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OBJECTIVE: Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. METHODS: Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. RESULTS: Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. CONCLUSION: Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The goals of this study were to determine 1) the occurrence of various dissociative phenomena in patients with somatization disorder, 2) the occurrence of six different types of childhood interpersonal trauma in these patients, and 3) the nature of these patients' early family environment. METHOD: Twenty-two patients with somatization disorder and 19 medical comparison subjects completed the Structured Clinical Interview for DSM-IV Dissociative Disorders, the Childhood Trauma Interview, and the Family Functioning Scale. RESULTS: The somatization disorder patients reported significantly higher level of dissociative amnesia than the comparison subjects. The two groups reported similar levels of depersonalization, derealization, identity confusion, and identity alteration. Somatization disorder patients reported significantly greater childhood emotional abuse and more severe forms of physical abuse, relative to the comparison subjects, with chronic emotional abuse being the best predictor of unexplained symptoms. Childhood sexual abuse, separation/loss, and witnessing violence were equally common in the two groups. The somatization disorder group reported significantly more family conflict and less family cohesion. CONCLUSIONS: Only some types of dissociation are more severe in patients with somatization disorder, relative to medical comparison subjects. Many patients with somatization disorder are raised in an emotionally cold, distant, and unsupportive family environment characterized by chronic emotional and physical abuse. Sexual abuse is not a necessary prerequisite for the disorder. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to compare the rehospitalization rates of patients discharged from the hospital while being treated with risperidone, olanzapine, or conventional antipsychotics.Method: By using Israel's National Psychiatric Hospitalization Case Registry, rehospitalization status was monitored for all patients with schizophrenia who were discharged from any inpatient psychiatric facility in Israel while taking risperidone (N=268) or olanzapine (N=313) between Jan. 1, 1998, and Dec. 31, 1998, and a group of patients discharged during that time who were treated with conventional antipsychotics (N=458). Time to readmission over the course of 2 years was measured by the product-limit (Kaplan-Meier) formula.Results: The readmission rate for patients discharged while taking conventional antipsychotics was higher than the rates for patients treated with either risperidone or olanzapine. At 24 months, 67% of the risperidone-treated patients and 69% of the olanzapine-treated patients remained in the community, as compared to 52% of the patients treated with conventional antipsychotics.Conclusions: This study suggests that the rehospitalization rates of patients taking the novel antipsychotics risperidone and olanzapine are not different from each other and are considerably lower than the rate for patients treated with conventional antipsychotics. The results confirm findings of previous studies suggesting that the levels of overall effectiveness of risperidone and olanzapine are not very different and offers evidence that these drugs are more effective in preventing rehospitalization than conventional antipsychotic drugs. [ABSTRACT FROM AUTHOR]

Objective: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system., Methods: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group., Results: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine., Conclusions: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice.

Objective: The authors sought to characterize the symptoms of patients later hospitalized for psychotic disorders in primary mental health outpatient settings, and to investigate whether these symptoms can be used to predict later onset of psychotic illness., Method: This was a population-based historical prospective cohort study using national registers of clinical psychiatric services. The sample (N=114,983) comprised 18- to 21-year-olds serving in the Israeli military and examined in military mental health outpatient clinics across 72 consecutive months., Results: Overall, 1,092 individuals (0.95%) not diagnosed with a psychotic disorder at the time of examination were hospitalized for nonaffective psychotic disorder up to 9 years after the index examination. A principal components analysis of symptoms presented at index examination found that a symptom cluster of thought disorder, perceptual abnormalities, poor orientation, and suicidality was associated with an increased risk for hospitalization for nonaffective psychotic disorder within 14 days after examination (hazard ratio=45.80, 95% CI=22.87-91.73), 15-111 days after examination, (hazard ratio=19.59, 95% CI=13.08-29.33), 112-365 days after examination (hazard ratio=4.94, 95% CI=2.59-9.40), and 1-3.5 years after examination (hazard ratio=3.42, 95% CI=2.21-5.28), but not for hospitalization 3.5 years or more after examination (hazard ratio=1.57, 95% CI=0.91-2.71). Despite the increased risk, the positive predictive values of this symptom cluster were low, ranging from 0.54% to 1.99%., Conclusions: In 18- to 21-year-olds, the presence of psychotic symptoms was associated with later hospitalization for a nonaffective psychotic disorder. However, the low positive predictive values of symptoms elicited in primary mental health care settings suggest that symptoms alone are not useful in predicting later hospitalization for nonaffective psychotic disorder.

Objective: The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT 2A receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia., Method: The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days' withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia., Results: A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score., Conclusions: MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

Objective: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines., Method: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus., Results: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients., Conclusions: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

Objective: Cognitive impairment is a major determinant of functional outcome in schizophrenia. Treatment of cognitive impairment at the time of the first episode may have the potential to change functional outcomes of the illness. This study examined changes associated with treatment with risperidone compared with haloperidol in aspects of cognitive functioning known to be associated with functional outcomes. The study was conducted in a large group of patients experiencing their first episode of schizophrenia., Method: Cognitive assessments were conducted in 533 patients experiencing their first episode of schizophrenia or a related psychosis who had been randomly assigned to receive low doses of risperidone or haloperidol. The cognitive assessments were repeated at several different follow-up intervals; 359 patients were reexamined at the 3-month follow-up. The assessments included examinations of verbal and visuospatial episodic memory, vigilance, executive functioning, processing speed, and verbal fluency. Patients' clinical symptoms were also rated with the Positive and Negative Syndrome Scale., Results: Improvements from baseline were found in the risperidone-treated patients for episodic memory, verbal fluency, vigilance, executive functioning, and visuomotor speed. Haloperidol-treated patients also showed improvements from baseline in episodic memory, vigilance, and visuomotor speed but not in executive functioning or verbal fluency. Comparison of differential treatment effects on a composite measure of cognitive functioning found that risperidone was significantly more beneficial than haloperidol after 3 months of treatment. Changes in Positive and Negative Syndrome Scale scores were correlated overall with improvement in the haloperidol-treated patients but not in the risperidone-treated patients., Conclusions: Treatment with risperidone at the time of the first episode of schizophrenia is associated with wide-ranging improvements in cognitive functioning. Overall improvement is significantly greater with risperidone than with haloperidol. Further, cognitive improvement associated with treatment with risperidone was not influenced by changes in symptoms, but that relationship was significant in haloperidol-treated patients.

Objective: The prevalence of cigarette smoking among schizophrenia patients is significantly higher than in the general population; this may reflect self-medication of symptoms and/or adverse effects of neuroleptics. The authors examined the prevalence of cigarette smoking in apparently healthy adolescents later hospitalized for schizophrenia., Method: Each year, a random sample of male Israeli military recruits, who have been screened and found not to be suffering from major psychopathology, complete a smoking questionnaire. Through the Israeli National Psychiatric Hospitalization Case Registry, 14,248 of these adolescents were followed to determine later psychiatric hospitalization., Results: Of the 14,248 adolescents assessed, 4,052 (28.4%) reported smoking at least one cigarette a day. Over a 4-16-year follow-up, the prevalence of schizophrenia in the entire cohort was 0.3% (N=44). Smokers were at greater risk for later schizophrenia; the adjusted relative risk was 1.94, and the 95% confidence interval (CI) was 1.05-3.58. The number of cigarettes smoked was significantly associated with the risk for schizophrenia. Compared to nonsmokers, adolescents who smoked 1-9 cigarettes/day were 1.38 times (95% CI=0.48-4.00) as likely to be hospitalized later for schizophrenia, and adolescents who smoked 10 cigarettes/day or more were 2.28 times (95% CI=1.19-4.34) as likely; the latter difference was statistically significant., Conclusions: Taken together with the existing data on abnormalities in nicotinic transmission in patients and their relatives, this higher prevalence of smoking in future schizophrenia patients, before the onset of their illness, might indicate that impaired nicotinic neurotransmission is involved in the pathophysiology of schizophrenia.

Objective: Investigating the relationship between premorbid and prodromal status and the clinical manifestations of the first psychotic episode is relevant for understanding the pathophysiology of psychosis and for improving management of the disease. This study examined patterns of premorbid functioning of persons interviewed during their first episode of psychotic illness and examined the relationship of premorbid characteristics with symptom severity and cognitive functioning during the first illness episode., Method: The data were derived from the baseline assessments of a multicenter international drug trial that enrolled 535 patients in their first episode of psychosis. Subjects' scores on the Premorbid Adjustment Scale were used to assign them to groups according to whether their premorbid functioning was stable-good, stable-poor, or deteriorating. The three groups' scores on the Positive and Negative Syndrome Scale, Clinical Global Impression (CGI) severity scale, and a cognitive battery were compared., Results: Almost half of the patients (47.5%) had stable-good premorbid functioning, 37.3% had stable-poor premorbid functioning, and 15.1% had initially good, but later deteriorating, premorbid functioning. Compared to the stable-poor and deteriorating groups, the stable-good group had lower (better) negative syndrome and general psychopathology scores on the Positive and Negative Syndrome Scale and a lower CGI severity scale score. Differences between the stable-poor and stable-good groups were also found on some cognitive measures and on the positive syndrome subscale of the Positive and Negative Syndrome Scale., Conclusions: More than half of the subjects, who were interviewed during their first episode of psychotic disorder, had evident premorbid behavioral disturbances. Poor premorbid functioning before onset of psychosis was associated with more severe symptoms and more severe cognitive manifestations of illness during the first illness episode.

Objective: The premorbid intellectual, language, and behavioral functioning of patients hospitalized for schizophrenia, schizoaffective disorder, or nonpsychotic bipolar disorder was compared with that of healthy comparison subjects., Method: The Israeli Draft Board Registry, which contains measures of intellectual, language, and behavioral functioning for the unselected population of 16- to 17-year-olds, was merged with the National Psychiatric Hospitalization Case Registry, which contains diagnoses for all patients with psychiatric hospitalizations in Israel. The database was used to identify adolescents with no evidence of illness at their draft board assessment who were later hospitalized for nonpsychotic bipolar disorder (N=68), schizoaffective disorder (N=31), or schizophrenia (N=536). The premorbid functioning of these subjects was compared to that of nonhospitalized individuals matched for age, gender, and school attended at the time of the draft board assessment. The diagnostic groups of hospitalized subjects were also compared., Results: Relative to the comparison subjects, subjects with schizophrenia showed significant premorbid deficits on all intellectual and behavioral measures and on measures of reading and reading comprehension. Subjects with schizophrenia performed significantly worse on these measures than those with a nonpsychotic bipolar disorder, who did not differ significantly from the comparison subjects on any measure. Subjects with schizoaffective disorder performed significantly worse than the comparison subjects only on the measure of nonverbal abstract reasoning and visual-spatial problem solving and performed significantly worse than subjects with nonpsychotic bipolar disorder on three of the four intellectual measures and on the reading and reading comprehension tests., Conclusions: The results support a nosologic distinction between nonpsychotic bipolar disease and schizophrenia in hospitalized patients.

Objective: The goal of the current study was to compare premorbid behavioral and cognitive functioning between co-twins discordant for psychotic disorder and between these pairs of twins and pairs of twins with no psychotic disorders., Method: The authors linked data from the Israeli Draft Board Registry, which contains cognitive and behavioral assessments of all 16-17-year-old male Israeli twins, with data from the National Psychiatric Hospitalization Case Registry. Pairs of male twins who were healthy at the time of testing but discordant for psychoses later on were compared with one another and with pairs of healthy male twins., Results: The affected twins performed significantly worse than healthy twins on measures of individual autonomy, social functioning, and physical activity and nonsignificantly worse on measures of abstract reasoning. There were no significant differences in cognitive or behavioral scores between the co-twins who did or did not develop psychotic disorders., Conclusions: The authors conclude that these findings underscore the familial nature of behavioral and cognitive deficits antecedent to psychoses.

Objective: Subtle behavioral and intellectual abnormalities are often present in apparently healthy adolescents who later develop schizophrenia. The authors investigated whether these abnormalities can predict vulnerability for schizophrenia before the first psychotic manifestation., Method: The study consisted of linking the Israeli Draft Board Registry with the National Psychiatric Hospitalization Case Registry. The draft board tests measure intelligence, social functioning, organizational ability, interest in physical activity, and individual autonomy. Patients (N = 509) were compared to nonpatients, i.e., adolescents not appearing in the National Psychiatric Registry (N = 9,215), matched to patients by age, gender, and school attended at time of testing., Results: Healthy male adolescents who were later hospitalized for schizophrenia had significantly lower test scores on all measures than adolescents not reported to the National Psychiatric Registry. The strongest predictors for schizophrenia were deficits in social functioning, organizational ability, and intellectual functioning. When patients were compared to matched nonpatients, the prediction model had a 75% sensitivity, a 100% specificity, a positive predictive value of 72%, and an overall rate of correct classification of 87.5%. Applied to the Israeli Draft Board Registry, the model yielded a sensitivity of 74.7%, a validated specificity of 99.7%, and a positive predictive value of 42.7%., Conclusions: This study demonstrated that simple assessment tools can predict predisposition to schizophrenia in healthy male adolescents. The model's predictive ability does not change as a function of the time elapsed between testing and first hospitalization. This suggests that the model identifies apparently healthy individuals who will manifest the disease later who are not prodromal to psychosis. Easily applied tools allowing early identification of schizophrenia or vulnerability to it may enable early intervention.

Objective: Although many geriatric patients with schizophrenia have been referred to nursing home care, little is known about their characteristics. Across nursing home and chronic hospital settings, the authors directly assessed poor outcome geriatric patients with schizophrenia and contrasted their cognitive, symptomatic, and adaptive functioning to that of acutely admitted patients with a better outcome over the lifetime course of the illness., Method: The subjects were 97 chronically hospitalized patients with schizophrenia, 37 patients with chronic schizophrenia who lived in nursing homes, and 31 acutely admitted geriatric patients with schizophrenia. These patients were rated with the Positive and Negative Syndrome Scale, tested with a neuropsychological battery, evaluated with the Mini-Mental State examination, and rated on a scale of social and adaptive deficits, the Social Adaptive Functioning Evaluation scale., Results: Each group of patients proved discriminable from the other two: nursing home patients displayed the most severe adaptive deficits, and acutely admitted patients were the least cognitively impaired. Cognitive impairment was the strongest predictor of adaptive deficits for all three groups, and negative symptom differences among the groups were smaller than differences in cognitive impairment. Nursing home patients had the least severe positive symptoms, and the acutely ill and chronic hospital patients did not differ on positive symptoms., Conclusions: Cognitive impairment is a predictor of both overall outcome and specific adaptive deficits. These data suggest that interventions aimed at cognitive impairment may have an impact on overall functional status. In comparison, positive symptom severity is less strongly correlated with overall adaptive outcome and is uncorrelated with specific deficits in adaptive skills.

Objective: This study used a cross-sectional design to examine the frequency of occurrence and severity of 10 different signs of thought disorder in schizophrenic patients across the lifespan., Method: Schizophrenic patients, who ranged in age from 19 to 96 years (N = 392), were examined with the Scale for Assessment of Thought, Language, and Communication. The cognitive functioning of the geriatric patients (patients over the age of 64, N = 120) was also assessed., Results: Poverty of speech was more common and more severe in geriatric patients, while four different signs of thought disorder that reflect disconnected speech were less common and less severe in geriatric patients. Analysis of covariance found that the lower severity of disconnection thought disorders in the older patients was not attributable to differences in the amount of speech produced., Conclusions: Aspects of disconnected speech were less severe in older patients, while the severity and frequency of poverty of speech were greater. These findings suggest that the two previously identified separate dimensions of communication disorder in schizophrenia vary differently with age and possibly in their cognitive and biological underpinnings.

Objective: Previous studies have suggested that geriatric inpatients with chronic schizophrenia manifest profound cognitive impairments. This study investigated how these cognitive impairments resemble those seen in degenerative dementing conditions., Method: The neuropsychological battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), widely used to characterize the cognitive deficits of patients with Alzheimer's disease, was used to compare patterns of cognitive impairment in 66 triads of subjects consisting of one elderly patient with Alzheimer's disease, one elderly, institutionalized patient with chronic schizophrenia, and one elderly, cognitively normal comparison subject who were matched on age, gender, and education. For some analyses, the two groups of patients were divided into subgroups according to the degree of their cognitive impairment (mild, moderate, or severe) as determined by their scores on the Mini-Mental State examination., Results: Relative to the comparison subjects, both groups of patients showed cognitive deficits on each of the neuropsychological measures. The schizophrenic patients performed worse than the patients with Alzheimer's disease on tests of naming and constructional praxis but were less impaired on the test of delayed word recall. These differences were consistent across all levels of severity of globally measured cognitive impairment., Conclusions: Consistent with earlier findings from postmortem studies, these findings suggest that major differences exist in the neurobiologic mechanisms responsible for cognitive impairment in schizophrenia and Alzheimer's disease. Effects directly attributable to social and environmental differences between these two groups of patients may also play a role.

Objective: Subtypologies of schizophrenia based on cross-sectional criteria, such as the nomenclature of the DSMs, have not been successful in identifying valid diagnostic subgroups among patients with schizophrenia. A subtypology that uses criteria to classify individuals on the basis of longitudinal deficits in self-care may identify a more valid subgroup of schizophrenic patients., Method: This study describes the clinical characteristics of a group of schizophrenic patients identified on the basis of a longitudinal criterion: at least 5 years of continuous and complete dependence on others for obtaining and maintaining the basic necessities of life, including food, clothing, and shelter., Results: Sixty-one "Kraepelinian" schizophrenic inpatients, when compared to 80 non-Kraepelinian schizophrenic inpatients who were similar in years of illness, age, and education, demonstrated more severe negative symptoms and more severe formal thought disorder; yet the severity of their delusions, hallucinations, and bizarre behavior did not differ significantly. None of the Kraepelinian patients and eight non-Kraepelinian patients met DSM-III-R criteria for schizoaffective disorder., Conclusions: Data from this replication study suggest that Kraepelinian schizophrenic patients, identified on the basis of a longitudinal course characterized by severe dysfunctions in self-care, may represent an alternative, and possibly more valid, method of subtyping schizophrenia.

Objective: The goal of this study was to characterize the symptoms of geriatric, chronically ill, institutionalized schizophrenic patients and investigate age-related differences in schizophrenic symptoms and cognitive performance from early adulthood to late senescence., Method: The Positive and Negative Syndrome Scale and the Mini-Mental State examination were used to assess the schizophrenic symptoms and cognitive performance, respectively, of 393 institutionalized schizophrenic patients stratified into seven groups designated by 10-year age intervals from 25 years to over 85 years., Results: In the comparisons of the seven age groups, significant differences between groups in positive and negative subscale scores on the Positive and Negative Syndrome Scale and in Mini-Mental State scores were revealed. Significant correlations between Mini-Mental State scores and Positive and Negative Syndrome Scale negative symptom scores, but not positive symptom scores, were found for all age groups, except for the youngest patients studied. Current treatment with neuroleptics and prior treatment with ECT, insulin coma, or leukotomy could not account for the poor cognitive performance of the older schizophrenic patients., Conclusions: The older schizophrenic patients continued to experience psychotic and nonpsychotic symptoms in senescence. Their positive symptoms were moderately less severe and their negative symptoms and cognitive impairment were significantly more severe than those of the younger patients. Somatic treatment appeared not to be responsible for the severe cognitive impairment and negative symptoms of the older patients. These data are relevant to chronically hospitalized geriatric schizophrenic patients but not necessarily to all geriatric schizophrenic patients.

Forty schizophrenic patients were treated with clozapine for 5 weeks. Patients were then classified as treatment responders or nonresponders according to a priori established criteria. After only 1 week of treatment, the responders showed a significant decrease on the Brief Psychiatric Rating Scale (BPRS) total score and the psychosis and tension subscale scores. Higher BPRS scores at baseline and larger improvements in BPRS scores after the first week predicted a more favorable outcome in this trial and yielded good classification accuracy.

Objective: This study measured the annual rate of cognitive change in patients with Alzheimer's disease and determined the effects of clinical variables on that rate. It also compared the ability of two cognitive scales to measure change over the entire range of dementia severity., Method: The cognitive subscale of the Alzheimer's Disease Assessment Scale and the Blessed test for information memory and concentration were given to 111 patients with Alzheimer's disease and 72 nondemented elderly comparison subjects at 6-month intervals for up to 90 months. Longitudinal changes in scores on the cognitive subscale were measured with several different methods of data analysis., Results: For the patients with Alzheimer's disease, the annual rate of change in cognitive subscale scores showed a quadratic relationship with dementia severity in which deterioration was slower for mildly and severely demented patients than for patients with moderate dementia. Gender, age at onset, and family history of dementia had no effect on the rate of cognitive deterioration. The comparison group showed a slight improvement in cognitive performance over time. All data analytic methods gave similar results. The cognitive subscale of the Alzheimer's Disease Assessment Scale was more sensitive to change in both mild and severe dementia than was the Blessed test., Conclusions: These results suggest that cognitive deterioration is slow during the early and very late stages of Alzheimer's disease and more rapid during the middle stages. No clinical variables other than degree of cognitive impairment and previous rate of cognitive decline predicted rate of deterioration. These results have implications for treatment trials and attempts to identify subgroups.

The authors compared Alz-50 immunoreactivity in the brain tissue of nine cognitively impaired elderly schizophrenic patients and 13 elderly comparison subjects, both without neuritic plaques or neurofibrillary tangles, and 13 patients with Alzheimer's disease. Alz-50 reactivity was absent in the schizophrenic patients, indicating that geriatric, cognitively impaired patients are unlikely to display the pathology of Alzheimer's disease.

Objective: Clozapine is the only compound proven to be effective in the 20% of schizophrenic patients refractory to treatment with conventional neuroleptics. Although its mechanism of action has not been elucidated, clozapine appears, in contrast to most conventional neuroleptics, to be a potent serotonin (5-HT) antagonist. This study hypothesized that 5-HT function is increased in patients who benefit from clozapine treatment relative to patients who fail to improve on it., Method: The 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) was used as a probe to examine 5-HT function. MCPP (0.35 mg/kg p.o.) was administered in a placebo-controlled design after a 3-week drug-free period to 19 schizophrenic patients. ACTH, prolactin, body temperature, behavior, and MCPP blood level were measured. Patients were then treated with a conventional neuroleptic, and, having failed to respond to it, were treated with clozapine for 5 weeks (up to 600 mg/day)., Results: Patients who responded to clozapine had significantly higher ACTH responses to MCPP during the drug-free state than the patients who failed to benefit from clozapine. Moreover, the degree of improvement with clozapine, particularly the improvement in psychotic symptoms, was strongly correlated with the magnitude of MCPP-induced ACTH release. Other MCPP-induced responses and MCPP blood level were similar for the two groups and did not correlate with the degree of symptomatic improvement with clozapine., Conclusions: Results of this study suggest that MCPP-induced ACTH release, and by inference 5-HT receptor function, may be increased in patients who benefit from treatment with clozapine relative to patients who fail to improve on this drug.

Objective: The possible heterogeneity of the schizophrenia-related personality disorder traits associated with DSM-III criteria for schizotypal personality disorder was investigated using the family history method. A familial relationship to schizophrenia was hypothesized for schizophrenia-related personality disorder traits without coexisting affective personality disorder traits, pure schizophrenia-related personality disorder traits. Alternatively, a familial relationship with borderline personality disorder was hypothesized for schizophrenia-related personality disorder traits with comorbid affective personality disorder traits., Method: Criteria for schizophrenia-related and affective personality disorder traits were used to assess the 588 nonpsychotic first-degree relatives of 55 chronic schizophrenic probands and 67 probands with personality disorders. The probands with one or more DSM-III personality disorders were categorized as having schizotypal personality disorder without borderline personality disorder (pure schizotypal personality disorder), borderline personality disorder without schizotypal personality disorder (pure borderline personality disorder), both disorders, or neither., Results: The morbid risk of all cases of schizophrenia-related personality disorder traits was higher in relatives of probands with schizophrenia and pure schizotypal personality disorder than in relatives of probands with neither schizotypal nor borderline personality disorder; however, it differed only slightly from that observed in the relatives of probands with both schizotypal and borderline personality disorders and pure borderline personality disorder. In contrast, the risk of pure schizophrenia-related personality disorder traits was higher in relatives of probands with schizophrenia and pure schizotypal personality disorder, while the risk of coexisting schizophrenia-related and affective personality disorder traits was lower in both of these groups than among the relatives of probands with both schizotypal and borderline personality disorders and pure borderline personality disorder., Conclusions: These results offer preliminary indications that schizotypal personality disorder features present without comorbid affective personality disorder traits may more specifically characterize the personality characteristics familially related to schizophrenia. Furthermore, they indicate that schizotypal personality disorder features as currently defined are found in relatives of patients other than those with schizophrenia or schizotypal personality disorder.

CSF concentrations of homovanillic acid (HVA) were measured in 10 patients with schizotypal personality disorder and 14 patients with other personality disorders. The patients with schizotypal personality disorder had higher CSF HVA concentrations than the patients with other personality disorders. Furthermore, the psychotic-like schizotypal symptoms correlated positively with the CSF HVA concentrations. These results suggest a central dopaminergic dysfunction associated with the psychotic-like symptoms of schizotypal personality disorder.

The clinical correlates of hypothalamic-pituitary-adrenal (HPA) functioning were examined in 29 patients with probable Alzheimer's disease. The 8:00 a.m. postdexamethasone cortisol levels of these patients were highly correlated with higher agitation scores but not with the degree of depressed mood or memory impairment. The possible neural basis for the association between hypercortisolism and behavioral disturbance in Alzheimer's disease warrants further exploration and replication.

Objective: The initial hypothesis that schizophrenia is a manifestation of hyperdopaminergia has recently been faulted. However, several new findings suggest that abnormal, although not necessarily excessive, dopamine activity is an important factor in schizophrenia. The authors discuss these findings and their implications., Method: All published studies regarding dopamine and schizophrenia and all studies on the role of dopamine in cognition were reviewed. Attention has focused on post-mortem studies, positron emission tomography, neuroleptic drug actions, plasma levels of the dopamine metabolite homovanillic acid (HVA), and cerebral blood flow., Results: Evidence, particularly from intracellular recording studies in animals and plasma HVA measurements, suggests that neuroleptics act by reducing dopamine activity in mesolimbic dopamine neurons. Post-mortem studies have shown high dopamine and HVA concentrations in various subcortical brain regions and greater than normal dopamine receptor densities in the brains of schizophrenic patients. On the other hand, the negative/deficit symptom complex of schizophrenia may be associated with low dopamine activity in the prefrontal cortex. Recent animal and human studies suggest that prefrontal dopamine neurons inhibit subcortical dopamine activity. The authors hypothesize that schizophrenia is characterized by abnormally low prefrontal dopamine activity (causing deficit symptoms) leading to excessive dopamine activity in mesolimbic dopamine neurons (causing positive symptoms)., Conclusions: The possible co-occurrence of high and low dopamine activity in schizophrenia has implications for the conceptualization of dopamine's role in schizophrenia. It would explain the concurrent presence of negative and positive symptoms. This hypothesis is testable and has important implications for treatment of schizophrenia and schizophrenia spectrum disorders.

Objective: This study tested the hypothesis that the risk for affective and impulsive personality disorder traits commonly found in patients with borderline personality disorder would be greater in the first-degree relatives of probands with borderline personality disorder than in two comparison groups., Method: Blind family history interviews were conducted with family informants to assess the extent to which first-degree relatives of 29 probands with borderline personality disorder, 22 probands with other personality disorders who met three or fewer of the criteria for borderline personality disorder, and 43 probands with schizophrenia fulfilled operationalized criteria for the two kinds of personality disorder traits and for other diagnostic categories. The crude proportions of adult relatives with each diagnosis, as well as the age-adjusted morbid risks, were assessed in the three groups of relatives., Results: The risks for affective and impulsive personality disorder traits were independently greater in the 129 relatives of the borderline probands than in the 105 relatives of the probands with other personality disorders and the 218 relatives of the schizophrenic probands. There was no similarly greater risk for any other psychiatric disorder assessed, including major affective disorder. In addition, the relatives of borderline probands with current or past major depressive disorder showed a greater risk for major affective disorders than the relatives of never-depressed probands with other personality disorders but not the relatives of never-depressed borderline probands., Conclusions: These results suggest familial transmission of the hallmark borderline-related personality characteristics and raise the possibility that these familial traits may be partially independent.

Schizotypal patients were found to have a significantly higher mean plasma HVA concentration than normal comparison subjects. Furthermore, plasma HVA concentration positively correlated with "psychotic-like" schizotypal symptoms. These results implicate dopaminergic mechanisms modulating the psychotic-like symptoms of schizotypal personality disorder.

Eye tracking accuracy, which has been found to be impaired in schizophrenic patients and their relatives, was assessed in 26 patients with schizotypal personality disorder, 17 control subjects with other non-schizophrenia-related personality disorders, 29 normal control subjects, and 44 schizophrenic patients. Both schizotypal and schizophrenic patients, but not control subjects with other personality disorders, demonstrated significantly more impaired tracking than the normal control subjects. These results suggest that patients with clinically defined schizotypal personality disorder may be biologically related to schizophrenic patients as part of a spectrum of schizophrenia-related disorders.

CSF homovanillic acid levels showed a significant negative correlation with ventricle-brain ratios (VBRs) in a group of drug-free chronic schizophrenic male veterans, while CSF 5-hydroxyindoleacetic acid levels showed a similar, nearly significant trend. The response of plasma human growth hormone to 0.75 mg of apomorphine also demonstrated a significant negative correlation with VBR in this group, but other measures of central neurotransmitter activity were unrelated to ventricular size.

A diminished cAMP response to prostaglandin E1 (PGE1) in platelets from schizophrenic patients has been demonstrated previously. The authors report that among 35 actively psychotic male schizophrenic patients, the platelet cAMP response to PGE1 was negatively correlated with global symptom severity and with several indexes of positive symptom severity but not with negative symptom severity. If this subsensitivity of platelet PGE receptors extends to brain PGE receptors, schizophrenic patients may have an impairment in the ability of endogenous PGEs to inhibit dopaminergic transmission. Such impairment could have a permissive effect on the production of psychotic symptoms during exacerbations in schizophrenic patients.

The ventricle-brain ratio (VBR) of 28 drug-free male schizophrenic inpatients was significantly higher than that of 21 matched normal control subjects and was not related to severity of positive or negative symptoms. Response to haloperidol in an open 6-week trial using a fixed-dose schedule was not predicted by severity of positive or negative symptoms or by VBR. The nine severely deteriorated patients with chronic "Kraepelinian" schizophrenia had left lateral ventricles 28% larger than their right, whereas the control subjects and other schizophrenic patients did not show ventricular asymmetry.

Chronic schizophrenic patients with the most severe social deterioration have been shown to differ from other chronic schizophrenic patients with respect to measures of left-to-right ventricular asymmetry, negative symptoms, and response to haloperidol treatment. In the current study, the authors investigated the social antecedents of these characteristics of very poor outcome schizophrenia in 69 chronic schizophrenic patients. Poor premorbid sociosexual functioning was associated with more severe left-to-right ventricular asymmetry, greater severity of negative symptoms, fewer positive symptoms, and worse current social functioning. These data suggest that factors associated with severe social deterioration in the end stage of schizophrenia are also associated with premorbid sociosexual impairment.

The authors compared 21 "Kraepelinian" schizophrenic patients who had been ill and dependent on others for the past 5 years with 76 chronic schizophrenic patients in remission or with exacerbations requiring hospitalization. The Kraepelinian patients met the criteria for schizophrenia by more diagnostic systems than the exacerbated patients, were less responsive to haloperidol, had more severe negative symptoms, and had similarly severe positive symptoms. They had cerebral ventricles that were more asymmetrical and a greater family history of schizophrenia spectrum disorders than the other chronic patients. These data suggest that patients with 5 years of illness and complete dependency on others may represent a subgroup of schizophrenia.

Neuroleptic administration has been shown to be superior to placebo in prolonging schizophrenic remission. However, individual patients are able to maintain long periods of remission in the absence of neuroleptic treatment, while others relapse soon after neuroleptic withdrawal. This study attempted to predict time to relapse in 28 schizophrenic patients withdrawn from neuroleptics and challenged with L-dopa for 7 days, then followed until relapse. Time to relapse correlated significantly with L-dopa-induced increase in BPRS score (p = .006). Five of six patients who responded to L-dopa relapsed within 4 weeks after L-dopa administration, while only four of 22 who did not respond relapsed in a comparable period.

The authors found that growth hormone (GH) response to edrophonium was no different in 12 Alzheimer's disease patients than in eight healthy elderly subjects. Previously reported differences could be due to differences in gender or baseline GH concentrations between patients and control subjects.

Cholinergic neurotransmission has long been implicated in the development of depression. In this study seven patients with Alzheimer's disease were given oral oxotremorine, a long-acting cholinergic agonist, to assess the drug's effects on cognitive function. There were unexpected depressive reactions in five of the seven patients; three patients dropped out of the study because of the side effects. Cardiovascular effects of the drug were negligible, but its effect on memory and cognition remains unknown because of the small number of subjects who completed the study.

Thirty-nine patients with chronic schizophrenia for whom hospitalization was clinically indicated received haloperidol for 4 to 6 weeks in a standardized dose schedule. Responders were compared with nonresponders for family history, baseline symptom factors, and ventricle-brain ratio (VBR). The lifetime risk for schizophrenia spectrum disorders was higher among first-degree relatives of nonresponders than among first-degree relatives of responders. Treatment responders had higher baseline scores on the factors of activation and hostile-suspiciousness, but the groups did not differ in any other baseline symptom factor or in VBR. The authors suggest that there is an association between failure to respond to drugs and genetic loading for schizophrenia spectrum disorders.