Physiology of schizophrenia, bipolar disorder, and schizoaffective disorder

OBJECTIVE: Endophenotypes have been proposed to identify the genetic and biological substrates of complex disorders. Three physiological inhibitory endophenotypes of large effect size in schizophrenia include suppression of P50 auditory evoked responses, inhibition of leading (small anticipatory) saccades during smooth pursuit eye movements, and cancellation of reflexive saccades in the antisaccade eye movement task. The aim of this study was to determine if the pattern of endophenotype abnormalities within individuals with schizophrenia differed from that within individuals with bipolar disorder. A second aim was to determine whether subjects with schizoaffective disorder, bipolar type, were neurophysiologically more similar to subjects with schizophrenia or subjects with bipolar disorder. METHOD: Endophenotypes were recorded for subjects diagnosed with schizophrenia (N=29), bipolar disorder (DSM-IV-TR) (N=40), and schizoaffective disorder, bipolar type (N=18). Data from normal comparison subjects were used to establish normal performance. RESULTS: Logistic regression determined that P50 ratio and frequency of leading saccades identified subjects with schizophrenia and bipolar disorder with a sensitivity of 95% and a specificity of 83%. The schizoaffective disorder group was split, with six subjects physiologically classified as schizophrenia-like and 12 subjects as bipolar-like. Those classified as schizophrenia-like were significantly younger at illness onset and had higher symptom ratings. CONCLUSION: A composite endophenotype of P50 ratio and frequency of leading saccades is consistent with the current clinical nosology of schizophrenia and bipolar disorder and parses patients with schizoaffective disorder, bipolar type, into two subgroups.     

Early-onset psychotic disorders: course and outcome over a 2-year period

OBJECTIVE: To examine the course and outcome of early-onset psychotic disorders. METHOD: These are data from a longitudinal, prospective study of youths with psychotic disorders. Standardized diagnostic and symptom rating measures were used. RESULTS: Fifty-five subjects with the following disorders have been recruited: schizophrenia (n = 18), bipolar disorder (n = 15), psychosis not otherwise specified (n = 15), schizoaffective disorder (n = 6), and organic psychosis (n = 1). Follow-up assessments were obtained on 42 subjects at year 1 and 31 subjects at year 2. Youths with schizophrenia had more chronic global dysfunction, whereas subjects with bipolar disorder overall had better functioning, with a cyclical course of illness. However, according to results of a regression model, premorbid functioning and ratings of negative symptoms, but not diagnosis, significantly predicted the highest level of functioning over years 1 and 2. CONCLUSIONS: Course and level of functioning differentiated bipolar disorder from schizophrenia. However, premorbid functioning and ratings of negative symptoms were the best predictors of functioning over the follow-up period. These findings are consistent with the adult literature, and they further support that psychotic illnesses in young people are continuous with the adult-onset forms.     

DISC1 and neurocognitive function in schizophrenia

We recently reported an association between DISC1 and schizophrenia, schizoaffective disorder, and bipolar disorder. Convergent evidence suggests that DISC1 has a direct effect on central nervous system functioning. However, there is a paucity of data investigating the effects of DISC1 on neurocognition. Thus, we analyzed the relationship between five single-nucleotide polymorphisms that influenced risk for schizophrenia in our previous study and neurocognition in 250 patients with schizophrenia. DISC1 genotype was related to neurocognitive performance on measures of rapid visual search and verbal working memory, when controlling for age and premorbid intellectual capacity, and explained 3%-4% of the variance. These data suggest that DISC1 is associated with neurocognitive functioning in schizophrenia.     

Association between functioning in adolescence prior to first admission for schizophrenia and affective disorders and patterns of hospitalizations thereafter

BACKGROUND: Kraepelin and Blueler suggested that subtle manifestations of schizophrenia are present in some persons for many years before formal diagnosis and that the severity of these is associated with outcomes in schizophrenia. Empirical support for this hypothesis comes primarily from small samples using retrospectively collected data. AIMS: We tested this hypothesis, for the first time, using a population-based cohort. METHOD: The Israeli Draft Board Registry, which contains measures of intellectual and behavioral functioning for the unselected population of 17-year-olds, was merged with the National Psychiatric Hospitalization Case Registry that contains data on all psychiatric hospitalizations. The database was used to identify adolescents assessed by the draft board at least 1 year prior to their first hospitalization for schizophrenia (n=996) or affective disorder (n=335). RESULTS: Poorer social functioning and organizational ability prior to first admission were associated with more days per year in the hospital for the male schizophrenia group. There were no significant correlations between days per year in the hospital and any of the behavioral functioning measures for the affective group. Among females the higher the previous level of intellectual functioning the fewer the days per year in the hospital in both the schizophrenia group and affective groups. For males no such correlations were evident. The comparisons between patients who had one as opposed to more than one admission found that in both diagnostic groups female patients with one admission had higher pre-first hospitalization intellectual functioning. CONCLUSIONS: Gender and disease specific premorbid deficits have may have differential prognostic value for outcomes in schizophrenia and affective disorders.     

Clozapine in treatment-resistant patients with schizophrenia,schizoaffective disorder,or psychotic bipolar disorder: a naturalistic 48-month follow-up study

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and safety of clozapine in patients with treatment-resistant schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. METHOD: 101 patients with a DSM-III-R diagnosis of schizophrenia (N = 34); schizoaffective disorder, bipolar type (N = 30); or bipolar disorder with psychotic features (N = 37) were naturalistically treated with clozapine at flexible doses over a 48-month period. Data were collected from 1994 to 2000. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions-Severity of Illness scale total predicted scores over time were estimated with random-effects regression models. Time to response to clozapine, defined as 50% reduction of BPRS score, was analyzed in the 3 diagnostic groups using the Kaplan-Meier method. Survival curves were compared using the log-rank test. RESULTS: The BPRS total predicted score halved its baseline value in 3 months for bipolar disorder patients, in 6 months for schizoaffective disorder patients, and in 24 months for schizophrenia patients. The proportion of subjects who satisfied the criterion for response to clozapine after 48 months of follow-up was significantly (p <.01) higher in the schizoaffective and bipolar disorder groups (90.0% and 83.8%, respectively) than in the schizophrenia group (64.7%). Baseline scores on the Global Assessment of Functioning (GAF) showed low levels of psychosocial and occupational functioning in all 3 groups. After 48 months of treatment, GAF scores showed a functional improvement in all 3 groups, with significantly (p <.01) greater improvement in the bipolar disorder group compared with the other groups. CONCLUSION: The findings of this study confirm the efficacy and safety of clozapine for treatment-resistant patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. Patients with schizoaffective disorder and those with bipolar disorder show greater clinical improvement than those with schizophrenia. Patients with bipolar disorder have the shortest time to response and the highest psychosocial and occupational functioning levels. Patients with schizoaffective disorder have the lowest treatment discontinuation rate.     

Diagnostic specificity of poor premorbid adjustment: Comparison of schizophrenia, schizoaffective disorder, and mood disorder with psychotic features

Individuals with schizophrenia have significant deficits in premorbid social and academic adjustment compared to individuals with non-psychotic diagnoses. However, it is unclear how severity and developmental trajectory of premorbid maladjustment compare across psychotic disorders. This study examined the association between premorbid functioning (in childhood, early adolescence, and late adolescence) and psychotic disorder diagnosis in a first-episode sample of 105 individuals: schizophrenia (n=68), schizoaffective disorder (n=22), and mood disorder with psychotic features (n=15). Social and academic maladjustment was assessed using the Cannon-Spoor Premorbid Adjustment Scale. Worse social functioning in late adolescence was associated with higher odds of schizophrenia compared to odds of either schizoaffective disorder or mood disorder with psychotic features, independently of child and early adolescent maladjustment. Greater social dysfunction in childhood was associated with higher odds of schizoaffective disorder compared to odds of schizophrenia. Premorbid decline in academic adjustment was observed for all groups, but did not predict diagnosis at any stage of development. Results suggest that social functioning is disrupted in the premorbid phase of both schizophrenia and schizoaffective disorder, but remains fairly stable in mood disorders with psychotic features. Disparities in the onset and time course of social dysfunction suggest important developmental differences between schizophrenia and schizoaffective disorder.     

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

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

Premorbid behavioral and intellectual functioning in schizophrenia patients with poor response to treatment with antipsychotic drugs

INTRODUCTION: Approximately one third of schizophrenia patients show partial or no response to pharmacotherapy. Despite intensive investigations, the phenomenological and biological characteristics of such patients are far from elucidated. This study examined the premorbid behavioral and intellectual functioning of schizophrenia patients who showed poor response to antipsychotic treatment. METHOD: One hundred twenty-nine schizophrenia patients who showed poor response to treatment were ascertained from a national register and matched by gender, age and education to 129 patients who showed adequate response. The groups were compared on premorbid measures of behavioral and intellectual functions. RESULTS: As a group, treatment-resistant male patients had significantly lower (worse) social functioning [p=0.002], and individual autonomy [p<0.0001] scores before the onset of the illness compared to treatment non-resistant patients. Male and female treatment-resistant patients did not differ from non-resistant patients in premorbid intellectual functioning [p>0.1]. CONCLUSIONS: Low premorbid social functioning and individual autonomy, but not intellectual functioning, could serve as predictors of poor treatment response in schizophrenia.     

Attentional and neurocognitive characteristics of high-risk offspring of parents with schizophrenia compared with DSM-IV attention deficit hyperactivity disorder children

Offspring of individuals with schizophrenia are at increased baseline risk for a range of early mental disorders. Studies investigating the premorbid characteristics of individuals with schizophrenia indicate that they suffer from social, behavioral, attentional and neurocognitive impairments, often resembling attention deficit hyperactivity disorder (ADHD). In this study, we compared the executive functioning and general intelligence among three groups: (i) children and adolescents with DSM-IV ADHD (n=41), (ii) "high-risk" (HR) offspring of parents with DSM-IV schizophrenia, and (iii) normal comparison subjects (n=35). Our results indicated that both HR and ADHD groups had lower Verbal IQ scores. ADHD cases had significantly lower percent correct and total errors in Wisconsin Cart Sorting Test when compared with normal comparison subjects. The HR cases also had lower Performance IQ scores as well as worse abstraction--flexibility and comprehension performance. The HR group was further stratified with (HR-A) and without (HR-NA) comorbid ADHD, and HR-A subjects were significantly noted to be more impaired on most tests. The overall worse performance of HR offspring was attributable to significantly lower performance among the HR-A youth. Further, our results suggested that the most profoundly impaired HR subjects were in fact children and adolescents who also met criteria for ADHD. Future studies with broader neuropsychological test batteries are necessary to investigate the differences and similarities between ADHD and the HR-A subgroup.     

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.     

Clinical characteristics and length of hospital stay among older adults with bipolar disorder, schizophrenia or schizoaffective disorder, depression, and dementia

Although many older adults with serious psychiatric illnesses share common concerns, such as medical comorbidity, personal loss, greater propensity for adverse medication effects, and greater dependence on others for basic needs such as transportation, individualized treatment needs must be differentiated by underlying psychiatric disorders. This retrospective study evaluated clinical characteristics and resource use among 137 older adults with bipolar disorder, schizophrenia or schizoaffective disorder, depression, and dementia who were discharged from an urban, academic medical center's inpatient geropsychiatric unit. The authors found women to be significantly overrepresented among individuals with schizophrenia or schizoaffective disorder compared to those with bipolar disorder, depression, and dementia (P=.034). Among those with bipolar disorder, anticonvulsant medications were predominantly used as mood stabilizers, with only the rare use of lithium. Individuals with schizophrenia or schizoaffective disorder were the youngest group of patients; individuals with dementia were the oldest group (P<.001). This shows significant differences in clinical characteristics among hospitalized older adults with serious mental illnesses. Additional studies are needed on outcomes of serious chronic psychiatric illnesses in later life to optimize care environments for older adult psychiatric patients.     

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

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

Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder

OBJECTIVE: This study examined the treatment response of patients with first-episode schizophrenia and schizoaffective disorder and potential predictors of response. METHOD: First-episode patients were assessed on measures of psychopathology, cognition, social functioning, and biological parameters and treated according to a standardized algorithm. RESULTS: One hundred eighteen patients (52% male, mean age 25.2 years) entered the study. The cumulative percentage of patients responding by 1 year was 87%; the median time to response was 9 weeks. The following variables were significantly associated with less likelihood of response to treatment: male sex, obstetric complications, more severe hallucinations and delusions, poorer attention at baseline, and the development of parkinsonism during antipsychotic treatment. Variables not significantly related to treatment response were diagnosis (schizophrenia versus schizoaffective disorder), premorbid functioning, duration of psychotic symptoms prior to study entry, baseline disorganization, negative and depressive symptoms, baseline motor function, akathisia and dystonia during treatment, growth hormone and homovanillic acid measures, psychotic symptom activation to methylphenidate, and magnetic resonance measures. CONCLUSIONS: Patients with first-episode schizophrenia and schizoaffective disorder have high rates of response to antipsychotic treatment; there are specific clinical and pathobiologic predictors of response.     

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.     

Outcome of schizoaffective disorder at two long-term follow-ups: comparisons with outcome of schizophrenia and affective disorders

OBJECTIVE: This research assessed whether the outcome of schizoaffective disorder is more similar to that of schizophrenia or that of affective disorders. METHOD: The authors conducted a prospective follow-up study of 101 schizoaffective, schizophrenic, bipolar manic, and depressed patients assessed at three times: during hospitalization and 2 and 4-5 years later. The follow-up test battery involved detailed assessment of social functioning, work performance, symptoms, posthospital treatment, and rehospitalization. RESULTS: Outcome for schizoaffective patients 4-5 years after hospitalization differed significantly from that for patients with unipolar depression. However, the differences between schizoaffective and bipolar manic patients were more equivocal. Unlike the patients with bipolar disorder, only a limited number of patients with schizoaffective disorder showed complete recovery in all areas throughout the year preceding the 2-year follow-up and the year preceding the 4- to 5-year follow-up. The differences in outcome between schizoaffective and schizophrenic patients were also mixed. These two groups showed some similarities in outcome, but there were fewer schizoaffective than schizophrenic patients with uniformly poor outcome in all areas. CONCLUSIONS: Overall, schizoaffective patients showed some similarities to both schizophrenic and bipolar manic patients. Schizoaffective patients had somewhat better overall posthospital functioning than patients with schizophrenia, somewhat poorer functioning than bipolar manic patients, and significantly poorer functioning than patients with unipolar depression. The data suggest that when mood-incongruent, schizophrenic-like psychotic symptoms are present in the acute phase, they predict considerable difficulty in outcome, even when affective syndromes are also present, as in schizoaffective disorder. It is likely that schizoaffective disorder is not just a simple variety of affective disorder.     

Case report on the management of depression in schizoaffective disorder, bipolar type focusing on lithium levels and measurement-based care

There is little evidence supporting the management of depression in schizoaffective disorder, bipolar type. Managing bipolar depression can be a daunting task for clinicians. Most bipolar patients spend 80% of their time in the depressive phase of illness. In contrast with full-blown mania, patients and family frequently fail to recognize bipolar depression, which may interfere with early diagnosis and treatment. With only a few medications approved for bipolar depression, treatment becomes very challenging. There is evidence to support that schizoaffective depression has a worse outcome than psychotic depression and nonpsychotic depression. We report a patient with schizoaffective disorder, bipolar type with severe depression who responded to an adequate level of lithium and subsequently, on a combination of lithium and quetiapine. Finally, we emphasize the importance of measurement-based care. To our knowledge, this is the first case report focusing on the management of depression in schizoaffective disorder, bipolar type.     

Social competence in schizoaffective disorder, bipolar disorder, and negative and non-negative schizophrenia

Social skill and role functioning were assessed in matched groups of patients with DSM-III-R schizoaffective disorder, bipolar disorder, and schizophrenia. Schizophrenics were categorized as negative syndrome or non-negative on the basis of the SANS. The negative schizophrenics were significantly more impaired on almost every measure of social functioning. The other three groups were not consistently different from one another. The results suggest that when patients are comparable on dimensions such as duration and severity of illness, schizoaffectives do not occupy an intermediate position between schizophrenics without negative syndrome and bipolar patients. Rather, the three groups exhibit similar degrees of social disability. In contrast, negative syndrome schizophrenics were more impaired even when they were similar in chronicity and severity.     

Clozapine for treatment-refractory schizophrenia, schizoaffective disorder, and psychotic bipolar disorder: a 24-month naturalistic study

BACKGROUND: The aim of this study was to evaluate the 24-month response to clozapine in patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder. METHOD: Ninety-one psychotic patients with a principal DSM-III-R diagnosis of schizophrenia (N = 31), schizoaffective disorder (N = 26), or bipolar disorder with psychotic features (N = 34) were treated naturalistically with clozapine at flexible dosages over a 24-month period. Improvement was assessed by the 18-item Brief Psychiatric Rating Scale and the Clinical Global Impressions-Severity of Illness scale. RESULTS: All patients showed significant improvement 24 months from intake (p < .001). Such an improvement was significantly greater among patients with schizoaffective disorder or bipolar disorder than in patients with schizophrenia (p < .05). The presence of suicidal ideation at intake predicted greater improvement at endpoint. CONCLUSION: Clozapine appears to be effective and relatively well tolerated in acute and long-term treatment of patients with psychotic bipolar disorder or schizoaffective disorder who have not responded to conventional pharmacotherapies.