"Medscape Psychopharmacology Today" is a monthly column on issues
and topics that are new and important in psychiatry and psychopharmacology. Geared to the practicing clinician, it will provide
information about upcoming issues and advances in the field.
What dose of a particular medication
should be used for a particular patient?
Dosing questions are probably the most common and most difficult
questions that clinicians grapple with. We assume that there is some way to determine the appropriate dose before initiation
of treatment; however, usually the only definitive answer is, "Whatever ends up working the best."
The primary issues
related to dosing are (1) individual variation and (2) the discrepancy between the best dose for minimizing side effects and
the best dose for treatment response. Drug companies tend to focus on the former at the expense of the latter.
Individual variation includes not only differences among people
in terms of such issues as absorption and metabolism but also variations among the disorders themselves.
For example,
does everyone we diagnose with major depression have the same disorder? Probably not.
Everybody is different. Everyone
with ostensibly the same disorder does not respond to the same medication or at the same dose. It is intriguing to speculate
why, but no one really knows. It is particularly interesting to note that studies have shown no correlation between plasma
level and treatment response for selective serotonin reuptake inhibitors (SSRIs). Perhaps that suggests that it does not matter
very much what dose is administered to a patient.
Most of the time we give medicines by mouth, and this can account
for a great deal of variation, due in large part to big differences in our diets. People who live mostly on salads probably
absorb medicine differently than people who live mostly on cheeseburgers.
We also vary a great deal as to how fast
we metabolize medicine. Studies have shown that there is enormous variation between individuals, even those with
the same ethnic background, in terms of the potency of the various cytochrome P450 enzymes. These enzymes that are responsible
for much of drug metabolism may vary from person to person by as much as 30%. For example, the blood level of quetiapine,
at the same dose may vary as much as 40 times between patients.
Add in the other medications the patient is
taking that may or may not interfere with or induce metabolism, and it becomes extremely hard to predict an optimal dose.
It is important to remember that almost all drug interactions are reported retrospectively; despite all we know about
drug metabolism, specific and sometimes significant interactions are very hard to predict.
Usually, the smaller
the dose of a medication, the fewer side effects, although there are exceptions: Venlafaxine seems to
be tolerated better at higher rather than lower doses.
When pharmaceutical companies come out with a new drug, they
often try to market it at a very low dose to minimize side effects. As a result, clinicians can be unimpressed with the drug
until they try it at doses higher than the initial recommended dose.
Examples of this are olanzapine, nefazodone,
and quetiapine. Risperidone was marketed at too high a dose for the same reason: the clinical trials were designed
to find the highest dose at which side effects were minimal, not the highest treatment response. As a result, the drug was
originally marketed at 6 mg/day. Now we know that for most patients the drug works better, particularly for negative symptoms
of schizophrenia, in the 2- to 4-mg/day range.
What is the relationship between dose and response? For the most part,
it varies depending on the drug. As discussed above, for risperidone, a lower dose often produces a better response.
For
SSRIs, it gets flat - so that increasing the medication dose usually does not improve the patient and after a while, there
is no point increasing the dose if the patient isn't getting better.
For valproate, the more
medicine administered (and the higher the plasma levels), the more likely the patient will get better, but also the more likely
there will be side effects.
Another problem that is important to keep in mind is that there is no clear definition
of treatment response. We are generally clear about when a patient is better, but less clear on when they are able to
resume premorbid functioning levels and how long that should take. The scientific literature is, at best, confusing on the
subject.
Most studies are 6 weeks long. Is that long enough? How long does it take to get better? How much influence
does dose have on that? Do higher doses mean faster recovery? Although we have no definitive answers to any of these questions,
as clinicians we often behave as if we believe that more drug means better or faster.
If a patient is, for
example, somewhat better but not significantly better in 2 weeks, we will often increase the dose. If in 4 weeks they are
significantly improved, was it the increased dose, or would 2 more weeks on the original dose also have made them better?
We
tend to think of the dosing of a medication as a well-established procedure. It is not. In fact, many patients may have "failed"
medications that they would have responded to if they were given more time or a different dosage. The only way to dose
a new medication is to make an educated guess and adjust from there. There is no perfect starting dose or dosing strategy.
There is only the benefit of experience, 1 patient at a time.
(Everyone should ask the 3 questions below when
prescribed one of these drugs! Jean)
What is a mood stabilizer?
Lately,
we are being told that olanzapine is not only an antipsychotic, it is a mood stabilizer. This is not a big
surprise for those of us who have used this drug on psychotic bipolar patients and observed that it has positive effects beyond
its neuroleptic properties. Whether its mood-stabilizing effects are greater than or equal to its current competition, both
antipsychotics and mood stabilizers, remains very much an unanswered question.
Clozapine has been
shown recently to have excellent mood-stabilizing properties above and beyond its antipsychotic effect. All of this has precipitated
many discussions about the potential of new-generation (atypical) antipsychotics as mood stabilizers.
Santayana once
said, "Those that do not learn from history are doomed to repeat it." The current discussions are reminiscent of
the first discussions about antimanic agents.
The advent of lithium as the first approved antimanic
agent in the 1970s also brought a multitude of studies of many of the then widely used old-generation (typical) antipsychotics
as antimanic agents. Most of these studies had positive results. For example, chlorpromazine was shown to
be as effective as lithium in the treatment of mania. There was no widespread use of chlorpromazine as an alternative to lithium
in mania; however, clinicians were much more excited about lithium, and it quickly became the mainstay of treatment. Occasionally,
neuroleptics would be added, particularly in treatment-resistant cases.
Most of the current discussion about mood stabilizers
make it sound as if there is a particular magic to them, and often omit the fact that there are a lot of currently available
medications with antimanic or mood-stabilizing properties.
The bigger question is the clinical relevance of these meds.
Clozapine, for example, may be an excellent mood stabilizer, but its side-effect profile effectively
precludes its use as such in all but the most treatment refractory of cases.
The current challenges for a new
mood-stabilizing agent entering the market are:
(1) efficacy: does it work as well as or better than available alternatives?
(2) tolerability: what kind of impact
will its side effects have on the patient's life? and
(3) safety: if the patient takes this compound indefinitely, as is
usually the case with treatment for bipolar disorder, what might happen?
In my practice, in the early 1990s, I started
moving away from lithium and toward valproate as a first-line agent. The reason I did so was because of the
answers to the 3 questions above; it was at least as effective if not more so in certain groups of patients; it had a larger
therapeutic window and a somewhat milder side-effect profile that made it slightly more tolerable; and it may be safer
on thyroid and renal function in the long term.
Psychopharmacology needs to continue shifting its focus from efficacy
to effectiveness, taking into account tolerability, compliance, and safety.
Medications for symptoms
or side effects?
One question that must be asked about the use of a particular psychopharmacologic
agent is, What is the intent? Is the agent intended to treat a symptom, or a side effect of another agent?
Although
we are indeed fortunate in this field to have remarkably effective medications, they often have side effects that require
some sort of intervention, usually in the form of another pill.
Examples of this include benztropine
for extrapyramidal symptoms (EPS) of antipsychotics, trazodone or sedative/hypnotics for antidepressant-induced
insomnia, modafinil for oversedation of various psychotropics, and perhaps even the recent discussions about
adding topiramate to counteract medications that cause weight gain.
Ideally, this addition would do
nothing more than increase the effectiveness of the original medication. It is rarely that simple, however, when you add another
variable to the equation.
Benztropine is perhaps the worst example of an agent used to treat
a side effect. Given routinely to patients on antipsychotics, it can cause confusion, disorganization, and delirium, and
it also has some potential for abuse. These side effects of the side-effect medicine often prevent a patient with a psychotic
illness from functioning well enough to live or work in the community.
Even worse is that often the same antipsychotic
effect can be established with a lower dose of the antipsychotic medication, and the EPS resolves without benztropine at this
dose. Thus, we may be medicating side effects with benztropine rather than using the best possible treatment.
Sometimes
only 1 medicine works for a particular patient, and sometimes only at 1 dose. When this situation occurs, one needs to be
as aggressive as necessary to make sure the medication is as effective as possible, and that means doing whatever is necessary
to reduce or eliminate side effects.
If there is no reason to believe that we are stuck with 1 agent or 1 dose, however,
we are often not quick enough to change the dose or agent. In particular, we often assume that the same cocktail of medication
needed for acute illness is necessary for maintenance.
One example of this is fluoxetine-induced insomnia,
which is often treated with trazodone or a hypnotic agent at the beginning of treatment, then never
discontinued even though the patient may have only needed the extra medication for the first few weeks.
Modafinil
is underutilized to treat medication-induced sedation (overly sedated patients are less insistent about dealing with their
side effects), but in most cases this medication would only need to be used for a relatively limited time.
Patients
acclimate to their medicine, and the alert, involved clinician will often reduce dose for maintenance.
The
larger issue here is the difference between efficacy (ie, how well the medicine works) and effectiveness
(ie, whether it is also safe and tolerable enough to actually make the patient better).
With all of the psychotropic
agents currently available to us, and many more awaiting approval in the wings, we no longer need to settle for medications
with good efficacy, but we can hold out for effectiveness. Sometimes this requires adding another medication, sometimes switching
medications, and sometimes adjusting the dose.
A medication with good efficacy but horrible side effects is less effective
than one with the same efficacy but a significantly more benign side-effect profile. Fewer and milder side effects can
promote increased compliance, and lessen the likelihood of a medical reason to stop the medication
(eg, blood dyscrasias,
weight gain).
It can also offer greater long-term safety of use and as such increase the agent's effectiveness, or
increase the likelihood that it will actually work, and do so for as long as is necessary.
For too long we have
paid little attention to side effects and effectiveness because we have had so few choices.
Source
Medscape Psychopharmacology Today
Dosing, Target Symptoms,
and Mood Stabilizers
Thomas AM Kramer, MD
[Medscape Mental Health 5(2), 2000.
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