Hello, I'm Dr Stephen Strakowski. I'm professor of psychiatry, psychology, and biomedical engineering at the University of Cincinnati, where I also serve as senior vice president and chief strategy officer in UC Health, our affiliated health system.
Today I'm going to talk about polypharmacy in psychiatry. I'm going to use a specific patient example of mine and use that example to talk about general principles when dealing with prescribing multiple medications. My interest in this partly arises from my role as a regional consultant, where I frequently am sent complicated patients to help physicians manage them—and I have to say, many times my strong recommendation is to simplify their medication regimens.
Introducing Our Patient With Polypharmacy: Mr A
To frame our discussion, let's talk about a patient. We'll call him Mr A, and he is a 40-year-old man with established bipolar II disorder. He has had clear hypomanic episodes in the past, but most of the time has struggled with depression and anxiety, which is fairly typical in bipolar II disorder. He came to me initially on a consultation, but eventually transferred his care to our practice.
Despite years of treatment and a lot of medications, Mr A continued to have significant depressive and anxiety symptoms—specifically a lot of lethargy and hypersomnolence, and then alternating with anxiety and restlessness that he found very troubling. He wasn't making progress with his psychiatrist.
In fact, when Mr A showed up in my office, he was on nearly a dozen medications that included lorazepam up to 4 mg daily, amphetamine mixed salts (Adderall®) 40 mg daily, buspirone 30 mg daily, lithium 900 mg daily, topiramate 300 mg daily, escitalopram (Lexapro®) 30 mg daily, temazepam 60 mg daily at bedtime, ziprasidone (Geodon®) 80 mg a day, paliperidone (Invega®) 6 mg daily, and metformin 1000 mg daily. He actually hadn't had a lithium level checked in quite some time.
So Mr A shows up on this large list of medications and is doing poorly. The question you want to ask yourself when you're facing a patient like this is, why are we using all these medicines if the patient is not benefiting? When speaking with Mr A, it was clear that there was no way for me to separate potential side effects of the medication from symptoms of his diagnosis. If someone who was medication-naive were to take his medication regimen, it would knock them out for days, so it was impressive that he was able to function at all. Nevertheless, he was functioning very poorly.
What happened with Mr A is common. When I was a resident, I was taught that we treat symptoms because we don't know enough about diagnoses. That's what was happening with Mr A. His psychiatrist was chasing symptoms rather than proactively treating a diagnosis. We do have evidence and algorithms to manage bipolar II disorder, schizophrenia, depression, and most of the conditions we see. The first rule of thumb is to really follow the algorithm, and those algorithms never include this many medications.
My Three-Medication Rule
Those of you who've followed my blog posts before have read that I have a three-medication rule: After exceeding three medications, I think the psychiatrist is the major problem.
I haven't chosen three medications arbitrarily. We have a large number of single-medication, placebo-controlled trials that are used for US Food and Drug Administration registration. That's what most of the studies we have that drive our evidence base are, so that's important to keep in mind.
There's a fairly good number of add-on or augmentation studies that include two medications, and that helps us get some data around combining certain medications. There are very few controlled trials of three medications, and these are not particularly strong. As far as I know, there are no controlled four-medication combination trials in psychiatry.
Once you've left three medications, you've abandoned any evidence-based pathway. Typically, even at three, that's also true. As you look at your own practice or as you get consultations like this, be aware that after you've exceeded a maximum of three medications, you no longer are following any evidence-based treatment pathways and are just treating symptoms—which leads to the kind of mess that Mr A was struggling with.
A second issue was that Mr A wasn't even able to tell me why he was on about half of the medications. It wasn't communicated clearly, or if it was, he couldn't remember it. Obviously it wasn't helping him, because he was continuing to struggle with the same symptoms.
Again, there's a tendency, as patients have fluctuations in symptoms that wax and wane over time that are part of virtually every illness we treat, to often chase those with medications. There will then be some improvement, which may in fact have simply been the natural course of the illness anyway. But then everyone gets anxious about stopping medications if there's any perceived risk or minimal benefit. We have to keep in mind the context of these conditions and, while we're treating them, to not do this. If a medication is really not providing significant benefit, it should be stopped and not maintained over time.
Mr A worked with a psychiatrist who's a reasonable, friendly person whom he trusted, so he was reluctant to change his medication and was not completely sure whether that's the problem. Similarly, his family was anxious about making changes. Oftentimes, you have to work with them around a medication reduction strategy to win them over.
What I usually do is start by talking about this—for example, by saying that this dose of medication is going to make almost anyone feel terrible, and it's no wonder they're struggling.
Second, let's really look at [the medications] critically and see whether we can identify one or maybe two medications that were really helpful at some point, and then think about those as our backbone in treatment, at least for now.
Similarly, are there one or two medications that we really don't think have added anything? If so, let's start by getting rid of those. Then, we'll taper them slowly, so as to be able to make sure that it isn't helping or doing something that we're not aware of. That will often help with this anxiety about making changes.
The goal then is to get from 10 medications to three medications. With Mr A, he was pretty convinced that the lithium was very helpful, so we established that as his "anchor" medication. He also found lorazepam to be helpful with anxiety. In long-term management, this may or may not be the best decision, but at this point, those were two medications that he found were helpful.
Mr A had no idea why he was on the ziprasidone, which doesn't have a particularly strong record in bipolar depression anyway. We started by tapering the ziprasidone first and then addressed the paliperidone. Usually I recommend trying to do one medication at a time, but he was on so many that a couple of times, we tapered two medications at a time. When we tapered them, we were careful. By doing that, Mr A learned that he could not get worse when these medications were tapered—but in many cases he did in fact start feeling better.
Identifying Duplicate Therapy
My second strategy is to identify things that are really just duplicate therapy and probably don't add anything. Again, in Mr A's case, being on two different benzodiazepines is very, very hard to justify. They really are doing virtually the same thing. They just have slight differences in their pharmacokinetic profiles, and that doesn't warrant combining them. So we can stop the lorazepam or temazepam. Similarly, with ziprasidone and paliperidone, there is really no evidence for combining atypical antipsychotics.
This is another way to start getting early wins, because we are not really altering the treatment that much; we're simply removing one of two drugs. Any of these medications on its own is probably saturating the receptors, so adding a second medication does almost nothing.
Again, these are lifelong illnesses, so we don't need to hurry. We should document every change carefully, so that over time, we can show patients that simplifying their regimen is what's helping them the most. It's very important to be systematic and proactive with these changes to help take care of the side-effect burden and risks.
As we simplified Mr A's regimen over about an 18-month period, he went from 10 medications to just three medications. His energy improved, his lethargy went away, he quit gaining weight, and his mood was better. We ended up switching to a combination of lithium and lamotrigine, which is a good medication combination for this type of illness. He's gone on to do just marvelously well after years of doing very, very poorly.
As psychiatrists, let's be careful to make sure we're treating a diagnosis, that we're remembering the three-medication rule, and that we're preventing these massive polypharmacy situations. If we do have to manage one of these situations, let's see whether we can bring it back to a more rational combination of treatments. I've talked about this before, and in my blog posts I mentioned a couple of books we've recently published as part of the Oxford American Psychiatric Library on major depressive disorder and bipolar disorder, so please look into those two publications if you're interested in learning more.[1,2]
I hope this has been helpful. Let's try to maximize the outcomes of our patients with good, rational polypharmacy care. Thank you.