Thomas AM Kramer, MD


Medscape General Medicine. 2000;2(2) 


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.

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.

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.