Significant Cognitive Defects in Those At High Risk of Psychosis

Treatment: Mental Health
Treatment: Mental Health
Studying cognition deficits during the clinical high risk period allows researchers to look at changes in the near psychotic state before chronicity and long-term medication use obscure the core deficits.

In a study published in JAMA Psychiatry, researchers found that those who were in a clinical high risk (CHR) state of psychosis, or “near psychotic,” were significantly more cognitively impaired than healthy controls.1

“Neurocognitive dysfunction is a hallmark of schizophrenia2 and, to a lesser extent, of other psychoses,”3 wrote Larry J. Seidman, PhD, of Harvard Medical School and Massachusetts General Hospital in Boston,and colleagues.

There is evidence of significant but milder impairments during the premorbid phase, greater impairments during the prodromal or CHR period of psychosis, and severe cognitive deficits during the first episode of psychosis and during chronic phases, suggesting a progression of cognitive dysfunction.4

“The CHR period6 is of interest because it offers a temporal window into the changes occurring during the ‘near psychotic’ state, before confounders, such as chronicity and long-term medication use, obscure the core deficits,” the authors wrote.

The researchers recruited 689 CHR participants (398 men, 291 women) and 264 healthy controls (HC) (137 men, 127 women) ages 12 to 35 across 8 university-based outpatient programs from the North American Prodome Longitudinal Study (NAPLS2). Data was collected from January 2009 to April 2013.In the CHR group, 397 (57.6%) were white and 127 (18.4%) were Hispanic, and in the HC group, 145 (54.9%) were white and 45 (17%) were Hispanic.

The participants underwent 19 neuropsychological tests, with 4 main factors analyzed: executive and visuospatial abilities, verbal abilities, attention and working memory abilties, and declarative memory abilities. Effects of medication on neurocognition were also examined.

The researchers found that:

  • Compared with healthy controls, there was a large effect size for attention and working memory abilities in clinical high risk participants who converted to psychosis (n= 89) (Cohen d, approximately 0.80).
  • Compared with high risk participants who did not convert to psychosis, those who did convert were significantly impaired in attention and working memory abilities and declarative memory. Declarative memory abilities in combination with unusual thought content or suspiciousness predicted conversion to psychosis.

The researchers also examined the effects of medication on cognition. “Treated groups, including those taking antipsychotic medications, were largely comparable to those without treatment, except they had somewhat greater attention and working memory abilities impairment,” they wrote. “These observations emphasize the essential nature of neurocognitive impairment in the CHR stage and de-emphasize the role of medication use as confounders in our results.”

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The researchers noted that their study cannot make conclusions about causality, and concluded that future studies should examine how medication use effects neurocognition in CHR populations.

Summary & Clinical Applicability

Neurocognitive impairment is common in those at risk for developing psychosis, and especially in those who go on to develop it. Targets for early interventions should include attention and working memory abilities, as well as declarative memory abilities.

“The results [of this study] provide a new reference point for clinicians and researchers by elucidating the profile of neurocognitive deficits associated with the prodrome as well as their potential as risk-markers for conversion to clinical psychosis,” wrote Abraham Reichenberg, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and Josephine Mollon, MSc, of King’s College London, in an accompanying editorial.5


  • Tasks analyzing declarative memory cannot identify specific mechanisms underlying the deficits.
  • Order effects of the tests cannot be ruled out because the order was not randomized or counterbalanced.
  • The number of converters to psychosis was small, which limits the study’s power to analyze different subgroups.
  • This study population is mixed, but analysis of categorical diagnoses such as schizophrenia and psychotic bipolar disorder could be valuable.


  1. Seidman LJ, Shapiro DI, Stone WS, et al. Association of neurocognition with transition to psychosis: Baseline functioning in the second phase of the North American prodrome longitudinal study. JAMA Psych. 2016; doi:10.1001/jamapsychiatry.2016.2479.
  2. Mirsky AF. Neuropsychological bases of schizophrenia. Annu Rev Psychol. 1969;20:321-348.
  3. Lewandowski KE, Cohen BM, Ongur D. Evolution of neuropsychological dysfunction during the course of schizophrenia and bipolar disorder. Psychol Med. 2011;41(2):225-241.
  4. Woodberry KA, Giuliano AJ, Seidman LJ. Premorbid IQ in schizophrenia: a meta-analytic review. Am J Psychiatry. 2008;165(5):579-587.
  5. Reichenberg A, Mollon J. Challenges and opportunities in studies of cognition in the prodrome to psychosis: No detail is too small. JAMA Psych. 2016; doi:10.1001/jamapsychiatry.2016.2655.