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Schizophrenia prodrome therapies show promise: early intervention with antipsychotics and CBT appears to delay or prevent psychotic breaks.

ATLANTA -- Both behavioral and drug therapies during schizophrenia prodrome can delay and possibly prevent a subsequent psychotic break, Scott W. Woods, M.D., said at the annual meeting of the American Psychiatric Association.

Recent studies have shown independent therapeutic effects of antipsychotic medication and cognitive-behavioral therapy during the interval between the first noticeable prepsychotic changes and the onset of positive psychotic symptoms--findings that should compel investigators to ramp up research efforts to identify optimal prodromal management strategies, he said.

"There are still more questions than answers about the schizophrenia prodrome, especially in terms of drug treatment. When we talk about pharmacotherapy for this early phase of the disease, it's all off-label use, which is absolutely necessary because currently there are no FDA-approved medications for schizophrenia prodrome," said Dr. Woods, director of the Prevention through Risk Identification, Management, and Education (PRIME) Research Clinic at Yale University, New Haven, Conn.

Current treatment guidelines apply only to the psychotic phase of the disease, when patients already have measurable cognitive impairment, gray matter loss on MRI, and damaging social developmental losses and stigma. Yet the main rationale for more aggressive intervention in the prodromal period is to prevent the emergence of chronic and disabling symptoms in the first place, Dr. Woods noted.

Toward this end, "our group and others are trying to prepare the field of intervention research by describing characteristics of prodrome as best we can," he said. "We've been able to show that it is reliably diagnosable using the Scale of Prodromal Symptoms," which includes a schizotypal personality disorder checklist, a family history questionnaire, the Global Assessment of Functioning scale, and an assessment of three potential prodromal syndromes.

"In general, prodromal patients are highly symptomatic and they already have mild cognitive and substantial functional impairment," Dr. Woods explained.

Some of the signs and symptoms of the prodromal phase include anxiety, blunted affect, depression or dysphoric mood, irritability, loss of initiative, low energy, poor concentration, sleep disturbance, social isolation and withdrawal, and suspiciousness. Attenuated positive symptoms and mild disorganization, including overly abstract or concrete thinking, may also be present.

Typically, the prodromal phase begins around puberty and functional decline is rapid. "Without treatment, between 30% and 50% of these individuals are at risk of becoming schizophrenic within 1 year of their symptoms, and generally these patients are seeking treatment and are very appreciative to have treatment once they've found it," he said.

Early pharmacologic intervention is not universally applauded, however, because many of the patients--50%-70% according to some reports--who meet the prodromal criteria do not go on to develop psychosis.

For this reason, he added, "when we talk about intervention research, it's important to put it in the light of both treatment and prevention: treat current symptoms and deficits and prevent schizophrenia. If we focus only on prevention, we invite fairly dicey ethical dilemmas if half of the individuals would not become schizophrenic without treatment."

In terms of therapeutic interventions, a number of recent studies have delivered promising findings, Dr. Woods reported.

He said that Patrick McGorry, M.D., and his colleagues at the Early Psychosis Prevention and Intervention Centre in Melbourne, Australia, conducted a randomized, controlled trial in 59 patients that compared a specific preventive intervention with a needs-based intervention. Both interventions comprised psychosocial support and antidepressant medications if warranted. The 31 patients randomized to the preventive intervention also received low-dose, open-label risperidone treatment and cognitive-behavioral therapy, while the 28 patients in the needs-based arm did not (Arch. Gen. Psychiatry 2002;59:921-8).

At 6 months, only 10% of the patients in the prevention arm converted to psychosis, compared with 36% of the patients in the needs-based arm.

"The statistically significant difference was promising, although there could be a placebo effect because the drug treatment was open label. Also, the medication group got CBT as well, and there's no way to determine whether the drug therapy or the CBT was the reason for the therapeutic effect," said Dr. Woods.

For these reasons, and because the investigation did not include data on improvement of current symptoms or adverse effects, Dr. Woods and his PRIME Research Clinic colleagues designed a second trial that was conducted at four sites: Yale, the University of North Carolina at Chapel Hill, the University of Toronto, and Foothills Hospital in Calgary, Alberta.

The randomized, double-blind study compared olanzapine with placebo for the treatment of prodromal states over 1 year. Of the 60 patients who met criteria for the prodrome of schizophrenia, 31 received 5-15 mg of olanzapine and 29 received placebo. All received psychotherapy support as needed. Over the first 8 weeks, the placebo patients experienced "very little" change on their Scale of Prodromal Symptoms measures, indicating no measurable symptom reduction, while the patients taking olanzapine had significantly reduced measures. Individuals in the active therapy group did experience a highly significant average weight gain of 10 pounds compared with 1 pound for the placebo group (Biol. Psychiatry 2003;54:453-64).

Although the 1-year results have yet to be published, "the Kaplan-Meier survival plot comparing the two groups shows a high rate of conversion to psychosis throughout 365 days in the placebo group, while there were five in the olanzapine group who converted quickly within the first month and none after that," said Dr. Woods.

The low conversion rate in the olanzapine study was similar to that seen in the Melbourne study, possibly suggesting that the therapeutic effect in the latter was medication related. However, a third randomized, controlled trial by Anthony Morrison, Ph.D., and colleagues at the University of Manchester, England, which compared cognitive therapy with treatment as usual in 58 "ultra-high-risk" patients, showed that cognitive therapy significantly reduced the likelihood of progression to psychosis over 1 year as defined on the Positive and Negative Syndrome Scale, and it significantly reduced the likelihood of meeting DSM-IV criteria for a diagnosis of a psychotic disorder and of being prescribed antipsychotic medication (Br. J. Psychiatry 2004;185:291-7).

These findings raise the possibility that the therapeutic effect in the Melbourne study could have been associated with the behavioral therapy component of the intervention, but despite the uncertainty over the source of the therapeutic effect, "we're in a good place," Dr. Woods said. "These landmark results suggest we need to do more intervention studies in this population to tease out which therapies are effective for which patients."

Additionally, antipsychotics are not necessarily the last word in drug therapy for prodrome. "There's some evidence that younger patients are actually at higher risk for side effects than older ones, and as a result we should look beyond antipsychotics as well," Dr. Woods said.

Among the other medications being considered is the amino acid glycine. In an open-label study conducted by Dr. Woods and his associates, oral glycine led to improvement and, in some cases, complete remission of prodromal symptoms in only 8 weeks. "It is possible that glycine may restore normal functioning of certain glutamate receptors in the brain," he said. If these findings can be replicated in future studies, glycine might be an effective option for treating prodromal syndromes with fewer side effects, adverse events, and long-term health risks than antipsychotic medications.

More research is needed before the findings from these early studies can be applied to universal practice, but the results to date clearly indicate that "this is a clinical population in need of a definition of standard of care, and we should be moving full force in that direction," Dr. Woods concluded.


New England Bureau
Cognitive Therapy Reduced Progression to Psychosis in Patients at
'Ultra-High Risk'

 Cognitive therapy Monitoring
 (n = 35) (n = 23)

Made PANSS transitions to psychosis 6% 22%
Met criteria for diagnosis of DSM-IV 6% 26%
Received antipsychotic medication 6% 30%

Note: Therapy was provided over 6 months, and all patients were
monitored for 12 months.
Source: British Journal of Psychiatry

Note: Table made from bar graph.
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Title Annotation:Adult Psychiatry
Author:Mahoney, Diana
Publication:Clinical Psychiatry News
Geographic Code:1USA
Date:Oct 1, 2005
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