SAN DIEGO (FRONTLINE MEDICAL NEWS) – According to Dr. Joseph P. McEvoy, early recognition and treatment of first-episode psychosis affords the best opportunity for a positive outcome.

“In the United States, we do a very poor job detecting psychosis early,” Dr. McEvoy, professor and I. Clark Case Chair in Psychotic Disorders at the Medical College of Georgia, Augusta, said at the annual U.S. Psychiatric and Mental Health Congress.

“The sooner you identify them and get them into treatment the better they do in the long run. Treatment of these folks cannot be done by the smartest, best, most decent, overworked person doing 15-minute medication checks. It just can’t happen. You need a team,” he said.

Current estimates suggest that only 20%-40% of people who meet clinical high-risk criteria for a first episode of psychosis (FEP) convert to psychosis within 2-4 years. A challenge for clinicians, he continued, is that the criteria for identifying individuals at risk for FEP have a low predictive value, which raises concern about unnecessary and potentially harmful interventions. “Any interventions we would want to try now for somebody we’re worried about should have a very low burden of toxicity: antipsychotic medications at very low doses, cognitive-behavioral therapy to reduce or delay the onset of psychosis, and the use of long-chain polyunsaturated fatty acids,” he said.

In a study led by Dr. McEvoy, researchers used a lipidomics platform to measure individual lipid species in 20 drug-naive patients with a first episode of schizophrenia, 20 patients with chronic schizophrenia who had not adhered to prescribed medications, and 29 controls without schizophrenia ( PloS One. 2013;8[7]:e68717 ). They found that, compared with controls, patients with a first episode of schizophrenia demonstrated significant downregulation of several n3 polyunsaturated fatty acids, including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes.

In a separate trial, 81 individuals at high risk of psychotic disorder received 1.2 g/day omega-3 fatty acid or placebo for 12 weeks, followed by a 40-week monitoring period ( Arch Gen Psych. 2010;67[2]:146-54 ). At the end of the 1-year study, 5% of 2 of 41 individuals (5%), in the omega-3 group and 11 of 40 (28%) in the placebo group had transitioned to psychotic disorder (P = .007). “There are several groups around the world that are trying to replicate this,” Dr. McEvoy said. “But can you imagine if we can draw a blood test, identify an 11-year-old with a 70%-plus likelihood of getting a psychotic disorder later, and affect them favorably, protect them with something as simple as long chain fatty acids? I hope so.”

Study after study shows that the shorter the duration of untreated psychosis, the greater the response to antipsychotic treatment. “At the time of treatment initiation, shorter duration of untreated psychosis is associated with reduced severity of negative symptoms such as a motivation and impaired communication,” said Dr. McEvoy, who is also director of public psychiatry at East Central Regional Hospital in Augusta. “Negative symptoms may be the way that the duration of untreated psychosis trumps future function. If you’ve got big negative symptoms, who’s going to hire you? Who’s going to date you? It’s a powerful prognostic factor, and there are probably ways you can modify it.”

Intervening sometime during the first 3 months of untreated psychosis is ideal, he said, “but once you get out past a year, you are in serious trouble. After that time, the likelihood of the person working, having a social life, going back to being a ‘regular person’ is really going down.”

In Scandinavia, researchers used a combination of easy-access detection teams and a massive information campaign about the signs and symptoms of psychosis. It reduced the duration of untreated psychosis in first-episode schizophrenia from 16 to 5 weeks ( Schizophr Bull. 2008;34[3]:466-72 ). Youth at risk for psychosis prioritize getting a job, education that will lead to a job, independent living, and a social life. Or, as Dr. McEvoy put it, “the three C’s: a cell phone, a car, and a condo.” In fact, a combined employment and education program for people with a first episode of psychosis led to higher rates of employment and class completion, compared with usual services ( Psychiatr Rehabil J. 2012;35[6]:421-7 ).

In Dr. McEvoy’s opinion, family members are “grossly underused” in attempts to help FEP patients. “We have more than 30 years of evidence that family intervention clearly reduces relapse rates and enhances medication compliance,” he said. “The burden of care may be reduced by psychosocial interventions, but the specific effects of interventions for caregivers themselves are not usually reported or are seen as secondary outcomes. Caregiver-focused interventions appear to improve the experience of caring and the quality of life of those caring for people with severe mental illness, and these benefits may be gained in first-episode psychosis.”

Current evidence indicates that low-dose antipsychotic treatment during the FEP is associated with symptomatic and functional improvement. “We have a variety of drugs that have one common feature: They sit on dopamine receptors in the limbic system and they protect them from storm,” Dr. McEvoy said. “If we give [patients] too much of these drugs, they get side effects they don’t need. First-episode psychosis patients are discriminating consumers. If you give them drugs that jack up their prolactin or make them sleep 18 hours a day, they’re unhappy.” He favors a “succeed first” strategy with very lose dose first-generation antipsychotics such as haloperidol, perphenazine, or loxapine. “Selection of antipsychotic medications that do not produce extrapyramidal side effects, weight gain/metabolic side effects, sedation, or sexual dysfunction at reasonable doses is now possible,” he said.

According to results from up to 10 years of follow-up in patients who experienced FEP, 60%-70% will achieve remission (defined as key positive and negative features rated mild or less) at some point, but the numbers for sustained remission are substantially lower. In addition, 10%-20% of patients will achieve recovery (defined as good social and occupational functioning in the community) at some point, but the numbers for sustained recovery are lower. Relapse rates are high, even with continued treatment. For example, among patients enrolled in an FEP program in Spain, 21% relapsed by the end of year 1, 41% by the end of year 2, and 65% by the end of year 3 ( J Psychiatr Res. 2012;46[8]:1099-1105 ). And in an FEP program in New York, 5 years after initial recovery, the cumulative first relapse rate was 82%. Discontinuing antipsychotic drug therapy increased the risk of relapse by almost fivefold ( Arch Gen Psychiatry 1999;56[3]:241-7 ).

A novel study led by Jean Addington, Ph.D., of the University of Calgary (Alta.), underscores the importance of early treatment of FEP patients. The researchers enrolled 404 individuals with FEP who presented for treatment at 34 nonacademic medical centers in 21 states ( Psychiatr Serv. 2015;66[7]:753-6 ). The mean duration of untreated psychosis was 74 weeks. “This is like someone coming to you a year-and-a-half after developing untreated hypertension, with changes in the vascular system, the kidneys, and the heart,” said Dr. McEvoy, who was not involved with the study. “You can’t reverse some of these changes.”

Correlates of longer duration of untreated psychosis included earlier age at first psychotic symptoms, substance use disorder, positive and general symptom severity, poorer functioning, and referral from outpatient treatment settings.

Dr. McEvoy disclosed that he has received research grants from Alkermes, Avanir Pharmaceuticals, Ameritox, Auspex Pharmaceuticals, and Otsuka Pharmaceutical. He also is a member of the advisory boards for FORUM Pharmaceuticals, Otsuka, and Lundbeck.


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