The incidence of negative symptoms in early schizophrenia, mania and other psychoses

Despite increasing interest in negative symptoms in schizophrenia there has been little work on their incidence in early schizophrenia or in other psychoses. This study examined 79 nondepressive psychotics within 2 years of onset of illness, diagnosed by Research Diagnostic Criteria and assessed for negative symptoms using the Scale for the Assessment of Negative Symptoms. Marked negative symptoms were observed in nearly half of patients diagnosed as suffering definite schizophrenia and were rarely found in other psychoses. Negative symptoms were not significantly correlated with positive symptoms, depression or exposure to neuroleptics, but were correlated with developing extrapyramidal side effects.     

Duration of untreated negative symptoms and duration of active negative symptoms: proof of concepts

Aim: Negative symptoms are responsible for enormous burden in schizophrenia; yet they remain under‐recognized and under‐treated. There is mounting evidence that early intervention is crucial and that response to treatment falls away with chronicity. Current measures of illness duration fail to adequately capture the true time course of negative symptoms and new concepts are required to correct this and to focus clinical attention. The aim of this paper is to introduce accurate measures of negative symptom duration. Methods: Two new concepts, the duration of untreated negative symptoms (DUNS) and the duration of active negative symptoms (DANS), were trialled in a first‐episode sample with primary negative symptoms. Results: The new measures were easy to calculate and more accurately reflected the total duration of negative symptoms than currently available measures. The mean duration of untreated psychosis was 23 weeks, whereas the DUNS was 93.79 weeks. Conclusions: Applicability of the concepts needs confirming by replication with a larger cohort. Introduction of these concepts may have widespread implications for the timely and efficient treatment of negative symptoms and the reduction of the total burden of illness of schizophrenia within society.     

Gender differences in the incidence of definite schizophrenia and atypical psychosis--focus on negative symptoms of schizophrenia.

In a catchment area study of 101 first inceptions of schizophrenia, mania and atypical psychoses, women were significantly more likely to have atypical psychosis and men were more likely to have definite schizophrenia. Negative symptoms such as affective flattening and poverty of speech were already present in many cases, and were significantly increased in patients with definite schizophrenia (geometric mean 5.6) compared with those with atypical psychosis (geometric mean 3.2) and mania (geometric mean 1.5). Negative symptoms were also twice as severe in men (geometric mean 5.5) than women (geometric mean 2.6). There was a significant increase in negative symptom severity with longer illness and greater depression, but the diagnosis and the sex effects were not caused by these factors. We suggest that our findings are further support for the hypothesis that men have a greater biological vulnerability to negative symptoms and consequent social disability in the face of psychosis, particularly a schizophrenic psychosis, and that this may be one explanation for the apparently greater risk of definite schizophrenia and its poorer prognosis in men.     

Genetic antecedents of dopamine dysfunction in schizophrenia.

BACKGROUND: Relatives of schizophrenic probands frequently manifest attenuated features of this illness including the negative symptoms and the milder positive psychotic symptoms. These two symptom dimensions are hypothesized to be associated with decreased and increased brain dopamine (DA) functions, respectively, raising the possibility that DA abnormalities may be present in the relatives of schizophrenic probands. METHODS: Plasma homovanillic acid (HVA), the major DA metabolite and an indicator of brain DA activity, was measured in nonpsychotic, physically healthy first-degree relatives (n = 55) of schizophrenic probands and in normal subjects (n = 20) without a family history of schizophrenia. RESULTS: Plasma HVA inversely correlated with negative symptoms and positively correlated with attenuated positive symptoms. Also, relatives had decreased plasma HVA compared to normal subjects, consistent with the fact that these relatives are characterized by negative symptoms. These findings were not related to major peripheral factors that could affect plasma HVA suggesting that the findings may reflect changes in brain DA activity. CONCLUSIONS: Negative symptoms indicating a genetic diathesis to schizophrenia in relatives may have a biologic basis in reduced DA activity and the DA dysfunction of schizophrenia may have genetic antecedents. This opens an important new avenue for further study of DA in this illness.     

Structural magnetic imaging of the hippocampus in early onset schizophrenia.

BACKGROUND: Previous literature suggests that hippocampal volume reductions in schizophrenia may occur either during adolescence or at the point of transition to overt psychosis. The authors tested these hypotheses by examining the hippocampal formation in adolescents with recent onset schizophrenia. METHODS: We compared the volumes of the left and right hippocampus, obtained using stereologic methods from magnetic resonance brain images, from 40 adolescents with recent onset schizophrenia to those of an equal number of matched healthy control subjects. Symptoms were rated using the Positive and Negative Syndrome Scale. RESULTS: Compared with control subjects, adolescents with schizophrenia had reduced whole brain volume. After adjusting for brain volume, no group differences were observed in hippocampal volume. Duration of illness was negatively correlated with the volume of the left hippocampus. We found no effect of pregnancy and birth complications or family history of psychosis on hippocampal volumes. There was a negative correlation between severity of psychopathology and hippocampal volumes, which was significant for negative symptoms. CONCLUSIONS: Specific hippocampal volume reductions in early onset schizophrenia do not seem to predate the onset of or to occur at the point of transition to psychosis but may develop in adolescence during the early stages of the illness.     

Natural history of schizophrenia subtypes. II. Positive and negative symptoms and long-term course.

The natural history and long-term course of schizophrenia divided by pervasiveness of positive and negative symptoms was explored among 187 schizophrenic patients from the Chestnut Lodge follow-up study. Schizophrenia with many negative symptoms was associated with poor premorbid functioning, insidious onset, partial or no remissions during the first several years of illness, and in most cases a progressive course leading to permanent disability. Schizophrenia with few negative symptoms was associated with good premorbid functioning, acute onset, intermittent early course, and a better prognosis. Positive symptoms predicted future hospitalizations but were less powerful and specific as indicators of differential illness history, course, and long-term functional incapacity. As predictors of long-term outcome, negative symptoms were of greater value measured at index admission several years after illness onset than at first hospital admission. Multivariate analyses indicated that two negative symptoms (anhedonia and affective flattening) contribute significantly to outcome variance independent of their association with premorbid functioning or positive symptoms. Patients with the poorest long-term outcome tended to show an increase in negative symptoms during the early years of their illness. Progressive negative symptoms early in the course of schizophrenia may thus reflect or signal a process leading to long-term functional disability.     

The power to resist: The relationship between power,stigma, and negative symptoms in schizophrenia

Stigmatizing beliefs about mental illness can be a daily struggle for people with schizophrenia. While investigations into the impact of internalizing stigma on negative symptoms have yielded mixed results, resistance to stigmatizing beliefs has received little attention. In this study, we examined the linkage between internalized stigma, stigma resistance, negative symptoms, and social power, or perceived ability to influence others during social interactions among people with schizophrenia. Further, we sought to determine whether resistance to stigma would be bolstered by social power, with greater power in relationships with other possibly buffering against motivation/pleasure negative symptoms. Fifty-one people with schizophrenia or schizoaffective disorder completed measures of social power, internalized stigma, and stigma resistance. Negative symptoms were assessed using the Clinical Assessment Interview for Negative Symptoms (CAINS). Greater social power was associated with less internalized stigma and negative symptoms as well as more stigma resistance. Further, the relationship between social power and negative symptoms was partially mediated by stigma resistance. These findings provide evidence for the role of stigma resistance as a viable target for psychosocial interventions aimed at improving motivation and social power in people with schizophrenia.     

Negative symptoms of schizophrenia and compliance with medication

Poor compliance with medication has been reported in up to 40 percent of outpatients with schizophrenia. This study examines the relationship between compliance with depot neuroleptic medication and severity of negative symptoms of schizophrenia. Compliance with depot neuroleptic medication during the preceding year was calculated for 64 patients with a DSM-III-R diagnosis of schizophrenia. The severity of negative symptoms was assessed using the Scale for the Assessment of Negative Symptoms (SANS). Patients who complied poorly with medication had significantly greater severity of negative symptoms of schizophrenia, especially avolition, apathy, and alogia. Duration of illness and duration of prescribed medication were independently associated with compliance, but no other features were associated in the multiple regression model. These findings suggest that negative symptoms are one of the factors of importance in determining whether a patient will attend for depot neuroleptic medication.     

Symptomatological and cognitive predictors of insight in chronic schizophrenia

Studies of schizophrenia show lack of agreement about the relationship of symptomatological and cognitive factors to insight. In this study, positive and negative symptomatology and cognitive function were assessed by the Positive and Negative Syndrome Scale (PANSS), the Wisconsin Card Sorting Test (WCST), and the Wechsler Adult Intelligence Scale Revised (WAIS-R) in male chronic schizophrenic patients in relation to level of insight measured with the Japanese version of the Schedule for the Assessment of Insight (SAI-J). Negative symptoms were significantly and negatively associated with overall insight, particularly with treatment compliance and recognition of mental illness. The present findings suggest that aspects of insight such as treatment compliance and recognition of mental illness are negatively associated with negative symptoms.     

Longitudinal study of cognitive function in first-episode and recent-onset schizophrenia.

OBJECTIVE: Whether cognitive function in schizophrenia deteriorates, improves, or remains stable is a crucial question. Few studies have examined the longitudinal stability of cognitive function and the relationship between cognitive performance and clinical symptoms over time in a cohort of well-treated patients with schizophrenia. METHOD: In the present study, 54 patients with first-episode and recent-onset schizophrenia completed a comprehensive cognitive test battery and were rated on symptom measures at index hospitalization and again after 5 years. RESULTS: Performance IQ and full-scale IQ significantly improved, whereas verbal IQ did not change. Group performance improved on some of the neuropsychological tests, including the Circle A letter-cancellation task, free recall of logical memory test score, and the Wisconsin Card Sorting Test. Mean finger-tapping performance worsened over time, whereas performance on other neuropsychological tests did not change. Negative, psychotic, and disorganized symptoms significantly improved over the time period. Changes in negative symptoms were correlated with performance changes in verbal IQ and full-scale IQ but not performance IQ. Improvement in verbal cognition was observed when negative symptoms improved. Psychotic and disorganized symptom dimensions were not correlated with any IQ measure. CONCLUSIONS: These results indicate that in a cohort of young patients receiving neuroleptic treatment early in their illness, cognitive performance does not deteriorate--and may improve. Only one of the three symptom dimensions--negative--was associated with change in cognitive performance. This study supports the view that negative symptoms are associated with a poor long-term cognitive outcome and may be closely related to the primary cognitive deficit in schizophrenia.     

Symptoms and cognition in geriatric schizophrenia

From the first manifestation of schizophrenic psychosis onwards numerous psychopathological symptoms and cognitive impairments occur, which are affected by age and the aging process. Clinical trials report a pronounced incidence of positive symptoms in late-onset schizophrenia. Negative symptoms are often observed in chronic-course psychosis, but occur infrequently in late-onset-schizophrenia. With respect to cognitive performance neuropsychological studies have shown a decrease in the test performance of permanently hospitalised patients with chronic schizophrenia as age and illness duration increased. Comparative studies of early and late-onset patients in most cases have reported no differing profiles of cognitive performance. Some investigators propose that late-onset schizophrenia may be a prodromal symptom of dementia. However, current studies show that late-onset schizophrenia is basically comparable to its early-onset counterpart. The manifestation in youth and early adulthood may be prevented by specific protective factors until aging-related parameters lead to the onset of symptoms during late life.     

Experimental models of schizophrenia

The Kraepelinian subtypes, developed early in the century, recognize the heterogeneity of schizophrenia but do not reliably predict differences in response to classical neuroleptics. The newer distinction of positive and negative syndromes in schizophrenia carry promise as an approach to identifying meaningful clinical and neurobiological dimensions. The present review summarizes the supportive evidence from a series of investigations using the Positive and Negative Syndrome Scale (PANSS), and a hypothesis on the pathophysiology of negative and positive symptoms is advanced. Our data suggest that: (a) positive and negative syndromes in schizophrenia represent stable, independent dimensions and not co-exclusive subtypes; (b) both are unrelated to the progression of illness; (c) they are differentially related to fundamental aspects of schizophrenia, including premorbid adjustment, cognitive development, family psychiatric history, the cognitive and neuropsychiatric profiles, dopaminergic functions, drug response, and subsequent course; (d) together with depression and excitement, they comprise the fundamental symptomatic components of schizophrenia, which, in their interaction, can account for the specific Kraepelinian subtypes. We have proposed that negative symptoms represent the core pathology in schizophrenia and may be understood as a variant of parkinsonism, hence characterized by dopaminergic deficiency and increased cholinergic activity. This view is supported by the striking overlap with Parkinsonism in regard to clinical features, neurochemistry, pharmacology, neuropathology, and neuroradiology. Positive symptoms are thought to reflect increased dopaminergic activity, which may arise as a compensatory adaptive mechanism to overcome the progressive dopamine loss in the maturing brain. The early onset of schizophrenia by comparison to Parkinson's disease may explain why schizophrenia entails more pronounced positive symptoms, development deficits, and cognitive, social, and emotional impairments. We describe evidence that pineal calcification, which may reflect disturbance of melatonin functions, appears to be a nongenetic factor in schizophrenia associated with perinatal injury. This may in part underlie the negative syndrome and its response to antipsychotic compounds with serotonergic (5-HT) antagonism.     

Are negative symptoms associated with functioning deficits in both schizophrenia and nonschizophrenia patients? A 10-year longitudinal analysis

The current analyses assess the functional correlates of negative symptoms across diagnoses and across time to assess the appropriateness of a dimensional approach to the study of negative symptoms--specifically, whether negative symptoms should be studied as a single construct across diagnostic groups. Seventy-two schizophrenia/schizoaffective, 36 other psychotic, and 42 nonpsychotic depressed patients were recruited at index hospitalization and were followed up 4.5, 7.5, and 10 years later. At each followup assessment, data were collected on symptoms and adaptive and cognitive functioning. Analyses indicated that negative symptoms showed some similar functional associates in all three diagnostic groups, although results were strongest for the schizophrenia spectrum patients. Negative symptoms at the 10-year followup were associated with different patterns of social deficits prior to index hospitalization in the three diagnostic groups. The data provide some support for a dimensional approach to the study of mental illness, with negative symptoms associated with deficits across diagnosis, but also provide evidence of some diagnostic differences.     

Clinical heterogeneity in schizophrenia and the pattern of psychopathology in relatives: results from an epidemiologically based family study

Individuals with schizophrenia vary widely in their symptoms, course of illness and outcome. Family background is the strongest known risk factor for schizophrenia. We know little of the relationship between clinical variability in this disorder and the level of familial vulnerability to schizophrenia and other major mental disorders. Therefore, in schizophrenic probands meeting DSM-III-R criteria (n= 126) from the epidemiologically based Roscommon Family Study, we systematically assessed 9 major symptoms, course, global outcome, Schedule for Negative Symptoms and the Levels of Functioning Scale. These clinical characteristics were related to the risk of mental disorders in first-degree relatives assessed by personal interview or hospital records (n= 354) utilizing both the “familial/sporadic” and the Cox proportional hazard models. Using either statistical method, no consistent and significant relationship was found between any of our measures of symptoms, course or outcome and the risk for schizophrenia or schizophrenia spectrum disorders in relatives. Similarly, no relationship was found between these clinical measures and the risk for affective illness, alcoholism or anxiety disorders. Our results are not consistent with previously articulated hypotheses that negative symptoms or poor outcome in schizophrenia reflect a high familial liability to illness. While familial factors contribute substantially to an individual's vulnerability to schizophrenia, our results suggest that once an individual is affected, these same factors do not strongly influence either the kinds of symptoms displayed or the course and outcome of the illness.     

Food and Drug Administration perspective on negative symptoms in schizophrenia as a target for a drug treatment claim

Negative symptoms of schizophrenia are not adequately addressed by available treatments for schizophrenia. Thus, it is reasonable to consider them as a target for a drug claim. This article describes the thought process that the Food and Drug Administration (FDA) will undertake in considering negative symptoms of schizophrenia as a novel and distinct drug target. Beyond this basic question, this article identifies a number of design issues that the FDA needs to consider regarding how best to conduct studies to support claims for this target. These design issues include (1) what population to study, (2) what phase of illness to target, (3) whether to focus on the negative symptom domain overall or on some specific aspect of negative symptoms, (4) the role of functional measures in negative symptom trials, and (5) optimal designs for targeting drugs for add-on therapy or broad-spectrum agents.     

Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study

It was reported that ritanserin, a 5HT2A/2C antagonist, improves negative symptoms when added to neuroleptics in inpatients with predominantly negative symptoms. Nevertheless, the results of published studies are contradictory so far. This study was designed to investigate the effect of ritanserin added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double blind and randomized clinical trial. Eligible participants in this study were 40 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion, 20 to risperidone 6 mg/day plus ritanserin 12 mg/day (6 mg bid) and 20 to risperidone 6 mg/day plus placebo. The principal measure of the outcome was Positive and Negative Syndrome Scale (PANSS). Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and ritanserin showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores. The present study indicates ritanserin as a potential adjunctive treatment strategy for the negative symptoms of schizophrenia. Nevertheless, results of larger controlled trials are needed, before recommendation for a broad clinical application can be made.     

Quality of life and psychopathology during the course of schizophrenia

Objective

This study evaluated a population of outpatients with stable schizophrenia to analyze if relationships between patterns of symptomatology and quality of life (QOL) change during the time course of illness.

Methods

We recruited 168 outpatients with stable schizophrenia, and we further divided our sample into 3 groups of patients (≤36, 37-72, and >72 months of illness). Psychiatric assessment included the Quality of Life Scale, the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, and the Clinical Global Impression-Severity Scale. All clinical variables significantly related to Quality of Life Scale scores were subsequently analyzed using a multiple stepwise regression to assess their independent contribution to QOL in the 3 patient groups.

Results

Quality of life and symptoms profiles were similar among patient groups. After controlling for potentially confounding variables, multiple regression revealed that depressive symptoms appeared to have a stronger relationship with QOL during the early 3-year course of the illness.In the period between 4 and 6 years of illness, negative symptoms were the most reliable predictors of QOL. After the 6-year course of illness, negative symptoms remained the most reliable predictors of QOL, together with severity of illness, whereas positive and depressive symptoms had a minor role.

Conclusions

Despite similar QOL and symptoms profiles, these findings suggested that relationships among patterns of symptomatology and QOL change during the course of schizophrenia.     

Impact of primary negative symptoms on functional outcomes in schizophrenia

ObjectiveNegative symptoms are known to undermine functional outcomes in people with schizophrenia; however, most studies have not accounted for whether these symptoms were primary or secondary to other psychopathological factors. The present study examined the impact of primary negative symptoms on functional outcomes in patients with schizophrenia.MethodThe sample included 1427 patients with schizophrenia who completed the baseline visit in the CATIE study. Symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary Depression Scale, extrapyramidal side effects with the Simpson-Angus scale, and functional status with the Heinrichs-Carpenter Quality of Life Scale.ResultsNegative symptoms were significantly and inversely related to each domain of functioning examined. These relationships remained after statistically controlling for the influence of potential sources of secondary negative symptoms. In addition, the relationships between negative symptoms and specific domains of functioning remained in patients who had mild/absent positive, depressive, anxiety and extrapyramidal symptoms. Negative symptoms were associated with functional outcomes even in antipsychotic-free patients.ConclusionsPrimary negative symptoms significantly contribute to the functional impairment seen in people with schizophrenia. A better understanding of the etiology and pathobiology of these symptoms is required to guide the search for effective therapeutics that promote functional recovery.     

Decreased 5-HT1A receptor binding in amygdala of schizophrenia.

BACKGROUND: On the basis of postmortem data and the pharmacological action of atypical antipsychotics, serotonin-1A receptors are of interest in the study of the pathophysiology of schizophrenia. To investigate serotonin-1A receptors in schizophrenia and their relation to symptoms, we measured the availability of serotonin-1A receptors in patients with schizophrenia using positron emission tomography with [carbonyl-(11)C]WAY-100635. METHODS: Serotonin-1A receptor binding of 11 patients with schizophrenia (8 drug-naive and 3 drug-free) was compared with that of 22 age-matched and gender-matched healthy control subjects. Symptoms were assessed using the Positive and Negative Syndrome Scale. Serotonin-1A receptor binding in selected regions of interest was quantified by binding potential obtained by the reference tissue method. RESULTS: The regional binding potential value was lower in the amygdala by about 19% in patients with schizophrenia than in normal controls. A significant negative correlation was observed between binding potential in the amygdala and the negative and depression/anxiety symptom scores on the five-symptom subscale of the Positive and Negative Syndrome Scale. CONCLUSIONS: Decreased serotonin-1A receptor binding in the amygdala may underlie the affective components included in the symptoms of negative and depression/anxiety in schizophrenia.