One of the most difficult decisions in treating depressed patients is which antidepressant to choose. Even more complicated than this problem is what to do when a patient does not respond to an initial antidepressant. There is hope now to these clinical dilemmas in the advancing field of human genomics. I know most of us believe that the human genome is an esoteric study with little relevance to our lives but this thinking couldn’t be more wrong.
The burgeoning information that is being produced from this research is challenging our abilities to process the data. New super computers will need to be created just to apply the data that is emanating from these genomic revelations. There is great promise in both the field of genomics and proteonomics to effect treatments in psychiatric clinical practice. We detail here one use of genomics to effect treatment and solve complex decisions such as treatment choices in refractory depressed patients or even the selection of an antidepressant in patients who encounter frequent or serious side effects..
It is well known that that the liver enzymes CYP450 2D6 and CYP450 2C19 cause individual patients to either under metabolize or over metabolize particular antidepressants thus effecting responsiveness and side effect profiles of patients. Until now there has been no way to identify these patients and this leads to Physician/Patient frustrations and often recriminations. It is now possible in a cost effective manner ($250-$500) to identify these patients. The FDA approval of theAmpliChip CYP450 Test that genotypes for two cytochrome P450 2D6 (CYP2D6) and 2C19 (CYP2C19) genes allows psychiatrists to identify slow metabolizers or fast metabolizers. The currently available technology simply helps clinicians and selected patients to decide if they should “not take that drug” or “take this low or high dose,” an application called “safety pharmacogenetics.” Below are recommendations from an article in Psychosomatics 47:1, January-February 2006 titled Clinical Guidelines for Psychiatrists for the Use of Pharmacogenetic Testing for CYP450 2D6 and CYP450 2C19 by Jose De Leon, M.D. Scott C. Armstrong, M.D. Kelly L. Cozza, M.D. They recommend the following regarding the selection of antidepressants or antipsychotics in patients that may require these drugs.
Note: PM: poor metabolizer; UM: ultra-metabolizer; TCA: tricyclic antidepressant; TDM: therapeutic drug-monitoring; ADRs: adverse drug reactions
APPENDIX 1. Clinical Guidelines for Using CYP2D6 and CYP2C19 Genotypes in Patients Taking Antidepressants11,29–39
A. CYP2D6 PM
1. Suspecting a CYP2D6 PM
a. Clinical information
i) Poor tolerance of typical TCA doses (and perhaps to venlafaxine)
ii) Normal tolerance of antidepressants not dependent on CYP2D6 is expected
iii) Other (see Appendix 2 for response to antipsychotics)
b. Laboratory evidence
i) TCA C/D: 4–6b in absence of CYP inhibitors
ii) Some limited information on venlafaxine TDM
iii) See Appendix 2 if antipsychotic TDM is available
2. Treating a CYP2D6 PM
a. Use antidepressants not dependent on CYP2D6 (bupropion, citalopram, escitalopram, mirtazapine, or sertraline)
b. If using TCAs, use half of TCA dose;11 if using venlafaxine, use lower venlafaxine dose
c. If using paroxetine and fluoxetine, be careful and consider low doses
B. CYP2C19 PM
1. Suspecting a CYP2C19 PM
a. Clinical information
i) Poor tolerance of usual doses of some TCAs
ii) Possible poor tolerance of usual doses of citalopram, escitalopram, or sertraline
iii) Poor tolerance of antidepressants not dependent on CYP2C19 is not expected
iv) Other (low tolerance of usual diazepam doses and no problems with other benzodiazepines)
2. Treating a CYP2C19 PM
a. Use antidepressants not dependent on CYP2C19 (bupropion, fluvoxamine, mirtazapine, or paroxetine)
b. If using TCAs,f use half of TCA dose; if using citalopram, use half of citalopram dose; if using escitalopram or sertraline, it may be safer to use lower dose
C. PM for both CYP2D6 and CYP2C19
1. Suspecting a PM for both CYP2D6 and CYP2C19
a. Remember these are extraordinarily rare cases (Table 2).
b. They may have had problems with antidepressants dependent on CYP2D6 and/or CYP2C19. Although there is no published experience with these subjects, they should have problems with many but not all antidepressants (and some antipsychotics).
2. Treating a PM for both CYP2D6 and CYP2C19
a. Avoid antidepressants dependent on CYP2D6 or CYP2C19. Bupropion or mirtazapine may be good choices
D. CYP2D6 UM
1. Suspecting a CYP2D6 UM
a. Clinical information
i) Lack of response to usual doses of TCAs
ii) See Appendix 2 for response to antipsychotics
b. Laboratory evidence
i) TCA C/D _0.5k in absence of CYP inducers
ii) See Appendix 2 if antipsychotic TDM is available
2. Treating a CYP2D6 UM
a. Use antidepressants not dependent on CYP2D6 (bupropion, mirtazapine, citalopram, escitalopram, or sertraline)
b. If using TCAs, you may need to use high doses and TDM. Dosing may depend on the number of active alleles.
c. There are not enough data on venlafaxine, paroxetine, and fluoxetine (possibly, high doses are needed).
APPENDIX 2. Clinical Guidelines for Using CYP2D6 Genotypes in Patients Taking Antipsychotics
A. CYP2D6 PM
1. Suspecting a CYP2D6 PM
a. Clinical information
i) Poor tolerance of typical antipsychotics a or risperidone
ii) Normal tolerance of other atypical APs (not dependent on CYP2D6) is expected
iii) Other (see Table 3 for response to antidepressants)
b. Laboratory evidence
i) Risperidone/9-hydroxyrisperidone_1.0c in absence of CYP2D6 inhibitor/drugs
ii) Limited information on haloperidol TDM
iii) See Appendix 2 if antidepressant TDM is available
2. Treating a CYP2D6 PM
a. Use antipsychotic not dependent on CYP2D6 (clozapine, olanzapine, quetiapine, or ziprasidone)
b. If using risperidone, use no more than half dose used in normal circumstancese,
c. It appears to be safer to avoid phenothiazines and haloperidol
B. CYP2D6 UM
1. Suspecting a CYP2D6 UM
a. Clinical information
i) Possible lack of response to usual doses of risperidone
ii) Possible lack of response to typical antipsychotics
iii) See Appendix 2 for TCA
b. Laboratory evidence
i) Risperidone/9-hydroxyrisperidone _0.10 is highly sensitive but not specific
ii) Limited information on haloperidol TDM
iii) See Appendix 2 for TCA TDM
2. Treating a CYP2D6 UM
a. Use antipsychotic not dependent on CYP2D6 (clozapine, olanzapine, quetiapine, or ziprasidone)
b. If using risperidone, use higher doses of what you would normally use.
c. It appears to be easier and safer to avoid phenothiazines and haloperidol.
These recommendations may seem complicated but their relevance in clinical practice are enormous for selected patients. You should ask your psychiatrist if they understand these new strategies in prescribing medications and if they don’t politely request that they inquire about them. Fortunately, most patients respond to a first prescribed antidepressant but for those that don’t (upwards of 30%) these assessments of metabolic polymorphisms are important and applicable in clinical practice. The future of psychiatry and the dramatic improvements in treatments will evolve almost exclusively from the fields of Genomics and Proteonomics. Psychiatrists will have to stay current in these fields and their impact on treatments.