By Neil Sandson, MD
[Winter 2007; Vol. 33, No. 2; Pg 5, 11]
It
is with some sadness that I am writing my last article for this column in the
Maryland Psychiatrist. I
recently became the co-editor of the Med-Psych Drug-Drug Interactions column in
the journal Psychosomatics, and unfortunately, that will make it very difficult
for me to maintain this column.
Having this forum to share psychopharmacology issues has been a wonderful
opportunity. I would
like to thank all of you who have provided me with feedback, whether critical or
appreciative.
For
this column I have two items to discuss.
The first is one of the most intriguing drug interactions that I’ve
ever seen. The second
is a managed care behavior of recent concern.
Much
of my focus on drug interactions has dealt with pharmacokinetics, but this time
the issue is pharmacodynamic.
Cracking this case was one of my few true “Columbo” moments.
Many of the details have been altered to ensure anonymity, but the core
concepts have been preserved.
A
Case of Polyuria
A
46 year old female with a history of bipolar I disorder had been stable while
maintained on a combination of lithium, 900 mg/day (blood level = 0.8 mEq/L) and
sertraline (Zoloft), 75 mg/day.
About 10 years earlier, the patient was diagnosed with major depressive
disorder and was being treated with sertraline.
After several months of taking the sertraline, the patient had her first
manic episode, and lithium was added to her regimen.
She had never received lithium without the sertraline.
Since then, her urinalyses and serum creatinine values had been
consistently normal. However,
the patient had a friend who recently experienced acute renal failure due to
some unrelated cause, and this led her to become more concerned about possible
nephrotoxicity associated with long-term lithium treatment.
The patient and her psychiatrist collaborated on a plan to transition her
to monotherapy with valproate.
Initially, divalproex sodium, 250 mg b.i.d.
was added to her regimen, which she tolerated without difficulty.
One week later, her sertraline was decreased to 50 mg/day, and then
further decreased by 25 mg/week until it was discontinued.
Although the patient did not experience any typical serotonin withdrawal
symptoms, within two days of completely stopping the sertraline, she did report
marked and troubling polyuria.
Although it was not firmly quantified, she reported that she was
urinating “constantly”. Over
the next several days, the patient experienced dizziness (probably due to
dehydration) and disruption of her sleep.
Although the psychiatrist did not understand how the discontinuation of
the sertraline might have led to the patient’s polyuria, the chronology of
events implicated this as the most likely causative factor.
The psychiatrist therefore restarted the sertraline, and within 3 days,
her polyuria had almost completely resolved.
Discussion:
Although no urinalyses or serum electrolytes were obtained during this course of
events, I think the following is the only plausible explanation for this
peculiar vignette.
Lithium
is well known to produce some degree of increased urine production in all
individuals through antagonism of the action of antidiuretic hormone at the
collecting tubule of the nephron.
In some individuals, this effect can be quite troublesome, producing
frank diabetes insipidus. This
patient’s history suggests that she was one of those unfortunate individuals
who had an exceptional degree of increased urinary production when exposed to
lithium. However, it
seems that she was fortunate that sertraline produced a counteracting effect
that enabled her to tolerate lithium treatment, namely a syndrome of
inappropriate antidiuretic hormone production (SIADH).
SIADH occurs in many individuals (most often in the elderly) who take a
selective serotonin reuptake inhibitor, and this effect seems to result from
increased serotonin neurotransmission.
Thus, for this patient, the offsetting exposures to both a SIADH-producing
agent (sertraline) and an antidiuretic hormone antagonist (lithium) allowed her
to tolerate the combined regimen without difficulty.
However, when the sertraline was discontinued, lithium’s propensity to
increase urine production was no longer inhibited, leading to the development of
marked polyuria.
Managed
Care Threat
Recently,
one of my colleagues at Sheppard Pratt discharged a patient on a regimen of
venlafaxine (Effexor XR), 150 mg/day and risperidone (Risperdal M-tabs), 6
mg/day. The patient
was doing well, with no discernable side-effects.
When the patient attempted to fill his prescriptions at the pharmacy, he
was informed that the managed care company covering his pharmacy benefits would
only pay for 4 mg/day of risperidone.
Their rationale was that the venlafaxine would raise the blood level of
the risperidone to an extent that 4 mg/day would roughly equal the levels
produced by 6 mg/day of risperidone if it was given as monotherapy.
The
first issue to address is the notion that 150 mg/day of venlafaxine would raise
risperidone levels by 50% (more or less).
Of course, this is lunacy, but let’s try to see how this notion could
have arisen.
I’m
guessing that the managed care company had stumbled onto an article by Amchin et
al. 1999, in which venlafaxine was found to increase the area under the curve (AUC)
of risperidone, at a dosage of one mg/day, by an average of 32%.
So already we have a couple of problems. First of all, AUC is not the
same as trough concentration.
To the extent that there has been research correlating risperidone
pharmacokinetic parameters to efficacy, they have tended to utilize trough serum
concentrations, not AUC. Second, 4 mg/day of risperidone would be only (roughly)
one-fourth as susceptible to competitive inhibition at cytochrome P450 2D6 by a
given quantity of venlafaxine than would one mg/day.
However,
we have not yet addressed the most egregious flaw in the managed care
company’s reasoning. A blood level of risperidone, as an isolated measurement,
is virtually meaningless. What
is meaningful to measure is the sum of the concentrations of risperidone and its
equipotent 9-hydroxyrisperidone metabolite. In the literature, this sum is
referred to as the “risperidone active moiety”.
Cytochrome P450 2D6 catalyzes the transformation of risperidone to its
9-hydroxy metabolite, so even a weak competitive inhibitor of 2D6 (like
venlafaxine) can raise the ratio of risperidone to 9-hydroxyrisperidone
concentrations, but such (relatively) pure 2D6 inhibition does not alter the
total levels of the moiety. In fact, that was the finding of the Amchin article!
Risperidone active moiety levels did not change significantly when risperidone,
one mg/day, was combined with venlafaxine. This refusal to fill the prescription
was based on a gross misunderstanding of risperidone pharmacokinetics and a
fundamentally flawed misreading, whether accidental or intentional, of the
article in question.
My
colleague is pursuing this matter, and I hope that this pursuit will help
eliminate what may be the beginning of a dangerous trend. I wonder how many
patients have already been deterred from filling appropriate prescriptions by
this irresponsible and dangerous policy. How many other interactions are being
targeted by managed care companies as a rationale for obstructing appropriate
prescribing? Even if other managed care forays into the realm of drug
interactions are more intellectually coherent than the above example, this is an
inappropriate use of this information. At this time, appropriate prescribing of
psychotropic medications is an individualized and empirically-guided enterprise.
As you all know, I’m all for dissemination of information about drug
interactions. Knowledge
of drug interactions can guide clinicians to safer treatment choices and higher
indices of suspicion of adverse events with certain combinations. However, one
cannot accurately predict the import or significance of a given drug interaction
for a specific patient when one has no clinical information pertaining to that
patient. To develop policies that purport to do just that, in the name of cost
savings, threatens the welfare of our patients. We need to fight this
aggressively, as it represents an ominous and utterly inappropriate intrusion
into our role as treating physicians.
Thank
you all again for your support and interest over the past three years.
I wish you all good fortune and safe prescribing.
May all your interactions be benign.