Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder

CONTEXT: Variation at the DAOA/G30 locus has been described to be associated with both schizophrenia and bipolar disorder, but there is little consistency between studies of the tested polymorphisms or variants showing association. OBJECTIVES: To obtain a stringent replication of association in large samples of both disorders using consistent clinical and laboratory methods, and to test the hypothesis that association at DAOA/G30 identifies an underlying domain of psychopathological abnormalities that cuts across traditional diagnostic categories. DESIGN: A systematic study of polymorphisms at DAOA/G30 using genetic case-control association analysis. SETTING: Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. PARTICIPANTS: White persons from the United Kingdom meeting criteria for DSM-IV schizophrenia (n = 709) or bipolar I disorder (n = 706) and 1416 ethnically matched controls. METHODS: Nine polymorphisms that tag common genetic variations at DAOA/G30 were genotyped in all of the individuals, and comparisons were made between affected and unaffected individuals. RESULTS: We identified significant association (P = .01-.047) between 3 single-nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence (P = .002-.02) for association with 4 single-nucleotide polymorphisms in the subset of cases (n = 818) in which episodes of major mood disorder had occurred (gene-wide P = .009). We found a similar pattern of association in bipolar cases and in schizophrenia cases in which individuals had experienced major mood disorder. In contrast, we found no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred (all P>.08). CONCLUSIONS: Despite being originally described as a schizophrenia susceptibility locus, our data suggest that variation at the DAOA/G30 locus does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, our results imply that variation at the DAOA/G30 locus influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories.     

The genetics of psychotic bipolar disorder

Psychotic features, defined as delusions or hallucinations, commonly occur in bipolar disorder (BP) and may be indicative of a more homogeneous form of the illness, with possible etiologic ties to schizophrenia. Several studies have shown that psychotic features aggregate in bipolar families, and increased interest in the molecular genetics of psychotic BP is emerging. Although preliminary, linkage studies of psychotic BP show replicated evidence for suggestive genome-wide linkage to chromosomes 8p and 13q, which have been implicated in prior linkage studies of schizophrenia and BP. Association studies of psychotic BP and sub-types such as mood-incongruent psychotic BP have uncovered modest positive results for several candidate schizophrenia susceptibility genes, including dysbindin, DAOA/G30, Disrupted-in-Schizophrenia-1, and neuregulin 1. These tentative results are consistent with the hypothesis that the subphenotype of psychotic BP may represent a clinical manifestation of “overlap” genes between schizophrenia and mood disorder syndromes.     

Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia

Müller DJ, Zai CC, Shinkai T, Strauss J, Kennedy JL. Association between the DAOA/G72 gene and bipolar disorder and meta‐analyses in bipolar disorder and schizophrenia.
Bipolar Disord 2011: 13: 198–207. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objective: The d ‐amino acid oxidase activator (DAOA, or G72) is involved in the oxidation of d ‐serine, an endogenous modulator of N‐methyl‐d ‐aspartate receptors and thus represents an important candidate in psychotic disorders. Several studies reported the DAOA/G72 gene to be associated with schizophrenia (SZ) and bipolar disorder (BD); however, the associated polymorphisms varied between SZ and BD. This study attempts to replicate the DAOA/G72 findings in BD and to conduct subgroup analyses based on the presence or absence of psychotic symptoms. Methods: Five polymorphisms of the DAOA/G72 gene (rs1341402, rs1935062, rs2391191, rs947267, and rs778294) were analysed for association with BD in a family‐based study design (303 core families including 916 individuals). We also conducted a meta‐analysis of DAOA/G72 polymorphisms in BD and SZ. Results: Marker rs1935062 was significantly associated with BD diagnosis in our sample (Z‐score for C‐allele = ?2.33, p = 0.02, uncorrected for genome‐wide multiple comparisons). When we examined the subset of BD patients with psychotic symptoms (157 families), no significant results were obtained. Our meta‐analysis yielded negative findings for DAOA/G72 markers in BD and positive findings for marker rs2391191 in SZ in East Asians. However, significant heterogeneity across studies limits interpretation. Conclusions: Our results provide evidence that suggests a possible role of the DAOA/G72 gene in BD and SZ. Marker rs1935062 may be specifically associated with BD, while marker rs2391191 may be associated with SZ but not with BD. Together with previous studies, these findings suggest that the DAOA/G72 gene confers susceptibility to both BD and SZ, but that different polymorphisms may potentially differentiate between these two disorders.     

The familial aggregation of psychotic symptoms in bipolar disorder pedigrees

OBJECTIVE: Symptomatic overlap between affective disorders and schizophrenia has long been noted. More recently, family and linkage studies have provided some evidence for overlapping genetic susceptibility between bipolar disorder and schizophrenia. If shared genes are responsible for the psychotic manifestations of both disorders, these genes may result in clustering of psychotic symptoms in some bipolar disorder pedigrees. The authors tested this hypothesis in families ascertained for a genetic study of bipolar disorder. METHOD: Rates of psychotic symptoms-defined as hallucinations or delusions-during affective episodes were compared in families of 47 psychotic and 18 nonpsychotic probands with bipolar I disorder. The analysis included 202 first-degree relatives with major affective disorder. RESULTS: Significantly more families of psychotic probands than families of nonpsychotic probands (64% versus 28%) contained at least one relative who had affective disorder with psychotic symptoms. Significantly more affectively ill relatives of psychotic probands than of nonpsychotic probands (34% versus 11%) had psychotic symptoms. An analysis of clustering of psychotic subjects across all families revealed significant familial aggregation. Clustering of psychosis was also apparent when only bipolar I disorder was considered the affected phenotype. CONCLUSIONS: Psychotic bipolar disorder may delineate a subtype of value for genetic and biological investigations. Families with this subtype should be used to search for linkage in chromosomal regions 10p12-13, 13q32, 18p11.2, and 22q11-13, where susceptibility genes common to bipolar disorder and schizophrenia may reside. Putative schizophrenia-associated biological markers, such as abnormal evoked response, oculomotor, and neuroimaging measures, could similarly be explored in such families.     

Is there an association between duration of untreated psychosis and 24-month clinical outcome in a first-admission series?

OBJECTIVE: The authors examined the duration of untreated psychosis, defined as the interval from first psychotic symptom to first psychiatric hospitalization, in a county-wide sample of first-admission inpatients who had received no previous antipsychotic medication. Differences between diagnostic groups in 24-month illness course and clinical outcomes as well as relationships between outcomes and duration of untreated psychosis were evaluated. METHOD: The data were derived from subjects in the Suffolk County Psychosis Project who were diagnosed at 24-month follow-up according to DSM-IV as having schizophrenia or schizoaffective disorder (N=155), bipolar disorder with psychotic features (N=119), or major depressive disorder with psychotic features (N=75). Duration of untreated psychosis was derived from the Structured Clinical Interview for DSM-III-R, medical records, and information from significant others. Measures at 24-month follow-up included consensus ratings of illness course, Global Assessment of Functioning Scale scores for the worst week in the month before interview, and current affective and psychotic symptoms. RESULTS: The median duration of untreated psychosis was 98 days for schizophrenia, 9 days for psychotic bipolar disorder, and 22 days for psychotic depression. Duration of untreated psychosis was not significantly associated with 24-month illness course or clinical outcomes in any of the diagnostic subgroups. CONCLUSIONS: Although these findings require replication in other epidemiologically based first-admission samples, at face value they do not support the suggestion of a psychotoxic effect of prolonged exposure to untreated psychosis.     

Obsessive-compulsive and panic symptoms in patients with first-admission psychosis

OBJECTIVE: The occurrence, persistence and specificity of the association between comorbid obsessive-compulsive and panic symptoms and three psychotic disorders--schizophrenia/schizoaffective disorder, bipolar disorder with psychosis, and major depression with psychosis--were examined in a first-admission, epidemiologically defined group of patients with psychotic symptoms. METHOD: The Structured Clinical Interview for DSM-III-R obsessive-compulsive and panic modules were administered at baseline and 24-month follow-up to patients with schizophrenia/schizoaffective disorder (N=225), bipolar disorder with psychosis (N=138), and major depression with psychosis (N=87) participating in the Suffolk County (N.Y.) Mental Health Project. The rates of subsyndromal symptoms and disorder criteria met were compared across the three psychosis groups. Recognition and treatment of anxiety symptoms at initial discharge and impact of the baseline presence of anxiety symptoms on 24-month clinical status were also examined. RESULTS: Obsessive-compulsive and panic symptoms were present at baseline in 10%-20% of all three groups. There was no specific association between obsessive-compulsive symptoms and any specific psychosis diagnosis; however, women with major depression with psychosis had a significantly higher rate of panic symptoms than the other two groups, and schizophrenia/schizoaffective disorder patients with baseline panic symptoms were significantly more likely to exhibit positive symptoms of psychosis after 24 months. CONCLUSIONS: The authors found no specific association between obsessive-compulsive symptoms and diagnosis early in the illness course, but the finding of an association between panic symptoms and psychotic depression among female patients and between baseline panic and positive psychotic symptoms in schizophrenia/schizoaffective disorder patients at 24 months suggests the need for further study.     

Age of onset in bipolar and unipolar illness with and without delusions or hallucinations

This study examined the differential association of unipolar and bipolar major affective disorder and the presence or absence of delusions or hallucinations with a number of age of onset indices. Earlier age of onset tended to be found in bipolar patients and patients with psychotic features. When the joint effect of polarity and psychotic features were examined, polarity was more highly related to various age of onset indices than psychotic features. However, these features were uniquely associated with a subset of indices beyond that accounted for by bipolarity. The implications of these findings are discussed.     

Cognitive endophenotypes of psychosis within dimension and diagnosis

This study sought to characterize the psychosis phenotype, contrasting cognitive features within traditional diagnosis and psychosis dimension in a family sample containing both schizophrenia and psychotic bipolar I disorder. Seventy-six probands with psychosis [44 probands with schizophrenia, 32 probands with psychotic bipolar I disorder] and 55 first-degree relatives [30 relatives of schizophrenia probands, 25 relatives of bipolar probands] were recruited. Standardized clinical and neuropsychological measures were administered. No differences in cognitive performance emerged between probands with schizophrenia and probands with psychotic bipolar disorder, or between relatives of probands with schizophrenia and relatives of probands with bipolar disorder in the domains of working and declarative memory, executive function and attention. Relatives overall showed higher cognitive performance compared to probands, as expected. However, when we segmented the probands and relatives along a psychosis dimension, independent of diagnostic groups, results revealed lower cognitive performance in probands compared to relatives without psychosis spectrum disorders, whereas relatives with psychosis spectrum disorders showed an intermediate level of performance across all cognitive domains. In this study, cognitive performance did not distinguish either probands or their first-degree relatives within traditional diagnostic groups (schizophrenia and psychotic bipolar disorder), but distinguished probands and relatives with and without lifetime psychosis manifestations independent of diagnostic categories. These data support the notion that schizophrenia and psychotic bipolar disorder present a clinical continuum with overlapping cognitive features defining the psychosis phenotype.     

Psychosis and Dandy-Walker syndrome: a case report and review of the literature

Dandy-Walker syndrome (DWS) is a group of brain malformations which sometimes present with psychotic symptoms. We present the case of a patient diagnosed with Dandy-Walker variant who presented with schizophrenia-like psychosis. A man in his 30s was admitted to an acute psychiatric unit presenting with persecutory delusions, auditory hallucinations and violent behaviour. The MRI performed showed the typical alterations of Dandy-Walker variant: vermian hypoplasia and cystic dilatation of the fourth ventricle. He also suffered from mild intellectual disability. After being treated with olanzapine 10 mg/d for a month, his psychotic symptoms greatly improved and he was discharged. In conclusion, DWS may cause psychosis through a dysfunction in the circuit connecting prefrontal, thalamic and cerebellar areas. The association between these two conditions may contribute to the understanding of the aetiopathogenesis of schizophrenia.     

Insight into illness in schizophrenia, schizoaffective disorder, and mood disorders with psychotic features

OBJECTIVE: Deficits in insight have been found in one study to be more common and severe in patients with schizophrenia than in patients with schizoaffective and major depression with and without psychosis but not more severe than they are in patients with bipolar disorder. The goals of this study were to replicate this finding independently and to clarify whether patients with schizophrenia differ from patients with bipolar disorder in a larger study group. METHOD: Using the Scale to Assess Unawareness of Mental Disorder, the authors evaluated 29 inpatients with schizophrenia, 24 with schizoaffective disorder, and 183 with mood disorders with psychotic features (153 with bipolar disorder and 30 with unipolar depression). RESULTS: Patients with schizophrenia had poorer insight than patients with schizoaffective disorder and patients with psychotic unipolar depression but did not differ from patients with bipolar disorder. CONCLUSIONS: The lack of significant differences between patients with schizophrenia and patients with bipolar disorder was not a result of low statistical power. This replication and more detailed examination of diagnostic group differences in insight have clinical, theoretical, and nosological implications.     

Early onset psychotic disorders: Diagnostic stability and clinical characteristics

Objectives: To examine the clinical features and diagnostic stability of early-onset psychotic disorders. Methods: These data are from a two-year longitudinal prospective study of youth with psychotic disorders. Standardized diagnostic assessments are administered at baseline and at one and two-year's follow-up. Results: Fifty-one subjects have been recruited to date; 18 with schizophrenia, 14 with bipolar disorder, 7 with schizoaffective disorder, 1 with an organic psychosis, and 11 subjects whose symptoms where either questionable and/or did not meet diagnostic criteria for another disorder (classified as psychosis nos). Thirty-nine subjects were reassessed at year one, twenty-four at year two. Three subjects have been lost to follow-up. The study diagnosis was the same as the first onset diagnosis (prior to entering the study) in 50 % of subjects. Over the two-year period of the study, the diagnosis remained unchanged in over 90 % of subjects. Subjects with schizophrenia had higher ratings of premorbid impairment, including social withdrawal and dysfunctional peer relationships, than those with bipolar disorder. At the one-year follow-up, subjects with schizophrenia and schizoaffective disorder had significantly higher rates of delusions, bizarre behavior, and negative symptoms than those with bipolar disorder. Subjects with bipolar disorder tended to have cyclical courses, whereas those with schizophrenia and schizoaffective disorder were often chronically impaired. Subjects with psychosis nos had higher rates of dissociative symptoms and histories of child maltreatment. Conclusions: Early-onset psychotic disorders can be reliably diagnosed using standardized assessments and are stable over a two-year period. Compared to bipolar disorder, schizophrenia is associated with a poorer premorbid history, and persistent positive and negative symptoms.     

Psychotic symptoms and age of onset in affective disorders.

Prevalence of hallucinations and delusions was studied in 1,763 patients with unipolar major depression, bipolar affective disorder, and schizoaffective disorder. The authors found that the presence of psychotic features was negatively associated with age of onset for the group as a whole, and bipolar affective disorder (manic or mixed type) specifically. The clinical implications of the findings are discussed.     

The psychological effect of an urban environment on individuals with persecutory delusions: the Camberwell walk study

BACKGROUND: Epidemiological studies have found that individuals who live in urban areas are at increased risk of developing psychosis. However it is unknown whether exposure to urban environments exacerbates psychotic symptoms in people who have a diagnosed psychotic disorder. The aim of the study was to examine the psychological and clinical effects of exposure to one specific deprived urban environment on individuals with persecutory delusions. It was predicted that the urban environment would affect emotional and reasoning processes highlighted in a cognitive model of persecutory delusions and would increase paranoia. METHOD: Thirty patients with persecutory delusions were randomised to exposure to a deprived urban environment or to a brief mindfulness relaxation task. After exposure, assessments of symptoms, reasoning, and affective processes were taken. Thirty matched non-clinical participants also completed the study measures to enable interpretation of the test scores. RESULTS: In individuals with persecutory delusions, exposure to the urban environment, rather than participation in a mindfulness task, increased levels of anxiety, negative beliefs about others and jumping to conclusions. It also increased paranoia. The individuals with persecutory delusions scored significantly differently from the non-clinical group on all measures. CONCLUSIONS: For individuals with psychosis, spending time in an urban environment makes them think more negatively about other people and increases anxiety and the jumping to conclusions reasoning bias. Their paranoia is also increased. A number of processes hypothesised in cognitive models to lead to paranoid thoughts are exacerbated by a deprived urban environment. Further research is needed to clarify which aspects of urban environments cause the negative effects. Methodological challenges in the research area are raised.     

Early onset psychotic disorders: Diagnostic stability and clinical characteristics

To examine the clinical features and diagnostic stability of early-onset psychotic disorders. These data are from a two-year longitudinal prospective study of youth with psychotic disorders. Standardized diagnostic assessments are administered at baseline and at one and two-year’s follow-up. Fifty-one subjects have been recruited to date; 18 with schizophrenia, 14 with bipolar disorder, 7 with schizoaffective disorder, 1 with an organic psychosis, and 11 subjects whose symptoms where either questionable and/or did not meet diagnostic criteria for another disorder (classified as psychosis nos). Thirty-nine subjects were reassessed at year one, twenty-four at year two. Three subjects have been lost to follow-up. The study diagnosis was the same as the first onset diagnosis (prior to entering the study) in 50% of subjects. Over the two-year period of the study, the diagnosis remained unchanged in over 90% of subjects. Subjects with schizophrenia had higher ratings of premorbid impairment, including social withdrawal and dysfunctional peer relationships, than those with bipolar disorder. At the one-year follow-up, subjects with schizophrenia and schizoaffective disorder had significantly higher rates of delusions, bizarre behavior, and negative symptoms than those with bipolar disorder. Subjects with bipolar disorder tended to have cyclical courses, whereas those with schizophrenia and schizoaffective disorder were often chronically impaired. Subjects with psychosis nos had higher rates of dissociative symptoms and histories of child maltreatment Early-onset psychotic disorders can be reliably diagnosed using standardized assessments and are stable over a two-year period. Compared to bipolar disorder, schizophrenia is associated with a poorer premorbid history, and persistent positive and negative symptoms.     

The interaction of affective with psychotic processes: A test of the effects of worrying on working memory,jumping to conclusions,and anomalies of experience in patients with persecutory delusions

Worry has traditionally been considered in the study of common emotional disorders such as anxiety and depression, but recent studies indicate that worry may be a causal factor in the occurrence and persistence of persecutory delusions. The effect of worry on processes traditionally associated with psychosis has not been tested. The aim of the study was to examine the short-term effects of a bout of worry on three cognitive processes typically considered markers of psychosis: working memory, jumping to conclusions, and anomalous internal experience. Sixty-seven patients with persecutory delusions in the context of a non-affective psychotic disorder were randomised to a worry induction, a worry reduction, or a neutral control condition. They completed tests of the cognitive processes before and after the randomisation condition. The worry induction procedure led to a significant increase in worry. The induction of worry did not affect working memory or jumping to conclusions, but it did increase a range of mild anomalous experiences including feelings of unreality, perceptual alterations, and temporal disintegration. Worry did not affect the occurrence of hallucinations. The study shows that a period of worry causes a range of subtle odd perceptual disturbances that are known to increase the likelihood of delusions. It demonstrates an interaction between affective and psychotic processes in patients with delusions.     

Current Paranoid Thinking in Patients With Delusions: The Presence of Cognitive-Affective Biases

Background: There has been renewed interest in the influence of affect on psychosis. Psychological research on persecutory delusions ascribes a prominent role to cognitive processes related to negative affect: anxiety leads to the anticipation of threat within paranoia; depressive negative ideas about the self create a sense of vulnerability in which paranoid thoughts flourish; and self-consciousness enhances feelings of the self as a target. The objective of this study was to examine such affective processes in relation to state paranoia in patients with delusions. Methods: 130 patients with delusions in the context of a nonaffective psychosis diagnosis (predominately schizophrenia) were assessed for contemporaneous levels of persecutory ideation on 5 visual analog scales. Measures were taken of anxiety, depression, threat anticipation, interpretation of ambiguity, self-focus, and negative ideas about the self. Results: Of the patients, 85% report paranoid thinking at testing. Symptoms of anxiety and depression were highly prevalent. Current paranoid thinking was associated with anxiety, depression, greater anticipation of threat events, negative interpretations of ambiguous events, a self-focused cognitive style, and negative ideas about the self. Conclusions: The study provides a clear demonstration that a range of emotion-related cognitive biases, each of which could plausibly maintain delusions, are associated with current paranoid thinking in patients with psychosis. We identified biases both in the contents of cognition and in the processing of information. Links between affect and psychosis are central to the understanding of schizophrenia. We conclude that treatment of emotional dysfunction should lead to reductions in current psychotic experiences.Key words: delusions, paranoia, cognition, anxiety, depression, schizophrenia     

Diagnostic stability 2 years after treatment initiation in the early psychosis intervention programme in Singapore

OBJECTIVE: To evaluate the diagnostic stability of psychotic disorders over a 2 year period in patients presenting with first-episode psychosis. METHODS: One hundred and fifty-four patients were recruited from an early psychosis intervention programme (EPIP). They were diagnosed by the attending psychiatrist using the Structured Clinical Interview for DSM-IV Axis I at first contact (baseline) and after 24 months. The diagnoses were classified into the following categories: schizophrenia spectrum disorders (schizophrenia, schizophreniform disorder and schizoaffective disorder), affective psychosis (bipolar and major depressive disorders with psychotic symptoms), and other non-affective psychosis (delusional disorder, psychosis not otherwise specified and brief psychotic disorder). Two measures of stability, the prospective and the retrospective consistency were determined for each diagnosis. RESULTS: The diagnoses with the best prospective consistency were schizophrenia (87.0%) and affective psychosis (54.5%). The shift into schizophrenia spectrum disorder was the most frequent diagnostic change. Duration of untreated psychosis was found to be the only significant predictor of shift. CONCLUSION: It is difficult to make a definitive diagnosis at first contact. The clinical need to review the diagnosis throughout the period of follow up is emphasized.     

Psychosis in a pediatric mood and anxiety disorders clinic: phenomenology and correlates

OBJECTIVES: To examine the demographics and phenomenology of psychosis in a sample of children and adolescents referred to a mood and anxiety disorders clinic. METHOD: Patients (N = 2,031) were assessed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Episode version and classified as definite, probable, or nonpsychotic. Clinical and demographic characteristics of the groups were compared,and symptoms of psychosis were analyzed using factor analysis. RESULTS: Definite psychotic symptoms were seen in approximately 90 (4.5%) patients: 80% of these reported hallucinations (mainly auditory), 22% delusions, and 3.3% thought disorder. Of the patients with definite psychotic symptoms, 24% had bipolar disorder, 41% had major depression, 21% had subsyndromal depression, and 14% had schizophrenia spectrum disorders (schizophrenia and schizoaffective disorders). Factor analysis of the definite psychotic symptoms yielded 4 factors: hallucinations, thought disorder, delusions, and manic thought disorder. Psychotic patients had a higher frequency of comorbid disorders and suicidal ideation than nonpsychotic patients. CONCLUSIONS: Outpatient youngsters with mood disorders frequently present with psychotic symptoms, in particular auditory hallucinations. These patients commonly have comorbid psychiatric disorders and suicidal ideation.     

Stability of psychotic symptomatology (delusions,hallucinations), affective syndromes,and schizophrenic symptoms (thought disorder,incongruent affect) over episodes in remitting psychoses

Summary A study was made on 140 schizophrenics, 40 schizoaffectives, 59 unipolar depressives, and 30 bipolar affective disorder patients in order to determine the quality of psychopathology over multiple episodes. The schizoaffectives were the most likely to have multiple episodes. Among the schizophrenics, there were few episodes that lacked psychotic symptoms, but almost half of the episodes for the schizoaffectives were asscociated with an absence of psychotic symptoms. Three-quarters of the patients with unipolar depression and bipolar illness showed no psychotic symptoms either congruent or noncongruent. There was a striking finding that all diagnoses were associated with a decrease in psychotic symptoms over time. These psychotic symptoms (delusions and hallucinations) became particularly more scarce among the schizoaffectives, unipolars, and bipolars. There was a 50% to 67% decrease of episodes with psychotic symptoms as more episodes occurred. For schizophrenia and schizoaffective disorder the first ten episodes were very similar to each other for affective syndromes, formal thought disorder and/or incongruent affect, and delusions and hallucinations. It was not until much time had passed that the symptom pictures changed.