A multivariate prediction model of schizophrenia

Univariate prediction models of schizophrenia may be adequate for hypothesis testing but are narrowly focused and limited in predictive efficacy. Therefore, we used a multivariate design to maximize the prediction of schizophrenia from premorbid measures and to evaluate the relative importance of various predictors. Two hundred twelve Danish subjects with at least one parent diagnosed in the schizophrenia spectrum (high risk) and 99 matched subjects with no such parent (low risk) were assessed on 25 premorbid variables in seven domains (genetic risk, birth factors, autonomic responsiveness, cognitive functioning, rearing environment, personality, and school behavior) when the subjects averaged 15 years of age. Twenty-five years later, 33 subjects had received lifetime diagnoses of schizophrenia. Discriminant function analyses were used to discriminate schizophrenia outcomes from no mental illness and nonschizophrenia outcomes on the basis of premorbid measures. Regardless of the comparison group used, schizophrenia was predicted by the interaction of genetic risk with rearing environment, and disruptive school behavior. Within the high-risk group, two-thirds of schizophrenia outcomes were correctly predicted by these premorbid measures; three-quarters of those with no mental illness were also correctly predicted. Prediction was enhanced among those with two schizophrenia spectrum parents, lending support to a multiplicative gene x environment model. Implications for early identification/primary prevention efforts are discussed.     

Relationship between premorbid functioning and symptom severity as assessed at first episode of psychosis

OBJECTIVE: Investigating the relationship between premorbid and prodromal status and the clinical manifestations of the first psychotic episode is relevant for understanding the pathophysiology of psychosis and for improving management of the disease. This study examined patterns of premorbid functioning of persons interviewed during their first episode of psychotic illness and examined the relationship of premorbid characteristics with symptom severity and cognitive functioning during the first illness episode. METHOD: The data were derived from the baseline assessments of a multicenter international drug trial that enrolled 535 patients in their first episode of psychosis. Subjects' scores on the Premorbid Adjustment Scale were used to assign them to groups according to whether their premorbid functioning was stable-good, stable-poor, or deteriorating. The three groups' scores on the Positive and Negative Syndrome Scale, Clinical Global Impression (CGI) severity scale, and a cognitive battery were compared. RESULTS: Almost half of the patients (47.5%) had stable-good premorbid functioning, 37.3% had stable-poor premorbid functioning, and 15.1% had initially good, but later deteriorating, premorbid functioning. Compared to the stable-poor and deteriorating groups, the stable-good group had lower (better) negative syndrome and general psychopathology scores on the Positive and Negative Syndrome Scale and a lower CGI severity scale score. Differences between the stable-poor and stable-good groups were also found on some cognitive measures and on the positive syndrome subscale of the Positive and Negative Syndrome Scale. CONCLUSIONS: More than half of the subjects, who were interviewed during their first episode of psychotic disorder, had evident premorbid behavioral disturbances. Poor premorbid functioning before onset of psychosis was associated with more severe symptoms and more severe cognitive manifestations of illness during the first illness episode.     

The level of illicit drug use is related to symptoms and premorbid functioning in severe mental illness

Objective: There is conflicting data on drug abuse and outcome in severe mental illness. This study aims to investigate if the amount of illicit psychoactive drug use is related to symptom load or premorbid functioning across diagnosis in patients with severe mental illness. Method: Symptom load, sociodemographic status, premorbid functioning and the level of use of illicit psychoactive drugs were assessed in 423 subjects with schizophrenia or bipolar disorder in a cross‐sectional study. Results: High amount of illicit drug use was associated with poorer premorbid academic functioning. In schizophrenia, there was a significant positive association between amount of drug use and severity of psychiatric symptoms. The association between symptom load and drug use was significant after controlling for premorbid functioning. Conclusion: The results suggest a direct association between the quantity of current drug use and more severe symptoms in schizophrenia. Poor premorbid functioning was related to high amount of use, but did not explain the difference in symptom load.     

Premorbid functioning in schizophrenia: relation to baseline symptoms, treatment response, and medication side effects

Impaired premorbid functioning prior to the onset of acute psychosis has frequently been noted in schizophrenia. This study examined retrospectively the premorbid status of patients in their first episode of psychosis in order to determine relationships with baseline symptoms, treatment response, and medication side effects. One hundred eleven schizophrenic and schizoaffective patients participating in a large prospective study of first episode schizophrenia were evaluated with the Premorbid Adjustment Scale (PAS). Premorbid functioning in males became progressively worse over time. Deficit state patients exhibited worse premorbid functioning. A third of patients exhibited sustained poor premorbid functioning. At various developmental stages, lower "sociability and withdrawal" scores correlated with increased time to treatment response, more severe negative symptoms, increased drug-induced parkinsonism, and deterioration of premorbid functioning. Various mean PAS scores predicted susceptibility to tardive dyskinesia. Our findings suggest that prior to acute psychosis onset there are certain behavioral precursors reflected in premorbid functioning that may predict subsequent illness manifestations. Measures of premorbid functioning indicate that disease pathogenesis is manifest, albeit more subtly, prior to presentation of first psychotic symptoms.     

Premorbid IQ as a predictor for the course of IQ in first onset patients with schizophrenia: a 10-year follow-up study

The aim of the present study was to examine the longitudinal course of IQ and its heterogeneity in patients with schizophrenia, from the perspective of the two main "subtypes" of schizophrenia described in the literature: progressive cognitive deficit versus cognitive stabilisation or recovery. Premorbid IQ scores and WAIS IQ scores of 100 first onset patients were obtained at first hospitalization (T1) and after 10 years (T2). Significant changes in IQ over time were found, representing (i) at T1, a deterioration compared to premorbid intelligence (B=-6.3, 95% CI -9.5 to -3.0, p<0.0001), followed by (ii) a recovery at T2 where IQ matched premorbid intelligence again (B=0.5, 95% CI -3.1 to 4.0, p=0.79). In addition, a significant interaction was found between course of IQ over time and estimated premorbid IQ, demonstrating that subjects with lower premorbid IQ levels remained stable over time whereas in individuals with higher premorbid IQ levels a pattern of deterioration was evident at T1, followed by a recovery up to premorbid level at T2. The data confirm the importance of estimated premorbid IQ as an indicator of the longitudinal course of cognitive functioning in patients with schizophrenia and add evidence to the hypothesis of heterogeneity or "subtypes" of schizophrenia. The data, however, do not confirm the existence of progressive deterioration of cognitive functioning. Rather, catching up of cognitive function later in the course of the illness may take place in those whose deficits become apparent in the early phases of illness, whereas those with the most severe premorbid impairments remain stable.     

Impairment of olfactory identification ability in individuals at ultra-high risk for psychosis who later develop schizophrenia

OBJECTIVE: Previous investigation has revealed stable olfactory identification deficits in neuroleptic-naive patients experiencing a first episode of psychosis, but it is unknown if these deficits predate illness onset. METHOD: The olfactory identification ability of 81 patients at ultra-high risk for psychosis was examined in relation to that of 31 healthy comparison subjects. Twenty-two of the ultra-high-risk patients (27.2%) later became psychotic, and 12 of these were diagnosed with a schizophrenia spectrum disorder. RESULTS: There was a significant impairment in olfactory identification ability in the ultra-high-risk group that later developed a schizophrenia spectrum disorder but not in any other group. CONCLUSIONS: These findings suggest that impairment of olfactory identification is a premorbid marker of transition to schizophrenia, but it is not predictive of psychotic illness more generally.     

Low birthweight in schizophrenia: prematurity or poor fetal growth?

In the general population, low birthweight (LBW) is associated with neurological and psychological problems during childhood and adolescence. LBW may result from premature birth or poor fetal growth, and the independent effects of these two events on childhood development are not fully understood. The rate of low weight births is increased in schizophrenia and is associated with social withdrawal during childhood and an early onset of illness. However, it is unclear whether this LBW reflects poor fetal growth or premature birth, or whether these two risk factors have distinct implications for childhood functioning and age at onset of schizophrenia. Subjects included 270 patients with schizophrenia for whom a detailed history of obstetric events could be obtained. The rate of low weight births was high and was associated with poorer premorbid functioning and an earlier age at illness onset. The rate of both premature births and poor fetal growth was high relative to the normal population. Prematurity, but not poor fetal growth, was associated with premorbid social withdrawal and an early age at illness onset. Poor fetal growth, but not prematurity, was associated with low educational achievement. These results suggest that poor fetal growth and prematurity are associated with distinct patterns of childhood maladjustment in individuals who develop schizophrenia.     

Correlates of substance misuse in patients with first-episode schizophrenia and schizoaffective disorder.

OBJECTIVE: To identify factors associated with substance misuse in first-episode patients with schizophrenia or schizoaffective disorder. METHOD: Twenty-seven patients with a past or current history of substance misuse were compared with 91 patients with no history of misuse on demographic and psychopathological measures before being treated for their first episode of psychosis, and on cognitive measures after 6 months of treatment. RESULTS: There were no statistically significant differences between groups for sex, schizophrenia subtype, marital status, education, family history of schizophrenia, course of illness, age of onset, baseline symptoms, time to treatment response, medication side effects, attention span, memory and executive functioning. However, dual diagnosis patients were found to have a higher parental social class, better premorbid cognitive functioning, higher IQ and better language skills. CONCLUSION: First-episode patients with a history of substance misuse have higher intellectual functioning, which may be associated with higher premorbid socioeconomic status and cognitive functioning.     

Risk Factors,Clinical Features,and Polygenic Risk Scores in Schizophrenia and Schizoaffective Disorder Depressive-Type

There is controversy about the status of schizoaffective disorder depressive-type (SA-D), particularly whether it should be considered a form of schizophrenia or a distinct disorder. We aimed to determine whether individuals with SA-D differ from individuals with schizophrenia in terms of demographic, premorbid, and lifetime clinical characteristics, and genetic liability to schizophrenia, depression, and bipolar disorder. Participants were from the CardiffCOGS sample and met ICD-10 criteria for schizophrenia (n = 713) or SA-D (n = 151). Two samples, Cardiff Affected-sib (n = 354) and Cardiff F-series (n = 524), were used for replication. For all samples, phenotypic data were ascertained through structured interview, review of medical records, and an ICD-10 diagnosis made by trained researchers. Univariable and multivariable logistic regression models were used to compare individuals with schizophrenia and SA-D for demographic and clinical characteristics, and polygenic risk scores (PRS). In the CardiffCOGS, SA-D, compared to schizophrenia, was associated with female sex, childhood abuse, history of alcohol dependence, higher functioning Global Assessment Scale (GAS) score in worst episode of psychosis, lower functioning GAS score in worst episode of depression, and reduced lifetime severity of disorganized symptoms. Individuals with SA-D had higher depression PRS compared to those with schizophrenia. PRS for schizophrenia and bipolar disorder did not significantly differ between SA-D and schizophrenia. Compared to individuals with schizophrenia, individuals with SA-D had higher rates of environmental and genetic risk factors for depression and a similar genetic liability to schizophrenia. These findings are consistent with SA-D being a sub-type of schizophrenia resulting from elevated liability to both schizophrenia and depression.     

Differential patterns of premorbid social and academic deterioration in deficit and nondeficit schizophrenia

Numerous studies indicate that social dysfunction is associated with negative symptoms of schizophrenia during the chronic phase of illness. However, it is unclear whether social abnormalities exist during the premorbid phase in people who later develop schizophrenia with prominent negative symptoms, or whether social functioning becomes progressively worse in these individuals from childhood to late adolescence. The current study examined differences in academic and social premorbid functioning in people with schizophrenia meeting criteria for deficit (i.e., primary and enduring negative symptoms) (DS: n = 74) and non-deficit forms of schizophrenia (ND: n = 271). Premorbid social and academic functioning was assessed for childhood, early adolescence, and late adolescence developmental periods on the Premorbid Adjustment Scale (PAS). Results indicated that both DS and ND participants showed deterioration in social and academic functioning from childhood to late adolescence. However, while ND schizophrenia demonstrated greater deterioration of academic compared to social premorbid functioning from childhood to late adolescence, the DS group exhibited comparable deterioration across both premorbid domains, with more severe social deterioration than the ND group. Findings suggest that people with DS show poorer social premorbid adjustment than those with ND as early as childhood, and are particularly susceptible to accelerated deterioration as the onset of schizophrenia becomes imminent. Thus, poor premorbid social adjustment and significant social deterioration from childhood to adolescence may be a hallmark feature of people who later go on to develop prominent negative symptoms and a unique marker for the DS subtype of schizophrenia.     

The relationship of premorbid functioning to illness course in schizophrenia and psychotic mood disorders during two years following first hospitalization

Studies suggest that better premorbid functioning is associated with better outcomes in chronic schizophrenia. Yet first admission studies, which are more appropriate to examine this, are less conclusive. Also, little attention has been given to whether these findings hold for other psychoses. We examined the relationship of premorbid functioning using the Premorbid Adjustment Scale and outcomes in first admission psychoses (schizophrenia, N = 177; bipolar disorder, N = 106; major depression, N = 68) in the Suffolk County-wide mental health project. Poor premorbid functioning was associated with worse outcomes in all three diagnostic groups. Specifically, it was associated with more negative symptoms early in the course of illness, less improvement in negative symptoms, poorer overall clinical functioning, and poorer social functioning. Consistent with new epidemiological research, early assessment of premorbid functioning could provide an avenue for targeted interventions that might improve outcomes.     

A population-based cohort study of premorbid intellectual,language, and behavioral functioning in patients with schizophrenia,schizoaffective disorder,and nonpsychotic bipolar disorder

OBJECTIVE: The premorbid intellectual, language, and behavioral functioning of patients hospitalized for schizophrenia, schizoaffective disorder, or nonpsychotic bipolar disorder was compared with that of healthy comparison subjects. METHOD: The Israeli Draft Board Registry, which contains measures of intellectual, language, and behavioral functioning for the unselected population of 16- to 17-year-olds, was merged with the National Psychiatric Hospitalization Case Registry, which contains diagnoses for all patients with psychiatric hospitalizations in Israel. The database was used to identify adolescents with no evidence of illness at their draft board assessment who were later hospitalized for nonpsychotic bipolar disorder (N=68), schizoaffective disorder (N=31), or schizophrenia (N=536). The premorbid functioning of these subjects was compared to that of nonhospitalized individuals matched for age, gender, and school attended at the time of the draft board assessment. The diagnostic groups of hospitalized subjects were also compared. RESULTS: Relative to the comparison subjects, subjects with schizophrenia showed significant premorbid deficits on all intellectual and behavioral measures and on measures of reading and reading comprehension. Subjects with schizophrenia performed significantly worse on these measures than those with a nonpsychotic bipolar disorder, who did not differ significantly from the comparison subjects on any measure. Subjects with schizoaffective disorder performed significantly worse than the comparison subjects only on the measure of nonverbal abstract reasoning and visual-spatial problem solving and performed significantly worse than subjects with nonpsychotic bipolar disorder on three of the four intellectual measures and on the reading and reading comprehension tests. CONCLUSIONS: The results support a nosologic distinction between nonpsychotic bipolar disease and schizophrenia in hospitalized patients.     

Self-reported mental health difficulties and subsequent risk for schizophrenia in females: a 5-year follow-up cohort study

BACKGROUND: Patients with schizophrenia often report a history of premorbid mild to severe psychological distress. We investigated the association between self-reported mental health difficulties and later psychiatric hospitalization for schizophrenia. METHODS: 13,357 females aged 17, mandatory assessed by the Israeli Draft Board were followed up over 5 years for psychiatric hospitalization by means of the Israeli National Psychiatric Hospitalization Case Registry. Seventeen females, judged healthy at Draft Board assessment, were hospitalized for schizophrenia or schizoaffective disorder over the follow-up period. RESULTS: There was a significant monotonic association between increasing self-reported mental health difficulties (psychological distress and increasing need for psychological counseling) and prevalence of schizophrenia [odds ratios over four levels: 1.56; 95% CI:1.04 to 2.34; chi2 (1) = 4.62, p = 0.03], after controlling for low IQ, immigration, SES, and presence of psychiatric disorders at age 17. Increasing severity of self-reported mental health difficulties was related to earlier age of first hospitalization [r = -0.48, p = 0.05]. CONCLUSIONS: Increased undifferentiated self-reported mental health difficulties are associated with increased risk of later hospitalization for schizophrenia prior to age 23 in females. This may reflect the prodromal phase of the illness.     

Cannabis use and premorbid functioning as predictors of poorer neurocognition in schizophrenia spectrum disorder

BackgroundEvidence of associations between neurocognitive function and cannabis use in schizophrenia is inconclusive. However, direct measures of cannabis intake and premorbid function are rarely explored in this context. We investigated the relation between cannabis use, determined by its presence in urine, and neurocognitive functioning in schizophrenia controlling for the potential bias of premorbid functioning.MethodsNaturalistic study of 364 patients with schizophrenia spectrum disorder from catchment areas in Oslo, Norway. Hierarchical multiple regression analyses were used to assess the relationship between cannabis in urine and measures of neurocognitive functioning, with adjustment for confounders, including premorbid functioning.ResultsCannabis was detected in the urine of 21 patients, who had significant dysfunction in several neurocognitive domains independent of a current diagnosis of cannabis abuse. However, level of premorbid functioning explained the associations for all measures.ConclusionDifferences in premorbid functioning may explain apparent differences in neurocognitive function between schizophrenia spectrum patients using cannabis or not. The findings suggest that illness-related traits present early in life can affect both later cannabis use and neurocognition, probably by complex mechanisms.     

Childhood-onset schizophrenia: rare but worth studying.

Childhood-onset schizophrenia (defined by an onset of psychosis by age 12) is a rare and severe form of the disorder that is clinically and neurobiologically continuous with the adult-onset disorder. There is growing evidence for more salient risk or etiologic factors, particularly familial, in this possibly more homogeneous patient population. For the 49 patients with very early onset schizophrenia studied to date at the National Institute of Mental Health, there were more severe premorbid neuro-developmental abnormalities, a higher rate of cytogenetic anomalies, and a seemingly higher rate of familial schizophrenia and spectrum disorders than later onset cases. There was no evidence for increased obstetric complications or environmental stress. These data, while preliminary, suggest that a very early age of onset of schizophrenia may be secondary to greater familial vulnerability. Consequently, genetic studies of these patients may be particularly informative and may provide important etiologic information.     

The relationship of early premorbid adjustment with negative symptoms and cognitive functions in first-episode schizophrenia: A prospective three-year follow-up study

Premorbid adjustment is an important prognostic factor of schizophrenia. The relationships between sub-components of premorbid adjustment and outcomes on symptoms and cognition in first-episode schizophrenia were under-studied. In the current study, we prospectively followed up 93 patients aged 18–55 years presenting with first-episode schizophrenia-spectrum disorder. Psychopathological and cognitive assessments were conducted at baseline, clinical stabilization, 12, 24 and 36 months. Premorbid adjustment was sub-divided into discrete functional domains, developmental stages and premorbid-course types based on ratings of the Premorbid Adjustment Scale (PAS). The study focused on early developmental stages to minimize contamination by prodromal symptoms. Results indicated that gender differences in premorbid functioning were primarily related to early-adolescence adjustment and academic domain. Social domain was more strongly related to negative symptoms, while academic domain was more consistently linked to cognitive outcome (Wisconsin Card Sorting test and verbal fluency). Patients with stable-poor premorbid course had more severe negative symptoms and cognitive impairment. In conclusion, in a Chinese cohort of first-episode schizophrenia-spectrum disorder, sub-components of early premorbid adjustment were shown to be differentially related to clinical and cognitive measures. The results highlighted the importance of applying a more refined delineation of premorbid functioning in studying illness outcome.     

The ESSEN study of childhood-onset schizophrenia: Selected results

Introduction: We present the results of a 42 year long-term follow-up of 44 patients (19 males, 25 females) with childhood-onset schizophrenia (COS, age at onset: 7-14 years) who could be traced for a second follow-up examination 27 years after the first follow-up. Methods: Data from interviews, clinical records, premorbid and social disability assessments were evaluated for statistical analyses. The symptomatology observed during the whole course of illness was rediagnosed by DSM-IV criteria. Results: The paranoid, catatonic, and schizoaffectives subtypes appeared most frequently. There have been no gender differences in age of first psychiatric symptoms (AFS), AFPS, and age of first hospitalization. Kaplan-Meier's survival-analysis carried out for AFPS with sex as the grouping factor revealed that the cumulative prevalence appears to be earlier in females (between 7 and 15 years) than in males (between 10 and 18 years). Of the 44 patients 50 % had a continuing severe course. Patients with onset before 12 years of age were characterized by a chronic/insidious onset, marked premorbid abnormalities, and by a poorer remission. Premorbid features of social withdrawal and reluctance indicated a risk for social disability within the later course. Conclusion: COS, as a rare but severe variant of schizophrenia, frequently develops from premorbid social maladaptation to an insidious onset but is subsequently followed by a transition to a course and outcome not distinguishable from that of adult-onset schizophrenia.     

Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder

BACKGROUND: We examined relapse after response to a first episode of schizophrenia or schizoaffective disorder. METHODS: Patients with first-episode schizophrenia were assessed on measures of psychopathologic variables, cognition, social functioning, and biological variables and treated according to a standardized algorithm. The sample for the relapse analyses consisted of 104 patients who responded to treatment of their index episode and were at risk for relapse. RESULTS: Five years after initial recovery, the cumulative first relapse rate was 81.9% (95% confidence interval [CI], 70.6%-93.2%); the second relapse rate was 78.0% (95% CI, 46.5%-100.0%). By 4 years after recovery from a second relapse, the cumulative third relapse rate was 86.2% (95% CI, 61.5%-100.0%). Discontinuing antipsychotic drug therapy increased the risk of relapse by almost 5 times (hazard ratio for an initial relapse, 4.89 [99% CI, 2.49-9.60]; hazard ratio for a second relapse, 4.57 [99% CI, 1.49-14.02]). Subsequent analyses controlling for antipsychotic drug use showed that patients with poor premorbid adaptation to school and premorbid social withdrawal relapsed earlier. Sex, diagnosis, obstetric complications, duration of psychotic illness before treatment, baseline symptoms, neuroendocrine measures, methylphenidate hydrochloride challenge response, neuropsychologic and magnetic resonance imaging measures, time to response of the initial episode, adverse effects during treatment, and presence of residual symptoms after the initial episode were not significantly related to time to relapse. CONCLUSIONS: There is a high rate of relapse within 5 years of recovery from a first episode of schizophrenia and schizoaffective disorder. This risk is diminished by maintenance antipsychotic drug treatment.