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Deterioro neuropsicológico en esquizofrenia desde el periodo premórbido al inicio de la enfermedad

Deterioro neuropsicológico en esquizofrenia desde el periodo premórbido al inicio de la enfermedad

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Article
Neuropsychological Decline in Schizophrenia From thePremorbid to the Postonset Period: Evidence Froma Population-Representative Longitudinal Study
Madeline H. Meier, Ph.D.Avshalom Caspi, Ph.D.Abraham Reichenberg, Ph.D.Richard S.E. Keefe, Ph.D.Helen L. Fisher, Ph.D.HonaLee Harrington, B.S.Renate Houts, Ph.D.Richie Poulton, Ph.D.Terrie E. Mof 
󿬁
tt, Ph.D.
Objective:
 Despite the widespread belief that neuropsychological decline is a cardi-nal feature of the progression from thepremorbid stage to the chronic form of schizophrenia, few longitudinal studieshave examined change in neuropsycho-logical functioning from before to afterillnessonset.Theauthorsexaminedwhetherneuropsychological decline is unique toschizophrenia, whether it is generalized orcon
󿬁
nedtoparticularmentalfunctions,andwhether individuals with schizophreniaalso have cognitive problems in everydaylife.
Method:
 Participants were members of a representative cohort of 1,037 individu-alsborninDunedin,NewZealand,in1972and 1973 and followed prospectively toage 38, with 95% retention. Assessment of IQ and speci
󿬁
c neuropsychological func-tions was conducted at ages 7, 9, 11, and13, and again at age 38. Informants alsoreportedon any cognitiveproblemsat age38.
Results:
 Individuals with schizophreniaexhibited declines in IQ and in a range of mental functions, particularly those tap-ping processing speed, learning, executivefunction, and motor function. There waslittle evidence of decline in verbal abilitiesor delayed memory, however, and thedevelopmental progression of de
󿬁
cits inschizophreniadifferedacrossmentalfunc-tions. Processing speed de
󿬁
cits increasedgradually from childhood to beyond theearly teen years, whereas verbal de
󿬁
citsemerged early but remained static there-after. Neuropsychological decline was spe-ci
󿬁
c to schizophrenia, as no evidence of decline was apparent among individualswith persistent depression, children withmild cognitive impairment, individualsmatched on childhood risk factors forschizophrenia, and psychiatrically healthyindividuals. Informants also noticed morecognitive problems in individuals withschizophrenia.
Conclusions:
 There is substantial neuro-psychological decline in schizophreniafrom the premorbid to the postonsetperiod, but the extent and developmen-tal progression of decline varies acrossmental functions. Findings suggest thatdifferent pathophysiological mechanismsmay underlie de
󿬁
cits in different mentalfunctions.
(Am J Psychiatry 2014; 171:91
 –
101)
N
europsychological impairment is a core feature of schizophrenia (1), and understanding the nature andcourse of neuropsychological functioning in schizophrenia may have important pathophysiological implications.It is widely believed that individuals diagnosed withschizophrenia experience neuropsychological decline fromthe premorbid to the postonset period, but relatively few studies have examined change in neuropsychologicalfunctioning from before to after the onset of schizophre-nia. In this study, we provide a rigorous test of neuro-psychological changes in schizophrenia using a battery of tests administered during childhood (ages 7, 9, 11, and 13)and adulthood (age 38) as part of an ongoing population-representative longitudinal study.There is clear evidence of mild neuropsychologicalde
󿬁
cits among children who later develop schizophrenia (2). Neuropsychological de
󿬁
cits are even more pronouncedamong adults diagnosed with schizophrenia. For example,meta-analysesshowanaveragepremorbid8-pointIQde
󿬁
cit(SD=0.50) among individuals who later develop schizophre-nia (3) but a 14- to 21-point IQ de
󿬁
cit (SD=0.90
1.40) among 
󿬁
rst-episode and chronic schizophrenia patients (1, 4, 5).These
 󿬁
ndings suggest that individuals with schizophrenia experience a relative decline in neuropsychological func-tioning over time from before to after illness onset, withstabilizationinneuropsychologicalfunctioningthereafter(6,7), or at least until older adulthood (8
10).In line with cross-sectional evidence, the few longitudi-nal studies that have addressed neuropsychologicalchanges in schizophrenia from before to after illness onsethave consistently shown evidence of neuropsychologicaldecline (Table 1). However, these studies suffer from variouslimitations. First, the majority of the studies are based onclinical samples, which may not be representative of the full
This article is featured in this month
s AJP
 Audio
 and is discussed in an
 Editorial
 by Dr. Dickinson (p. 9)
 Am J Psychiatry 171:1, January 2014 ajp.psychiatryonline.org 
 91
 
population of individuals with schizophrenia (22). Second,the age at baseline assessment varies considerably, withmany studies assessing neuropsychological functioning for the
 󿬁
rst time in adolescence or adulthood, whenprodromal symptoms (and altered neuropsychologicalfunctioning) tend to be present (23
25). Thus, thesestudies may underestimate the magnitude of the decline infunctioning. Third, only 
 󿬁
ve of the studies includedacomparisongroup,whichisneededtoprovidearigoroustest of change in functioning. Fourth, many of thesestudies employed different neuropsychological testsacross time, making it dif 
󿬁
cult to ascertain true change infunctioning. Fifth, these studies focused exclusively on IQ(or IQ proxies). Since different neural systems underlieperformance on different neuropsychological tests, otherimportant mental functions, such as memory and execu-tive function, should be examined as well. Sixth, none of the studies examined whether, in addition to poor IQ testperformance, individuals with schizophrenia experiencecognitive problems in their daily life.In a previous report of our population-representativecohort followed prospectively from birth, we showed thatchildren who later developed schizophrenia had IQde
󿬁
cits, and we mapped changes in the speci
󿬁
c mentalfunctions that constitute the IQ across four measurementoccasions from ages 7 to 13 years (26). Now that this cohorthas been followed to age 38 and undergone additionalneuropsychological testing, we examined change in IQ, as well as more speci
󿬁
c neuropsychological functions, frombefore (ages 7
13) to after (age 38) the onset of schizophre-nia using the same measures across time. In the presentstudy, we tested four hypotheses. First, we tested the
 
IQdecline
 hypothesis to determine whether individuals withschizophrenia experience a decline in IQ from before toafter illness onset. We compared the group of individuals withschizophreniatoapsychiatricallyhealthygrouptoallofor an accurate interpretation of test-retest performance.Second, we tested the
 
generalized decline
 hypothesis todetermine whether decline is apparent broadly acrossdifferent neuropsychological domains: verbal IQ, perfor-mance IQ, learning and memory, processing speed, execu-tive function, and motor function. Third, we tested the
speci
󿬁
city 
 hypothesis to address whether neuropsycho-logical decline is speci
󿬁
c to schizophrenia. We comparedneuropsychological decline in schizophrenia to decline inthree other groups: a persistent depression group, a mildcognitive impairment group, and a group at risk forschizophrenia. We evaluated neuropsychological decline inindividualswithpersistentdepressiontotestwhetherdeclineis common to other psychiatric disorders. Depression ischaracterized by neuropsychological impairment (27, 28),butitisnotclearwhetherthereisneuropsychologicaldeclinefrom before to after illness onset. We evaluated neuro-psychological decline in children with mild cognitiveimpairment because they, like children with schizophrenia,exhibit cognitive dif 
󿬁
culties early in life. However, unlike inschizophrenia, these children do not develop a psychoticcondition. We also evaluated neuropsychological decline in
at-risk 
 individuals who did not develop schizophrenia but who matched those who did on key childhood risk factors(low IQ, family history of psychotic illness, low socioeco-nomic status). Fourth, we queried third-party informants totestthe
everydaycognition
hypothesisthatindividualswithschizophrenia experience cognitive problems in daily life.
Method
Participants
Participants are members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of 
TABLE 1. Characteristics of Studies Assessing Neuropsychological Decline From Before to After the Onset of Schizophrenia
a
Study N (Cases)Baseline Age orAge Range (Years)Follow-Up Age orAge Range (Years)ComparisonGroupSame TestAcross Time Neuropsychological Tests FindingKremen et al. (11) 10 5 or 9 Late 30s Yes Yes Peabody PictureVocabulary TestRelativedeclineSeidman et al. (12) 26 7 35 Yes Yes Two IQ subtests DeclineCaspi et al. (13) 44 16
 – 
17 20s Yes Yes Army Induction Tests DeclineSchwartzman andDouglas (14)50 20s 30s Yes Yes Army Induction Tests DeclineBilder et al. (15) 39 17 20s Yes No Scholastic Aptitude Test, IQ DeclineGochman et al. (16) 18 Childhood Adolescence,adulthoodNo Yes IQ DeclineRussell et al. (17) 34 8
 – 
25 17
 – 
59 No Yes IQ No declineLubin et al. (18) 159 18 18
 – 
51 No Yes Army Induction Tests DeclineSheitman et al. (19) 27 9
 – 
17 18
 – 
60 No No Various IQ tests DeclineRappaport andWebb (20)10 Adolescence 15
 – 
28 No Yes, no
b
Various IQ tests DeclineAlbee et al. (21) 112 Childhood Adulthood No No Various IQ tests No decline
a
Studies are ordered by methodology and date, with the most methodologically rigorous and recent studies listed
 󿬁
rst. The
 󿬁
rst two studies(11, 12) used epidemiological samples; all the others used clinical samples.
b
The same test was used across time within participants, but not between participants.
92
 ajp.psychiatryonline.org  Am J Psychiatry 171:1, January 2014
NEUROPSYCHOLOGICAL DECLINE IN SCHIZOPHRENIA 
 
the health and behavior of a complete birth cohort of consecutivebirths 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 thefull range of socioeconomic status in the general population of New Zealand
s South Island and are primarily of white Europeanancestry. 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 period2010
2012.The study protocol was approved by the institutional ethicalreview boards of the participating universities, and study membersgave informed consent before participating.
Schizophrenia
Schizophrenia was assessed at ages 21, 26, 32, and 38. Wepreviously 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 withthe Diagnostic Interview Schedule (DIS) (31, 32). We took severalsteps to enhance the validity of our research diagnosis. First, werequired the presence of hallucinations (not substance use-related) in addition to at least two other positive symptoms. Thisrequirement is stricter than that of DSM-IV, which does notrequire hallucinations, although requiring them has been shownto reduce overdiagnosis (33). Second, because self-reports canbe compromised by poor insight in schizophrenia, we requiredobjective evidence of impairment resulting from psychosis, asreported by informants and as recorded in the study 
s life-history calendars, which document continuous histories of employmentand relationships. Third, in our research, the DIS is administeredby experienced clinicians, not lay interviewers. These cliniciansrecord detailed case notes. Our staff also rate observable symp-toms manifested in affect, grooming, and speech during the fullday that participants spend at our research unit. Fourth, parti-cipants bring their medications, which are then classi
󿬁
ed by a pharmacist. Fifth, informants report study members
 positive andnegative psychotic symptoms via postal questionnaires. Finally,study members
 parents were interviewed about their adult child
spsychotic symptoms and treatment as part of the Dunedin Family Health History Study (2003
2005). These data, accumulated inthe Dunedin study at ages 21, 26, 32, and 38, were compiled intodossiers reviewed by four clinicians to achieve best-estimatediagnoses with 100% consensus. By age 38, 2% of the cohort(N=20) met criteria for schizophrenia and had, according to themultisource information collected in the dossiers, beenhospitalized for schizophrenia (totaling 1,396 days of psychiatrichospitalization, according to of 
󿬁
cial New Zealand administrativerecord searches) or received prescriptions for antipsychoticmedications. An additional 1.7% (N=17) met all criteria forschizophrenia, had hallucinations, and suffered signi
󿬁
cant lifeimpairment but had not, to our knowledge, been treated speci-
󿬁
cally for psychotic illness. Together, these two groups consti-tuted a total of 37 cases of diagnosed schizophrenia in the cohort.Of these 37 individuals, four died before the age-38 neuropsy-chological assessment and two declined to participate, leaving aneffective group size of 31 for this study.Of the 31 individuals in the schizophrenia group, the majority (N=17; 55%) had received treatment speci
󿬁
cally for psychoticillness. Of those who, to our knowledge, had not receivedtreatment speci
󿬁
cally for psychotic illness, nearly all reportedreceiving 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 evenreceipt of government bene
󿬁
ts, suggesting that the groups arecomparably impaired. The notable exception was that those whohad not received treatment for psychotic illness were fromfamilies with lower socioeconomic status.The cohort
s 3.7% prevalence rate of schizophrenia is high andshould be understood in the context of three methodologicalaspects of our study. First, our birth cohort, with a 95%participation rate, allows us to count psychotic individualsoverlooked by previous surveys because individuals with psy-chotic disorders often decline to participate in surveys or dieprematurely (34), and surveys often exclude homeless orinstitutionalized individuals with psychosis. Second, our cohortmembers are all from one city in the South Island of NeZealand. It is possible, given geographical variation in rates of schizophrenia (35
37), that the prevalence is somewhat elevatedthere. No data exist to compare prevalence rates of schizophre-nia in New Zealand to rates in other countries, but the highprevalence of suicide in New Zealand could be consistent with anelevated prevalence of severe mental health conditions (38).Third, our research diagnoses did not make
 󿬁
ne-graineddistinctions among psychotic disorders (e.g., schizophrenia versus schizoaffective disorder). Thus, the cohort membersdiagnosed with schizophrenia here might not be considered by all clinicians to have schizophrenia. We note, however, that overhalf of those we diagnosed were con
󿬁
rmed by receipt of treatment.Moreover, etiological mechanisms appear to be similar across thecontinuum of psychosis (39).
Persistent Depression
Depression was assessed by DSM criteria at ages 18, 21, 26, 32,and 38 using the DIS. Cohort members who were diagnosed withdepression on two or more occasions between ages 18 and 38 were classi
󿬁
ed into the persistent depression group. We focusedon persistent depression in an effort to make this group morecomparable to the schizophrenia group in terms of chronicity and severity of illness. Neuropsychological data were incompletefor six of the 191 cohort members in the persistent depressiongroup, leaving an effective group size of 185.
Mild Cognitive Impairment 
Individuals with a childhood IQ (averaged across ages 7
13) inthe range of 80
89 were considered to have mild cognitiveimpairment (N=120).
Neuropsychological Functioning 
 We assessed neuropsychological functioning using tests of IQ,learning and memory, processing speed, executive function, andmotor function. Full-scale IQ can be thought of as an omnibusmeasure of general intellectual ability, because it captures overallability across differentiable components of intellectual function-ing (i.e., verbal IQ and performance IQ). Verbal and performanceIQ can be further
 
unpacked
 to make
 󿬁
ner-grained distinctionsin ability. Learning and memory, processing speed, executivefunction, and motor function represent even more basic mentalfunctions.IQ was assessed in childhood at ages 7, 9, 11 and 13 (beforethe 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 werestandardized to population norms with a mean of 100 anda standard deviation of 15; subtest scaled scores werestandardized to population norms with a mean of 10 anda standard deviation of 3. Learning and memory, processing speed, executive function, and motor function were eachassessed at ages 13 and 38 using, respectively, the Rey Auditory  Verbal Learning Test (42), the Trail Making Test (43), and theGrooved Pegboard Test (42). (For details about each test, see
 Am J Psychiatry 171:1, January 2014 ajp.psychiatryonline.org 
 93
MEIER, CASPI, REICHENBERG, ET AL.

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