TCPR: Dr. Ongur, I know you’ve been interested in creative ways of helping patients with psychosis function well in the community. Are we not doing very well as a field in improving the functioning of our schizophrenic patients?
Dr. Ongur: We actually do very well when using antipsychotics to treat positive symptoms, whether those are symptoms of schizophrenia or manic episodes. We can take patients who are psychotic, put them on an antipsychotic, and over the ensuing weeks most of the positive symptoms will come under control. If they are hearing voices, we can quiet the voices, and we can improve their delusional thinking so that they can do reality testing. And for patients who are manic, we can treat grandiosity and excessive activity.
TCPR: And isn’t that enough to improve patients’ functioning in the community?
Dr. Ongur: There are a couple of lines of research showing that treating the positive symptoms is not sufficient. The first line of research has focused on the relationship between positive symptoms and functioning in the community, broadly defined as living on your own, holding down a job, and having meaningful relationships. As it turns out, the positive and manic symptoms are not directly related to these abilities. In other words, some patients are free of these positive symptoms and yet not able to live independently, and then other patients have significant positive symptoms and can function very well. What does seem to predict functioning, however, is cognitive functioning and negative symptoms.
TCPR: Can you give us some examples?
Dr. Ongur: For example, a patient may be treated with antipsychotics and be free of hallucinations and delusions, but if he has cognitive impairment, he will have a hard time with an entry-level job. He may be working at a grocery store, bagging groceries and holding a gallon of milk, but then he can’t remember if he scanned the milk. “Did I just scan this or not?” This is an example of impaired working memory. By contrast, you might have a patient who hears voices and who is concerned that he may be in danger because of being monitored by the CIA, but he is cognitively preserved. That person could get a job—he might be quite vigilant about his environment, but he can work.
TCPR: How solid is the research showing no relationship between positive symptoms and functioning?
Dr. Ongur: Very solid and well-established. In the late 1990s and 2000s, [Duke University psychology professor] Richard Keefe, PhD, and others did much work on this topic (for example, see Keefe RS, J Clin Psychiatry 2007;68 Suppl 14:8–13). He looked at cross-sectional studies, studies in which researchers collected data on symptoms and data on community functioning. These studies inevitably found that the positive symptoms have no relationship with how the patient is functioning, whether he or she is living independently, has friendships, etc. Instead, it is the negative symptoms and cognitive impairment that are correlated with functioning.
TCPR: As psychiatrists, what can we do to improve functioning? Are there certain medications that treat negative symptoms and cognitive impairment better than others?
Dr. Ongur: There is no strong evidence that any one of the antipsychotic medications improves negative symptoms and cognitive deficits better than the others. The more recent research actually shows that medications may impede community functioning. In one study done in the Netherlands, researchers recruited about 400 patients with first episode psychosis (Wunderink L et al, JAMA Psychiatry 2013;70(9):913–920). These patients ranged in age from 18 to 25 years old, and they were all treated with standard doses of antipsychotics (both first and second generation antipsychotics), and were followed for two years. Most of them did well, in terms of reductions in positive symptoms. Then, at the two-year mark, these patients were randomized into two different arms. One group stayed on the same dose of medication (the maintenance treatment or MT group), and the other group attempted to decrease or discontinue their medications (the dose reduction or DR group).
TCPR: Was this a double-blind study?
Dr. Ongur: No, the patients were randomly assigned but they knew which condition they were in, as did their doctors.
TCPR: Were patients able to get off of their medications?
Dr. Ongur: Many were—40% of the patients in the DR group completely discontinued the medication. The remaining 60% ended up on lower doses. On average these patients ended up on about 2 mg risperidone dose equivalents. The patients in the maintenance group ended up on 4 mg risperidone dose equivalents. As you might expect, there was a higher relapse rate in the DR group—43% vs. 21% in the MT group. But then the patients were followed for another five years, and interestingly, the patients in the DR group were more than twice as likely to recover (40% in the DR group vs. 18% in the MT group). “Recovery” meant that they were functioning well and had no psychotic symptoms.
TCPR: This is an interesting result. Basically if you’re willing to pay the price of some extra symptoms of psychosis in the short run, you might do much better in the long run by lowering the dose or discontinuing antipsychotics.
Dr. Ongur: Yes, it appears that tapering or discontinuing meds might yield a long-term benefit of helping patients get out into the community and function normally.