Are brain structural abnormalities useful as endophenotypes in schizophrenia?

Endophenotypes, which represent intermediate phenotypes on the causal pathway from the genotype to the phenotype, can help unravel the molecular etiopathology of complex psychiatric disorders such as schizophrenia. Several candidate endophenotypic markers have been proposed in schizophrenia, including neurocognitive and neurophysiological impairments. Over the past three decades, there has been an impressive body of literature in support of brain structural alterations in schizophrenia, but few studies have critically examined whether these abnormalities can be considered useful endophenotypic markers. We critically reviewed the extant literature on the neuroanatomy of schizophrenia in this paper to evaluate their candidacy as endophenotypes. Structural brain changes are robustly associated with schizophrenia, are state independent and may cut across the diagnostic boundaries of major psychotic illnesses. Brain morphometric measures are heritable, co-segregate with the broadly defined neurocognitive and behavioural phenotypes within the first degree relatives of schizophrenia patients and are present in unaffected family members more frequently than in the general population. Taken together, brain morphometric alterations appear largely to meet the criteria for endophenotypes in psychotic disorders. Further work is needed to examine how specific genes and their interactions with the environment may produce alterations in brain structure and function that accompany psychotic disorders.     

Are psychological concepts of Japanese origin relevant?]

This paper was originally given as a lecture in English at the XII World Congress of Psychiatry held in Yokohama, August 2002. Its primary aim was to introduce Morita therapy and the amae psychology to participants from abroad, not as something exotic, but as something intrinsically relevant to them. In my opinion, Morita therapy is based upon Morita's discovery that certain neurotics, whom he eventually named as shinkeishitsu, can recover spontaneously from severe anxiety when placed in isolation and forced to rest in bed without any diversion under the doctor's strict supervision. In other words, only those patients who follow the doctor's advice faithfully through initial isolation and subsequent work-stages can benefit from Morita therapy. It is further argued that it does not do justice to Morita to speculate that he developed his theory and therapy under the influence of Zen. Apropos of the amae psychology what is most noteworthy about it is that its genuine feeling can be conveyed only nonverbally unlike love which one can express verbally when one says "I love you". It is understood that ambivalence refers to the co-existence of love and hate. This love, however, had better be called amae since it is usually nonverbal and not even acknowledged. Narcissism also entails amae, in fact amae turned upon itself, because narcissism consists in denying one's virtual dependence. Interestingly, the word amae alone may suggest a narcissistic state when it is used in the sense of self-indulgence, the usage which is now becoming quite common. Apart from elucidating two psychiatric terms, the concept of amae turns out to be quite handy in describing what transpires in the psychotherapeutic situation including that of Morita therapy. The concluding remark is to emphasize the importance of psychological concepts against the prevailing view of evidence-based psychiatry. It is argued that the objectivity of scientific findings is in the final analysis a postulate guaranteed by the conscience of individual scientists. If so, the same kind of objectivity may be attributed to the observations made by the doctor when he maintains the psychotherapeutic relationship against all odds and also without any compromise of his conscience.     

Are deficits in executive sub-processes simply reflecting more general cognitive decline in schizophrenia?

BACKGROUND: Schizophrenia is associated with both global and specific cognitive deficits. We sought to investigate whether deficits in executive subcomponents differed in their relationship to global cognitive impairments. METHOD: 95 patients were classified according to pre-morbid and current general cognitive ability as having either (a) intact pre-morbid and current general cognitive ability; (b) intact pre-morbid but deteriorated current ability, and (c) deteriorated both pre-morbid and current cognitive ability. All patients completed measures of verbal and spatial working memory, sustained selective attention, attentional set sifting, and inhibitory control. RESULTS: Deficits on both measures of working memory were associated with general cognitive ability. None of the attentional control deficits observed were associated with general ability. Further, spatial working memory deficits were also associated with more severe negative symptoms. CONCLUSIONS: These results provide further evidence of the discreet nature of attentional deficits in schizophrenia. By contrast, this study suggests that working memory deficits may to some extent index more general cognitive decline. Awareness of such overlap is important for schizophrenia genetics studies where working memory measures has been used to index supposedly discreet aspects of cognitive dysfunction.     

Sleep state misperception in schizophrenia: Are negative symptoms at work?

ObjectiveThis study investigates subjective and objective sleep quality to ascertain whether there is a sleep state misperception in schizophrenia patients, as well as analyze potential effect factors.MethodsA total of 148 inpatients with schizophrenia admitted to Beijing HuiLongGuan Hospital were enrolled in this study. The quality of objective sleep was assessed by polysomnography (PSG). On the second day after the successful completion of the PSG evaluation, an interview was arranged to collect patients' recorded subjective evaluation on sleep time, sleep latency, and wake times. Demographic information was collected from an interview, medical records were reviewed, and psychiatric symptoms were assessed using the Positive And Negative Symptom Scale (PANSS).ResultsThe main finding of this study was that schizophrenic patients exhibited sleep state misperception with a pattern of overestimation of total sleep time (TST) as well as sleep efficiency (SE), and an underestimation of sleep onset latency (SOL). Regarding the ± standard deviation of the differences between subjective and objective TST as a clinical acceptable range, the patients were divided into three groups: the overestimate group, the normal group, and the underestimate group. The differences of total PANSS score, especially the PANSS-N score in the overestimate group, the normal group and the underestimate group were significant, and there were significant differences between the overestimate group and the other groups.ConclusionA comprehensive evaluation of the subjective and objective sleep quality in patients with schizophrenia is needed, especially when negative symptoms are severe.     

Are semantic deficits in schizophrenia due to problems with access or storage?

Semantic processing deficits are central to cognitive abnormalities in schizophrenia. Such semantic deficits may be related to either poor access or poor storage of semantic knowledge. 32 schizophrenia patients and 32 matched normal controls performed five semantic processing tasks that examined item-specific consistency over time, the word frequency effect and semantic priming. A subgroup of patients performed tasks on three separate occasions. It is generally assumed that a storage deficit is signalled by item-specific consistent performance, an exaggerated effect of word frequency, and the occurrence of hyperpriming; an access deficit is signalled by the absence of these effects. The data demonstrated item-specific consistency, a frequency effect and significant hyperpriming. The pattern is consistent with a storage deficit of semantic memory in schizophrenia.     

Placebo-controlled trials in schizophrenia: are they ethical? Are they necessary?

The current controversy as to the proper role of the placebo control in the evaluation of new treatments for schizophrenia requires an analysis that is sensitive to both ethical and scientific issues. Clinical equipoise, widely regarded as the moral foundation of the randomized controlled trial (RCT), requires the use of best available treatment as the control in RCT. Scientific criticisms of the use of an active control are examined and none present an insuperable barrier to the use of an active control. Indeed, scrutiny of the most recent argument for the use of placebo controls, 'assay sensitivity', suggests that the use of placebo may be the cause of the problem pointed to. Scientific, regulatory, ethical and legal advantages of the use of an active control are described. While the use of a placebo control may be acceptable in carefully defined circumstances, in most cases the use of an active control in schizophrenia research is ethically and scientifically preferable.     

Are schizophrenia and schizoaffective disorder neuropsychologically distinguishable?

This study sought to objectify the distinction between schizophrenia and schizoaffective disorder in terms of standard tasks measuring verbal and non-verbal cognitive ability, auditory working memory, verbal declarative memory and visual processing speed. Research participants included 103 outpatients with a diagnosis of schizophrenia, 48 with schizoaffective disorder, and 72 non-patients from the community. Schizophrenia patients were impaired on all cognitive measures relative to schizoaffective patients and non-psychiatric participants. Regression-based prediction models revealed that cognitive measures classified schizophrenia patients accurately (91%), but not patients with schizoaffective disorder (35%). In addition, there was no statistical evidence for the unique predictive validity of any specific cognitive task. Patients with schizophrenia were significantly more symptomatic and had greater community support requirements than those with schizoaffective disorder. However, group differences in cognitive performance are insufficient to separate these syndromes of psychotic illness.     

Are relational style and neuropsychological performance predictors of social attributions in chronic schizophrenia?

Attributional style is defined as the pervasive tendency to explain the cause of social actions in terms of oneself, or others, or the context of the event. While the clinical correlates of this aspect of social cognition have been widely researched, its links with relationship style and neuropsychological performance, although hypothesised, have received less attention. This study investigated whether attributional style is predicted by variance in either relationship style or neuropsychological performance in schizophrenia. We assessed attributional style (using the Internal, Personal and Situational Attributions Questionnaire [IPSAQ]), relationship style (using Bartholomew and Horowitz's Relationship Questionnaire), and neuropsychological function (using the Wechsler Abbreviated Scale of Intelligence, the Wechsler Memory Test, and the Cambridge Automated Test Battery) in 73 stabilised outpatients with chronic schizophrenia and 78 controls matched for age and gender. 'Externalising bias' (attributing positive rather than negative events to oneself) was predicted by verbal ability in both patients and controls. 'Personalising bias' (attributing negative events to others rather than to situational factors) was predicted by higher secure relationship style ratings, but only in the patient group. This study highlights the importance of relationship style and neuropsychological performance for different aspects of attributional style in schizophrenia.     

Quality of life and new antipsychotics in schizophrenia. Are patients better off?

The recent introduction of several antipsychotic medications has raised expectations for better pharmacological management of schizophrenia. Although conventional and new neuroleptics (Risperidone, Olanzapine, Seroquel and soon to be released Ziprasidone) are generally comparable in terms of efficacy; the new antipsychotic medications possess a better side-effects profile and are overall, much better tolerated. The reintroduction of Clozapine as an effective antipsychotic for treatment refractoriness has also improved management for a segment of the schizophrenic population who failed to respond adequately to other antipsychotic medications. Such increased benefits from new antipsychotic medications come with a higher acquisition cost that has somewhat strained the historically low psychiatric budgets. The question then was whether the expected benefits of the new antipsychotics can offset the high cost of these medications in the long-term. In that context, quality of life assessment has provided a tool for the comparative analysis of new and conventional antipsychotic medications, particularly regarding their impact on functional status and satisfaction. In a recently concluded study, we demonstrated that the new antipsychotic medications are subjectively much better tolerated and have a more favourable impact on quality of life compared with conventional neuroleptics. The ultimate question is whether such favourable benefits can translate in the future into better compliance with medications and improved long-term outcomes.     

Are we witnessing the disappearance of catatonic schizophrenia?

The decrease in the frequency of diagnosed catatonic subtypes among schizophrenic disorders as a whole during the last 50 years has long been regarded as an established fact. Until now the factors responsible for this development have been under discussion. As it is not clear if there is a true decrease or an ostensible one due to other factors such as changed diagnostic habits or neuroleptic treatment, we examined 174 consecutively admitted schizophrenic patients from three different psychiatric institutions diagnosed according to DSM-IV and Leonhard's criteria. It turned out that-depending on the diagnostic system-the rates of diagnosed catatonias were 10.3% (DSM-IV) and 25.3% (Leonhard's criteria). Comparison of the two original Leonhard cohorts (1938 to 1968, 1969 to 1986) with our own (1994 to 1999) shows a decrease in the frequency of catatonias from 35% to 25%, which-albeit statistically significant-is much less pronounced than in studies that used a narrower definition of catatonia. Here, besides sociocultural developments, the use of neuroleptics seems to effect the decrease in the frequency of catatonias in two ways: on one hand, they cause a decrease of hyperkinesia, excitement, or impulsivity; while on the other hand, they themselves produce motor abnormalities like rigidity, effects that favor the attribution of motoric symptoms to neuroleptics.     

Are cognitive impairments associated with sensitivity to stress in schizophrenia? An experience sampling study

OBJECTIVE: Patients with a diagnosis of schizophrenia display cognitive impairments and abnormal sensitivity to stress. However, little is known about the relationship between these two endophenotypes. METHOD: Neuropsychological tests were administered to 42 patients with schizophrenia or other psychosis to assess cognitive functioning, and the experience sampling method (a structured diary technique assessing current context and mood in daily life) was used to assess 1) appraised subjective stress related to daily events and activities and 2) emotional reaction to these daily life stressors. RESULTS: Multilevel random regression analyses showed that in some instances, cognitive functioning did not alter emotional reaction to stress. In other instances, an inverse relationship was found, indicating that a better performance on neuropsychological tests was related to greater emotional reaction to stress. CONCLUSIONS: The results indicate that emotional reaction to stress in the daily lives of patients with schizophrenia may not be a consequence of cognitive impairments and that the two mechanisms may act through different pathways. Such pathways may be related to the extremes of clinical outcome that have been observed in schizophrenia: an episodic, reactive, good outcome and a more chronic form characterized by high levels of negative symptoms and cognitive impairments.     

Emotion–cognition interactions in schizophrenia

Abstract

Objectives. Negative emotion exerts a considerable influence on cognitive processes. This may have clinical implications in mental illnesses, such as schizophrenia, where negative emotions often prevail. Experimentally this influence can be studied by using olfactory emotion induction. Methods. Fourteen schizophrenia patients and 14 healthy volunteers were investigated with functional magnetic resonance imaging with respect to the neural correlates of emotion–cognition interactions. Emotion was induced by odorants during an n-back working memory task. Results. Similar detrimental effects of negative stimulation on working memory performance were observed in patients and control subjects. Among the neural correlates modulating this interaction a decreased activation emerged in patients in the anterior cingulate and the medial superior frontal cortex and increased activation in the medial orbitofrontal and middle frontal area. Conclusions. During emotion–cognition interaction hypoactivations were found in regions crucial for the monitoring/control of ongoing processes but also for emotion regulation. Decreased activations may reflect failure to adapt to higher task requirements. In contrast, increased activations could be indicative of a greater emotional response and irritation induced by the odour. These patterns may represent the neural correlates of an inefficient control of emotional influences on cognitive processes in patients with schizophrenia.     

Are there subtypes of suicidal schizophrenia? A prospective study

BACKGROUND: Tragically, suicide is not uncommon in schizophrenia. The principal objective of this study was to examine possible subtypes of suicidal schizophrenic patients and identify their clinical and psychopathological profiles at long-term follow-up. METHOD: The study involved 62 patients diagnosed with schizophrenia according to ICD-10 criteria, who were consecutively admitted following a suicide attempt. Of these subjects, 47 (75.8%) could be re-evaluated after 1 year. Sociodemographic, general clinical, and psychopathological variables were evaluated. RESULTS: Two predominant subgroups were identified according to suicidal motivation: psychotic motivation and depressive motivation. At re-evaluation after 1 year, the depressive motivation subgroup showed higher depression and hopelessness scores. This subgroup also had greater educational level, age, and duration of illness, and more frequent existence of previous suicide attempts compared to the psychotic motivation subgroup. Of note in the psychotic motivation subgroup was the presence of hopelessness. The variables of educational level, duration of illness, and previous suicide attempts were the ones that best distinguished these subgroups. CONCLUSION: These findings reinforce the notion that meaningful subgroups occur among suicidal schizophrenic patients. The different psychopathological profiles of the two prominent subgroups suggest the need for a different management approach in each case. The identification of these profiles in both subtypes at long-term follow-up may facilitate their detection by clinicians and, therefore, foster the adoption of appropriate preventive measures against subsequent suicidal behavior.     

Are communication deviance and expressed emotion related to family history of psychiatric disorders in schizophrenia?

Studies have reported that certain measures of intrafamilial transactions are associated with an increased risk both for the initial onset of schizophrenia and for its recurrence following the initial episode of disorder. Two of the most studied of these are communication deviance (CD), a measure of subclinical thought disorder expressed in speech, and expressed emotion (EE), defined as notable attitudes of criticism and/or emotional overinvolvement manifested in a semistructured interview. A previous study (Goldstein et al. 1992) examined whether these two measures were associated with the presence of a diagnosable psychiatric disorder in the biological parents of recent-onset schizophrenia patients. In general, they were not. The present study went one step further. It examined whether these same measures were correlated with family history of schizophrenia or affective disorder in the biological parents and siblings of these same parents. High EE was not associated with a greater family history of schizophrenia spectrum disorders among the parent's parents and siblings but was unexpectedly found to be inversely associated with familial affective disorders. In contrast, CD was associated with a family history of schizophrenia spectrum disorders among the parent's parents and siblings. The findings are consistent with the possibility that CD may be an indicator of a genetic vulnerability factor for schizophrenia.     

Are there common mechanisms in sensation seeking and reality distortion in schizophrenia? A study using memory event-related potentials

A growing literature suggests that the characteristics of sensation seeking and reality distortion expressed in schizophrenia share several mechanisms. In a previous study, the comparison of patients with high vs. low reality distortion using event-related potentials (ERPs) recorded in a recognition memory task for unfamiliar faces identified neural and cognitive anomalies specifically related to the expression of these symptoms. As a follow-up, this study investigated the ERP correlates of sensation seeking in schizophrenia using the same recognition memory protocol. ERPs have been recorded in controls (N=21) and schizophrenia patients separated into high (HSS; N=13) and low (LSS; N=17) scorers according to Zuckerman's Sensation Seeking Scale. The results show a reduced P2a that was found unrelated to reality distortion in the previous study of reality distortion. It identifies interference inhibition impairment as being specifically related to sensation seeking. On the other hand, HSS scorers display enhanced fronto-central and normal P600 effects also found in high reality distortion patients. These results indicate inappropriate context processing and mnemonic binding common to sensation seeking and reality distortion. LSS scorers also display a reduced temporal N300 similar to that found in low reality distortion patients. This anomaly could reflect the lower reactivity to emotionally significant stimuli that underlies anhedonia symptoms. Finally, the N400 effect and a late frontal effect are found in both HSS and LSS. Since they were unrelated to reality distortion, these indices have been related to basic aspects of schizophrenia, e.g., deficient knowledge integration, or other mechanisms, e.g. anxiety or impulsivity. In summary, the present study examines the strategy of investigating variables, such as temperamental characteristics, in addition to symptoms, to show how discrete impairments may contribute to the expression of the illness.     

Are the cognitive deficits associated with impaired insight in schizophrenia specific to executive task performance?

Although impaired insight in schizophrenia has been associated with deficits in executive task performance, the relationship remains unclear. We aimed to clarify this relationship by fractionating executive functioning into the theoretically derived functions of inhibition, working memory, set shifting, and sustained attention. We compared the performance of patients showing impaired insight, patients showing good insight, and a matched control group on measures of each of these executive functions, along with measures of current cognitive functioning and memory. We found that while patients with impaired insight performed significantly below those with good insight on our working memory task, they also performed poorly on measures of general cognitive functioning and memory. We conclude that while impaired insight does appear to be associated with executive deficits, this association may not be specific but may instead relate to cognitive deficits more generally.     

Are impairments of action monitoring and executive control true dissociative dysfunctions in patients with schizophrenia?

OBJECTIVE: Impaired self-monitoring is considered a critical deficit of schizophrenia. The authors asked whether this is a specific and isolable impairment or is part of a global disturbance of cognitive and attentional functions. METHOD: Internal monitoring of erroneous actions, as well as three components of attentional control (conflict resolution, set switching, and preparatory attention) were assessed during performance of a single task by eight high-functioning patients with schizophrenia and eight comparison subjects. RESULTS: The patients exhibited no significant dysfunction of attentional control during task performance. In contrast, their ability to correct errors without external feedback and, by inference, to self-monitor their actions was markedly compromised. CONCLUSIONS: This finding suggests that dysfunction of self-monitoring in schizophrenia does not necessarily reflect a general decline in cognitive function but is evidence of disproportionately pronounced impairment of action monitoring, which may be mediated by a distinct subsystem within the brain's executive attention networks.