYP3A4: lurasidone, cariprazine, brexpiprazole

•ABC1 transporter?

Brenner MD. Pharmacogenomics. 2014 Apr;15(6):869-84

•Pharmacodynamic Variants•Dopamine 2 receptor variants (DRD2) associated with hyperprolactinemia, risk of tardive dyskinesia, weight gain and treatment response•5HT2A receptor (HTR2A) influences second generation agent binding

Pharmacogenetics in Newer Antipsychotics

Brenner MD. Pharmacogenomics. 2014 Apr;15(6):869-84Zhang et al. Schizophr Bull. 2016 May 23. pii: sbw058Max et a. Pharmacogenomics J. 2016 Jun 7. doi: 10.1038/tpj.2016.44

Pharmacogentics of Metabolic Changes•5HT2C receptor (HTR2C) antagonism associated with increased oral intake, satiety, and hepatic/peripheral glucose uptake impairment•5HT1A receptor (HTR1A) antagonism associated with increased oral intake, impaired glucose sensitivity in pancreas•H1 receptor antagonism associated with increased oral intake and sedation•M1 and M3 muscarinic receptors antagonism associated with anticholinergic side effects, impaired glucose sensitivity, and reduced insulin secretion

Balt et al. Clin Pharmacol Ther. 2011 Jul;90(1):179-83

A Newer Antipsychotic for Patient JS?Gene Protein/Receptor Phenotype Affected Antipsychotics



HTR2A 5HT2A Receptor Normal activity Atypicals

DRD2 D2 Receptor Normal activity All

• Newer Antipsychotic Options: • Appropriate with Reduced Dose:

A Newer Antipsychotic for Patient JS?Gene Protein/Receptor Phenotype Affected Antipsychotics

CYP2D6 CYP2D6 Poor metabolizer Brexpiprazole, iloperidone, risperidone, aripiprazole, clozapine

CYP1A2 CYP1A2 Intermediate metabolizer Asenapine*, clozapine, olanzapine

HTR2A 5HT2A Receptor Normal activity Atypicals

DRD2 D2 Receptor Normal activity All

• Newer Antipsychotic Options: Lurasidone, Cariprazine, Asenapine*• Appropriate with Reduced Dose: Brexpiprazole, iloperidone

*Dose adjustment recommendations not made by manufacturer; increased monitoring prudent

Summary•Variation in pharmacokinetic, pharmacodynamic or etiologic genes impacts treatment tolerability and response

•Despite pharmacogentic tests being available, they are not widely employed in clinical practice currently

•Treatment customization based on pharmacogenetics is likely to improve adherence, tolerability, and outcomes in mentally ill patients