Neuropsychological Decline in Schizophrenia From the Premorbid to the Postonset Period: Evidence From a Population-Representative Longitudinal Study

Participants are members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of the health and behavior of a complete birth cohort of consecutive births between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand. The cohort of 1,037 children (91% of eligible births; 52% boys) was constituted at age 3 years. Cohort families represent the full range of socioeconomic status in the general population of New Zealand’s South Island and are primarily of white European ancestry. Follow-up assessments were conducted at ages 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, and, most recently, 38 years, when 95% of the 1,007 living study members underwent assessment in the period 2010–2012.

The study protocol was approved by the institutional ethical review boards of the participating universities, and study members gave informed consent before participating.

Schizophrenia was assessed at ages 21, 26, 32, and 38. We previously described the schizophrenia cases up to age 32 (26, 29, 30), and here we update this information with data from age 38. DSM criteria for schizophrenia were assessed at each age with the Diagnostic Interview Schedule (DIS) (31, 32). We took several steps to enhance the validity of our research diagnosis. First, we required the presence of hallucinations (not substance use-related) in addition to at least two other positive symptoms. This requirement is stricter than that of DSM-IV, which does not require hallucinations, although requiring them has been shown to reduce overdiagnosis (33). Second, because self-reports can be compromised by poor insight in schizophrenia, we required objective evidence of impairment resulting from psychosis, as reported by informants and as recorded in the study’s life-history calendars, which document continuous histories of employment and relationships. Third, in our research, the DIS is administered by experienced clinicians, not lay interviewers. These clinicians record detailed case notes. Our staff also rate observable symptoms manifested in affect, grooming, and speech during the full day that participants spend at our research unit. Fourth, participants bring their medications, which are then classified by a pharmacist. Fifth, informants report study members’ positive and negative psychotic symptoms via postal questionnaires. Finally, study members’ parents were interviewed about their adult child’s psychotic symptoms and treatment as part of the Dunedin Family Health History Study (2003–2005). These data, accumulated in the Dunedin study at ages 21, 26, 32, and 38, were compiled into dossiers reviewed by four clinicians to achieve best-estimate diagnoses with 100% consensus. By age 38, 2% of the cohort (N=20) met criteria for schizophrenia and had, according to the multisource information collected in the dossiers, been hospitalized for schizophrenia (totaling 1,396 days of psychiatric hospitalization, according to official New Zealand administrative record searches) or received prescriptions for antipsychotic medications. An additional 1.7% (N=17) met all criteria for schizophrenia, had hallucinations, and suffered significant life impairment but had not, to our knowledge, been treated specifically for psychotic illness. Together, these two groups constituted a total of 37 cases of diagnosed schizophrenia in the cohort. Of these 37 individuals, four died before the age-38 neuropsychological assessment and two declined to participate, leaving an effective group size of 31 for this study.

Of the 31 individuals in the schizophrenia group, the majority (N=17; 55%) had received treatment specifically for psychotic illness. Of those who, to our knowledge, had not received treatment specifically for psychotic illness, nearly all reported receiving treatment for another mental health problem (Table 2). The two groups appeared similar on a variety of correlates, including adult IQ, personality functioning, substance dependence, and even receipt of government benefits, suggesting that the groups are comparably impaired. The notable exception was that those who had not received treatment for psychotic illness were from families with lower socioeconomic status.

The cohort’s 3.7% prevalence rate of schizophrenia is high and should be understood in the context of three methodological aspects of our study. First, our birth cohort, with a 95% participation rate, allows us to count psychotic individuals overlooked by previous surveys because individuals with psychotic disorders often decline to participate in surveys or die prematurely (34), and surveys often exclude homeless or institutionalized individuals with psychosis. Second, our cohort members are all from one city in the South Island of New Zealand. It is possible, given geographical variation in rates of schizophrenia (35–37), that the prevalence is somewhat elevated there. No data exist to compare prevalence rates of schizophrenia in New Zealand to rates in other countries, but the high prevalence of suicide in New Zealand could be consistent with an elevated prevalence of severe mental health conditions (38). Third, our research diagnoses did not make fine-grained distinctions among psychotic disorders (e.g., schizophrenia versus schizoaffective disorder). Thus, the cohort members diagnosed with schizophrenia here might not be considered by all clinicians to have schizophrenia. We note, however, that over half of those we diagnosed were confirmed by receipt of treatment. Moreover, etiological mechanisms appear to be similar across the continuum of psychosis (39).

Depression was assessed by DSM criteria at ages 18, 21, 26, 32, and 38 using the DIS. Cohort members who were diagnosed with depression on two or more occasions between ages 18 and 38 were classified into the persistent depression group. We focused on persistent depression in an effort to make this group more comparable to the schizophrenia group in terms of chronicity and severity of illness. Neuropsychological data were incomplete for six of the 191 cohort members in the persistent depression group, leaving an effective group size of 185.

Individuals with a childhood IQ (averaged across ages 7–13) in the range of 80–89 were considered to have mild cognitive impairment (N=120).

We assessed neuropsychological functioning using tests of IQ, learning and memory, processing speed, executive function, and motor function. Full-scale IQ can be thought of as an omnibus measure of general intellectual ability, because it captures overall ability across differentiable components of intellectual functioning (i.e., verbal IQ and performance IQ). Verbal and performance IQ can be further “unpacked” to make finer-grained distinctions in ability. Learning and memory, processing speed, executive function, and motor function represent even more basic mental functions.

IQ was assessed in childhood at ages 7, 9, 11 and 13 (before the onset of schizophrenia) and again in adulthood at age 38. We report a comparison of scores on the WISC-R (40) and the WAIS-IV (41). Full-scale, verbal, and performance IQ were standardized to population norms with a mean of 100 and a standard deviation of 15; subtest scaled scores were standardized to population norms with a mean of 10 and a standard deviation of 3. Learning and memory, processing speed, executive function, and motor function were each assessed at ages 13 and 38 using, respectively, the Rey Auditory Verbal Learning Test (42), the Trail Making Test (43), and the Grooved Pegboard Test (42). (For details about each test, see Table S1 in the data supplement that accompanies the online edition of this article.)

Informant reports of study members’ cognitive function were obtained at age 38. Study members nominated people “who knew them well.” These informants were mailed questionnaires and asked to complete a checklist, including whether the study member had problems with his or her attention and memory over the past year. The informant-reported attention problems scale consisted of four items: “Is easily distracted, gets sidetracked easily,” “Can’t concentrate, mind wanders,” “Tunes out instead of focusing,” and “Has difficulty organizing tasks that have many steps” (internal consistency reliability=0.79). The informant-reported memory problems scale consisted of three items: “Has problems with memory,” “Misplaces wallet, keys, eyeglasses, paperwork,” and “Forgets to do errands, return calls, pay bills” (internal consistency reliability=0.64). Informant-reported cognitive problems (attention and memory problems combined) were correlated with adult full-scale IQ (r=−0.22, p<0.0001).

DSM cannabis and alcohol dependence were assessed at ages 18, 21, 26, 32, and 38, and DSM hard drug (e.g., heroin, cocaine, amphetamines) dependence was assessed at ages 26, 32, and 38. Study members who were diagnosed with dependence at two or more assessments were considered persistently dependent on these substances.

We compared the schizophrenia and persistent depression groups to a healthy group (a group of individuals in the cohort who had no current psychiatric disorder; N=518) on change in neuropsychological functioning from childhood to adulthood. Change scores were created by subtracting the childhood test score (averaged across ages 7–13 for the IQ tests and subtests) from the adulthood test score. Negative scores indicate neuropsychological decline. In Tables 4 and 5, childhood and adulthood test scores as well as change scores are presented in standard deviation units (mean=0.00, SD=1.00). Standardized scores reflect effect sizes for how different each group is from the cohort norm. Differences between pairs of groups can also be interpreted as effect sizes. Effect sizes of 0.20, 0.50, and 0.80 reflect small, medium, and large effects, respectively (44). Statistical tests involved planned orthogonal comparisons of each psychiatric group to the healthy group and were adjusted for sex, although results were unchanged when sex was excluded from the model.

Figure 1A shows that, consistent with findings from meta-analyses, the schizophrenia group evidenced a 9-point IQ deficit in childhood relative to the healthy group, and a 15-point deficit in adulthood. The greater relative deficit in adulthood was due to an average 6-point IQ decline in the schizophrenia group from childhood to adulthood (from a mean of 93.63 in childhood to 87.92 in adulthood). There was no evidence of IQ decline for the healthy group (from 102.71 in childhood to 102.44 in adulthood), and IQ decline was significantly greater in the schizophrenia group than in the healthy group (p=0.0009). IQ decline in the schizophrenia group was not attributable to current antipsychotic medication use, as an almost 6-point IQ decline (from 95.29 in childhood to 89.88 in adulthood; paired t=2.83, p=0.0094) was still apparent among the 24 individuals who did not use antipsychotic medication during the year before adult neuropsychological testing.

Relative to the healthy group, the persistent depression group showed a statistically significant 3-point IQ deficit in both childhood and adulthood (Figure 1A). There was no evidence of IQ decline for the persistent depression group (from 99.30 in childhood to 99.05 in adulthood), and estimates of IQ change for the persistent depression and healthy groups did not differ.

Figure 1B expands the analysis to show that full-scale IQ was relatively stable for the schizophrenia, persistent depression, and healthy groups from ages 7 to 13 but dropped substantially for the schizophrenia group between ages 13 and 38. As a further comparison, we also evaluated IQ decline from childhood to adulthood among children with mild cognitive impairment and children at risk for developing schizophrenia. Children with mild cognitive impairment are of interest because, like children with schizophrenia, they exhibit cognitive difficulties early in life, but unlike those with schizophrenia, they do not develop a psychotic condition. Figure 1B shows that, in contrast to children who develop schizophrenia, children with mild cognitive impairment did not show evidence of IQ decline.

Next, we used data from our cohort to match schizophrenia cases to “at-risk” individuals who did not develop schizophrenia but who shared key childhood risk factors with schizophrenia cases. Low IQ, low socioeconomic status, and a family history of schizophrenia are well-established risk factors for developing schizophrenia (45–47). We used propensity score matching to identify individuals who matched our schizophrenia cases on these risk factors but did not develop psychotic illness (Table 3). IQ decline was not apparent among individuals at risk for schizophrenia. The at-risk group, with a childhood liability to develop schizophrenia similar to that of members of the schizophrenia group, showed an IQ decline of 0.01 standard deviations, whereas the schizophrenia group showed a decline of 0.39 standard deviations. Thus, at-risk children who did not develop schizophrenia showed less IQ decline than their matched counterparts who did (F=8.57, df=1, 91, p=0.0043). In sum, IQ decline was unique to those diagnosed with schizophrenia.

Table 4 lists test scores (in standard deviation units) in childhood and adulthood for the healthy, schizophrenia, and persistent depression groups on a range of mental functions: IQ (and the subtests of different cognitive abilities that constitute the IQ), learning (total recall on the Rey Auditory Verbal Learning Test), delayed memory (delayed recall on the Rey test), processing speed (Trails A), executive function (Trails B), and motor function (Grooved Pegboard Test). Table 4 also indicates the change in test performance (in standard deviation units) from childhood to adulthood.

Relative to the healthy group, the schizophrenia group showed significantly greater decline on all mental functions except verbal IQ and delayed memory (Rey delayed recall). Inspection of the means suggests that the greatest declines occurred for processing speed (digit symbol coding, Trails A), learning (Rey total recall), executive function (Trails B), and motor function (Grooved Pegboard Test). By comparison, the persistent depression group generally did not show neuropsychological decline on any mental function.

Figure 2 expands the analysis to show that the progression of neuropsychological deficits from ages 7 to 38 varies across mental functions. Given our earlier report that children who later develop schizophrenia show developmental lags from ages 7 to 13 in processing speed, working memory, and attention but static deficits in verbal abilities (26), we elected to show results for the two IQ subtests most representative of these processes: the digit symbol coding test and the similarities test. Figure 2A shows that deficits on the digit symbol coding test were not apparent at age 7 but emerged gradually from ages 7 to 38. Figure 2B shows that deficits on the similarities test emerged by age 7 but remained relatively stable from ages 7 to 38.

We ruled out three alternative explanations for the observed association between schizophrenia and neuropsychological decline, namely, that these effects could be explained by cannabis dependence, alcohol dependence, or hard drug dependence. We recalculated the mean change in full-scale IQ for the healthy, schizophrenia, and persistent depression groups, excluding individuals with each form of substance dependence. We elected to show results only for full-scale IQ for this analysis because this measure captures overall intellectual functioning. Table 5 shows that excluding individuals with each form of substance dependence did not alter the initial finding; effect sizes, representing within-person IQ change, remained virtually the same and remained statistically significant. Moreover, even after statistically adjusting IQ change scores for cannabis, alcohol, and hard drug dependence conjointly, members of the schizophrenia group still showed a significantly greater IQ decline than members of the healthy group (mean decline, 0.34 standard deviations and 0.03 standard deviations, respectively; p=0.005).

Table 6 summarizes ratings of informant-reported attention and memory problems (in standardized units) for each group at age 38. Members of the schizophrenia group were rated 1.00 and 0.95 standard deviations above the cohort mean on attention and memory problems, respectively, whereas members of the healthy group were rated 0.18 and 0.16 standard deviations below the mean. By comparison, informants reported less pronounced attention and memory problems for the persistent depression group.