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October 17, 2018 by Pauline Anderson | Medscape

Schizophrenia in Youth Not a Neurodegenerative Illness

(Medscape) – Young patients with recent-onset schizophrenia do not show signs of cognitive deterioration or disruption of ongoing brain development in the first years following illness onset, new research shows.

Results of a large longitudinal study show that young patients with schizophrenia experience cognitive impairment prior to the onset of psychotic symptoms, but the trajectory of their neurobehavioral development and performance is comparable to that of healthy control persons.

“The study results suggest that whatever effect cognition has in schizophrenia seems to happen before people develop clinical symptoms, the psychotic symptoms,” study investigator Cameron S. Carter, MD, professor of psychiatry and psychology, and director of the Schizophrenia Research and Education Program, Department of Psychiatry and Behavioural Sciences, University of California, Davis, told Medscape Medical News.

“So cognitive dysfunction is already there when people come in for treatment,” he said.

The findings are in line with the neurodevelopmental model of schizophrenia. This model hypothesizes that prenatal central nervous system insultsand/or genetic alterations during early brain developmentinteract with environmental risk factors and lead to the onset of psychosis in late adolescence or early adulthood.

“The study confirms our sense that schizophrenia is not a neurodegenerative disorder; the brain does not necessarily deteriorate after people become ill and develop these symptoms,” said Carter.

“In fact, these young people have the capacity to continue to improve and develop to the same degree as typical individuals,” he said.

The study was published online October 3 in JAMA Psychiatry.

Poorly Understood

The investigators note that the extent of cognitive deterioration after the onset of schizophrenia is poorly understood, largely because previous longitudinal studies “used small samples of older individuals with established illness.”

To examine the association of age at onset and subsequent longitudinal course of prefrontal activity during the first 2 years of illness in youth with schizophrenia, the investigators analyzed data from 87 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder and 93 matched healthy control persons.

Study participants were between the ages of 12 and 25 years, although the majority were in their teens. Patients with schizophrenia had experienced symptom onset within the previous 12 months.

The age range of study participants covers the typical window for psychosis onset and is the critical period of prefrontal brain development. Cognitive functioning in healthy people typically improves during adolescence and early adulthood.

Investigators rated patient symptoms on the 24-item Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. They carried out fMRI and clinical assessments at baseline and after 6, 12, and 24 months.

During fMRI, participants completed the AX version of the Continuous Performance Task (AX-CPT), an established measure of cognition related to the dorsolateral prefrontal cortex (DLPFC).

The investigators used mixed-model analysis to examine age-related differences between the two groups at baseline, as well as differences in the pattern of changes within and between these groups over time.

No Deterioration

For the longitudinal analysis, researchers used left and right DLPFC regions of interest (ROIs) associated with goal maintenance. They modeled changes in brain activity across time.

Results showed deficits in cognitive control (AX-CPT) in the schizophrenia group relative to control participants at baseline (estimated difference, -0.571; < .001).

Patients with schizophrenia exhibited significantly lower bilateral DLPFC activation during cognitive control–associated trials compared with control persons (left DLPFC: estimated difference, -0.285; <.05; and right DLPFC: estimated difference, -0.469; <.01).

Comparable DLPFC deficits were observed in the schizophrenia group regardless of age at onset.

The analysis showed that over time, behavioral performance on the AX-CPT of patients with schizophrenia paralleled that of control persons.

“What we see over time is that the trajectory that is followed by the young people with psychosis isn’t really different from that followed by healthy young people; that is to say, cognition generally improves over time, which is what we see during this adolescent period,” said Carter.

“Even though it starts out at a lower point, it certainly doesn’t get worse, which is what some more neurodegenerative models of schizophrenia would suggest,” he said.

Prefrontal function among young schizophrenia patients “kind of stabilizes,” he added. “It doesn’t deteriorate or change relative to the pattern that is seen in healthy subjects.”

No Link Between Meds and Cognitive Deficits

Researchers examined the impact of antipsychotic medication. About 75% of the schizophrenia group were taking such medication.

They found differences at baseline between control persons and nonmedicated patients for behavioral performance and between the medicated and the nonmedicated patients with schizophrenia. For left and right DLPFC, the differences between medicated and nonmedicated schizophrenia patients were not significant.

“What this strongly suggests is that the cognitive deficits we see in young people in the early phase of psychotic illness aren’t the result of antipsychotic medication,” said Carter. “They are not a side effect; they are part of the illness.”

Young people with psychosis benefit from treatments that require use of the prefrontal cortex, “such as psychotherapies, rehabilitation therapies, and therapies that target that part of the brain, such as cognitive remediation therapies,” said Carter.

In exploratory analyses, researchers assessed the role of sex (83.9% of the schizophrenia group and 49.5% of control persons were male) and of duration of untreated psychosis (the mean was 4.9 months).

They found that neither sex nor duration of untreated psychosis was associated with performance or DLPFC activation, on average, across the age span.

Although the findings of this new study are confirmatory and helpful, they’re not particularly surprising, said Carter.

“Whilst there is still controversy about the natural history of cognition in schizophrenia, and this study doesn’t answer all the questions about that by any means, we expected to see this more developmental pattern rather than some kind of neurodegeneration-type pattern,” he added.

Future research, the investigators note, should examine the effects of specific interventions, including cognitive remediation, psychotherapy, medication, supported education, and employment “on the trajectory of cognitive control deficits in psychotic illness.”

Pessimism Unwarranted

Commenting on the article for Medscape Medical News, Robin M. Murray, MD, professor of psychiatric research, Department of Psychosis Studies, King’s College London, United Kingdom, said it’s “very important” because it dispels the notion that patients with schizophrenia will deteriorate cognitively.

“There are a lot of very pessimistic psychiatrists out there who say to patients, ‘You have schizophrenia and things are going to get terrible, and you won’t, for example, be able to go back to university,’ ” said Murray.

“This is a pessimistic, deteriorating view, and this study shows that that’s not the case,” he said.

Murray noted that the new study used more sophisticated neuropsychological testing and imaging than past research, some of which used simple IQ testing.

Also commenting on the study for Medscape Medical News, Terry Goldberg, PhD, professor of medical psychology in psychiatry at Columbia University Irving Medical Center, New York City, said the study was “very well-conducted.”

The investigators, said Goldberg, “show convincingly that individuals with schizophrenia very early in their disease course demonstrate substantial impairments in neural responsivity in prefrontal cortex and reduced cognitive control on a test of target detection, the AX-CPT.”

Over time, patients with schizophrenia showed improvements in neural responsivity and neurobehavioral performance that paralleled that of control persons, but not deterioration, “as some might have premised,” said Goldberg.

“So the questions left to be determined are, When do the impairments begin? In early childhood? In adolescence? And what self-arrests the process that compromised prefrontal circuitry in the first place?”

The research was supported by a National Association for Research on Schizophrenia and Depression Young Investigator Grant from the Brain and Behavior Research Foundation and by grants from the National Institute of Mental Health. Dr Carter, Dr Goldberg, and Dr Murray have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online October 3, 2018. Abstract



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