BETHESDA, MD—Treating a complex disease like schizophrenia is difficult, and that difficulty is only compounded when it comes to prescribing medications to treat the disease. The antipsychotics generally used to treat schizophrenia are accompanied by a variety of sometimes-powerful, often inconvenient, side effects.

Physicians find themselves having to juggle the need to treat a patient’s psychosis with the patient’s need to function unimpeded by involuntary movement, sedation, or weight gain. Such tough decisions will likely continue to be a part of treating schizophrenia at least for the near future, explained Jerry Overman, PharmD, clinical pharmacy specialist at NIH’s Clinical Center, at a lecture on the NIH campus last month.

Archaic Treatment

Schizophrenia is a complex brain disorder with many possible etiologies—biological, psychological, and environmental. It’s accompanied by a wide variety of symptoms: the positive symptoms (delusions and hallucinations), negative symptoms (emotional numbness, inappropriate affect), and cognitive deficits.

Even under the most optimal clinical conditions, schizophrenia is a difficult disease to treat, and long-term outcomes remain poor. Approximately 50% of people discharged on conventional antipsychotics will be rehospitalized within one year. About two-thirds of first-episode patients continue to have positive symptoms after one year, and lifetime suicide risk is approximately 10%.

Medications do help, and even the older antipsychotics work better than placebo. However, the field of schizophrenia treatment, at least when it comes to pharmaceuticals, is still constrained by the limited understanding of the mechanisms of schizophrenia and how they can be chemically modified. “Right now we’re still using drugs that just affect the body at various receptor sites,” Overman said.

Pharmaceuticals with a narrow focus might not be the optimal way of treating what is a very complex disease, he stated. “We’re still treating schizophrenia in an almost archaic way. We’re using drugs that affect individual receptors when we know that there’s a whole lot more going on, especially with what we know of genetics and what’s going on with second messenger systems—things that go beyond the receptors.

“(NIMH director) Tom Insel talks about cure therapeutics, where sometime in the future we’ll be able to cure these diseases instead of just treating the symptoms. But right now we’re just treating the symptoms.”

Juggling Side Effects

The ideal antipsychotic has a rapid onset of action, once-daily dosing, and minimal side effects. With antipsychotics, having no side effects at all is just unrealistic, according to Overman.

With the first generation drugs—the typical antipsychotics—the problem is movement disorders. These drugs, which include Thorazine®, Haldol®, and Prolixin®, among others, tend to be D2 blockers that bind to dopamine receptors. Most create mild to severe movement disorders in those taking them, ranging from parkinsonism and acute dystonia, to tardive dyskinesia, characterized by involuntary hand and mouth movement, and akathesia.

“Akathesia is internal restlessness. As a clinician, I hear that this can be just bloody murder for patients,” Overman said. “A complete inability to sit still. They’ll just sit on their hands. They can’t stop moving. You’ll see patients pacing back and forth.”

The newer generation of drugs—the atypical antipsychotics—exhibit fewer movement issues, but have their share of side effects. Drugs such as clozapine, risperidone, and quetiapine, among many others, interact with dopamine receptors in the same way their predecessors do, but also act as serotonin antagonists. They also interact with other receptors, including histaminergic, muscarinic, and adrenergic receptors. This receptor blockade is associated with a number of adverse side effects, including sedation, weight gain, dry mouth, urinary retention, blurred vision, constipation, sinus tachycardia, cognition and memory problems, reflex tachycardia, and sexual dysfunction.

Overman said it’s very hard for clinicians to compare side effects between drugs. “When you’re looking at 20% [of patients having side effects] to 23%, what does it really matter when you’re picking a drug?”

The juggling of side effects depends on the patient. “If we’ve got a student who wants to continue studying, we might start with drugs that are more activating and less sedating. Of course we’re going to look and see if they’ve responded to something in the past.”

The biggest difference between the new drugs and the old ones is not just the side effects, but in the philosophy of how schizophrenia patients can and should be treated. “If you look at the old era as far as social, cognitive, and vocational efficacy [was concerned], it was disappointing. It was just accepted that patients are not going to be socially aware,” Overman noted. “These new drugs have given hope, because they do seem to be somewhat more effective on the negative symptoms, possibly due to the serotonin effect.”

Metabolic Syndrome

With the new drugs, though, there is the growing concern of metabolic syndrome—a group of risk factors that occur together and increase the risk for coronary artery disease and diabetes. Some studies have noted prevalence rates of metabolic syndrome over 50% in groups taking atypical antipsychotics.

“With the old era drugs, we didn’t even look at it,” Overman said. “We didn’t think about patients gaining weight on an old drug. Glucose and lipid problems? We didn’t look at those with the old drugs. Now it’s a major health issue. With these new era drugs, it’s a major health problem that leads to patient death.”

How much of this is due to the drugs and how much is part of the general environment is unclear. Rates of obesity have risen dramatically in the US in the last 20 years, and patients suffering from schizophrenia, even those that remain untreated, have an increased risk for CV disease.

No matter how much of the CV risk is due directly to the drugs, it is still another factor that clinicians must take into account when treating schizophrenia, which will likely continue to remain a difficult task until science better understands the disease, Overman noted. “We’re still learning a lot. As we learn things from the basic science, pharmacy follows and responds.”

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