Schizophrenia Spectrum Personality Disorders Research Articles

The Neurobiology of Personality Disorders: Implications for Psychoanalysis

As advances in neuroscience have furthered our understanding of the role of brain circuitry, genetics, stress, and neuromodulators in the regulation of normal behavior and in the pathogenesis of psychopathology, an increasing appreciation of the role of neurobiology in individual differences in personality and their pathology in personality disorders has emerged. Individual differences in the regulation and organization of cognitive processes, affective reactivity, impulse/action patterns, and anxiety may in the extreme provide susceptibilities to personality disorders such as borderline and schizotypal personality disorder. A low threshold for impulsive aggression, as observed in borderline and antisocial personality disorders, may be related to excessive amygdala reactivity, reduced prefrontal inhibition, and diminished serotonergic facilitation of prefrontal controls. Affective instability may be mediated by excessive limbic reactivity in gabaminergic/glutamatergic/cholinergic circuits, resulting in an increased sensitivity or reactivity to environmental emotional stimuli as in borderline personality disorder and other cluster B personality disorders. Disturbances in cognitive organization and information processing may contribute to the detachment, desynchrony with the environment, and cognitive/perceptional distortions of cluster A or schizophrenia spectrum personality disorders. A low threshold for anxiety may contribute to the avoidant, dependent, and compulsive behaviors observed in cluster C personality disorders. These alterations in critical regulatory domains will influence how representations of self and others are internalized. Aspects of neurobiological functioning themselves become cognized through the medium of figurative language into an ongoing narrative of the self, one that can be transformed through the analytic process, allowing for the modulation of genetic/biological thresholds.

Clinical predictors of severe behavioural problems in people with intellectual disabilities referred to a specialist mental health service

Associations between demographic and clinical variables and severe behavioural problems in people with intellectual disabilities were examined in a cross-sectional survey of 408 adults consecutively referred to a specialist mental health service. Severe behavioural problems were present in 136 (33.3%) of the sample. The demographic and clinical predictors of severe behavioural problems in this sample were identified by logistic regression. Age and gender were not associated with severe behavioural problems. The presence of severe ID independently predicted the presence of severe behavioural problems. Schizophrenia spectrum disorders and personality disorders independently predicted the presence of severe behavioural problems, whereas the presence of an anxiety disorder independently predicted their absence. There is an increasing evidence base of relationships between mental disorders and behavioural problems in people with ID although the pattern of these relationships remains unclear.

Psychophysiological and behavioural characteristics of individuals comorbid for antisocial personality disorder and schizophrenia-spectrum personality disorder

Few studies have examined people with comorbid schizophrenia-spectrum personality disorder and antisocial personality disorder, a subgroup who may differ psychophysiologically and behaviourally from those with either condition alone. To test whether individuals with both types of personality disorder are particularly characterised by reduced orienting and arousal and by increased criminal offending. In a community adult sample, self-reported crime and skin conductance orienting were collected on four diagnostic groups: schizophrenia-spectrum personality disorder only; antisocial personality disorder only; comorbidity of the two disorders; and a control group. The comorbid group showed significantly higher levels of criminal behaviour than the other three groups. They also showed reduced skin conductance orienting to neutral tones compared with the other groups, and significantly reduced arousal and orienting to significant stimuli compared with the control group. Reduced orienting may reflect a neurocognitive attentional risk factor for both antisocial and schizotypal personality disorders that indirectly reflects a common neural substrate to these disorders.

Avoidant personality disorder is a separable schizophrenia-spectrum personality disorder even when controlling for the presence of paranoid and schizotypal personality disorders: The UCLA family study

It is unresolved whether avoidant personality disorder (APD) is an independent schizophrenia (Sz)-spectrum personality disorder (PD). Some studies find APD and social anxiety symptoms (Sxs) to be separable dimensions of psychopathology in relatives (Rels) of schizophrenics while other studies find avoidant Sxs to be correlated with schizotypal and paranoid Sxs. Rates of APD among first-degree Rels of Sz probands, attention-deficit/hyperactivity disorder (ADHD) probands, and community control (CC) probands were examined. Further analyses examined rates when controlling for the presence of schizotypal (SPD) and paranoid (PPD) personality disorders, differences in APD Sxs between relative groups, and whether APD in Rels of Szs reflects a near miss for another Sz-spectrum PD. Three hundred sixty-two first-degree Rels of Sz probands, 201 relatives of ADHD probands, and 245 Rels of CC probands were interviewed for the presence of DSM-III-R Axis I and II disorders. Diagnoses, integrating family history, interview information, and medical records, were determined. APD occurred more frequently in Rels of Sz probands compared to CC probands ( p < 0.001) and also when controlling for SPD and PPD ( p < 0.005). Two Sxs of APD were most characteristic of the Rels of Sz probands: “avoids social or occupational activities…” and “exaggerates the potential difficulties…” 65% of the Rels of Sz probands who had diagnoses of APD were more than one criterion short of a DSM-III-R diagnosis of either SPD or PPD. This indicates that APD is a separate Sz-spectrum disorder, and not merely a sub-clinical form of SPD or PPD.

Social anhedonia and schizotypy: The contribution of individual differences in affective traits, stress, and coping

While social anhedonia is a promising indicator of vulnerability to schizophrenia, it remains uncertain whether anhedonia is a core feature of schizotypy or merely a secondary associated characteristic. This issue was examined by comparing dimensional scores on schizophrenia spectrum personality disorder symptoms derived from clinical interviews among three groups: a) “pure” social anhedonics with high scores on the Revised Social Anhedonia Scale (SAS; [Eckblad, M.L., Chapman, L.J., Chapman, J.P., Mishlove, M., 1982. The Revised Social Anhedonia Scale. Unpublished test, University of Wisconsin, Madison.]) and low scores on the Magical Ideation Scale (MIS, [Eckblad, M.L., Chapman, L.J., 1983. Magical ideation as an indicator of schizotypy. Journal of Consulting and Clinical Psychology, 51, 215–225.]), b) subjects with high MIS and low SAS scores, and c) controls with low scores on both scales. This study also sought to identify individual differences in stress reactivity, personality, coping style, and social support that might be related to severity of clinical symptoms among at-risk subjects. Compared to controls, the SAS group had higher levels of schizotypal, schizoid, and paranoid symptoms and the MIS group had higher schizotypal symptoms. Among social anhedonics, individual differences in perceived stress, trait negative affectivity, and coping style accounted for over 40% of the variance in schizotypal and paranoid symptoms. This cross-sectional study bolsters support for the validity of social anhedonia as a primary feature of schizotypy. Longitudinal studies are required to determine whether these individual differences potentiate clinical outcomes among social anhedonics.

Deficits on the continuous performance test within the schizophrenia spectrum and the mediating effects of family history of schizophrenia.

Individuals with schizophrenia spectrum personality disorders (SSPD) and schizophrenia show similar cognitive impairments. The authors examined the contributions of SSPD symptoms and familial risk for schizophrenia to impairments on the Continuous Performance Test--Identical Pairs Version. Participants included 103 schizophrenia patients, 66 first-degree relatives (29 SSPD), and 103 community controls (26 SSPD) screened for family history of psychosis. Patients and SSPD relatives performed significantly worse than non-SSPD relatives and SSPD and non-SSPD community controls. No differences in performance were observed among non-SSPD relatives and SSPD and non-SSPD community controls. Results suggest a continuum in which risk for schizophrenia-related cognitive impairments is highest among patients and SSPD relatives, intermediate among non-SSPD relatives, and lowest among SSPD and non-SSPD community controls. Results suggest that SSPD in the absence of a family history of psychosis may be a phenocopy.

Amphetamine, psychosis, and cognition in the schizophrenia spectrum

We previously reported that subjects with a schizophrenia spectrum personality disorder (ie, an odd cluster personality disorder), of which the prototype is schizotypal personality disorder, show cognitive impairment in circumscribed areas (working memory) compared with healthy control subjects, and that amphetamine administration improves working memory in subjects with schizotypal personality disorder. In this larger series, we wanted to determine whether amphetamine treatment ameliorates working memory impairment using three groups: subjects with a schizophrenia spectrum personality disorder (ie, schizotypal, paranoid, or schizoid personality disorder), other (subjects with nonschizophrenia spectrum) personality disorder, and healthy volunteers. We hypothesized that amphetamine treatment would improve cognitive function in domains in which subjects with schizophrenia spectrum personality disorder show impairment compared with healthy volunteers and the other personality disorder group. Overall, amphetamine treatment did not improve performance in any task compared with placebo, and there was no group by drug interaction in the total sample. However, when the sample was restricted to the subjects who showed impairment at baseline, amphetamine treatment improved visuospatial working memory. In the total patient sample, amphetamine treatment reduced negative symptoms, whereas positive symptoms remained unchanged. Amphetamine treatment improves working memory in those subjects with cognitive impairment at baseline, most of whom meet criteria for a schizophrenia spectrum disorder.

Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction.

Research suggests that first-degree relatives and individuals with schizophrenia spectrum personality disorders (SSPD) may represent nonpenetrant carriers of the genetic diathesis for schizophrenia. This study examined visuospatial working memory (SWM) as a cognitive endophenotype of schizophrenia by expanding the concept of risk for pathophysiological dysfunction beyond overt psychosis. Risk was thus defined by familial status and the presence or absence of SSPD. SWM was assessed in the following groups, in order of decreasing likelihood of genetic vulnerability: 23 patients with schizophrenia, 17 SSPD relatives of patients with schizophrenia, 23 non-SSPD relatives of patients with schizophrenia, 14 SSPD community members with no family history of psychosis, and 36 non-SSPD community members. SWM performance during a computer task was quantified by A-Prime. Relative risk ratios for SWM deficits were compared among the groups. Compared with community non-SSPD volunteers, relative risk (RR) of SWM deficits was significantly elevated in patients with schizophrenia (RR = 3.76, p = .002) and SSPD family members (RR = 2.97, p = .027), but not in the family non-SSPD (RR = 1.88, p = .241) or community SSPD (RR = 1.03, p = .971) groups. The pattern of SWM performance deficits reflected the proposed model of latent genetic liability, upholding SWM as a viable cognitive endophenotype. The results underscore the importance of including both familial liability and the schizophrenia spectrum when considering risk for schizophrenia and schizophrenia-related traits. This is particularly relevant for research efforts to identify pathophysiological components of the disease.

Personality traits in schizophrenia and related personality disorders

We investigated whether schizophrenia spectrum disorders share common personality characteristics or traits. Participants with a diagnosis of schizophrenia or schizoaffective disorder (SZ) or with a schizophrenia spectrum personality disorder (schizophrenia spectrum PD: schizoid, paranoid, and schizotypal personality disorder) were compared with non-psychiatric control subjects on the five-factor model of personality and the psychosis-proneness scales. On the five-factor personality scales, SZ subjects showed higher levels of neuroticism, and lower levels of openness, agreeableness, extraversion, and conscientiousness than control subjects. Higher scores on openness and lower scores on neuroticism distinguished schizophrenia spectrum PD from SZ. On the psychosis-proneness scales, both PD and SZ participants scored high relative to non-psychiatric control participants on magical ideation and perceptual aberration, while PD participants scored intermediate between non-psychiatric control participants and SZ on social anhedonia. Discriminant analysis indicated that schizophrenia spectrum patients could be distinguished from PDs by more severe social withdrawal and maladjustment, while subjects with PDs could be best distinguished from control subjects on the basis of odd or novel ideation and decreased conscientiousness.

Validity of the family history method for diagnosing schizophrenia, schizophrenia-related psychoses, and schizophrenia-spectrum personality disorders in first-degree relatives of schizophrenia probands

This study examined the validity of the family history method for diagnosing schizophrenia, schizophrenia-related psychoses, and schizophrenia-spectrum personality disorders in first-degree relatives of schizophrenia probands. This is the first large-scale study that examined the validity of the family history method for diagnosing DSM-III-R personality disorders. The best estimate DSM-III-R diagnoses of 264 first-degree relatives of 117 adult-onset schizophrenia probands based on direct structured diagnostic interviews, family history interview, and medical records were compared to Family History Research Diagnostic Criteria (FH-RDC) diagnoses based on the NIMH Relative Psychiatric History Interview and to family history Structured Clinical Interview for DSM-III-R: Personality Disorders (SCID-II) diagnoses based on the SCID-II adapted to a third person format. Diagnoses of relatives were made blind to proband diagnostic status. The median sensitivity for schizophrenia and the related psychoses was 29% (range 0–50%), the median specificity 99% (range 98–100%), and the median positive predictive value (PPV) 67% (range 20–80%). The median sensitivity for the personality diagnoses was 25% (range 14–71%), the median specificity 100% (range 99–100%), and the median PPV 100% (range 67–100%). The family history method has low sensitivity but has excellent specificity and PPV for schizophrenia, schizophrenia-related psychoses, and schizophrenia-spectrum personality disorders. The κ coefficient for the family history method was moderately good for the psychoses (0.598) and for paranoid and schizotypal personality disorder (0.576). Using the family history method, the validity of making schizophrenia-related personality disorder diagnoses was comparable to that of making psychotic disorder diagnoses.

Using neurophysiological markers of genetic risk to define the boundaries of the schizophrenia spectrum phenotype.

There is considerable evidence that schizophrenia spectrum personality (SSP) disorders mark genetic risk for schizophrenia. Use of the spectrum phenotype in genetic and neurophysiological studies may prove informative. However, the degree to which the current diagnostic criteria correspond with genetic risk is unclear. This can be assessed by observing how measures of liability among SSP subjects change as a function of diagnostic criteria. In this study the generalized estimating equation method was used to assess changes in eye-tracking performance among SSP and non-SSP family and community groups employing various diagnostic criteria. Eye-tracking deficits among SSP relatives remained statistically higher compared with the other groups across progressively more liberal SSP criteria. The results suggest that fewer traits than are used in clinical diagnoses can effectively identify the spectrum phenotype among relatives of schizophrenia patients. Thus, reduced criteria may be used in research to increase "high risk" sample size and power to detect neurophysiological and genetic differences. Our results provide suggestive evidence that the use of clinical criteria in research may, in fact, underidentify at-risk individuals--potentially distorting genetic and neurophysiological findings.

Clinical characteristics of adolescents later hospitalized for schizophrenia.

Intellectual and behavioral abnormalities, non-psychotic psychiatric disorders, and drug abuse are sometimes present in adolescents who later develop schizophrenia. We followed a population-based cohort of adolescents with baseline assessments of intellectual and behavioral functioning, non-psychotic psychiatric disorders and drug abuse, and ascertained future hospitalization for schizophrenia. Results of the medical and mental health assessments on 16- to 17-year-old male adolescents screened by the Israeli Draft Board, were cross-linked with the National Psychiatric Hospitalization Case Registry, which contains data on all psychiatric hospitalizations in the country. Male adolescents who were later hospitalized for schizophrenia had significantly poorer test scores on all measures in comparison with adolescents not reported to the Psychiatric Registry, the magnitude of the differences was 0.3-0.5 standard deviation (SD). Adolescents (1.03%) of assigned a non-psychotic psychiatric diagnosis, compared to of the adolescents without any psychiatric diagnosis (0.23%), were later hospitalized for schizophrenia. Patients with schizophrenia (26.8%), compared to only 7.4% in the general population of adolescents, had been assigned a non-psychotic psychiatric diagnosis in adolescence (overall OR = 4.5, 95% CI = 3.6-5.6), ranging from OR = 21.5, (<2 >95% CI = 12.6-36.6) for schizophrenia-spectrum personality disorders to OR = 3.6 (<2 >95% CI = 2.1-6.2) for neurosis. The prevalence of self-reported drug abuse was higher in adolescents later hospitalized for schizophrenia (12.4%), compared to the prevalence of drug abuse in adolescents not later hospitalized (5.9%); adjusted RR = 2.033, 95% CI = 1.322-3.126. These results reflect the relatively common finding of impaired intellectual and behavioral functioning, the presence of non-psychotic psychiatric disorders, and drug abuse, in adolescents later hospitalized for schizophrenia, together with the relatively low power of these disorders in predicting schizophrenia.

Genetic heterogeneity in schizophrenia II: conditional analyses of affected schizophrenia sibling pairs provide evidence for an interaction between markers on chromosome 8p and 14q

Information from multiple genome scans and collaborative efforts suggests that schizophrenia is a heterogeneous, complex disorder with polygenic and environmental antecedents. In a previous paper we demonstrated that stratification of families on the basis of co-segregating phenotypes (psychotic affective disorders (PAD) and schizophrenia spectrum personality disorders (SSPD) in first-degree relatives of schizophrenic probands increased linkage evidence in the chromosome 8p21 region (D8S1771) among families with co-segregating SSPD. We have now applied a method of conditional analysis of sib-pairs affected with schizophrenia, examining shared alleles identical-by-descent (IBD) at multiple loci. The method yields enhanced evidence for linkage to the chromosome 8p21 region conditioned upon increased allele sharing at a chromosome 14 region. The method produces a more refined estimate of the putative disease locus on chromosome 8p21, narrowing the region from 18 cM (95% confidence interval) in our previous genome scan, to approximately 9.6 cM. We have also shown that the affected siblings sharing two alleles IBD at the chromosome 8p21 region and one allele IBD at the chromosome 14 region differ significantly in clinical symptoms from non-sharing affected siblings. Thus the analysis of allele sharing at a putative schizophrenia susceptibility locus conditioned on allele sharing at other loci provides another important method for dealing with heterogeneity.

Non-psychotic, non-major affective psychiatric disorders in adolescent boys were associated with greater schizophrenia risk

(2001) Arch Gen Psychiatry 58, 959. Weiser M, Reichenberg A, Rabinowitz J . , et al. . Association between nonpsychotic psychiatric diagnoses in adolescent males and subsequent onset of schizophrenia....

Association between nonpsychotic psychiatric diagnoses in adolescent males and subsequent onset of schizophrenia.

Nonpsychotic psychiatric symptoms may occasionally herald the later development of schizophrenia. This study followed a population-based cohort of adolescents with nonpsychotic, non-major affective psychiatric disorders to ascertain future hospitalization for schizophrenia. Results of the medical and mental health assessments on 124 24416- to 17-year-old males screened by the Israeli draft board were cross-linked with the National Psychiatric Hospitalization case registry, which contains data on all psychiatric hospitalizations in the country, during a 4- to 8-year-long follow-up through age 25 years. In the cohort, 9365 adolescents were assigned a nonpsychotic, non-major affective diagnosis by the draft board. After excluding 167 adolescents who were hospitalized before or up to 1 year after the draft board assessment, 1.03% of the adolescents assigned a nonpsychotic, non-major affective psychiatric diagnosis, compared with only 0.23% of the adolescents without any psychiatric diagnosis, were later hospitalized for schizophrenia. Of the patients with schizophrenia, 26.8%, compared with only 7.4% in the general population, had been assigned a nonpsychotic, non-major affective psychiatric diagnosis in adolescence (overall odds ratio [OR], 4.5; 95% confidence interval [CI], 3.6-5.6), ranging from OR, 21.5 (95% CI, 12.6-36.6) for schizophrenia spectrum personality disorders to OR, 3.6 (95% CI, 2.1-6.2) for neurosis. These results reflect the relatively common finding of impaired functioning in patients later hospitalized for schizophrenia and the relatively low power of these disorders in predicting schizophrenia.

Genetic epidemiology and schizophrenia: a study of reproductive fitness

Genetic epidemiological studies have demonstrated markedly reduced rates in reproduction among schizophrenic patients. According to evolutionary theory, behavioral and psychological phenotypes are selected based on ecological ‘fit’. Where differential survival or reproductive success exists, genotype frequencies are altered in subsequent generations. In the case of schizophrenia, lower rates of reproduction constitute a negative selection factor that should reduce genes in the population associated with the expression of the disease — ultimately leading to decreases in prevalence. However, studies reveal a stable prevalence of about 1% over time. Attempts to explain the apparent contradiction between negative selection and stable prevalence have taken several forms. One explanation suggests that reproductive rates in relatives of schizophrenic patients are increased — compensating for reproductive loss in affected family members. Family data from schizophrenic patients at the Maryland Psychiatric Research Center were compared with those of healthy volunteers and volunteers with schizophrenia spectrum personality (SSP) disorders. Controlling for important socio-cultural and demographic variables, a multiple regression model revealed a significant increase in the number of siblings associated with schizophrenia. No differences in reproductive fitness were found among normal and SSP volunteers. This observed pattern in reproductive fitness provides one mechanism by which prevalence rates can remain stable despite lower reproductive rates among individuals with schizophrenia. Evidence of increased reproductive fitness in relatives suggests the need to consider the complex interactions of proximate and ultimate (evolutionary) mechanisms in the expression of schizophrenia.

Genetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes.

Despite considerable effort to identify susceptibility loci for schizophrenia, none have been localized. Multiple genome scans and collaborative efforts have shown evidence for linkage to regions on chromosomes 1q, 5q, 6q, 8p, 13q, 10p and 22q.(1-9) Heterogeneity is likely. We previously mapped schizophrenia susceptibility loci (SSL) to chromosomes 13q32 (P = 0.00002) and 8p21-22 (P= 0.0001) using 54 multiplex pedigrees and suggested linkage heterogeneity. We have now stratified these families based on co-segregating phenotypes in non-schizophrenic first degree relatives (schizophrenia spectrum personality disorders (SSPD); psychotic affective disorders (PAD)). Genome scans were conducted for these phenotypic subgroups of families and broadened affected phenotypes were tested. The SSPD group provided its strongest genome-wide linkage support for the chromosome 8p21 region (D8S1771) using either narrow (non-parametric lod (NPL) P= 0.000002) or broadened phenotypes (NPL P = 0.0000008) and a new region of interest on 1p was identified (P = 0.006). For PAD families, the peak NPL in the genome scan occurred on chromosome 3p26-p24 (P = 0.008). The identification of multiple susceptibility loci for schizophrenia may be enhanced by stratification of families using psychiatric diagnoses of the non-schizophrenic relatives.

Effects of Amphetamine on Visuospatial Working Memory Performance in Schizophrenia Spectrum Personality Disorder

Our objective was to determine if amphetamine improves visuospatial working memory, which is impaired in the schizophrenia spectrum and may be modulated by dopamine in prefrontal cortex. To this end, oral amphetamine (30 mg) was administered to 12 patients with schizophrenia spectrum personality disorders and 13 patients with other, nonschizophrenia-related personality disorders. Visuospatial working memory was assessed using the Dot test; a test in which subjects are asked to memorize and reproduce the position of a dot on a sheet of paper. Patients with schizophrenia spectrum personality disorders performed significantly worse than the comparison group in the placebo condition and showed significantly greater improvement after amphetamine, as compared to a nonschizophrenia-related personality disorder comparison group. Patients with greatest impairment at baseline improved most. Amphetamine tended to improve negative symptoms; whereas, positive symptoms remained unchanged. Amphetamine may improve visuospatial working memory in schizophrenia spectrum patients.

The factor structure of schizophrenia spectrum personality disorders: signs and symptoms in relatives of psychotic patients from the UCLA family members study

The dimensions and limits of the concept of schizotypy are examined using an exploratory factor analysis of the 36 signs and symptoms in the Cluster A DSM-III-R personality disorders as well as those in Borderline Personality Disorder and Avoidant Personality Disorder in the 307 first-degree relatives and half-siblings of 123 probands with schizophrenia/schizoaffective disorder. The personality disorders examined were assessed using sections of the Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II) and hospital and clinic records. Interviewers were blind to the proband diagnosis. The resulting six-factor solution accounted for 40% of the variance. The results of the six-factor solution accounted for the greatest variance and gave the most easily interpretable simple structure of all the solutions examined. The six factors are labeled as (1) Borderline Symptoms, (2) Schizoid Symptoms, (3) Paranoid Symptoms, (4) Avoidant Symptoms, (5) Positive Schizotypy Symptoms, and (6) Disorganized Symptoms. The Schizotypal Personality items are spread across all but the ‘Borderline Symptoms’ factor. We conclude schizotypy is a multidimensional construct that is not adequately characterized by any one DSM-III-R personality disorder. It appears to consist of six distinct dimensions, which, interestingly, parallel current thinking on dimensions in schizophrenia.

The Dutch famine and schizophrenia spectrum disorders.

In the Dutch Hunger Winter at the end of World War II a combination of circumstances created the conditions of a natural experiment. Unlike other famines, the Dutch famine struck at a precisely circumscribed time and place, and in a society able to document the timing and severity of the nutritional deprivation as well as the effects on fertility and health. Because the Dutch maintained comprehensive military and health records, it was possible to compare the incidence of neurodevelopmental disorders in adulthood for birth cohorts exposed versus those unexposed to prenatal famine. We have conducted several studies guided by the hypothesis that prenatal micronutrient deficiencies can cause neurodevelopmental schizophrenia or related personality disorders. In this paper we shall summarize our previous work and combine the outcome data of the different studies. Early prenatal famine was found to be specifically and robustly associated with each of three conditions: (1) congenital anomalies of the central nervous system, (2) schizophrenia, and (3) schizophrenia spectrum personality disorders. We found that the greatest increase in the risk of schizophrenia spectrum disorder- schizophrenia plus spectrum personality disorder- occurred among males born in the famine cities in December 1945 (relative risk = 2.7; 95% confidence interval = 1.5-5.1). Persons born in December 1945 were generally conceived at the absolute peak of the famine (March-April 1945). In the hope that the associations we have found may offer clues to the aetiology of schizophrenia, we are currently tracing and examining the cases of schizophrenia after prenatal exposure to famine.