LAS VEGAS – Calibration of treatment response is a major challenge in patients with schizophrenia, according to Dr. Peter J. Weiden.

“On some level all of our patients with schizophrenia are both responders and nonresponders to medication at the same time,” Dr. Weiden said at the annual psychopharmacology update held by the Nevada Psychiatric Association. “What I mean is that the vast majority of patients with schizophrenia have fewer symptoms on antipsychotic medication, but very few patients on medicine will be perfectly OK without any symptoms or problems.”

Dr. Weiden, professor of psychiatry at the University of Illinois at Chicago, went on to note that clinicians tend to calibrate medication response as the improvement in psychotic symptoms or stability, compared with how the person would be without medication. But the patient will not see it that way. Instead, the patient will calibrate how he is doing with medication, compared with how he felt before the illness started – or how he is compared with others without a diagnosis of schizophrenia.

“We still don’t cure schizophrenia; patients want to be normal,” he said. “We don’t make them normal with our medications, and medications don’t always work as expected. At the very least, when we talk about response and nonresponse, we need to be respectful of the patient’s point of view.”

The same calibration dilemma happens with the side effect burden from antipsychotics. While the side effect burden from current antipsychotics is much better than it used to be in the preclozapine era, patients are still likely to have to put up with a variety of bothersome side effects. Telling the patient: “You should be grateful, because it used to be a lot worse!” somehow doesn’t come across as helpful.

Factors affecting calibration of treatment include the acuity of the patient’s illness, duration of illness, relative engagement in the treatment process (meaning “our outcomes should be a lot better for patients who are engaged in our treatment, who come to treatment, than those who don’t,” he said), comorbidities that may limit efficacy, the clinician’s philosophy of treatment, and the patient’s access to “best practices” care.

Although all antipsychotics can be used for all phases of schizophrenia, Dr. Weiden cautioned that individual antipsychotics are not interchangeable. “There’s always some efficacy risk when changing from an antipsychotic known to be effective for an individual patient,” he said. “Control of psychotic symptoms is always important. If you work in an inpatient unit, there’s a lot of stress and a lot of drive toward rapid resolution of symptoms in a way that’s easy and a way that’s safe.”

Desirable characteristics of pharmacologic agents for immediate initiation of acute treatment, he continued, include rapid onset of action, low toxicity, availability in multiple routes of administration, ease of use, low potential for drug-drug interactions, and ease of crossover to an oral antipsychotic agent. However, managing the acute psychosis in an ER or hospital setting “isn’t all about the medication,” he said.

“It’s very traumatic to be held down. It’s humiliating. It’s disruptive. Yes, we need to hospitalize people when they’re unsafe, but a lot of nonpharmacologic things we do are very important and will reduce the risk of complications from medication.” These include reassuring the patient, making him or her physically comfortable, reducing triggers that may escalate the situation, contacting the family, and educating the staff about the treatment plan.

In his clinical opinion, the inpatient use of a haloperidol p.r.n. regimen often is unsound and unsafe. “Very often on an inpatient unit, the haloperidol p.r.n. orders are done separately from the standing orders,” Dr. Weiden explained. “So you’ll have a clinician do a careful evaluation and write the standing orders of the medication, but the p.r.n.s are kind of boilerplate, and they get Haldol. The brain cannot ‘tell’ the difference between a standing order and a p.r.n. order of haloperidol. It is dangerous; patients die from this. It’s not common to have a life-threatening reaction to p.r.n. haloperidol, but it’s not rare, either, and the automatic use of haloperidol p.r.n. certainly no longer meets any reasonable standard of safety.”

The same antipsychotic medication can be used acutely and in maintenance, Dr. Weiden said, but if the patient relapses, you might consider changing to another agent. “If you know the patient well, and you know that the last medicine helped keep the patient stable but they still have lots of symptoms and a pretty crummy life, you might want to consider that as an opportunity to change the medicine,” he said. ‘However, if the patient came in because they went out drinking with their buddies and they got intoxicated, you really should not change the medicine, because in this situation, it was not a pharmacologic failure of the medication regimen,” Dr. Weiden said. To change or not to change medication “is a really big issue for someone’s life trajectory.”

There are 12 Food and Drug Administration–approved atypical antipsychotics for schizophrenia, which can be overwhelming for clinicians who do not specialize in treating the disorder. “While these meds are not perfect, each of these can help some people who are not helped otherwise, and each of these has a different side effect profile,” Dr. Weiden said. “So while we can’t completely cure schizophrenia, we will have a lot more luck in getting a patient on a medication that is not too burdensome for them. The downside is that we don’t have any biologic predictors as to who will respond to what agent.”

Dr. Weiden said he thinks of recovery from schizophrenia as a process in which the choice of goals is decided primarily by the patient and guided by the clinician. “The good thing is, there’s no shortage of symptoms you can work on,” he said. “You don’t have to fix everything, but you and the patient should come together to goal-set and pick one or two that are the priorities. That will keep you from getting overwhelmed and burned out trying to ‘fix’ everything at once.”

Nonpharmacologic causes of persistent symptoms warrant investigation as well, such as substance comorbidities, medical comorbidities such as obstructive sleep apnea, treatment access barriers, and adherence challenges. While discontinuation of the medication class is not an option, “We have dose adjustment; we can substitute, go from one antipsychotic to another; we have route of delivery, you can add a new medication to the regimen, either within the class or a new class, and we can discontinue one or more medications from the current regimen,” Dr. Weiden said. “That is one strategy we often forget: getting the person off a medication that may be causing a problem.”

When positive symptoms persist, make sure that the patient’s current antipsychotic medicine is optimized. “The dose response of these different antipsychotics is not the same,” he said. “Some meds have a very steep dose response; others are more flat. How far you push may depend on the specific agent. You want to do what’s easy first. So raising the dose for persistent positive symptoms is a good idea, except if you think it’s behavioral toxicity.”

Switching to a new agent takes more work than changing the dose of a current agent. He characterized clozapine as “the anchor” for persistent positive symptoms. “No patient is clearly refractory of positive symptoms until they’ve either failed or refused clozapine,” he said. “Combining antipsychotics is not a substitute for clozapine. It’s a lot easier to do, but it’s not a substitute.

“Should the patient seem to have suboptimal response to a few first-line antipsychotics, it is important to tell the patient and family about clozapine even if you are not ready to recommend it right now. Likewise, it is crucial to inform all stakeholders about the suicide prevention indication of clozapine for any schizophrenia patient with any suicide history, even if the overall circumstances are not yet amenable to starting clozapine right away.”

During a separate presentation, Dr. Weiden encouraged meeting attendees to think about adherence to antipsychotics as not an outcome, but rather as an important mediator of outcome.

“As clinicians, we get stuck on [the notion of] ‘you’re not doing what I recommended,’ ” he said. One indirect consequence of adherence is poor information, which obscures assessment of treatment response, and also creates safety risks. When Dr. Weiden meets with patients for the first time, he tells them, “It’s very important that I know what you’re really doing, both in terms of your drugs and the drugs I’ve prescribed for you,” he said. “I make it safe for them. I say, ‘I may disagree, but I’m not going to get mad.’ I give them advance information about how I would respond, because different clinicians respond differently. Some take it personally and some don’t. I don’t take it personally.

“The other thing I say is that, ‘It’s not just about you’re obeying me, but it’s for your safety. It’s less safe if you don’t tell me.’ Safety is less pejorative than adherence.” Other strategies that can be used to track adherence include recommending long-acting therapies such as routine, supervision of oral therapy, and using pharmacy refill data. “Many patients don’t pick up their medications or don’t fill their prescriptions,” he said.

Gradual dose lowering is a feasible strategy, he said. “It can be successful, but not always. We have to advise patients that even brief medication gaps are a bad thing, but gradual dose lowering may be achievable and helpful.”

Dr. Weiden reported having numerous financial ties to the pharmaceutical industry, as well as being a stockholder of Delpor.

dbrunk@frontlinemedcom.com

Calibration of schizophrenia treatment is a delicate balancing act