1. Pharmacogenetic testing:
To what extent can it help in guiding treatment decisions in schizophrenia-like psychosis?
A first episode schizophrenia treatment group discussion
November 21, 2017
Erik Messamore, MD, PhD
Associate Professor of Psychiatry, Northeast Ohio Medical University
Medical Director, Best Practices for Schizophrenia Treatment (BeST) Center
Option 1

2. Best Practices in Schizophrenia Treatment (BeST) Center at NEOMED
The BeST Center’s mission:
Promote recovery and improve the lives of as many individuals with schizophrenia as quickly as possible
Accelerate the use and dissemination of effective treatments and best practices
Build capacity of local systems to deliver state-of-the-art care to people affected by schizophrenia and their families
The BeST Center offers:
Training
Consultation
Education and outreach activities
Services research and evaluation
The BeST Center was established:
Department of Psychiatry, Northeast Ohio Medical University in 2009
Supported by The Margaret Clark Morgan Foundation and other private foundations and governmental agencies

3. The Promise

4. The Peril
Worsening of depression and onset of suicidality following gene-guided medication switch.
Extensive prolongation of psychotic symptoms because a pharmacogenetic report predicted better response to meds other than clozapine, and predicted “poor response” to clozapine.
Eventually, clozapine was prescribed and resulted in rapid improvement
Rahman, T., Ash, D. M., Lauriello, J. & Rawlani, R. Misleading Guidance From Pharmacogenomic Testing. Am J Psychiatry 174, 922–924 (2017).

5. The Rationale
Polymorphisms in the genes for the cytochrome P450 ‘drug metabolism’ genes may confer higher or lower enzyme activity.
High-activity enzyme  lower drug level in vivo  requires higher dose or alternative medication
Low-activity enzyme  higher drug level in vivo  requires lower dose or alternative medication

6. Adjusting dose according to PGx?

7. But… to what extent does dose relate to efficacy of psychotropics?
For most SSRI/SNRI drugs, there is no relationship between oral dose and likelihood of benefit
Lack of dose-response relationship is described in Prescribing Information for most SSRI/SNRI medication

8. Dose, concentration, occupancy Sertraline
ED50 for sertraline
9.1 mg/day
Meyer et al. Am J Psychiatry
161: , 2004

9. Dose, concentration, occupancy Fluoxetine
ED50 for fluoxetine
2.7 mg/day
Meyer et al. Am J Psychiatry
161: , 2004

10. Dose, concentration, occupancy Venlafaxine (XR)
ED50 for venlafaxine xr
5.8 mg/day
Meyer et al. Am J Psychiatry
161: , 2004

11. Some conclusions
We don’t measure blood levels of SSRIs because there is no relationship between blood levels and clinical response
There are no dose-response relationships between AD oral dose and clinical response – possibly because these meds are possibly “overdosed” at their FDA-reviewed doses

12. Alternative views of antidepressant mechanism
Harmer et al., Am J Psychiatry
161: , 2004

13. Similar story for antipsychotic medications
Adjustments of 20% (or more) are likely to have only minimal impact on D2 occupancy in many cases.

16. Arguments against PGx-guided treatment
Genes are only one of many determinants of drug level.
Smoking, gender, age, diet, other meds are also strong determinants of drug metabolism
Knowing genotype does not allow prediction of drug level.
For drugs where blood level is important, laboratory tests exist.

17. Blood level test availability for antipsychotic medications
Generic Name
Trade Name
Blood levels test available?
Chlorpromazine
Thorazine
Yes
Fluphenazine
Prolixin
Haloperidol
Haldol
Loxapine
Loxitane No
Molindone
Moban
Perphenazine
Trilafon
Thiothixene
Navane
Trifluoperazine
Stelazine
Aripiprazole
Abilify; Maintena; Aristada
Asenapine
Saphris
Brexipiprazole
Rexulti
Cariprazine
Vraylar
Clozapine
Clozaril, Fazaclo
Lurasidone
Latuda
Iloperidone
Fanapt
Olanzapine
Zyprexa; Relprevv
Paliperidone (9-OH risperidone)
Invega, Sustenna, Trinza
Risperidone
Risperdal; Consta
Quetiapine
Seroquel
Ziprasidone
Geodon
Blood level testing is available for all LAI-formulated drugs

18. On the other hand…

19. Gene Products Involved in Antipsychotic Metabolism
CYP1A2
CYP2D6
CYP3A4
CYP2C19
Asenapine, Chlorpromazine, Clozapine, Haloperidol, Loxapine, Olanzapine, Perphenazine, Thioridazine, Thiothixene, Trifluoperazine
Aripiprazole, Asenapine, Chlorpromazine, Clozapine, Fluphenazine, Haloperidol, Iloperidone, Olanzapine, Perphenazine, Risperidone, Thioridazine
Aripiprazole, Asenapine, Clozapine, Haloperidol, Iloperidone, Loxapine, Lurasidone, Pimozide, Quetiapine, Risperidone, Sertindole, Ziprasidone
Aripiprazole, Clozapine, Olanzapine
Slide presenter: Erik Messamore
Light font: primary pathways Dark font: secondary pathways

20. Treatment Decisions Possibly Influenced by CYP Enzyme Genetics
FDA approves use of CYP2D6 PGx data to guide antipsychotic medication dose decisions
Recommends inclusion in drug labels lower dosing of CYP2D6 substrate drugs for non-extensive metabolizers
CYP2D6 is highly expressed in the brain where it can covert p-tyramine into dopamine
The clinical significance of this observation is unknown
Slide presenter: Erik Messamore

21. Potential Clinical Value of CYP2C19
CYP2C19 participates in clozapine metabolism
Also converts long-chain fatty acids (linoleic, arachidonic, EPA, DHA) into epoxide-metabolite signaling molecules
The *2 gene variant confers slow enzyme activity
*2/*2 homozygotes have 2- to 3-fold higher blood clozapine levels
(Jaquenoud et al., 2009)
*17 variant confers high enzyme activity
*17 carriers treated with clozapine had lower levels of glucose and Hgb A1c
*17/*17 homozygotes treated with clozapine had lower incidence of diabetes and higher rates of therapeutic response to clozapine (Piatkov et al., 2017)
This finding has not yet been replicated
Slide presenter: Erik Messamore

22. Genes Implicated in Antipsychotic Drug Treatment Response
Slide presenter: Erik Messamore
Source: Pouget et al., 2016

23. Genes Implicated in Antipsychotic Drug Treatment Response
Dopamine Receptors
DRD2 codes for the D2 subtype, the major target of antipsychotic drugs (except for clozapine, cariprazine)
DRD3 codes for the D3 subtype (a target of cariprazine)
Serotonin Receptors
HTR1A and HTR2A code for 1A and 2A subtypes of the serotonin receptor
These are targeted by atypical antipsychotic drugs, including clozapine
ZNF804A
A ‘Zinc Finger’ protein
Recently discovered by genome-wide association scan as a schizophrenia-related gene
Slide presenter: Erik Messamore

24. Genes Implicated in Antipsychotic Drug Adverse Effects: Tardive Dyskinesia
Slide presenter: Erik Messamore
CYP2D6: drug metabolism enzyme
DRD2: Dopamine receptor, subtype 2
HTR2A: Serotonin receptor, subtype 2a
HSPG2: heparan sulfate proteoglycan core protein
Source: Pouget et al., 2016

25. Placebo response has not been adequately controlled for in studies to date
Expectation bias is likely to be extremely strong in clinical studies of PGx-guided pharmacotherapy.
An adequate placebo control would entail either: a) active deception, or b) deliberately haphazard medication switch (to a potentially inferior medication) of the control group.

26. PGx-determination of “bad” or “inferior” medications have the potential to introduce nocebo effect, or outright harm
Medications from the ‘red box’ may evoke pessimism or fear from the patient or his/her family
‘Green box’ medications may include only options with high metabolic AE risk, biasing decision making toward possibly unnecessary side effect burden
Clinically useful, or best-in-class, meds may appear as ‘red box’ meds. Their avoidance may prolong illness/suffering.

27. How to answer patient questions? How to proceed in practice?
Discussion
How to answer patient questions? How to proceed in practice?