The risk for psychiatric disorders in relatives of schizophrenic and control probands: a comparison of three independent studies

BACKGROUND: Although replication is the heart of science, psychiatric geneticists rarely have the opportunity to replicate findings, especially more than once. METHODS: This article reviews results from three independent family studies of schizophrenia on which one of us conducted diagnostic reviews: the Danish Adoption Study (DAS), the Iowa 500 non-500 family study (IFS), and the Roscommon Family Study (RFS). We utilized DSM-III or DSM-III-R criteria and meta-analysis techniques. RESULTS: The odds ratios (OR) in personally interviewed, first degree biological relatives of schizophrenic and matched control probands for schizophrenia, other non-affective psychoses (ONAP), schizotypal personality disorder (SPD), unipolar affective illness (UPAI), bipolar affective illness (BPAI), and anxiety disorders were homogeneous across studies. For alcoholism, ORs were significantly heterogeneous. Schizophrenia, SPD and ONAP strongly aggregated in relatives of schizophrenic probands with decreasing common OR estimates of 16.2, 5.0 and 4.0, respectively. The common OR for anxiety disorders was 1.1, indicating no familial co-aggregation. For UPAI and BPAI, the common ORs exceeded unity (1.3 and 1.9, respectively), although only the former was statistically significant. CONCLUSIONS: Schizophrenia strongly aggregates in families and shares familial factors with SPD and ONAP but not anxiety disorders. The familial factors of aetiological importance for schizophrenia and affective illness may be weakly related. With the exception of alcoholism, the patterns of psychiatric disorders in relatives of schizophrenic and control probands in these three studies were sufficiently similar that, despite their methodological differences, they can probably be viewed as replications of one another.     

Implications of comorbidity for genetic studies of bipolar disorder: P300 and eye tracking as biological markers for illness

In large families with affective illness, identification of a biological variable is needed that reflects brain dysfunction at an earlier point than symptom development. Eye movement disorder, a possible vulnerability marker in schizophrenia, is less clearly associated with affective illness, although a subgroup of affective disorders shows smooth-pursuit eye movement disorder. The auditory P300 event-related potential may be a useful marker for risk to schizophrenia, but a role in bipolar illness is less certain. The distribution of these two biological variables and their association with symptoms in two multiply affected bipolar families is described. In a single, five-generation family identified for linkage studies through two bipolar I (BPI) probands, 128 members (including 20 spouses) were interviewed. The 108 related individuals had diagnoses of BPI (7), bipolar II (2), cyclothymia (3), or major depressive disorder (19). Eight others had generalised anxiety (1), minor depression (5), intermittent depression (1), or alcoholism (1). Sixty-nine subjects had no psychiatric diagnosis. P300 latency (81) and eye tracking (71) were recorded from a subgroup of relatives within the pedigree. Eye tracking was abnormal in 11 of 71 relatives (15.5%) and was bimodally distributed. In these 11 relatives, clinical diagnoses included minor depression (1), alcoholism (1) and generalised anxiety disorder (1). P300 latency was normally distributed and did not differ from controls. In a second family in which five of seven siblings have BPI illness, P300 latency and eye movement disorder were found in affected relatives and in some unaffected offspring. In these large families, clinical diagnoses of general anxiety, alcoholism and minor depression, when associated with eye tracking abnormality, may be considered alternative clinical manifestations of the same trait that in other relatives is expressed as bipolar illness.     

Contrast enhancement in the craniopharyngioma cyst wall caused by irradiation

OBJECTIVE: To determine the outcome of DSM-III-R schizophreniform disorder with good prognostic features. METHOD: A 6-year follow-up of 20 cases was conducted with structured interviews (comprehensive assessment of symptoms and history) and assessments of functioning scales (global assessment of functioning, Strauss-Carpenter Scale). RESULTS: Thirty-five percent of the cases had major affective disorders, 35% had schizophreniform episodes and major affective disorders, 5% had schizophreniform episodes only, 10% developed schizophrenia, and 15% had no disorders. CONCLUSION: The findings suggest an association between schizophreniform disorder with good prognostic features and affective illness.     

Handedness in first-episode psychotic patients and their first-degree biological relatives.

We evaluated the handedness of 58 schizophrenia patients and 54 of their relatives, 23 patients with major depression with psychosis and 24 of their relatives, 36 patients with bipolar psychosis and 33 of their relatives, and 119 nonpsychiatric Ss and 42 of their relatives. Computerized tomography measures were also available for a subset of the psychotic patients. The schizophrenia patients were significantly more left-handed than any of the other groups, and increased sinistrality was also associated with larger lateral ventricle to brain area ratios. The relatives of the schizophrenia patients did not significantly differ on handedness from either the relatives of the affective psychosis patients or the nonpsychiatric Ss. Findings do not support the notion that left-handedness in schizophrenia is genetically influenced. More research with larger family member data sets is warranted to further explore this possibility. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Early longitudinal course of acute-chronic and paranoid-undifferentiated schizophrenia subtypes and schizophreniform disorder.

This prospective longitudinal study examined symptoms and adjustment at 2 and 4 yrs posthospital discharge in Research Diagnostic Criteria (RDC) and Diagnostic and Statistical Manual of Mental Disorders (DSM-III) schizophrenia subtypes and in DSM-III schizophreniform disorder. Delusions, hallucinations, thought disorder, anxiety, depression, and specific areas of community adjustment were assessed at each follow-up. RDC acute and subacute schizophrenia and DSM-III schizophreniform disorder were associated with more satisfactory overall adjustment and lower frequencies of psychotic symptoms over time. No significant differences in the course of symptoms or adjustment were found between paranoid and undifferentiated schizophrenia subtypes. Schizophrenia subtyping schemes, based on length of illness features, appear more prognostically viable than do symptom-based approaches. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pkg2, a novel transmembrane protein Ser/Thr kinase of Streptomyces granaticolor

A pattern of negative symptoms associated with a high rate of ongoing brain and ventricular instability has been described in a cohort of schizophrenia spectrum probands (patients with schizophrenia, schizoaffective disorder depressed and bipolar, and psychosis NOS) (Garver, D.L., Nair, T.R., Christensen, J.D., Holcomb, J., Ramberg, J., Kingsbury, S., 1999. Differential patterns of premorbid functioning, symptoms and neuroleptic response in stable and unstable ventricular-volume schizophrenia. Neuropsychopharmacology 20, in press). The present study contrasts the prevalence of negative symptoms in first- and second-degree relatives of probands with unstable ventricle volume (UnsVV) and stable ventricle volume (SVV). One hundred and sixteen first- and second-degree relatives of 10 probands were interviewed using the SANS, the 'Characterization of Course: "Pattern of Symptoms"' [from Comprehensive Assessment of Symptoms and History (CASH)], SCID and SCID-II by interviewers blind to the status of the proband. Thirty-five of the 116 family members met DSM-IV criteria for schizophrenia, SA depressed, 'Cluster A' of the SCID-II (paranoid, schizotypal, schizoid personality disorder), psychosis NOS, or psychotic affective disorder. These 35 family members were defined as falling within a 'schizophrenia spectrum' as described by Farmer, A.E., McGuffin, P., Gottesman, I.I., 1987. Arch. Gen. Psychiatry 44, 634-641, but with the addition of DSM-IV affective psychosis. On that basis, the 35 members were considered 'affected family members' (AFMs). The remaining 81 family members were considered unaffected. The 'predominant symptoms of illness' (during the past 2-3 years) for 25 of the 35 AFMs could be characterized according to the 'Patterns of Symptoms' derived from the CASH. Twenty-five of the 35 AFMs were found to maintain a predominant symptom pattern during the course of illness, which could be characterized according to the 'Pattern of Symptoms' as 'predominantly positive' or 'predominantly negative'. Three of the probands had UnsVV; seven had SVV. Of the 35 AFMs, 11 were related to the UnsVV probands, and 24 were relatives of the SVV probands. The nine rated AFMs of the UnsVV probands showed a trend toward higher SANS scores (7.3 +/- 5.1) (mean +/- s.d.) than the 20 rated AFMs of SVV probands (4.3 +/- 5.1) (p = 0.08) at the time of the interview. Eighty-three per cent (eight of 10) of rated affected pedigree members of the pedigrees delineated by probands with UnsVV probands had a predominantly negative symptom course of illness, and 96% (23 of 24) of rated affected pedigree members of the pedigrees with SVV probands had a predominantly positive symptom course of illness during the preceding 2-3 years (p = 0.002). None of the 12 rated affected pedigree members within pedigrees having UnsVV probands were married at the time of the interview; 45% (14 of 31) of affected pedigree members having SVV probands were married (p = 0.004). A psychiatric disorder, characterized by unstable cerebral ventricles and predominant negative symptoms (including avoidance/failure of marital relationships) appears symptomatically to breed true in pedigrees containing schizophrenia-like illnesses.     

Nicotine and familial vulnerability to schizophrenia: A discordant twin study.

Tobacco use is significantly associated with schizophrenia. However, it is not clear if smoking is associated with the illness itself, treatment, or underlying vulnerability to the disease. Smoking was studied in a sample of schizophrenic probands (n = 24), their unaffected co-twins (n = 24), and controls (n = 3,347). Unaffected co-twins had higher rates of daily smoking than controls. Probands and co-twins were more frequently unsuccessful in attempts to quit than controls. Probands reported shaky hands and depression following smoking cessation more often than controls, whereas unaffected co-twins reported difficulty concentrating, drowsiness, nervousness, and headache following smoking cessation more often than controls. Results are consistent with the hypothesis that nicotine use is influenced by familial vulnerability to schizophrenia, not just clinical schizophrenia per se. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Psychometric detection of schizotypy: Perceptual aberration and physical anhedonia in relatives of schizophrenics.

Administered scales of Perceptual Aberration (PERAB) and Physical Anhedonia (PHYSAN), traits that may be related to risk for schizophrenia, to 54 schizophrenics, 146 of their 1st-degree relatives (evaluated for schizophrenia-related disorders), and 178 normal Ss (screened for psychotic disorders in them or their relatives). For both scales, there was a significant effect of group membership. For the PERAB scale, the schizophrenics had higher scores than the normal Ss, who had higher scores than the relatives. For the PHYSAN scale, schizophrenics had higher scores than their relatives, who had higher scores than the normal Ss. Patterns of familial correlations also suggested that physical anhedonia, but not perceptual aberration, may be familial among schizophrenics and their relatives. The PHYSAN scale, but not the PERAB one, may be a useful indicator of liability for schizophrenia among the relatives of affected probands. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Smooth-pursuit eye tracking in first-episode psychotic patients and their relatives.

In order to determine the specificity of smooth-pursuit eye tracking dysfunction to schizophrenia (SC) and the prevalences of dysfunction among functionally psychotic and normal individuals, the authors investigated pursuit tracking in a large sample of psychotic patients, normal Ss, and 1st-degree relatives (N?=?482). Ss were recruited as part of an epidemiological study of 1st-episode psychosis that used a broadly based referral network to identify all cases in a major metropolitan area over a 2.5-yr period. Ss received diagnoses of SC, schizophreniform disorder, psychotic mood disorder, and paranoid or other psychotic disorder based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-III). The distribution of tracking performance was bimodal for the SC Ss and their relatives, perhaps reflecting major gene action. Moreover, poor tracking ran in families. Pursuit tracking dysfunction was relatively specific to SC Ss and their relatives and occurred infrequently in other psychotic Ss and normal Ss. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Saccadic eye movements in families multiply affected with schizophrenia: the Maudsley Family Study

OBJECTIVE: Family studies have shown that abnormalities of smooth pursuit eye movement are increased in the adult relatives of schizophrenic probands as well as in the probands themselves. More recently, an inability of schizophrenic subjects to inhibit reflexive saccades reliably has been shown. This study aimed to test the hypothesis that the latter dysfunction is part of the extended schizophrenia phenotype. METHOD: With the use of infrared oculography, measurements of reflexive saccades and antisaccades were undertaken in 29 probands with schizophrenia, 50 of their nonpsychotic first-degree relatives, and 38 unrelated healthy volunteers. RESULTS: Probands, relatives, and healthy subjects showed no overall differences in the generation of reflexive saccades. However, in the antisaccade task, probands showed more saccadic distractibility when they were required to inhibit reflexive saccades. Analysis of corrective saccades showed that this was not due to failed comprehension or motivation. Relatives of the probands with high saccadic distractibility showed a higher distractibility rate than relatives of the probands with normal distractibility. Across all subjects, females showed a higher rate of distractibility errors than males. CONCLUSIONS: The ability to suppress reflexive saccades is an objective neurocognitive measure that is impaired in schizophrenic patients and in a proportion of their biological relatives. This antisaccade abnormality may be a vulnerability marker in a subset of schizophrenic patients and their families.     

Manic-depressive disease

Manic-depressive illness (MDI) is a periodic major affective disorder defined by successive depressive and manic episodes, separated by free intercritic periods. Unipolar manic-depressive illness is defined by successive depressive episodes, whereas bipolar manic-depressive illness is defined by successive depressive and manic episodes. Clinical, familial and biological studies have demonstrated the heterogeneity of unipolar depression and its relationship with bipolar depression leading to questions about common etiopathogeny of those two disorders. Manic-depressive heterogeneity led to the identification of several subgroups defining "manic-depressive spectrum". The reunion of these different clinical entities is based on phenomenological, clinical and familial arguments. MDI is an endogenous pathology, as vulnerability to this disorder is mostly determined by genetic and/or biological factors. Treatment consist first on treatment of major episodes, based on curative and consolidation treatment and secondly on prophylactic treatment.     

Study of human foamy virus proviral integration in chronically infected murine cells

BACKGROUND: An altered nocturnal sleep pattern and a dysfunction of the hypothalamic-pituitary-adrenocortical system are neurobiological abnormalities typical for depression. A persistence of these neurobiological alterations during remission has been shown to be associated with an increased risk for a relapse. However, it remains unclear whether these persisting abnormalities are trait markers indicative of an increased vulnerability for affective disorders or only represent 'biological scars' acquired during past episodes. Thus, respective examinations need to be performed in the premorbid state in order to answer this open question. METHODS: In the present article we have summarized the various results of the index investigation of a prospectively designed study in which we investigated 54 healthy first-degree relatives (high-risk probands; HRPs) of patients with an affective disorder using polysomnography, the combined dexamethasone corticotropine-releasing hormone (DEX-CRH) test and psychometric measurements. RESULTS: In the cross-sectional part of this study the HRPs, as a group, exhibited a 'depression-like' sleep EEG profile and DEX-CRH test result, while their psychometric profile was characterized by elevated scores on the measures 'Rigidity' and 'Autonomic lability'. On an individual level, 35% of the HRPs were identified as conspicuous in at least two of the three areas under investigation. CONCLUSIONS: The question of whether these abnormalities do indeed reflect trait markers indicative of an increased vulnerability for depression will be answered by the longitudinal part of the study that allows for the retrospective identification of the premorbid status of those HRPs who develop an affective disorder during the follow-up period.     

Risk factors for onset and persistence of psychosis

Clinical practice, training and evaluation of treatment in the functional psychoses continues to be carried out mostly along the traditional line of separation by diagnostic entity. However, the combined evidence from research on risk factors for onset and for persistence of psychotic illness indicates quantitative, but not qualitative, differences between categories of schizophrenia and affective psychosis. "Developmental" factors, such as childhood dysfunction, increased cerebral ventricle size and familial morbid risk of schizophrenia operate preferentially, though not specifically, at that end of the psychopathological spectrum characterised by a preponderance of negative features. On the other hand, "social" factors, such as ethnic group, adverse life events and familial morbid risk of affective disorder have a larger impact at the end associated with predominance of affective features. Heterogeneity in the functional psychoses may thus be best conceived as two discrete effects operating at different ends of a continuous psychopathological spectrum. The use of highly reliable but arbitrary diagnostic categories may introduce serious bias in aetiological and treatment research. Evidence supporting the validity of a model of shared risk factors for continuous characteristics needs to be further elaborated and incorporated into our concepts of psychotic illness.     

Family study of schizophrenia and personality.

The purpose of this study was to determine whether the abnormal characteristics observed in relatives of schizophrenics represent variations in normal personality. Relatives (N?=?340) of patients with schizophrenia, affective disorder, and medical or surgical conditions were personally interviewed about psychiatric symptoms and completed the Multidimensional Personality Questionnaire. Relatives who were themselves ill had elevated scores on some scales. Relatives of schizophrenics had normal scores on all personality scales, but relatives of affectively ill probands differed from other relatives on Well-Being and measures of Negative Emotionality. When schizophrenic probands were subtyped by symptoms, relatives of emotionally blunted schizophrenics were found to have slightly lower scores on Social Closeness than did relatives of controls. Overall, these results suggest that schizophrenia is unrelated to normal personality. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

How are psychotic symptoms perceived? A comparison between patients, relatives and the general public

OBJECTIVE: The aim of this study is to compare patients with schizophrenia with their relatives and the general public in their attitudes towards schizophrenic psychotic symptoms. METHOD: We used a case vignette depicting a person with typical schizophrenic psychotic symptoms and compared the attitudes of 44 inpatients and 47 outpatients with schizophrenia, 48 of their relatives and 43 members of the general public. We also compared the attitudes of patients with schizophrenia to their own symptoms and the symptoms described in the vignette. RESULTS: Subjects from the general public tended not to recognise psychotic symptoms as features of mental illness and tended not to consider drug treatment and hospitalisation as required. Sex, education level as well as previous contact with the mentally ill were found to be significant determinants of attitude. The levels of symptom awareness in patients with schizophrenia and their relatives are higher but still relatively low. In addition, we found that patients with schizophrenia who correctly appraised psychotic symptoms in another person were also aware of their own mental symptoms and need of treatment. CONCLUSIONS: The level of recognition of psychotic symptoms and awareness of a need for treatment are low in the general public, as well as in patients with schizophrenia and their relatives. These findings are discussed in relation to the assessment of insight in patients and a need for psychoeducational programs for each group.     

Follow-up and family study of postpartum psychoses. Part I: Overview

A group of 119 patients suffering from a severe psychiatric postpartum disorder who were admitted for the first time in their life to a psychiatric hospital has been investigated. The onset of illness occurred within 3 months following delivery. The patients represented 92% of the total sample fulfilling the inclusion criteria. A follow-up investigation was performed after a mean of 21 years (range 2-35 years). Of the patients 66% had nonpuerperal psychotic episodes in later life. The diagnosis, taking into account the long-term course, was affective psychosis in 57%, schizoaffective psychosis in 18%, schizophreniform psychosis in 12%, brief reactive psychosis in 4% and schizophrenia in 9%. A bipolar psychosis was found in 31%. The relation of unipolar to bipolar psychoses corresponded to that in a control group of affectively ill women without puerperal onset. The frequency of a manic syndrome in bipolar psychoses at the index episode was the same as in nonpuerperal episodes, which does not suggest a mania-provoking pathoplastic effect of the puerperium. The comparison with female nonpuerperal controls matched for age and diagnosis revealed evidence of a better long-term course in the index patients. The risk of a puerperal relapse for further pregnancies was 35%. The global morbidity risk for functional psychoses in first-degree relatives was 11%, with affective psychoses representing the majority of secondary cases (6.8%). The index patients showed a nonsignificant lower morbidity risk in relatives than a control group of psychotically ill women without puerperal onset. The major aetiological factor found for postpartum psychoses is the relation of these disorders to functional psychoses. There is strong evidence that the postpartum period tends to provoke affective psychoses and other nonschizophrenic psychoses, but not, or only to a lesser degree, narrowly defined schizophrenias. The liability to puerperal decompensations suggests some common pathophysiological mechanism, the nature of which remains unknown.     

Antisaccade performance in patients with schizophrenia and affective disorder.

The authors examined psychotic patients with schizophrenia, major depression, and bipolar disorder; "normal" participants; and 1st-degree relatives of patients with schizophrenia on an antisaccade task in which participants were instructed to move their eyes in the opposite direction of a target that moved unpredictably and abruptly either to the left or right of central fixation. Patients with schizophrenia were found to make significantly more errors than their relatives, and the latter made more errors than the controls. The poor performance of the relatives could not be attributed to their having a psychiatric disorder. Comparison of the 3 patient groups indicated that antisaccade deficits were more pronounced in schizophrenia and bipolar disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Co-occurrence and contransmission of affective disorders and alcoholism in families

The analysis of patterns of co-occurrence and cotransmission of affective disorders and alcoholism in families may provide clues for understanding the excess comorbidity between these conditions in clinical settings and in the general population. This paper reports the results of a family study of the relatives of patients with bipolar disorder, unipolar depression and alcoholism, and combinations thereof. Excess comorbidity between affective disorders and alcoholism was observed in all groups of relatives. However, the sharing of familial aetiological components was not a major contributor to the excess comorbidity between affective disorders and alcoholism. Unipolar depression and alcoholism segregated independently in families, whereas a modest correlation between familial components of alcoholism and bipolar disorder was observed.     

Dysthymia in the offspring of parents with primary unipolar affective disorder.

This study examined whether there is a familial relation between primary early-onset dysthymia and major affective disorder. In addition, it explored the prevalence of other forms of psychopathology and social impairment in the adolescent and young adult offspring of patients with primary unipolar affective disorder. Subjects included 47 offspring of patients with primary unipolar depression, 33 offspring of patients with chronic orthopedic and rheumatological conditions, and 38 offspring of randomly selected community controls with no personal or family history of psychiatric disorder. All offspring received structured diagnostic interviews. Diagnoses were derived blind to parental group by using multiple sets of diagnostic criteria. The offspring of unipolar patients exhibited significantly higher rates of affective disorder, major depression, and dysthymia than did the offspring of medical and normal controls. The groups did not differ on rates of nonaffective disorders. Parental characteristics associated with dysthymia in offspring included chronic depression, age of onset of major depression, number of hospitalizations, and multiple family members with major affective illness. These results support the view that at least some forms of early-onset dysthymia are variants of major affective illness. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Smooth-pursuit eye movement dysfunction and liability for schizophrenia: Implications for genetic modeling.

41 nonpsychiatric Ss, 38 probands with schizophrenia, and 99 of their relatives were studied. Oculomotor functioning was bimodally distributed for probands and relatives. Oculomotor dysfunction was not present in all families with a schizophrenic proband. In those families in which it was present, there were significant phenotypic correlations between oculomotor functioning and schizophrenia-related characteristics. The patterns of familial resemblance in the families in whom oculomotor dysfunction was present were consistent with nonadditive genetic variance contributing both to oculomotor dysfunction and to the relationship between oculomotor dysfunction and clinical symptoms. These results suggest that schizophrenia may be etiologically heterogeneous and that oculomotor dysfunction may help to identify nonadditive genetic variance for this disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)