Genome scan of schizophrenia families in a large Veterans Affairs Cooperative Study sample: evidence for linkage to 18p11.32 and for racial heterogeneity on chromosomes 6 and 14.

Genome-wide linkage analyses of schizophrenia have identified several regions that may harbor schizophrenia susceptibility genes but, given the complex etiology of the disorder, it is unlikely that all susceptibility regions have been detected. We report results from a genome scan of 166 schizophrenia families collected through the Department of Veterans Affairs Cooperative Studies Program. Our definition of affection status included schizophrenia and schizoaffective disorder, depressed type and we defined families as European American (EA) and African American (AA) based on the probands' and parents' races based on data collected by interviewing the probands. We also assessed evidence for racial heterogeneity in the regions most suggestive of linkage. The maximum LOD score across the genome was 2.96 for chromosome 18, at 0.5 cM in the combined race sample. Both racial groups showed LOD scores greater than 1.0 for chromosome 18. The empirical P-value associated with that LOD score is 0.04 assuming a single genome scan for the combined sample with race narrowly defined, and 0.06 for the combined sample allowing for broad and narrow definitions of race. The empirical P-value of observing a LOD score as large as 2.96 in the combined sample, and of at least 1.0 in each racial group, allowing for narrow and broad racial definitions, is 0.04. Evidence for the second and third largest linkage signals come solely from the AA sample on chromosomes 6 (LOD = 2.11 at 33.2 cM) and 14 (LOD = 2.13 at 51.0). The linkage evidence differed between the AA and EA samples (chromosome 6 P-value = 0.007 and chromosome 14 P-value = 0.004).

Antiretroviral antibodies: implications for schizophrenia, schizophrenia spectrum disorders, and bipolar disorder.

BACKGROUND: Some retroviral antigens share structural homology within a group of related retroviruses. It is possible that antibodies directed against one virus may cross-react with antigens from a different virus in the group. METHODS: Using this principle, the human immunodeficiency virus 1 (HIV-1) Western blot assay was used as an available source of human retroviral antigens to screen serum samples from an archived collection to ascertain whether there was an association between serum antiretroviral antibodies and mental illnesses. RESULTS: A statistically significant proportion (28/54, 52%) of patients suffering from psychiatric disorders had serum antibodies that recognized at least one antigen present on the blot, culminating in indeterminate HIV-1 tests. The majority of the reactive samples were directed against the HIV-1 group antigens p24 and p17. These findings contrast with those of nonpsychiatric patients, who had 4/16 (25%) indeterminate blots. CONCLUSIONS: The results suggest exposure to retroviral antigens related to those of HIV-1 in subpopulations of schizophrenic, schizophrenic spectrum disorder, and bipolar disorder patients.

PTSD and comorbid psychotic disorder: comparison with veterans diagnosed with PTSD or psychotic disorder.

Symptoms of posttraumatic stress disorder (PTSD), psychosis, general psychopathology, role functioning, violence potential, and cognitive and emotional aspects of psychotic states were compared in three groups of veterans. Groups were defined on the basis of their DSM-IV diagnoses: Psychotic disorder and war-related PTSD, war-related PTSD without psychotic symptoms, and psychotic disorder without PTSD. Veterans with PTSD and a comorbid psychotic disorder showed significantly higher levels of positive symptoms of psychosis, general psychopathology, paranoia, and violent thoughts, feelings, and behaviors than the other two groups. These data show that patients with comorbid PTSD and psychotic disorder show levels of cognitive, emotional, and behavioral disturbance that far exceed the levels of disturbance seen in patients with PTSD without psychosis or in patients with psychotic disorder.

Neuropsychological deficits in probands from multiply-affected schizophrenic families.

This study was designed to determine if schizophrenics from families with more than one psychotic relative show more severe neuropsychological deficits than schizophrenics with only one psychotic relative, non-familial schizophrenics, and a group of matched normal controls. Eighty-one schizophrenic-spectrum patients were divided into three groups on the basis of the presence of psychotic disorder among first- and second-degree relatives. The three groups of schizophrenics and the normal controls were compared for differences on a brief neuropsychological testing battery. The four groups showed significant multivariate differences. Patients from multiply-affected families showed significantly greater neuropsychological dysfunction on measures of abstract concept formation, visuomotor-coordination, and attention than patients from families that had only one psychotic relative. Schizophrenics from low-density families showed more severe deficits in fine motor-control than non-familial schizophrenics. These data suggest that abnormalities in those frontal systems that are likely to mediate fine motor control and abstract concept formation may be related to the degree of familial loading for psychotic disorder.

A preliminary study of the neuropsychological heterogeneity of familial schizophrenia.

This exploratory study describes the heterogeneity of the neuropsychological deficits that characterize familial schizophrenia. Forty-six familial schizophrenics showed significantly more variability in abstraction and problem-solving and motor control than 39 non-familial schizophrenics. Cluster analyses of these two neuropsychological parameters indicate that while the non-familial schizophrenics fall into one homogeneous cluster, the familial schizophrenics fall into three relatively distinct clusters which differ significantly in their morbid risk for schizophrenic-spectrum disorder. These preliminary data suggest that frontal lobe deficits are associated with an increased familial risk for schizophrenia.

Predictors of response to lithium in patients with psychoses.

OBJECTIVE: This study sought to characterize a subset of patients with DSM-III schizophrenia or schizophreniform disorder who respond to lithium. METHOD: Sixty-six psychotic patients were given a systematic therapeutic trial of lithium alone. Differences in demographic characteristics, symptoms, and family history of psychotic disorders between the responders and nonresponders to lithium were explored. RESULTS: Responders and nonresponders did not differ significantly in age, duration of illness, length of current episode, distribution of RDC and DSM-III diagnoses, or number of positive symptoms. However, the responders to lithium (N = 10) exhibited a paucity of negative symptoms and an absence of familial schizophrenic spectrum disorders. CONCLUSIONS: These preliminary results suggest the possibility of pretreatment identification of psychotic patients for whom neuroleptic medication could be avoided by therapeutic intervention with lithium alone.

Smooth pursuit eye movement differences between familial and non-familial schizophrenia.

Disrupted smooth pursuit eye tracking characterizes a greater proportion of individuals with schizophrenia than in the normal population. The finding of a similar increased incidence of eye tracking abnormality in first degree relatives of schizophrenics implicates this disorder as a potential biological marker for schizophrenia. To test the assumption that the eye tracking dysfunction of schizophrenics is genetically related, left and right smooth pursuit gain and phase shift were compared between 20 schizophrenics with a family history of schizophrenia or schizophrenia-related disorders, 18 schizophrenics without a family history, as well as for 18 normal controls. Subjects tracked pendular targets on an LED light bar moving at frequencies of 0.2 and 0.7 Hz. Horizontal eye movements were recorded using DC-electro-oculography. Results indicate that schizophrenics with a positive family history had significantly reduced right pursuit gain compared with controls, while right gain for negative family history schizophrenics did not differ from either group. Schizophrenic subjects also were administered neuropsychological tests. Linear regression by groups analyses reveal that neuropsychological measures significantly predicted right gain to slower targets (0.2 Hz) for the positive family history schizophrenics, but not for negative family history schizophrenics.

Patterns of neuropsychological deficit in cases of schizophrenia spectrum disorder with and without a family history of psychosis.

This study was designed to identify the types of neuropsychological deficits that are unique to familial and nonfamilial forms of schizophrenia. Seventy-two patients who met Research Diagnostic Criteria for schizophrenia or schizoaffective disorder, mainly schizophrenic, were divided into two groups on the basis of the presence or absence of a family history of psychosis. The two groups were then compared for differences on six neuropsychological parameters as well as for differences in psychotic symptoms. Multivariate analyses indicated that schizophrenic patients with a family history of psychosis showed significantly higher levels of overall neuropsychological deficit and significantly greater deficits on tests of motor-control and abstraction and problem-solving. Factor analyses indicate that schizophrenic patients with a family history of psychosis show a pattern of specific neuropsychological deficits, while schizophrenic patients without a family history show a pattern of more consistent cognitive deficits. The results of this study indicate that recent-onset schizophrenic patients with and without a family history of psychosis show distinctly different patterns of neuropsychological dysfunction. These data suggest that abnormalities in the dorsolateral prefrontal cortex and nonprimary motor areas may be associated with an increased familial risk for psychotic disorder.

Diagnosis, health beliefs, and risk of HIV infection in psychiatric patients.

OBJECTIVE: The study examined behavioral and cognitive factors that may place mentally ill persons at increased risk of infection by the human immunodeficiency virus (HIV). METHODS: Sixty-one patients consecutively admitted to a psychiatric inpatient unit of a public general hospital completed questionnaires focused on their knowledge about AIDS and their sexual practices. They also participated in a structured interview to assess how their beliefs about health related to changes in health behaviors. Responses of the psychiatric patients, of whom 54.5 percent were men and 61.5 percent were black, were categorized by diagnosis (schizophrenia, bipolar affective disorder, and depression) and were compared with responses of a control group of 32 patients with no identified psychiatric disorder who had been treated in the hospital's medical emergency room. RESULTS: Trends in the data suggested that the psychiatric patients were more likely than the control subjects to engage in high-risk sexual behaviors. Psychiatric patients with different diagnoses appeared to engage in different kinds of high-risk behaviors. Whereas control subjects seemed inclined to change their behaviors as their knowledge about HIV increased, schizophrenic patients appeared willing to change their behavior only if they believed their behavior could really make a difference in whether they would become infected. CONCLUSIONS: The relationship between specific psychiatric symptoms, knowledge about HIV, and factors influencing behavior need to be more thoroughly examined so that clinicians can develop interventions to reduce the risk of HIV infection in mentally ill persons.

The short-term course of familial and nonfamilial schizophrenic-spectrum disorder.

This study was designed to determine if familial and nonfamilial forms of schizophrenia show a different short-term illness course. Sixteen familial and 22 nonfamilial schizophrenics were evaluated on three occasions at regular 6-month intervals over an 18-month period. The familial and nonfamilial groups were compared for differences in positive and negative symptoms of psychosis and interpersonal and occupational role functioning. The data show that familial schizophrenics experience significantly higher levels of positive symptoms of psychosis and significantly worse occupational role functioning. Significant time by family history interactions indicates that the negative symptoms and interpersonal role functioning of the familial schizophrenics changed over the course of follow-up while remaining stable over time in the nonfamilial group. These data provide preliminary support for the hypothesis that familial schizophrenics show a higher degree of impairment during follow-up than nonfamilial schizophrenics.

The course of DSM-III-R schizophreniform disorder.

This study compared the course of illness of 36 patients who received a diagnosis of either DSM-III-R schizophreniform disorder or schizophrenia. Approximately 3.5 and 4.0 years after their index hospitalization, the two groups were compared for differences in positive and negative symptoms of psychosis, interpersonal and occupational role functioning, and other aspects of the deficit state. Multivariate data analyses indicate that the course of illness of the two groups is significantly different (p < .007), and the data also indicate that patient symptoms and functioning changed significantly over time (p < .008). The schizophreniform patients showed a low level of negative symptoms at both follow-ups; schizophrenics initially showed a higher level of negative symptoms, but these symptoms decreased significantly over time (p < .04). These data indicate that the course of DSM-III-R schizophreniform disorder is distinct from the course of schizophrenia.

Risk of HIV infection in the homeless and chronically mentally ill.

Recent data suggest that the homeless and those with chronic mental illness may be at increased risk for HIV infection. A review of the recent literature reveals insufficient rigorously collected data to identify with confidence any particular subgroup of chronically mentally ill patients at increased risk. Nonetheless, it seems reasonable to suspect that those with acute psychosis, a history of substance abuse, or a history of sexual abuse may be at higher risk. Conversely, some data currently support the conclusion that homeless persons are at increased risk for infection due to human immunodeficiency virus (HIV). Clinicians of all disciplines should be aware of these findings and be particularly vigilant when patients are members of both aforementioned groups. Future research should focus upon improving service delivery to the homeless and mentally ill, particularly with regard to sex education and substance abuse intervention. Also, continued research into causal influences of homelessness will ultimately lead to more definitive intervention.

Familial differences between rapid neuroleptic response psychosis and delayed neuroleptic response psychosis.

Recent data suggest that latency of neuroleptic response may be used to separate distinct subtypes of psychotic disorders. In this preliminary study we contrast family patterns of illness of rapid neuroleptic response psychotics and delayed neuroleptic response psychotics. The data show that first-degree relatives of delayed neuroleptic response psychotics evidence higher levels of psychiatric disorder than rapid responders: relatives of delayed neuroleptic response psychotics evidenced a morbid risk for schizophrenic-spectrum disorder that was more than twice as high as the morbid risk for such disorders among relatives of rapid neuroleptic response psychotics. Relatives of delayed neuroleptic responders that received a diagnosis of schizophrenia, schizoaffective, or schizophreniform disorder evidenced significantly more residual impairment than schizophrenic-spectrum relatives of rapid neuroleptic responders. These preliminary data indicate the possibility that latency of therapeutic response to neuroleptic medication may be used to discriminate two familially distinct psychotic disorders and they suggest that delayed neuroleptic response may characterize a familially transmitted poor-outcome disease.

Deficits in initial feature registration of schizophrenics and substance abusers.

Information processing deficits are consistently reported for schizophrenics. The present study evaluated if the longer duration required by schizophrenics to visually recognize a target may qualify, as proposed by previous studies, as a vulnerability and/or trait biological marker. Critical stimulus duration (CSD) was used as the index of initial target registration and recognition. The CSD is the minimal duration, in ms, to meet task criterion, which in the present study was seven consecutive identifications of the target letter 'T' or 'A'. There were 13 normal controls, 11 methadone maintenance experimental controls, 21 chronic schizophrenics and 12 subacute schizophrenics. Analysis of variance revealed that the CSDs of normal controls and subacute schizophrenics were not statistically different (p > 0.05); the CSDs of chronic schizophrenics were not statistically different from methadone controls (p > 0.05), while the chronic schizophrenics and the methadone controls' CSDs were statistically different from the normal controls and the subacute schizophrenics. The results support earlier reports of long target duration required by chronic schizophrenics for feature recognition. Since retarded CSDs were obtained for methadone control but not for acute schizophrenics, the CSD does not qualify as a specificity or a vulnerability index for schizophrenia. A neurophysiological explanation is proposed for the findings.

Schizophrenic feature recognition deficits are independent of task criterion.

The present study determined the minimal exposure time (i.e., critical stimulus duration (CSD) necessary for feature registration and recognition by normals and chronic schizophrenics. Our interest was whether the longer exposure times required by schizophrenics than by normals could be attributed to an inability of schizophrenics to maintain attention when the task criteria were stringent as opposed to 'loose'. The present findings support previous findings of impaired feature recognition by chronic schizophrenics. Chronic schizophrenics' and normals' CSDs were not affected by task criterion. The consistent performance by these groups on the 'loose' and 'rigid' task criteria suggest that if attentional lapses occur then they are as likely to occur for chronic schizophrenics as for normals and they are independent of the task's criterion. It is concluded that impaired feature registration for chronic schizophrenics is a consequence of a deficit at the earliest stage of encoding.

The integration of inpatient treatment and transitional day hospital: application of a problem-solving approach.

Because of the trend in inpatient psychiatry toward a marked decrease in length of hospitalization, clinicians must reconceptualize the manner in which psychosocial treatments are organized in the inpatient milieu. Considerable data suggest that problem-solving therapies may be a productive way to integrate the groups and activities in the therapeutic milieu. This paper describes the application of a problem-solving approach to the therapeutic milieu and indicates that the therapeutic gains from this approach may be enhanced by combining inpatient treatment with a transitional day hospital program. We identify the empirical underpinnings of this model and describe how it has been used to treat a schizophrenic patient. We suggest that problem-solving therapies are effective for promoting behavioral change on the general psychiatric inpatient unit.

A problem-solving approach to group psychotherapy in the inpatient milieu.

Because of the trend toward a marked decrease in length of psychiatric hospitalization, clinicians need to improve the organization of the therapeutic milieu so that behavioral changes can be effected more rapidly. A university general psychiatric unit has adapted a problem-solving model that integrates groups and activities so that each one focuses on complementary behavioral objectives for each patient with the aim of effecting more rapid behavior change. The stages of the model are incorporated in a weekly sequence that begins with a goal-setting group. In a series of subsequent groups, each patient tries to develop and implement a solution to the problem identified that week. At the end of each week, patients participate in a goal review group, with feedback from staff and peers and self-reinforcement. The model can be used with a diverse patient population without interfering with each patient's individual psychotherapy or pharmacotherapy.

Heterogeneity of schizophrenia: relationship to latency of neuroleptic response.

Patients with an index diagnosis of schizophrenia were compared to patients with an index diagnosis of schizophreniform disorder to determine if they differed in latency to therapeutic response to haloperidol. The results of a survival analysis showed that patients with a diagnosis of schizophreniform disorder responded to haloperidol significantly more rapidly than did patients with a diagnosis of schizophrenia. Inspection of time-to-response slopes revealed that approximately 75% of the schizophreniform patients responded to neuroleptics on or before day 8 of treatment, whereas only 20% of the schizophrenic patients responded this rapidly. Forty percent of schizophrenic patients responded between day 8 and day 18, and 30% between day 18 and day 36. These results indicate that schizophreniform disorder has been successfully separated from schizophrenia in DSM-III, at least in relationship to drug response.