Take a pass on cytochrome P450 polymorphism tests

Cytochrome P450 polymorphism tests aren’t ready for prime time, but they continue to be promoted to physicians and patients, according to Dr. Thomas Strouse.

The tests use a drop of blood or saliva or a cheek swab to detect genetic variations in cytochrome P450 (CYP450) drug-metabolism liver enzymes. The goal is to match drugs with patient metabolic profiles, thereby increasing efficacy and reducing side effects and drug-drug interactions.

It "would be really terrific" if they did that, but so far, having that information hasn’t made much difference in most drug trials. "I don’t think we’re there [yet]. We really don’t know much about [using] cytochrome P450 [variants to] predict adverse events" and outcomes, said Dr. Strouse, medical director of the University of California, Los Angeles, Resnick Neuropsychiatric Hospital.

Several studies have failed to show a relationship between poor metabolic status and clinical response. In one, P450 status did not predict citalopram response or toleration (PLoS One 2008;3:e1872).

Instead, what is emerging is evidence that variations in neurotransmitter receptor and transporter genes "are more relevant" for predicting drug response (J. Clin. Psychopharmacol. 2006;26:192-7), he said at the annual psychopharmacology update sponsored by the Nevada Psychiatric Association.

The search will continue for quick, inexpensive ways to better match patients with pharmaceuticals, Dr. Strouse added.

In the meantime, with polypharmacy on the rise in the treatment of psychiatric conditions, it’s best to avoid – when possible – drugs that significantly impact the blood levels of others. The list includes potent P450 inhibitors, such as fluoxetine and paroxetine, and P450 inducers such as carbamazepine. But it also includes alcohol, cigarette smoke, and to a lesser extent, nicotine patches and smoked marijuana. Tricyclic antidepressants and other drugs with narrow therapeutic indices are probably best avoided, as well.

It’s wise to select pharmaceuticals that are metabolized by more than one P450 pathway. Indiana University has a website, probably "the best online resource" for useful drug metabolism information, that can identify those drugs, he said.

"A lot of us have had the experience of inheriting patients who are on what looks like pretty insane polypharmacy" – eight or more psychiatric medications at once – "and yet the patient says, ‘This is really what it’s taken for me to stay well,’ " Dr. Strouse said.

Sorting out those patients’ potential drug interactions is "impossible," he cautioned. "The mathematical possibilities quickly approach googolplex" when people are on so many pharmaceuticals, he noted.

Some drugs, however, are particularly useful in those situations, because they don’t tweak P450 enzymes to any extent. The list includes lamotrigine, sertraline, and citalopram, although citalopram should be capped at 40 mg/day to prevent QTc interval prolongation.

"If you endeavor to simplify the regimen, you have to do it in a very cautious, stepwise fashion," he noted, with an eye out for clinical worsening, loss of benefit, and emerging side effects.

Let patients know about the potential problems, too. "I’ve found that when I engage my patients in the monitoring, it very much strengthens the therapeutic relationship," Dr. Strouse said.

He reported that he has no relevant financial conflicts.

[email protected]

Cytochrome P450 polymorphism tests aren’t ready for prime time, but they continue to be promoted to physicians and patients, according to Dr. Thomas Strouse.

The tests use a drop of blood or saliva or a cheek swab to detect genetic variations in cytochrome P450 (CYP450) drug-metabolism liver enzymes. The goal is to match drugs with patient metabolic profiles, thereby increasing efficacy and reducing side effects and drug-drug interactions.

It "would be really terrific" if they did that, but so far, having that information hasn’t made much difference in most drug trials. "I don’t think we’re there [yet]. We really don’t know much about [using] cytochrome P450 [variants to] predict adverse events" and outcomes, said Dr. Strouse, medical director of the University of California, Los Angeles, Resnick Neuropsychiatric Hospital.

Several studies have failed to show a relationship between poor metabolic status and clinical response. In one, P450 status did not predict citalopram response or toleration (PLoS One 2008;3:e1872).

Instead, what is emerging is evidence that variations in neurotransmitter receptor and transporter genes "are more relevant" for predicting drug response (J. Clin. Psychopharmacol. 2006;26:192-7), he said at the annual psychopharmacology update sponsored by the Nevada Psychiatric Association.

The search will continue for quick, inexpensive ways to better match patients with pharmaceuticals, Dr. Strouse added.

In the meantime, with polypharmacy on the rise in the treatment of psychiatric conditions, it’s best to avoid – when possible – drugs that significantly impact the blood levels of others. The list includes potent P450 inhibitors, such as fluoxetine and paroxetine, and P450 inducers such as carbamazepine. But it also includes alcohol, cigarette smoke, and to a lesser extent, nicotine patches and smoked marijuana. Tricyclic antidepressants and other drugs with narrow therapeutic indices are probably best avoided, as well.

It’s wise to select pharmaceuticals that are metabolized by more than one P450 pathway. Indiana University has a website, probably "the best online resource" for useful drug metabolism information, that can identify those drugs, he said.

"A lot of us have had the experience of inheriting patients who are on what looks like pretty insane polypharmacy" – eight or more psychiatric medications at once – "and yet the patient says, ‘This is really what it’s taken for me to stay well,’ " Dr. Strouse said.

Sorting out those patients’ potential drug interactions is "impossible," he cautioned. "The mathematical possibilities quickly approach googolplex" when people are on so many pharmaceuticals, he noted.

Some drugs, however, are particularly useful in those situations, because they don’t tweak P450 enzymes to any extent. The list includes lamotrigine, sertraline, and citalopram, although citalopram should be capped at 40 mg/day to prevent QTc interval prolongation.

"If you endeavor to simplify the regimen, you have to do it in a very cautious, stepwise fashion," he noted, with an eye out for clinical worsening, loss of benefit, and emerging side effects.

Let patients know about the potential problems, too. "I’ve found that when I engage my patients in the monitoring, it very much strengthens the therapeutic relationship," Dr. Strouse said.

He reported that he has no relevant financial conflicts.

[email protected]

Cytochrome P450 polymorphism tests aren’t ready for prime time, but they continue to be promoted to physicians and patients, according to Dr. Thomas Strouse.

The tests use a drop of blood or saliva or a cheek swab to detect genetic variations in cytochrome P450 (CYP450) drug-metabolism liver enzymes. The goal is to match drugs with patient metabolic profiles, thereby increasing efficacy and reducing side effects and drug-drug interactions.

It "would be really terrific" if they did that, but so far, having that information hasn’t made much difference in most drug trials. "I don’t think we’re there [yet]. We really don’t know much about [using] cytochrome P450 [variants to] predict adverse events" and outcomes, said Dr. Strouse, medical director of the University of California, Los Angeles, Resnick Neuropsychiatric Hospital.

Several studies have failed to show a relationship between poor metabolic status and clinical response. In one, P450 status did not predict citalopram response or toleration (PLoS One 2008;3:e1872).

Instead, what is emerging is evidence that variations in neurotransmitter receptor and transporter genes "are more relevant" for predicting drug response (J. Clin. Psychopharmacol. 2006;26:192-7), he said at the annual psychopharmacology update sponsored by the Nevada Psychiatric Association.

The search will continue for quick, inexpensive ways to better match patients with pharmaceuticals, Dr. Strouse added.

In the meantime, with polypharmacy on the rise in the treatment of psychiatric conditions, it’s best to avoid – when possible – drugs that significantly impact the blood levels of others. The list includes potent P450 inhibitors, such as fluoxetine and paroxetine, and P450 inducers such as carbamazepine. But it also includes alcohol, cigarette smoke, and to a lesser extent, nicotine patches and smoked marijuana. Tricyclic antidepressants and other drugs with narrow therapeutic indices are probably best avoided, as well.

It’s wise to select pharmaceuticals that are metabolized by more than one P450 pathway. Indiana University has a website, probably "the best online resource" for useful drug metabolism information, that can identify those drugs, he said.

"A lot of us have had the experience of inheriting patients who are on what looks like pretty insane polypharmacy" – eight or more psychiatric medications at once – "and yet the patient says, ‘This is really what it’s taken for me to stay well,’ " Dr. Strouse said.

Sorting out those patients’ potential drug interactions is "impossible," he cautioned. "The mathematical possibilities quickly approach googolplex" when people are on so many pharmaceuticals, he noted.

Some drugs, however, are particularly useful in those situations, because they don’t tweak P450 enzymes to any extent. The list includes lamotrigine, sertraline, and citalopram, although citalopram should be capped at 40 mg/day to prevent QTc interval prolongation.

"If you endeavor to simplify the regimen, you have to do it in a very cautious, stepwise fashion," he noted, with an eye out for clinical worsening, loss of benefit, and emerging side effects.

Let patients know about the potential problems, too. "I’ve found that when I engage my patients in the monitoring, it very much strengthens the therapeutic relationship," Dr. Strouse said.

He reported that he has no relevant financial conflicts.

[email protected]