Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients.

OBJECTIVE: Clozapine is underutilized in the management of treatment-resistant schizophrenia. To understand contributing factors, we analyzed the frequency and causes of clozapine discontinuations that occurred over a 15-year period in a clinical setting. METHOD: Data were extracted from computerized records and from mandatory termination reports for discontinuation events 1993-2007. The reasons for termination were analyzed. RESULTS: Over half of the patients (n = 183/320; 57%) had at least one discontinuation (median time 609 days). The two most common causes for discontinuation were non-adherence (35%) and side-effects (28%). Hematological side-effects accounted for 45% of all side-effect associated discontinuations; most such patients remained eligible for clozapine treatment, and a significant fraction remained on clozapine after rechallenge. Central nervous system side-effects accounted for 35% of side-effect induced discontinuations. General factors significantly associated with discontinuation were African American race, older age at initiation of clozapine and less improvement in psychiatric symptoms. CONCLUSION: In addition to anticipating and addressing causes of non-adherence, psychiatrists should consider clozapine rechallenge in eligible patients and implement measures to mitigate clozapine-associated sedation, seizures, and other side-effects. Future studies should particularly address why African American and older patients may be more likely to discontinue clozapine.

Cognition in schizophrenia and schizo-affective disorder: impairments that are more similar than different.

BACKGROUND: Cognition is increasingly being recognized as an important aspect of psychotic disorders and a key contributor to functional outcome. In the past, comparative studies have been performed in schizophrenia and schizo-affective disorder with regard to cognitive performance, but the results have been mixed and the cognitive measures used have not always assessed the cognitive deficits found to be specific to psychosis. A set of optimized cognitive paradigms designed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) Consortium to assess deficits specific to schizophrenia was used to measure cognition in a large group of individuals with schizophrenia and schizo-affective disorder. METHOD: A total of 519 participants (188 with schizophrenia, 63 with schizo-affective disorder and 268 controls) were administered three cognitive paradigms assessing the domains of goal maintenance in working memory, relational encoding and retrieval in episodic memory and visual integration. RESULTS: Across the three domains, the results showed no major quantitative differences between patient groups, with both groups uniformly performing worse than healthy subjects. CONCLUSIONS: The findings of this study suggests that, with regard to deficits in cognition, considered a major aspect of psychotic disorder, schizophrenia and schizo-affective disorder do not demonstrate major significant distinctions. These results have important implications for our understanding of the nosological structure of major psychopathology, providing evidence consistent with the hypothesis that there is no natural distinction between cognitive functioning in schizophrenia and schizo-affective disorder.

Neuropsychological impairments in deficit vs nondeficit forms of schizophrenia.

BACKGROUND: Previous studies have suggested that functional impairments of the frontal and parietal lobes are related to the deficit symptoms of schizophrenia. The purpose of the current study was to examine whether neuropsychological measures of frontal and parietal lobe function differentiated deficit from nondeficit patients. Neuropsychological measures of temporal lobe function were used as contrast measures. METHODS: The performance of 18 deficit and 21 nondeficit schizophrenic patients was examined on neuropsychological measures of executive, visuospatial, and memory functions, selected on the basis of their association with lesions of either the frontal, parietal, or temporal lobes. The results from the schizophrenic subgroups were compared with the results on the same measures obtained from 30 normal controls. RESULTS: Deficit patients performed more poorly than nondeficit patients on two frontal lobe measures, the Stroop Color-Word Interference and Trails Making B tests, and one parietal lobe measure, the Mooney Faces Closure Test. There were no differences in performance on the temporal lobe measures between the two groups. Both groups performed more poorly on the tests than the normal controls. CONCLUSIONS: The results suggest that deficit patients may have greater performance impairments on neuropsychological measures associated with frontal and parietal neuropsychological abnormalities.

Confirmation of an association between family history of affective disorder and the depressive syndrome in Alzheimer's disease.

OBJECTIVE: The authors' goal was to replicate an earlier finding of a familial liability for depression in Alzheimer's disease. METHOD: The family histories of depression and dementia were compared in 28 patients experiencing a first episode of major depression after onset of Alzheimer's disease and 74 nondepressed patients with Alzheimer's disease. RESULTS: Significantly more families of depressed dementia patients included depressed first-degree relatives. There was no difference between Alzheimer's disease patients with and without depression in the proportion of families with a history of dementia. CONCLUSIONS: Major depression in Alzheimer's disease is associated with a familial liability for depression that is independent of any familial liability for dementia.

Psychopharmacologic and clinical correlates of attention in chronic schizophrenia.

Distractibility and reaction time were measured in 25 clinically stable chronic schizophrenic subjects receiving psychotropic medications. Higher serum neuroleptic levels were associated with lessened distractibility. Extrapyramidal side effects and level of symptoms were each related to slow and variable reaction times.

Attentional impairments in deficit and nondeficit forms of schizophrenia.

OBJECTIVE: Previous studies of attention/information processing impairments in schizophrenia suggest that patients with the deficit syndrome should be characterized by impaired performance on measures of visual information processing. Therefore, the authors examined whether two measures of visual information processing, a degraded stimulus version of the continuous performance test and a forced choice span of apprehension task, were uniquely related to the deficit syndrome. METHOD: Performance on the continuous performance test and span of apprehension task was examined in 20 deficit and 56 nondeficit patients with schizophrenia and in 27 subjects in a normal comparison group. RESULTS: Deficit patients performed significantly less well than both nondeficit patients and the normal comparison group on the continuous performance test and span of apprehension task. There were no significant differences between the nondeficit patients and the normal group on the continuous performance test, but nondeficit patients performed significantly less well on the span of apprehension task than the normal group. Differences between the deficit and nondeficit patients in performance on the continuous performance test and span of apprehension task were not related to total scores on the Brief Psychiatric Rating Scale factor 1 or on the Thought, Language, and Communication scale or to neuroleptic level. CONCLUSIONS: The results suggest that deficit patients are uniquely characterized by impaired performance on the continuous performance test. The deficit patients' differential performance on the continuous performance test may be related to either an inability to activate and allocate attention or an impairment in the perceptual organization of visual information.

Serum levels of anticholinergic drugs and impaired recent memory in chronic schizophrenic patients.

The authors tested working or recent memory in 24 stabilized schizophrenic outpatients who were taking psychotropic medication. Memory performance did not correlate with severity of schizophrenic symptoms, verbal IQ, or serum neuroleptic levels, but there was a significant inverse correlation between serum anticholinergic levels and performance on the memory task. The results suggest that therapeutic doses of anticholinergics may cause subtle impairments of cognitive functions.

Clonazepam treatment of tardive dyskinesia: a practical GABAmimetic strategy.

Because of the efficacy of specific gamma-aminobutyric acid (GABA) agonists in tardive dyskinesia, the authors tested the benzodiazepine clonazepam in a 12-week, double-blind, placebo-controlled, randomized crossover trial in 19 chronically ill patients with tardive dyskinesia who were being treated with neuroleptics. They found a 35% decrease in dyskinesia ratings with clonazepam treatment. The six patients with predominantly dystonic symptoms showed greater benefit than the 13 patients with predominantly choreoathetoid dyskinesias. Tolerance developed to the antidyskinetic effect of clonazepam in the five patients whose long-term use of the drug was followed, but a 2-week clonazepam-free period recaptured its antidyskinetic effect.

Cognitive impairment in adolescents with schizophrenia.

OBJECTIVE: The purpose of this study was to determine whether adolescent schizophrenia is characterized by neuropsychological deficits. METHOD: The performance on a battery of neuropsychological tests of 17 adolescents with schizophrenia (mean age = 15.71 years) was compared with that of 17 normal adolescents (mean age = 15.12 years). RESULTS: Compared with the normal subjects, the patients were impaired on 10 of the 13 measures; larger effect sizes were shown for measures involving working memory and attention than for those involving secondary memory, generative naming, and executive functions. CONCLUSIONS: Adolescents with schizophrenia have generalized cognitive dysfunction, which is most apparent on tests of attention and working memory.

Are there neuropsychologic manifestations of the gene for Huntington's disease in asymptomatic, at-risk individuals?

It has recently been reported that persons at risk for Huntington's disease who test positive for the linked restriction fragment length polymorphism on chromosome 4 display neuropsychologic impairments when compared with at-risk subjects who test negative for this marker. We have studied a substantially larger series of at-risk subjects who have been thoroughly screened for the absence of neurologic or psychiatric features of Huntington's disease and have undergone predictive DNA testing. No evidence of cognitive or emotional differences between marker-positive and marker-negative individuals was found. Consideration of the designs and findings of the two studies indicates that it is premature to conclude that there are neuropsychologic impairments in Huntington's disease that precede the clinical onset of the illness.

Personality changes in Alzheimer's disease.

How personality changes in Alzheimer's disease is not well understood. Accentuations of premorbid personality, systematic shifts in personality traits, and specific personality changes affecting subtypes of patients have been postulated. To investigate which of these alternatives occurs in Alzheimer's disease, caregivers were given a comprehensive personality inventory standardized for use by informants. Caregivers observed more neurotic, less extroverted, and less conscientious behavior. To a smaller extent, patients with Alzheimer's disease were reported as becoming less agreeable and less open. The changes in reports of neuroticism, extroversion, agreeableness, and openness suggested consistent systematic shifts across all patients. Patients with depressive features were reported to have been more neurotic; those with paranoid delusions were reported as having been more hostile. Premorbid personality traits may predispose to subsequent psychiatric symptoms in Alzheimer's disease.

Premorbid personality and behavioral symptoms in Alzheimer disease. Some cautions.

OBJECTIVE: To evaluate the extent to which the previously reported relationship between premorbid personality and psychopathological symptoms after the onset of Alzheimer disease (AD) is due to the use of a single informant for both personality and symptom information. DESIGN: Premorbid personality descriptions of patients with AD were obtained from 2 sources, primary caregivers and secondary informants, using the Personality Assessment Schedule and NEO-PI-R Neuroticism Scale, respectively. All information regarding depression and anxiety since the onset of AD was obtained from primary caregivers using clinical interviews and the Cornell Scale for Depression in Dementia. RESULTS: When data were obtained from the same informant, significant relationships were found between premorbid personality and both presence of depression and the severity of anxiety symptoms. When data were obtained from 2 different informants, the only significant relationship was between premorbid neuroticism and anxiety severity. CONCLUSION: As in a previous report, there was a relationship between premorbid personality and depressive symptoms in AD, but only when personality and symptom information was obtained from the same informant. On the other hand, there was a relationship between premorbid personality and severity of anxiety symptoms both when personality and symptom information came from different informants as well as from the same informant. These data suggest that retrospective bias contributes to the apparent consistency between premorbid personality and some aspects of psychiatric symptoms in AD, specifically depression.

Effects of aging on visuospatial attention: an ERP study.

The effects of aging on visuospatial attention were investigated with event-related brain potentials (ERPs). A central arrow pointed towards (75% valid cues) or away from (25% invalid cues) the location of upcoming visual targets to which subjects made two choice discriminations. Young and older adults responded faster following valid than invalid cues. The absolute magnitude of the cueing effect was larger for older than young subjects, but cueing effects were similar between groups when estimated proportionally to overall response time. Under the present conditions, the electrophysiological manifestations of visuospatial attention were similar for young and older adults. Early ERP components following the target stimulus (P1, N1, Nd1) were slower for older than young subjects, but amplitude was similarly affected by cueing in each group. The temporal correspondence between component latencies and the observed cueing effects are consistent with theories positing that attention amplifies the sensory gain of early perceptual processes. The observation that aging slowed latency of the ipsilateral but not the contralateral P1, is consistent with age differences in interhemispheric transfer times. A broadly distributed 200-400 ms validity effect on ERP amplitude was similar between groups in timing, spatial distribution, and magnitude. The 200-400 ms attention effect appeared to be a modulation of the P3 in younger subjects, as earlier observed. However, the present study dissociated the 200-400 ms attention effects from the P3 component because the P3 did not peak until 526 ms in older subjects.

Neuropsychological function in mild sleep-disordered breathing.

Although a broad range of neuropsychological deficits has been reported in patients with severe sleep disordered breathing (SDB), little is known about the impact of mild SDB on neuropsychological performance. In this study, we compared neuropsychological test performance in two groups of carefully screened volunteers who differed clearly according to the respiratory disturbance index (RDI). Controls (n = 20) were identified on the basis of an RDI < 5; cases (n = 32) had an RDI in the range of 10-30. Cases and controls were well matched with regard to IQ, age, and sex. Cases had significantly more self-reported snorting and apneas and a higher body mass index than controls but did not differ according to sleepiness as measured by either the multiple sleep latency test or the Epworth sleepiness scale. An extensive battery of neuropsychological and performance tests was administered after an overnight sleep study. Cases performed significantly more poorly on a visual vigilance task (perceptual sensitivity, d': 2.24 +/- 0.64 vs. 2.70 +/- 0.53, p = 0.01, for cases and controls, respectively) and a test of working memory, the Wechsler adult intelligence scale-revised digits backwards test (6.12 +/- 2.20 vs. 7.55 +/- 2.22, p = 0.02), than controls. The groups did not differ in their performance on other tests of memory, information processing, and executive functioning. In summary, subjects with mild SDB may manifest a vigilance deficit in the absence of substantial sleepiness. Subjects with a mildly elevated RDI (10-30) without sleepiness do not appear to suffer appreciable deficits in more complex neuropsychological processes (e.g. executive functions).

Apathy in Alzheimer's disease.

Apathy, or loss of motivation, is arguably the most common change in behavior in Alzheimer's disease (AD) but is underrecognized. Apathy represents a form of executive cognitive dysfunction. Patients with apathy suffer from decreased daily function and specific cognitive deficits and rely on families to provide more care, which results in increased stress for families. Apathy is one of the primary syndromes associated with frontal and subcortical pathology, and apathy in AD appears to have multiple neuroanatomical correlates that implicate components of frontal subcortical networks. Despite the profound effects of this common syndrome, only a few instruments have been designed to specifically assess apathy, and these instruments have not been directly compared. Assessment of apathy in AD requires clinicians to distinguish loss of motivation from loss of ability due to cognitive decline. Although apathy may be misdiagnosed as depression because of an overlap in symptoms, current research has shown apathy to be a discrete syndrome. Distinguishing apathy from depression has important treatment implications, because these disorders respond to different interventions. Further research is required to clarify the specific neuroanatomical and neuropsychological correlates of apathy and to determine how correct diagnosis and treatment of apathy may improve patient functioning and ease caregiver burden.

Effects of anticholinergic medication on memory in schizophrenia.

Verbal memory and reaction time of ten schizophrenic patients were compared at two different serum anticholinergic levels. Verbal recall was worse at higher drug levels, while reaction time tended to be improved by anticholinergic treatment. Implications for studies of memory in schizophrenia are considered.

Emotional response as a function of symptoms in schizophrenia.

A group of 30 individuals with schizophrenia and a comparison group of 10 individuals who had never experienced a psychotic episode rated the pleasantness and arousal of 54 slides varying in normative pleasantness. Individuals with schizophrenia rated the slides as less pleasant than the comparison group. Positive symptom, negative symptom and disorganization symptom ratings were made for all patients with schizophrenia. Higher levels of disorganization symptoms were associated with lower ratings of pleasant slides and with more negative mood at the conclusion of the study. The conclusion from previous research that the self-reported emotional response of schizophrenia patients is not diminished compared to other groups may be premature, especially for patients with higher levels of disorganization.

Exploratory factor analysis of MRI brain structure measures in schizophrenia.

Much of the literature shows various regional structural brain abnormalities in schizophrenia, but the complexity and variability of brain makes it difficult to determine how these regions are related. Statistical methods which estimate factors underlying patterns of covariance have not been widely used, but could be useful for analyzing such complex data. We applied exploratory and confirmatory factor analysis procedures to specific cortical and subcortical regional brain volume measures from MRI data in 60 normal and 44 schizophrenic subjects. Basal ganglia, heteromodal cortical gray, and medial temporal lobe factors were present in both the normal and the schizophrenia groups. The factor structure observed in the normal group showed a high degree of bilateral symmetry which is present but disrupted in the schizophrenia group. In the bilateral data, the disruption is most pronounced with medial and lateral temporal lobe structures including entorhinal cortex and anterior and posterior superior temporal gyri. There was a significant correlation between the basal ganglia factor and the heteromodal cortical gray factor in the normal group that was not present in the schizophrenia group. In the unilateral data, left posterior superior temporal gyrus did not load onto any factor in the schizophrenia group. Confirmatory factor analyses showed significant differences between the two groups in factor structure. A number of specific brain regions are affected in schizophrenia, and structural relationships between groups of regions also are abnormal. The results suggest that heteromodal dorsolateral prefrontal and superior temporal cortical gray regions are structurally related, whereas inferior parietal cortical gray is less so. These results should be viewed as preliminary as the ratio of parameters to subjects was relatively low, and replication is needed. However, the results demonstrate the potential utility of latent structure methods such as factor analysis in study of complex relationships in neuropsychiatric data.

Relations of symptoms to cognitive deficits in schizophrenia.

Schizophrenia is characterized by a variety of cognitive dysfunctions. Information-processing dysfunctions differ between clinical subtypes such that nonparanoid schizophrenia patients attend less than paranoid schizophrenia patients to connotative or contextual aspects of stimuli. The positive and negative symptom dimensions are also associated with distinct cognitive deficits. In general, positive symptoms are related to auditory-processing deficits and negative symptoms to visual/motor dysfunctions. The interaction of frontal and septohippocampal brain systems, and failures of information-processing automaticity and self-monitoring, have been proposed as the bases of positive symptoms. Negative symptoms are thought to arise from abnormalities in the complex interactions of frontal and striatal systems. Recent theoretical analyses have recommended a focus on the cognitive and neuropsychological analysis of specific symptoms (e.g., hallucinations and delusions) instead of on the more heterogeneous symptom clusters or dimensions. Studies of specific symptoms indicate that patients with hallucinations have deficits in discriminating the source of information. Delusions have been related to abnormal inference processes as well as abnormal perceptual experiences. Studies should now examine the links between information-processing abnormalities and symptoms over time, as the latter change, within the framework of explicit, disconfirmable theoretical models.

Simple reaction time crossover occurs in schizophrenic outpatients.

A crossover pattern similar to that reported for inpatient schizophrenics (e.g., Bellissimo and Steffy 1972) has now been found for outpatients, and its frequency of occurrence in these outpatients is comparable to that reported for hospitalized patients by DeAmicas and Cromwell (1978). The process-reactive construct was unrelated to crossover in the current study, although crossover is found only in process patients in hospitalized samples. The difference in findings may be due to the insensitivity of the particular measure of this concept used here, or to the lack of validity for the construct in samples of chronic patients in the community and in treatment. The present results, together with DeAmicas and Cromwell's (1978) data suggestive of the presence of crossover in nondisturbed first degree relatives of schizophrenics, are consistent with an interpretation of this reaction time phenomenon as a behavioral marker of vulnerability. This hypothesis warrants study in a more extensive series of patients, and from a longitudinal perspective in which behavioral measures and clinical-social functioning variables are tracked across time.