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
CYP2C9 CYP2C9 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]
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)
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]
•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)
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]
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
CYP2D6 CYP2D6 Poor metabolizer
CYP2C19 CYP2C19 Extensive metabolizer
CYP2C9 CYP2C9 Extensive metabolizer
SLC6A4 SERT Normal activity
HTR2A 5HT2A Receptor 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
•Available Formulation•Oral
•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
AED Hypersensitivity Syndrome (AHS)
Alldredge B. Ped Neurol. 1994;10:169-71.
AED Hypersensitivity Syndrome (AHS)
•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
CYP2D6 CYP2D6 Poor metabolizer
CYP2C19 CYP2C19 Extensive metabolizer
CYP2C9 CYP2C9 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
JS is diagnosed with valproic acid-induced hyperammonemia and valproic acid is discontinued. What anticonvulsant would you recommend?
Case Presentation [Cont.]
Case Presentation [Cont.]
OPTIONS
• Brivaracetam (Briviact)
• Gabapentin (Neurontin)
• Levetiracetam (Keppra)
• Pregabalin (Lyrica)
• Ezogabine (Potiga)
• Lacosamide (Vimpat)
• Perampanel (Fycompa)
Case Presentation [Cont.]
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
•Available Formulation•Oral
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
•Available Formulation•Oral tablet
Brexpiprazole (Rexulti)
•Administration Considerations•With or without food
•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
•Available Formulation•Oral tablet
Citrome L.Clin Schizophr Relat Psychoses. 2016 Summer;10(2):109-19
Cariprazine (Vraylar)
•Administration Considerations•With or without food
•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
CYP2D6 CYP2D6 Poor metabolizer
CYP1A2 CYP1A2 Intermediate metabolizer
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
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)
1. Write down the course code. Space has been provided in the daily program-at-a-glance sections of your program book.
2. To claim credit: Go to www.cshp.org/cpe before December 1, 2016.
Session Code: