Early Treatment May Delay Schizophrenia Onset

What could be more wonderful news for young people at high risk for schizophrenia—and their parents—than learning that their illness can be delayed or even prevented?

Such a scenario may be more than fantasy, suggest very preliminary results from two research groups.

Thomas McGlashan, M.D., a professor of psychiatry at Yale University, and his colleagues are attempting to determine whether a yearly low-dose regimen of the antipsychotic drug olanzapine can delay or even prevent schizophrenia in young people at risk for the disease. They reported results from the first eight weeks of the study at APA’s annual meeting in Philadelphia last spring (Psychiatric News, June 21). Subjects who had gotten olanzapine for eight weeks showed a statistically significant reduction in prodromal symptoms compared with what they had experienced at the start of the study, whereas subjects getting a placebo did not.

Now a team of Australian scientists headed by Patrick McGorry, Ph.D., of the University of Melbourne, has attempted to determine whether a six-month low-dose regimen of the antipsychotic drug risperidone plus cognitive-behavior therapy can delay or even prevent schizophrenia in young people at extremely high risk of developing the disease. As they reported in the October Archives of General Psychiatry, the regimen seems to be capable of at least delaying psychosis since significantly fewer subjects on it, as compared with controls, had progressed to psychosis by the end of treatment; moreover, significantly fewer subjects who had conscientiously taken risperidone during treatment, as compared with controls, experienced psychosis in the six months following treatment.

In an interview with Psychiatric News, McGlashan said that he considered this study by McGorry and colleagues “a very important piece of work. It is the first randomized, controlled trial of treatment in this prepsychotic phase of schizophrenia. I think also for a study of its kind it is well designed. . . . The fact that [the researchers] had a positive result does indicate that active treatment could be useful in preventing or delaying the progression of prodromal symptoms to psychosis.”

William Carpenter Jr., M.D., director of the Maryland Psychiatric Research Center and a leading schizophrenia scientist, also had some good words to say about the study by McGorry and coworkers: “Detecting and treating illness early in its course is axiomatic in medical therapeutics. McGorry and colleagues demonstrate feasibility and desirability in persons with mild psychotic features. Whether pathophysiology is modified in the long term by this approach is unknown, but the opportunity for better functional outcomes by delaying the onset of disabling psychosis is real.”

The young people whom McGorry and his colleagues recruited for their investigation were between the ages of 14 and 30 and met criteria for one or more of three different groups. The first group consisted of persons with a family history of psychotic disorder in a first-degree relative plus nonspecific symptoms and impaired functioning resulting in a decrease of 30 points on the Global Assessment of Functioning scale within the previous 12 months. The second group comprised individuals with attenuated positive psychotic symptoms that, although sustained for at least a week, remained below the threshold for outright psychosis. The third group of persons was characterized by brief episodes of psychotic symptoms above the threshold for outright psychosis but not sustained beyond a week. Altogether they ended up with 59 subjects who, they explained in their study report, were highly symptomatic, moderately disabled by their symptoms, and aware that something potentially serious was happening to them, although none was as yet persistently psychotic.

McGorry and his coworkers then put 31 of these subjects on a treatment regimen for six months and the remaining 28 subjects on a control regimen for six months. The treatment regimen consisted of low-dose risperidone (mean dosage 1.3 mg/d) and cognitive-behavior therapy. Cognitive-behavior therapy was conducted according to a manual developed by the researchers’ group. Its aims were to develop an understanding of the symptoms experienced, to learn strategies to enhance control of these symptoms, and to reduce associated distress. It included stress management, depression/negative symptoms, positive symptoms, and other comorbidity such as substance abuse or obsessive-compulsive features. The control regimen, in contrast, consisted of psychosocial support and antidepressant or anti-insomnia medication as appropriate.

At the end of six months, McGorry and his coworkers compared the treatment group with the control group to see how many subjects in both had actually progressed to full-blown schizophrenia. Only three in the treatment group of 31 subjects had, compared with 10 in the control group of 28 subjects—a statistically significant difference. This finding suggested that the treatment regimen might be able to delay or even prevent schizophrenia.

Six months after treatment, McGorry and his colleagues compared the treatment group with the control group to see how many subjects in each had progressed to full-blown schizophrenia. Out of the treatment group of 31 subjects, six had, and out of the control group of 28 subjects, 10 had—a difference that was not statistically significant. This finding seemed to suggest that the treatment regimen was not able to delay or prevent schizophrenia.

However, McGorry and his team then zeroed in on the 14 subjects out of the 31 subjects in the treatment group who had fully complied with the risperidone regimen. Of this group of 14 subjects, only one had progressed to full-blown schizophrenia six months after treatment was over, compared with 10 in the control group of 28 subjects. This difference was statistically significant and suggested that the treatment regimen, at least if faithfully followed, might be able to delay or even prevent schizophrenia.

“This is the first study, to our knowledge, to suggest it may be possible to at least delay, and in some cases perhaps even avert, progression to full diagnostic threshold for psychotic disorder in individuals at ultra-high risk of schizophrenia and related psychotic disorders,” McGorry and his team concluded in their study report.

They acknowledged that only a large sample size and longer follow-up will reveal whether this is possible and that further study will be necessary to determine the relative contributions of antipsychotic medication and of cognitive-behavior therapy in achieving this aim.

The study was financed by a number of Australian organizations, such as the National Health and Medical Research Council in Canberra, Australia, as well as by two American organizations—the National Alliance for Research on Schizophrenia and Depression and the Stanley Foundation.

The study, “Randomized Controlled Trial of Interventions Designed to Reduce the Risk of Progression to First-Episode Psychosis in a Clinical Sample With Subthreshold Symptoms,” is posted on the Web at http://archpsyc.ama-assn.org/issues/current/rfull/yoa10072.html. ▪