Improved ethical guidance for the return of results from psychiatric genomics research.

There is an emerging consensus that genomic researchers should, at a minimum, offer to return to individual participants clinically valid, medically important and medically actionable genomic findings (for example, pathogenic variants in BRCA1) identified in the course of research. However, this is not a common practice in psychiatric genetics research. Furthermore, psychiatry researchers often generate findings that do not meet all of these criteria, yet there may be ethically compelling arguments to offer selected results. Here, we review the return of results debate in genomics research and propose that, as for genomic studies of other medical conditions, psychiatric genomics researchers should offer findings that meet the minimum criteria stated above. Additionally, if resources allow, psychiatry researchers could consider offering to return pre-specified 'clinically valuable' findings even if not medically actionable-for instance, findings that help corroborate a psychiatric diagnosis, and findings that indicate important health risks. Similarly, we propose offering 'likely clinically valuable' findings, specifically, variants of uncertain significance potentially related to a participant's symptoms. The goal of this Perspective is to initiate a discussion that can help identify optimal ways of managing the return of results from psychiatric genomics research.

The algorithmic complexity of multichannel EEGs is sensitive to changes in behavior.

Symbolic measures of complexity provide a quantitative characterization of the sequential structure of symbol sequences. Promising results from the application of these methods to the analysis of electroencephalographic (EEG) and event-related brain potential (ERP) activity have been reported. Symbolic measures used thus far have two limitations, however. First, because the value of complexity increases with the length of the message, it is difficult to compare signals of different epoch lengths. Second, these symbolic measures do not generalize easily to the multichannel case. We address these issues in studies in which both single and multichannel EEGs were analyzed using measures of signal complexity and algorithmic redundancy, the latter being defined as a sequence-sensitive generalization of Shannon's redundancy. Using a binary partition of EEG activity about the median, redundancy was shown to be insensitive to the size of the data set while being sensitive to changes in the subject's behavioral state (eyes open vs. eyes closed). The covariance complexity, calculated from the singular value spectrum of a multichannel signal, was also found to be sensitive to changes in behavioral state. Statistical separations between the eyes open and eyes closed conditions were found to decrease following removal of the 8- to 12-Hz content in the EEG, but still remained statistically significant. Use of symbolic measures in multivariate signal classification is described.

Anticholinergicity and cognitive processing in chronic schizophrenia.

Patients with chronic schizophrenia suffer from alterations in cholinergic functioning due to several factors, including the disease diathesis and pharmacologic treatments. Acetylcholine-cognition relationships are well explored in normals but are unclear in schizophrenia. Prior work indicated serum anticholinergicity does not cause global cognitive impairment in this group (Tracy et al., 1998a), raising the possibility that anticholinergicity normalizes an abnormal hyperactive cholinergic state. Serum anticholinergic levels were determined in 38 chronic schizophrenia patients using an established radioreceptor assay method. Six cognitive functions associated with cholinergic tone in normals were tested. The potential role of autonomic arousal and cigarette smoking were also assessed as both have been linked to cholinergic functioning. Regression analyses showed measures of inhibitory executive control and effortful memory accounted for a greater proportion of the variance in the anticholinergicity measure compared to the other variables. The data demonstrate a relationship between high anticholinergicity and worse performance on two types of attention-resource demanding cognitive processes and do not support the notion that reduced cholinergic tone normalizes a hyperactive cortical acetylcholine substrate. Relevant neuroanatomic structures and implications for models of cognitive deficits in schizophrenia are discussed.

Double-blind study of clozapine dose response in chronic schizophrenia.

OBJECTIVE: This study explored the relative efficacy of three different doses of clozapine. METHOD: Fifty patients who met Kane et al.'s criteria for treatment-refractory schizophrenia or schizoaffective disorder were studied. All subjects were randomly assigned to 100, 300, or 600 mg/day of clozapine for 16 weeks of double-blind treatment. Forty-eight patients completed this first 16 weeks. Of the 50 patients, 36 went on to second and third 16-week trials of double-blind treatment at the remaining doses. RESULTS: Four subjects (8%) responded to the first 16-week condition, and one subject (2%) responded to the next 16-week crossover condition. A chi-square comparison of the response rates from the three dose groups failed to show a significant effect. An analysis of variance (ANOVA) comparison of Brief Psychiatric Rating Scale-Anchored (BPRS-A) total change scores from baseline to last observation carried forward showed a significant dose effect (600>300>100 mg/day) at 16 weeks of treatment. A crossover ANOVA of the BPRS-A total scores from the 48-week study also showed that the main effect for dose was highly significant; the 100-mg/day dose gave the higher (poorer) values, and the 300- and 600-mg/ day doses gave equal (better) values. Gender played a role in clinical response to treatment at 100 mg/day. CONCLUSIONS: Clozapine treatment at 100 mg/day was less effective than at 300 or 600 mg/day. At 100 mg/day, women responded better than did men. The 600 mg/day group had the best results, but an occasional patient required up to 900 mg/day. Overall response rates were lower than expected.

Does akathisia influence psychopathology in psychotic patients treated with clozapine?

BACKGROUND: Akathisia has been reported to predict more severe symptoms and poorer treatment response to typical neuroleptics among patients with schizophrenia. Akathisia has also been associated with symptom exacerbation. This study addressed four questions: 1) Does akathisia predict greater severity in global psychopathology? 2) Is this effect global or specific? 3) Does clozapine treatment alter this relationship? 4) Does severity of psychopathology covary with the level of akathisia? METHODS: Akathisia and clinical symptoms were examined in 33 "treatment refractory" schizophrenic patients treated with clozapine across 16 weeks. Weekly ratings were Barnes Akathisia Rating Scale, Abbreviated Dyskinesia Rating Scale, and Brief Psychiatric Rating Scale (BPRS). Patients were classified as "with" (n = 15) or "without" (n = 18) akathisia. Data analyses involved independent t-test comparisons of selected variables, between-group multivariate analyses of variance across time for BPRS Total scores and Guy's five factors, and partial correlations to assess covariation between BPRS scores and level of akathisia. RESULTS: Akathisia predicted more severe global psychopathology, specific to the Activation (AC) and Thought Disturbance (TH) factors. These relationships did not change with clozapine treatment even when akathisia declined. Interestingly, level of akathisia did not covary with severity of psychopathology. CONCLUSIONS: In this sample, akathisia predicted more severe psychopathology, specific to AC and TH BPRS factor scores. Clozapine treatment did not alter this relationship. Although the presence of akathisia predicted more severe symptoms, the level of akathisia did not covary across time with severity of psychopathology, suggesting an "uncoupling" of these symptom domains.

Relation of serum anticholinergicity to cognitive status in schizophrenia patients taking clozapine or risperidone.

BACKGROUND: A potential beneficial outcome of treatment with certain of the atypical neuroleptics is the reduced risk of cognitive impairment, stemming from purported low affinity for cholinergic receptors. In vitro experiments have shown that clozapine is highly anticholinergic and risperidone is minimally so. In vivo tests of the anticholinergic burden imposed by these medications and its potential cognitive consequences are needed. This study examines anticholinergic burden in schizophrenia patients taking clozapine and risperidone and tests whether this burden is associated with cognitive deficits. METHOD: Serum anticholinergic levels were determined in a sample of 22 chronic schizophrenia patients using the radioreceptor assay method of Tune and Coyle (1980). Fifteen patients received clozapine; 7 received risperidone. Mean +/- SD age of the sample, comprising 12 men and 10 women (68% white), was 44.7 +/- 8.4 years. Mean +/- SD age at onset of schizophrenia illness was 23.5 +/- 7.4 years. Two anticholinergic assays based on blood samples collected 1 week apart were available on each patient. RESULTS: Data indicated that clozapine patients had significantly (p < .001) higher anticholinergic levels at both collection points, and levels for both drugs remained stable over time. The clozapine and risperidone patients had essentially equivalent scores on the cognitive measure. CONCLUSION: These data suggest that anticholinergicity distinguishes clozapine and risperidone in vivo but that this effect is not associated with differences in global cognitive functioning. Results suggest that clozapine, despite producing moderately high in vivo serum anticholinergic levels, still holds clinical advantage over standard neuroleptics in terms of cognitive side effects. Reasons for this lowered risk of cognitive impairment are discussed.

The effects of clozapine on symptom clusters in treatment-refractory patients.

Preliminary results of a double-blind clozapine study in a population of chronic psychotic patients at a state psychiatric facility are reported. Thirty "treatment-refractory" schizophrenic patients given a diagnosis according to DSM-III-R criteria (mean age of 44 +/- 9.1 years and a duration of illness of 24.9 +/- 8.8 years) who received 300 mg or 600 mg of clozapine and randomized in a double-blind fashion were analyzed. Subjects were evaluated using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale on a weekly basis for 16 weeks. Based on the changes in their CGI scores at week 16 of clozapine treatment, subjects were retrospectively categorized as "improvers" (N = 12) and "nonimprovers" (N = 18). The two groups were compared for changes in total BPRS and BPRS factor scores. In terms of total BPRS scores, we expected a difference between the two groups because they were categorized based on changes in their CGI scores. However, the total BPRS scores in improvers showed a significant decrease by week 6 of clozapine treatment. On analyzing the four BPRS factors, the improvers showed improvement in the thinking disturbance factor by week 1 that remained steady from week 7. On the hostility-suspiciousness factor, the improvers showed an improvement across time when compared with nonimprovers. The withdrawal-retardation factor showed improvement in both groups across time, whereas the anxiety-depression factor was least influenced by clozapine. These observations suggested that all BPRS symptom factors did not uniformly contribute to improvement in overall psychopathology, which was observed as a decrease in total BPRS scores.

A comparison of polydipsia prevalence among chronic psychiatric patients using three measurement approaches.

Many previous prevalence studies of polydipsia (PD) have utilized single and often non-biologic measures. In this study we estimated prevalence using specific gravity of urine (SPGU), normalized diurnal weight gain (NDWG), and staff identification (staff ID). Agreement between these two biologic and one behavioral measure was assessed. A total of 572 psychiatric inpatients were assessed for SPGU and NDWG. Unit staff were asked to identify PD patients. Positive and negative PD groups were formed separately based on the SPGU, NDWG, and staff ID data. All three measures were collected on the same day. Prevalence data for the biologic measures varied. The estimate for PD by SPGU (< 1.009 cutoff) was higher (43.4% of sample) than that of NDWG (> 2.5%; 25.4%) or staff ID (21.4%). These prevalence rates did not change substantially after exclusion of medical causes of polyuria. Agreement, assessed by the kappa statistic, was uniformly low among the measures. Weak association between the measures reflects their multidetermined, nonspecific nature, and highlights the lack of a diagnostic standard in the field. The observed prevalence rates must be considered rough approximations. Associations between the measures and certain subject characteristics suggest the measures may identify different types of potential PD patients. These different types of patients are discussed, as are other issues in the measurement of PD. The data suggest estimates of PD are a function of the type of measure used as even biologic measures vary greatly.

Detecting noise in a time series.

A numerical algorithm is presented for estimating whether, and roughly to what extent, a time series is noise corrupted. Using phase-randomized surrogates constructed from the original signal, metrics are defined which can be used to quantify the noise level. A saturation occurs in these metrics at signal to noise ratios (SNRs) of around 0 dB and below, and also at around 20 dB and above. In between these two regions there is a monotonic transition in the value of the metrics from one region to the other corresponding to changes in the SNR. (c) 1997 American Institute of Physics.

Clock drawing in schizophrenia.

The Clock Drawing Test, a task sensitive to cognitive decline in neurological groups, was administered to 27 patients with schizophrenia. Clock drawings were scored for over-all global performance and the frequency of specific qualitative errors. Mean global performance scores indicated a small proportion of the sample was below the threshold typically used to identify dementia, and the patients displayed qualitative Clock Drawing deficits not fully represented in the global performance measure. Qualitative analyses indicated that size errors, graphic difficulty, and spatial planning problems were most common. Lastly, duration of illness was not related to global performance, suggesting that the latter might not reflect deterioration but the stable trajectory of impairment that may be constant through the schizophrenia illness.

A comparison of reading and demographic-based estimates of premorbid intelligence in schizophrenia.

Estimating premorbid intelligence in schizophrenia is difficult because the illness affects aspects of premorbid and postmorbid functioning. We evaluated two qualitatively different estimates of premorbid intelligence in a sample of schizophrenia patients and tested whether: (1) the two indices were related and produced similar IQ estimates, and (2) either index was related to a measure of cognitive deterioration. The Barona Index (BI, a demographically-based instrument) and the National Adult Reading Test (NART, a reading test of irregularly-spelled words) were utilized. Subjects (n = 40) were adult neuroleptic-medicated inpatients with a DSM-III-R diagnosis of chronic schizophrenia (n = 35) or schizoaffective disorder (n = 5). Paired t-tests revealed statistically equivalent BI and NART estimates for Full Scale and Verbal IQs, but significantly higher NART Performance IQs (t[35] = -3.34, p < 0.01). Correlational analyses suggested the two indices were associated but shared modest variance. BI correlations revealed expected associations with education and social position. NART IQs were related to education and a measure of cognitive status. Regression analyses supported the association between NART estimates and cognitive deterioration. Results suggest BI may be a better estimate of premorbid intelligence in schizophrenia as it is less influenced by potential consequences of the disease.

Latent inhibition effects reflected in event-related brain potentials in healthy controls and schizophrenics.

The present study examined the effects of pre-exposure of an irrelevant stimulus on reaction time and the contingent negative variation (CNV) in healthy controls and schizophrenic patients. In Phase I, subjects were either pre-exposed (PE) or not pre-exposed (NPE) to repeated presentations of an auditory probe stimulus (white noise), while engaged in counting auditory nonsense syllables. In Phase II, all subjects were required to produce a rapid motor response to a visual imperative stimulus that was preceded by the previously irrelevant auditory stimulus. During Phase II in controls, for PE as compared to NPE subjects, the build-up of CNV across trials was delayed. In schizophrenics, for both PE and NPE subjects, there was no pre-exposure effect on the CNV component. These findings indicate that ERPs may be useful in explicating the normal latent inhibition effect (poor associative learning to a stimulus after it has been passively pre-exposed) and its disruption in schizophrenia.

Repetitive behaviors in schizophrenia: a single disturbance or discrete symptoms?

Schizophrenia patients often display multiple repetitive behaviors. We investigated relations among nine repetitive behaviors and evaluated the hypothesis that these behaviors are varied manifestations of a single underlying biobehavioral disturbance. Nine repetitive behaviors from the Elgin Behavioral Rating Scale were assessed in 400 schizophrenia patients residing at a state hospital. A majority of patients were smokers (76.3%) and very few had pica (3%). Several other repetitive behaviors showed substantial frequency. A principal components analysis revealed eight of nine behaviors shared at least 10% of their variance with a single, common component. However, a principal factor analysis suggested a five-factor model best represented the data. The five factors and items identifying them were: (1) 'oral consumption' behaviors-polydipsia and smoking; (2) 'Kluver-Bucy' behaviors-bulimia and hypersexuality; (3) 'movement' behaviors-mannerisms/postures and pacing; (4) 'bizarre use of objects'-bizarre grooming and hoarding; (5) 'Pica'. Associations among repetitive behaviors varied. Symptoms such as smoking and polydipsia appeared reliably related, and others such as pica appeared discrete and independent. Overall, the data did not support the 'single disturbance' hypothesis and suggested a multifactorial model is needed to characterize repetitive behavior disturbances in schizophrenia.

Medical comorbidity and schizophrenia: editors' introduction.

Schizophrenia is a heavily biologically determined psychiatric disorder with unequivocal evidence for a major genetic component in its transmission. In addition to its genetic determination, schizophrenia is also associated with increased morbidity and mortality with illness and suffering and with death rates that are higher than would be expected. One of the intriguing possibilities is that there may be some biological link between genetic predisposition to schizophrenia and to other medical diseases. This research on medical comorbidity, originally presented at the Tenth Annual Pennsylvania Conference on Schizophrenia at Norristown State Hospital, requires further research and understanding.

Problems and progress in the diagnosis and treatment of polydipsia and hyponatremia.

Fluid-electrolyte balance is regulated within a narrow range and disturbances in this system are unusual in animals and humans. Studies from the preneuroleptic era to date suggest that up to 25 percent of patients with schizophrenia have polydipsia, suggesting that it is related to the pathophysiology of the psychoses. Polydipsia and the related phenomenon of hyponatremia cause considerable mortality and morbidity. Prevalence studies are limited by imprecise measures available at present. The treatment was limiting water intake when patients reached critical levels of water retention, which however did not improve polydipsia. Recent case reports and open studies have shown that clozapine improves both polydipsia and water retention. The response occurs at low doses and is not related to improvement in psychosis. This may not be applicable to all patients and better understanding of the pathophysiology of polydipsia-hyponatremia would lead to more empirically derived treatments.

Transient fluctuations in cognitive functioning in schizophrenia based on single-case study methods.

The stability of cognitive performance in four schizophrenia patients was examined over a short time period. A cognitive battery highly sensitive to organismic state (the Repeatable Cognitive-Perceptual-Motor Battery, RCPM) was utilized. Single-case statistical methods tested for within-individual change across five assessments at two week intervals. All four subjects showed statistically significant post-baseline variation in a global measure of impairment (average impairment rating score) and in at least 50% of the individual tests having adequate test-retest reliability. Data are interpreted as providing suggestive evidence of transient fluctuations in performance within a stable window of impaired cognitive functioning. These fluctuations appear substantial enough to influence both research and clinical outcomes. The benefits of the single-case methodology employed are discussed. The data suggest that significant transient fluctuations in cognitive performance can be observed in schizophrenia in domains purported to represent vulnerability markers of the disorder. The importance of accounting for these transient fluctuations in the attempt to identify enduring, trait-like characteristics of cognitive functioning in schizophrenia is discussed.

Sensory gating deviance in schizophrenia in the context of task related effects.

To replicate the findings of a sensory gating deficit in schizophrenia, and to determine if normals and schizophrenics are equally affected by cognitively mediated task-relevant factors, 10 healthy and 10 schizophrenic young adults were tested in two experimental conditions. In the first condition a pair of identical auditory clicks (conditioning stimulus and testing stimulus) was administered at an inter-stimulus interval fixed at 500 msec. In the second condition, the second stimulus could have one of two possible frequencies, and subjects were required to count the presentations of one and ignore the other. Subjects also completed two matched blocks of single stimulus (i.e. testing only) presentations to provide a baseline for assessing the effect of the warning stimulus on the evoked response. We found, in disagreement with previous results, that in schizophrenics, passive exposure to the paired stimuli produced a suppression of P50 amplitude to the second stimulus, that did not differ from that found in normals. However, under paired presentation conditions, testing P50 amplitude in normals, but not in schizophrenics, was enhanced by the count/no-count task introduction. We suggest that both groups are equally susceptible to the task independent (possibly "hard-wired") suppressing effect of a conditioning stimulus presentation. However, only normals seem to exhibit a task-dependent effect, whose action at the P50 range demands the presence of a warning (conditioning) stimulus. Inspection of the full epoch data showed an apparently lesser task-related, warning dependent modulation of early ERP activity in schizophrenics, and a normal (or even supernormal) modulation of late activity. We consider this to support a notion of an early processing deficit in schizophrenia.

Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature.

Polydipsia among chronic psychiatric patients is poorly understood and underdiagnosed. It may have three stages: simple polydipsia, polydipsia with water intoxication, and physical complications. Epidemiological surveys have used staff reports and polyuria measures to identify polydipsic patients. Water intoxication has been screened by chart review, weight, or serum sodium data. According to these surveys, polydipsia, not explained by medically induced polyuria, may be present in more than 20% of chronic inpatients. Up to 5% of chronic inpatients had episodes of water intoxication although mild cases may have been missed. Single time point surveys show that 29% of polydipsic patients had presented water intoxication. Methodologically limited clinical studies suggest that polydipsia with water intoxication rather than simple polydipsia may be associated with poor prognosis in schizophrenia. Epidemiological surveys found polydipsia with water intoxication to be associated with chronicity, schizophrenia, smoking, some medications, male gender, and white race. New pathophysiological models need to elucidate these findings.

Attentional influence on the P50 component of the auditory event-related brain potential.

To determine if attentional factors influence the suppression of the auditory P50 in a conditioning-testing paradigm, known as the 'sensory gating' effect, we tested 10 healthy young adults in four experimental conditions. The first condition was the traditional passive conditioning-testing paradigm in which a pair of identical auditory clicks is administered at an interstimulus interval fixed at 500 ms. The effect of interest is a reduction of P50 amplitude in response to the second stimulus. In the next condition, the second stimulus could be one of two possible frequencies and subjects were required to count one and to ignore the other. The third and fourth experimental conditions involved a motor response. In the third condition, subjects were required to make a unimanual button press to the occurrence of the second stimulus. In the fourth condition, subjects were required to discriminate among two possible second stimuli, and make a unimanual button press to the occurrence of the designated stimulus. Subjects also completed four matched blocks of single stimulus (i.e., unpaired) presentations to provide a baseline for assessing the effect of the warning stimulus on the evoked response. We found, in agreement with previous results, that passive exposure to the paired stimuli produced a suppression of P50 amplitude to the second stimulus. However, we also found that suppression of P50 amplitude was not evident when subjects selectively counted the designated stimuli, and was reduced in magnitude when a simple motor response was required and when a selective motor response was based on stimulus discrimination. In addition, we observed that the amplitude of the P50 was larger with unpaired single stimuli than it was either with the first or second stimulus of a pair, regardless of processing demands. Furthermore, variations in processing demands did not affect P50 amplitude when a single stimulus was presented. This pattern of results suggests that the 'sensory gating' effect is not a simple 'hard-wired' inhibitory phenomenon. Rather, it may be one manifestation of an attention regulation process that is activated by a warning stimulus and has either inhibitory or excitatory effects on neural transmission, determined by variations in processing demands. Presentation of a warning stimulus may have an additional, unselective suppressing effect, operating independently of this attention regulating process.