September 25, 2013. The most comprehensive longitudinal study of cognitive deficits in schizophrenia published to date, with follow-up assessments spanning nearly four decades, finds substantial neuropsychological decline between childhood and the post-onset period of adulthood. Led by Terrie Moffitt of Duke University in Durham, North Carolina, researchers examined both general IQ as well as specific components of cognition and found that deficits in mental functions such as processing speed display different patterns of progression across development. Their findings were published online September 13, 2013, in the American Journal of Psychiatry.
SRF advisor Jim Gold of the University of Maryland called the paper “a powerful confirmation of several observations that have been in the literature for many years.” In his comment (see below), he added, “It is the first time that these key findings have all been demonstrated in the same subjects followed over time in a population-based sample.”
Several studies have demonstrated that people who later develop schizophrenia show cognitive deficits early in life (Dickson et al., 2011). However, previous longitudinal studies that have assessed neuropsychological functioning both before and after illness onset have been limited by the lack of a comparison group, the use of different cognitive measures across time, and/or a focus solely on global measures of cognition. Moffitt’s study, part of an ambitious, ongoing project called the Dunedin Multidisciplinary Health and Development Study and not subject to the same pitfalls as previous research, provides the most detailed picture of cognition in schizophrenia across development yet.
The Dunedin study has examined nearly all aspects of the physical and mental health of 1,037 babies born at a single hospital in Dunedin, New Zealand, over one year between 1972 and 1973. Participants have been followed roughly every other year from ages three to 18 and every few years after that until the most recent assessment at age 38.
“What's really special about the Dunedin study is a combination of three things," Moffitt wrote in an email to SRF. "First, it began with all the babies born in one city, so it fully represented variation in the population, with over 1,000 children from all walks of life and all ability levels. Second, [nearly] 40 years later, 95 percent of those original babies are still taking part, which means that individuals with mental health problems have not dropped out along the way. Third, data collection involves a full day in the lab for each study member, which allows us to take an amazingly broad set of measurements.”
So far, the study has generated over 1,000 research publications about a wide range of topics including cardiovascular, dental, and mental health (see SRF related news story and SRF news story). A previous study from Moffitt’s group found premorbid cognitive deficits in the children who later developed schizophrenia, including early deficits that remained stable throughout childhood as well as some that declined over time (Reichenberg et al., 2010).
In the current study, first author Madeline Meier and colleagues extended the previous findings into adulthood and added data on IQ changes, as well as component mental processes, from the most recent study follow-up. General intellectual ability was assessed at ages seven, nine, 11, 13, and 38 by using IQ tests that were broken down into two components—verbal and performance IQ—and which index different mental functions. In addition, even more specific domains of cognition (learning and memory, processing speed, executive function, and motor function) were assessed with independent tests at ages 13 and 38.
Change across time
Compared to 517 healthy controls, the 31 participants who later developed schizophrenia started off with lower IQs, showing a nine-point IQ deficit in childhood. By adulthood, the difference was an even more substantial 15 points. Indeed, the schizophrenia group lost an average of six IQ points between childhood and adulthood, while no such loss was observed in the controls. Lower IQ was present at the earliest age tested (seven years old) and remained constant until age 13 before dropping sharply. Additional analyses indicated that the IQ changes in schizophrenia were not the result of treatment with antipsychotic medication or dependence on cannabis, alcohol, or hard drugs.
The IQ decline was not present in 185 subjects with persistent depression or in 120 people with mild cognitive impairment during childhood (although a three-point deficit in IQ was observed in the depressed subjects in both childhood and adulthood). A separate analysis that matched individual schizophrenia subjects with “at-risk” participants who shared similar childhood risk factors for the illness (such as low socioeconomic status) found that those with a later diagnosis of schizophrenia had a significantly greater IQ decline than those who did not. Taken together, these findings are important, said Meier, because “they show that neuropsychological decline is really quite specific to schizophrenia.”
When the researchers “unpacked” IQ into specific mental functions, they found a decline in performance IQ, learning, processing speed, executive function, and motor function over time in schizophrenia subjects. Only the verbal IQ score and delayed memory performance of schizophrenia subjects were stable across time, though performance was still worse than that of the controls. Although a decline in cognition was present across several domains of function, the specific pattern of alterations varied across mental functions. For example, performance on the digit symbol test, an index of processing speed, was normal at age seven, but a deficit emerged slowly between ages seven and 38, reflecting “a gradual, progressive process of slowed growth ... that begins in childhood and continues beyond the early teen years,” according to Meier. In contrast, difficulties on the similarities test, a measure of verbal ability, were present by age seven and remained relatively stable through midlife.
In broad terms, "fluid" cognitive abilities such as processing speed, learning, and executive function showed the most substantial decline over time, while deficits in "crystallized" abilities such as verbal IQ emerged early and remained stable across time. This suggests that the two types of cognitive deficits may be the result of different pathophysiological mechanisms in the illness, say the authors.
The findings are “a particularly clear example of a moderate, generalized deficit in cognitive ability well before the onset of illness that, after onset, leads to further declines in fluid, but not crystalized intelligence,” wrote the University of Minnesota’s Angus MacDonald in a comment submitted to SRF (see below).
Sure of schizophrenia?
As any clinician can attest, diagnosing schizophrenia can be extremely complicated. It’s even trickier in population-based studies such as this one, which, unlike investigations of clinical cohorts, examine participants regardless of whether or not they have symptoms. In the Moffitt study, diagnoses of schizophrenia were made using the Diagnostic Interview Schedule (DIS). A lack of insight into one's illness can make relying on such self-reported information problematic, and prior attempts to use similar personal interviews, conducted by trained lay interviewers, have been unable to reliably diagnose schizophrenia (Kendler et al., 1996).
To circumvent these problems, Meier and colleagues used a clinician-administered DIS and relied on several additional pieces of information to make best-estimate diagnoses. They required the presence of hallucinations along with at least two other positive symptoms, a stricter criterion that can help to reduce overdiagnosis. Inclusion in the study also required evidence, obtained from a variety of sources, of objective impairments due to psychosis. Symptoms directly observed by the study’s clinicians, reports of mental illness symptoms and treatment from both parents and "informants" who knew the subjects closely, medication lists, and administrative hospital records were compiled into case files accumulated over assessments from ages 21 to 38. These dossiers were used to achieve 100 percent consensus diagnoses by four clinicians.
Using this approach, the prevalence rate of schizophrenia was higher than in many other studies, which could mean that not all members of the current group really had schizophrenia. By age 38, 2 percent of the original birth cohort met the study’s diagnostic criteria for schizophrenia and had previously been hospitalized for schizophrenia or received antipsychotic medications. Another 1.7 percent also met the criteria but had not specifically been treated for psychosis (though the majority had been treated for another mental health problem). The two groups were combined in all analyses.
However, the nature of the sample—a birth cohort with a very high participation rate—suggests that the study included some individuals who would be missed in other types of studies, say the authors. In addition, the findings that the premorbid and post-onset IQ scores for the schizophrenia group were very close to those recently identified in meta-analyses increases the researchers' confidence in the diagnostic criteria used (Mesholam-Gately et al., 2009). Moreover, both the subjects treated for psychosis (who received a formal diagnosis) and those who were not were nearly equivalent in adult IQ, substance abuse, and receipt of government benefits, as well as other variables. The authors argue that the similarities between the two groups suggest that both are representative of schizophrenia.—Allison A. Curley.
Meier MH, Caspi A, Reichenberg A, Keefe RS, Fisher HL, Harrington H, Houts R, Poulton R, Moffitt TE. Neuropsychological Decline in Schizophrenia From the Premorbid to the Postonset Period: Evidence From a Population-Representative Longitudinal Study. Am J Psychiatry. 2013 Sep 13. Abstract