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INTERIM
OLANZAPINE REPORT—
PRODROMALS
HAPPIER BUT HEAVIER
PHILADELPHIA—Can
you prevent or delay the onset of schizophrenia by giving
antipsychotic medications to patients in the prodrome? If
so, is this a safe and an ethical thing to do? Also, can
you be sure that you can identify prodromal patients?
Clearly, there are a lot of questions about the prodrome, and some new information, but no definitive answers to these questions. However, several speakers at the 2002 Annual Meeting of the American Psychiatric Association reported the interim results of the first placebo-controlled trial to be conducted in prodromal patients—a study that hopefully will provide some definitive answers when all the data have been collected.
Scott Woods, MD, Associate Professor of Psychiatry at Yale University School of Medicine, New Haven, Connecticut, chaired a session on the schizophrenia prodrome that drew its information from a four-center study in which 60 patients were randomized to olanzapine (average dosage, 8 mg/d) or placebo for one year, with follow-up scheduled for an additional year. The study was conducted at four sites: Yale University, the University of North Carolina at Chapel Hill, the University of Toronto, and the University of Calgary. Individuals were recruited to the study by various means, including print advertisements, TV and radio spots, and word of mouth among colleagues. Those with frank substance abuse were excluded if it was contributing to their prodromal symptoms.
The primary outcome measure—determining whether olanzapine will prevent or delay the onset of psychosis—will likely not be known for another 18 months. In the meantime, Dr. Woods reported interim secondary measure results. “Prodromal patients randomized to olanzapine improved to a significantly greater degree in their prodromal symptoms over an eight-week period compared to patients on placebo. However, the olanzapine-treated patients gained significantly more weight, so strategies need to be addressed to this problem.”
Of the 31 prodromal patients randomized to olanzapine and the 29 to placebo, approximately 30% in each group dropped out, he added. For the remaining patients, the Scale of Prodromal Symptoms (SOPS) score was roughly half during the first eight-week period in the olanzapine group compared with that in the placebo group, and it was significant for three of the four SOPS subscales. In contrast, Dr. Woods noted, for matters that were not directly related to psychosis severity, such as those revealed in the Global Assessment of Functioning scale, “there were no significant differences between olanzapine and placebo.”
Vital signs were similar, except for an increase in sitting pulse pressure in the olanzapine group of about 10 beats per minute and a weight gain of about 10 lb during an eight-week period in the olanzapine group versus a weight gain of only 1 lb in the placebo group. Dr. Woods said that before definitive conclusions can be drawn about prevention, this study, and studies of other medications, need to be extended to a longer period.
PERTINENT PRODROMAL PROBLEMS
While it is now known that unusual symptoms, such as suspiciousness, may appear a year or more before the onset of frank schizophrenia, there are many questions that remain unanswered about the prodrome, observed Thomas McGlashan, MD, Professor and Director of the Yale Psychiatric Institute. Dr. McGlashan noted that some people have concerns about giving placebo or no treatment to symptomatic, treatment-seeking people, thus highlighting the timely nature of research in this field. “If this trial demonstrates that we can prevent or delay the disease with one year of treatment, a later question will be: How long does it need to be used?”
How to determine whether someone is prodromal is an additional point of contention. Tandy Miller, PhD, Assistant Clinical Professor of Psychiatry at Yale, said the Structured Interview for Prodromal Syndromes (SIPS) takes about 30 to 40 minutes, on average, and is designed to diagnose both prodromal and frank psychosis.
Dr. Miller said that her group currently diagnoses three different syndromes. One of these is the Attenuated Positive Syndrome, which she said “is found more commonly in our subjects. It’s defined as the worsening in the last year of mild but not frankly psychotic symptoms occurring at least once a week in the last month.” The other two syndromes looked for are the Brief Intermittent Psychotic Syndrome and the Genetic Risk and Deterioration Syndrome.
Diana Perkins, MD, Assistant Professor in the Department of Psychiatry at the University of North Carolina at Chapel Hill, said that at her site and at the Toronto site, 36 patients with attenuated symptoms are undergoing both magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) studies. In the MRS studies, researchers are looking in particular at N-acetylaspartate (NAA), since this is thought to be a marker for neuronal integrity. The areas targeted are the hippocampus and the frontal lobes.
Dr. Perkins said that no difference in this marker had been found in either prodromal or healthy subjects in the MRS studies in these two areas of the brain, “although it’s interesting that prodromal patients had slightly less NAA in the basal ganglia.” The MRI studies revealed, however, that there was a decreased brain volume in the prodromal patients, especially in the medial temporal lobe structures and the medial temporal gyrus. In comparison with normal controls, overall brain volume was also slightly smaller, she said.
TIMING IS EVERYTHING
Alan Brier, MD, of Eli Lilly and Company in Indianapolis, said that his company had decided to sponsor this more rigorous study of prevention rather than an open-label trial and then to follow patients for a year to see if the illness recurred. “Is a year enough?” Dr. Brier wondered. “And is the illness going on beneath the surface, and will it show up as soon as you stop?”
He also noted that in the study the mean age was 17.8, with a range of 12 to 36. He said that 44% of patients had a first-degree relative with a history of psychosis. The most frequent symptoms were social isolation (78%), decreased role functioning (77%), avolition (67%), poor focus of attention (65%), dysphoric mood (58%), unusual thought content (48%), suspiciousness (60%), perceptual abnormalities (50%), and disorganized speech (48%). “We know from our clinical experience that this is the kind of negative symptomatology that alerts us that this person might be on the road to developing schizophrenia.”
Patients in this prodromal group were also symptomatic and treatment-seeking. Dr. Brier added that if someone converted to psychosis during the course of the study, there was a rescue arm that provided active, unblinded treatment with olanzapine for six months and assistance with a transition to a community provider.
—Jean McCann
Suggested Reading
Hoffman RE, McGlashan TH. Parallel distributed processing and the emergence of schizophrenic symptoms. Schizophr Bull. 1993;19:119-140.
McGlashan TH, Johannessen JO. Early detection and intervention with schizophrenia: rationale. Schizophr Bull. 1996;22:201-222.
Miller TJ, McGlashan TH, Rosen JL, et al. Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiatry. 2002;159:863-865.
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Assessing
Antipsychotic Drugs
in Schizophrenia
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Additional research into the safety and efficacy
of antipsychotic drug treatment in schizophrenia has
recently weighed in with some significant evidence.
Lamenting the paucity of information regarding any
association between weight gain and therapeutic response,
Pál Czobor, PhD, of the Nathan S. Kline Institute
for Psychiatric Research in Orangeburg, New York,
and colleagues investigated the association between
antipsychotic-induced weight gain and therapeutic
response to haloperidol, clozapine, olanzapine, and
risperidone.
The subjects were 151 patients with schizophrenia
and schizoaffective disorder enrolled in a 14-week,
double-blind experiment comparing the efficacy of
the four aforementioned drug treatments. Dr. Czobor
and colleagues compared the pretreatment baseline
body weight and body mass index (BMI) for both absolute
and relative weight gain over the duration of the
study and correlated these numbers with therapeutic
response as assessed by the total and subscale scores
of the Positive and Negative Symptom Scale.
Their results, reported in the June Journal of
Clinical Psychopharmacology, indicated that therapeutic
response for olanzapine and clozapine “was closely
related to an absolute and relative gain in weight
and to a gain in BMI.” No such association, however,
was found for risperidone or haloperidol. The findings
led Dr. Czobor and his collaborators to conclude that
“patients who are likely to have the maximal
benefits of olanzapine or clozapine treatment for
symptom alleviation are at the highest risk of a clinically
significant increase in weight gain.” Because
of the physiologic complications that can cascade
from such an increase, they suggest that clinicians
regularly monitor body weight in patients and that
further research address whether body weight regulation
is possible without a concomitant reduction in the
therapeutic benefit of these medications.
Similarly, the long-standing question of whether
initiating pharmacologic intervention during the prodromal
phase of schizophrenia can lead to greater benefits
in reducing deleterious aspects of the disease took
a cautious step towards resolution with the results
of a small Finnish investigation. Tyrone D. Cannon,
PhD, of the Departments of Psychology, Psychiatry,
and Human Genetics at the University of California,
Los Angeles, and colleagues at the University of Helsinki
conducted an open-label study to evaluate the safety
and tolerability of short-term treatment with risperidone
in four prodromal high-risk adolescents (mean age,
15.6) and six first-episode patients with schizophrenia
(mean age, 23.9). The study was published in the July
American Journal of Psychiatry.
Risperidone was administered to the two groups in
doses of 1.04 and 1.83 mg/d, respectively, for eight
to 12 weeks. No significant adverse effects were associated
with the treatment. At the 12-week follow-up, the
researchers found that, compared to baseline, prodromal
patients’ Child Behavior Checklist scores declined
by a significant 30% average in thought disorder,
attention symptoms, and overall symptoms, but not
in social functioning. First-episode patients’
Positive and Negative Syndrome Scale scores declined
overall, also by an average of 30%. For both
groups, performance on the California Verbal Language
Test improved significantly by 30% to 100%.
Dr. Cannon and colleagues concluded that “short-term
treatment with a low dose of risperidone was safe
and may have been associated with improvement in behavioral
and neurocognitive functioning in a small group of
adolescent patients with prodromal symptoms of schizophrenia.”
They cautioned, however, that “these findings
are preliminary and should not be used to guide health
care decisions” until randomized, controlled
trials determine whether antipsychotic drug treatment
of prodromal patients “can delay or prevent onset
or attenuate the clinical course of schizophrenia.”
—C. Justin Romano
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Suggested Reading
Cannon TD, Huttunen MO, Dahlström M, et al.
Antipsychotic drug treatment in the prodromal phase
of schizophrenia. Am J Psychiatry. 2002;159:1230-1232.
Czobor
P, Volavka J, Sheitman B, et al. Antipsychotic-induced
weight gain and therapeutic response: a differential
association. J Clin Psychopharmacol. 2002;22:244-251.
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