Poor Outcome In Schizophrenia Research Articles

Un trouble rare et peu étudié : la schizophrénie chez l’enfant. À propos d’une observation

Resume La schizophrenie a debut precoce, durant l’enfance, est un trouble rare : sa prevalence est environ 50 fois inferieure a celle des schizophrenies debutant a l’âge adulte. C’est un trouble aussi frequemment meconnu, en raison notamment de la variation de son tableau clinique en fonction de l’âge. Les auteurs rapportent ici l’observation d’une petite fille qui, a l’âge de 9 ans, a developpe un tableau clinique typique de schizophrenie, a debut brutal. A partir de cette observation, plusieurs points sont discutes au vu des donnees de la litterature : l’importance des alterations retrouvees dans l’histoire premorbide des enfants schizophrenes, l’importance des facteurs de vulnerabilite genetiques et des facteurs de stress precoces dans le determinisme des troubles observes, les difficultes liees au traitement de ces formes a debut precoce, enfin leur devenir, souvent pejoratif, notamment en termes d’adaptation psychosociale. Au total, et conformement aux donnees actuellement disponibles, cette observation suggere l’existence probable d’une continuite diagnostique entre l’enfance et l’âge adulte, les schizophrenies a debut precoce apparaissant a la fois plus severes et marquees par une plus grande vulnerabilite familiale que les schizophrenies debutant a la fin de l’adolescence ou a l’âge adulte.

Working Memory Performance in Poor Outcome Schizophrenia: Relationship to Age and Executive Functioning

Performance on the Letter-Number Sequencing (LNS) and Wisconsin Card Sorting Tests (WCST) have been shown to be significantly correlated in patients with schizophrenia, a relationship postulated to be due to working memory demands of the two tests (Gold, Carpenter, Randolph, Goldberg, & Weinberger, 1997). An alternative explanation for the association between these two tests is their sorting demands, in that both require sorting of information albeit in slightly different ways. If the latter explanation is valid, then working memory tasks that do not require sorting or other conceptualization demands should be less predictive of WCST performance than LNS. These hypotheses were examined in 34 poor outcome patients with schizophrenia, one-half of whom were over the age of 65. Patients were evaluated on Digit Span Forward, spatial working memory, LNS, and the WCST. It was found that WCST performance was significantly associated with performance on the LNS but no other working memory task. Age related performance differences were greatest on the WCST Categories and floor effects were noted on this test in one-half of the subjects. Analyses predicting WCST Categories in subjects whose scores were greater than zero (n = 16) also demonstrated that LNS, but not Digit Span or spatial working memory (any delay) predicted WCST performance. These findings indicate that LNS may be an index of executive functioning, particularly in patients who cannot perform the WCST.

Depressive symptoms and course identify two distinct clusters within very poor outcome schizophrenia

Depressive symptoms and course identify two distinct clusters within very poor outcome schizophrenia

Surgically Implantable Long-term Antipsychotic Delivery Systems for the Treatment of Schizophrenia

Non-adherence with medication remains a major correctable cause for poor outcome in schizophrenia. We describe a surgically implantable preparation of haloperidol with the aim that patients will have superior outcomes with improved medication adherence from implants. In contrast to depot formulations, implantable pellets could last many months, providing symptomatic improvement for periods of time never before possible. Additionally, in the event of unacceptable side effects, implants could be removed, offering a degree of reversibility not available with depot formulations. A surgically-implantable formulation of haloperidol has been created using biodegradable polymers. Implants have been characterized for in-vitro kinetics, as well as in-vivo bioactivity in rodents. Haloperidol implants demonstrate steady release of drug for 5 months. Animals treated with haloperidol implants display increased striatal D2 receptor expression as well as increased apomorphine stimulated locomotion. Surgically-implantable formulations are a viable approach to provide long-term delivery of antipsychotic medications to patients with psychotic disorders.

Longitudinal study of brain morphology in first episode schizophrenia

Background: Beginning with Kraepelin, schizophrenia has been viewed as a progressive disorder. Although numerous studies of the longitudinal course of schizophrenia have demonstrated the clinical deterioration that occurs predominantly in the early stages of the illness, the pathophysiology of this clinical phenomenon has not been established. This aspect of the illness may be of critical importance to understanding the pathogenesis of schizophrenia and determining preventive therapeutic strategies. Abnormalities in brain morphology have been consistently described in schizophrenia, but it is not known when in the natural history of the illness they arise and whether they are progressive. Previous studies of brain morphology have been inconclusive, in part because of the variability of methods for image acquisition and analysis, assessment of patients already at chronic stages of their illness with extensive prior treatment exposure, and inadequate periods of follow-up. Methods: To address these questions we examined 107 patients in their first episode of schizophrenia or schizoaffective disorder and 20 healthy volunteers using high resolution magnetic resonance imaging (MRI) and clinical assessments of psychopathology and treatment outcome for periods of up to 6 years. Fifty-one patients and 13 control subjects had MRIs after at least 12 months of follow-up. Results: Results confirm the findings of ventricular enlargement and anterior hippocampal volume reductions in first episode schizophrenia patients that have been previously reported. In addition, we found changes in selected structures over time in relation to treatment outcome, including increases in ventricular volume that were associated with poor outcome patients. Contrary to our hypothesis, there were no significant reductions in cortical and hippocampal volumes over time. Conclusions: The finding of progressive ventricular enlargement in patients with poor outcome schizophrenia is consistent with the hypothesis that persistent positive and negative symptoms result in progressive brain changes in the form of ventricular enlargement, possibly due to neurodegeneration rather than the confounding effects of treatment. Future studies of first episodes of schizophrenia should utilize higher resolution imaging techniques that compare clinically well characterized patients with and without poor outcome and recurrent symptoms to control subjects who are well matched to patients for age and gender. There is also a need to control for treatment effects of typical antipsychotic medication on brain structure.

Gender differences in poor outcome patients with lifelong schizophrenia.

Gender effects have been reported quite consistently in schizophrenia, with male patients having an earlier age of onset, poorer functional outcome, greater negative symptoms and cognitive impairment, and less severe positive symptoms. Because age of onset, cognitive impairments, and negative symptoms are all correlated with poorer functional status, it is not clear if previously reported gender differences in symptoms are just recapturing gender differences in functional outcome. In this study, 205 geriatric patients with lifelong poor-outcome schizophrenia (43% male) were examined for the severity of schizophrenic symptoms, cognitive impairments, and specific deficits in adaptive skills, as well as for demographic differences such as age at first psychiatric admission, premorbid education, and current treatment status. Previously reported gender differences were replicated in these patients with a uniformly poor functional outcome, with male patients having more severe negative symptoms and an earlier age of first psychiatric admission. No differences in cognitive functioning or specific functional deficits were found, however. These findings suggest that negative symptom severity is greater in male patients regardless of functional outcome and that the association of cognitive deficits with gender may be found only in patients with better functional outcome. The study of gender-related differences in brain structure or function and their interaction with overall course of illness might help understand these differences in symptom presentation.

Phasic and enduring negative symptoms in schizophrenia: biological markers and relationship to outcome

Negative symptoms have been associated with poor response to neuroleptics, enlarged ventricles, cognitive impairment, and poor outcome in schizophrenia. These associations appear, however, to be dependent on the phase of study, suggesting that acute-phase (phasic) negative symptoms may be pathophysiologically distinct from enduring negative symptoms that persist through the residual phase. To compare correlates of enduring and phasic negative symptoms, we studied 60 drug-free schizophrenic patients (DSM-III-R and SADS/RDC) at baseline, 4 weeks after neuroleptic treatment, and assessed the 1 year outcome. We rated positive and negative symptoms at baseline and 4 weeks after treatment. At baseline, premorbid function, neuropsychological function, ventricle–brain ratio (VBR) and symptom response to an anticholinergic agent were assessed, and a two-night sleep EEG and 1 mg dexamethasone suppression test (DST) were conducted. Phasic negative symptoms were defined as the change in negative symptoms (baseline to 4 weeks) and enduring negative symptoms as severity of negative symptoms at 4 weeks. Patients had varying proportions of phasic and enduring symptoms; the two did not define distinct subgroups. Phasic negative symptoms were significantly correlated with global treatment response, positive symptom treatment response, response to anticholinergic agent, baseline post-dexamethasone cortisol, and shortened REM latency. Enduring negative symptoms were significantly correlated with residual positive symptoms and global psychopathology, VBR, poor performance on neuropsychological testing, decreased slow-wave sleep, poor premorbid function, and poor 1 year outcome. These data suggest that phasic negative symptoms and enduring negative symptoms may be caused by different pathophysiological mechanisms.

Untreated initial psychosis: its relation to quality of life and symptom remission in first-episode schizophrenia.

Previous studies have suggested that there may be an association between longer duration of untreated psychosis and poor outcome in schizophrenia. These studies have been interpreted as providing evidence that untreated psychosis may constitute an "active morbid process" that is "toxic" to the brain. If untreated psychosis is neurotoxic, this would form a strong basis for early intervention in schizophrenia. Seventy-four neuroleptic-naive patients with DSM-IV schizophrenia were evaluated 6 months after their first inpatient hospitalization. The authors examined the relationship between untreated initial psychosis duration (measured from onset of first symptom as well as from onset of full positive syndrome) and quality of life, symptom severity, and time to remission of positive symptoms. Earlier age at illness onset was associated with longer duration of untreated prodromal psychotic symptoms. There were no significant gender differences in duration of untreated initial psychosis, nor were there any significant associations between untreated initial psychosis duration and premorbid functioning. After controlling for the effects of age at onset, the duration of untreated initial psychosis did not significantly impair subsequent quality of life, symptom severity, or remission of positive symptoms. Duration of untreated initial psychosis was not prognostic of poor outcome early in the course of schizophrenia. Biological measures of neurotoxicity are needed to examine the "toxic psychosis" hypothesis more directly.

566. The temporal relationship of cognitive and functional decline in poor outcome schizophrenia

566. The temporal relationship of cognitive and functional decline in poor outcome schizophrenia

108. Neurocognitive predictors of functional decline in poor-outcome schizophrenia

Although cognitive abilities have been shown to be directly related to social, occupational, and adaptive functioning in patients with schizophrenia, there is no evidence indicating that a specific neuropsychological index can predict decline in functional status. Impairments in verbal learning and memory, verbal skills, and executive functions correlate with functional impairments, and are predictive of functional ability over time. Yet, there is no evidence that impairment on a specific neurocognitive index is associated with functional decline, or whether these measures are all associated with functional impairments due to a global or specific cognitive deficit. In order to test whether any of these neuropsychological measures (Verbal Learning and Memory, Praxis, and Confrontational Naming) is most associated with functional decline, 68 subjects were chosen from a long-term study of the effects of aging in schizophrenia. Subjects were chosen specifically because they declined functionally from a mildly impaired level of functioning to a moderate or severely impaired level of functioning across two assessments (mean interval 5 1.89 years, sd 5 1.42 years), based on a global rating of functioning on the Clinical Dementia Rating Scale (CDR). Age and education corrected z-scores were derived for measures of verbal learning, delayed memory, praxic ability, and confrontational naming, based on performance of healthy controls on these measures as part of the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD). Change in performance on these neuropsychological measures was calculated by subtracting the standardized z-score of each measure at the follow-up assessment from the standardized score obtained on each measure at the initial assessment. A repeated measures ANOVA was used to determine if any of these measures were specifically associated with functional decline. Whereas the overall ANOVA was significant (F(1, 67) 5 14.49, p , .001), no specific measure of neurocognitive functioning was able to account for the decline in functional ability (Rao’s R (3, 65) 5 1.19, p , .321). These data suggest that the cognitive decline seen in these patients is generalized, rather than selective. It may be that this functional decline is related to low levels of cortical decline in patients with poor premorbid functioning and a chronic clinical course of illness.

Can chronic neuroleptic treatment promote sleep disturbances in elderly schizophrenic patients?

It has been proposed that sleep disturbances, especially reduced delta sleep, are related to a poor outcome in schizophrenia. To determine whether long-term treatment with neuroleptics can promote sleep disturbances by increasing the risk of a nocturnal myoclonus syndrome (NMS) (=periodic movements in sleep) related insomnia, we performed all-night polysomnography in 10 chronically ill schizophrenic patients who had been under neuroleptic therapy for a mean of 27 years. NMS-related insomnia was detected in all 10 patients. Potential pathophysiological relationships between long-term neuroleptic therapy and NMS occurrence are discussed. Our findings suggest that long-term administration of neuroleptics favours the appearance of insomnia.

370. Gender differences in poor outcome schizophrenia

370. Gender differences in poor outcome schizophrenia

Attentional and Clinical Neuroleptic Response in Schizophrenia: A Study with the Continuous Performance Test

Past research has confirmed the importance of vigilance deficits in schizophrenia. The present investigation examined the temporal relationship between treatment response of acute schizophrenic inpatients' (n = 13) psychopathology and their vigilance performance, using the Continuous Performance Test, at four time points over the course of an acute hospitalisation: at medication-free baseline and then weekly for 21 days after the initiation of neuroleptic treatment. A comparison group of stable schizophrenic outpatients (n = 12) receiving neuroleptics at all assessments were also tested during the same time period. For the acute group we found a significant improvement in both vigilance and symptoms over the course of neuroleptic treatment and the extent of improvement in vigilance performance was correlated with improvements in symptomatology. The control patients exhibited no CPT improvement or symptomatic changes. Because vigilance deficits correlate with poor outcome in schizophrenia, these data suggest that the medication-related changes in cognitive performance early in the course of neuroleptic treatment may provide clues to the expected course of illness in acute patients.

Course and outcome for schizophrenia versus other psychotic patients: a longitudinal study.

We studied 276 patients longitudinally, beginning at the acute phase and continuing at three successive followups over 7.5 years, comparing 74 schizophrenia patients with 74 other psychotic patients and 128 nonpsychotic patients on early course and outcome. Schizophrenia patients showed significantly poorer functioning than patients with other psychotic disorders at each of the three followups (p < 0.05). More schizophrenia patients than other psychotic patients showed consistent psychopathology and a course in which there was not complete remission at any of the three followups (p < 0.05). Most schizophrenia patients did not show severe decrements in social activity level. Poor outcome schizophrenia patients showed significantly slower recovery at each followup than did other psychotic patients with initial poor outcomes (p < 0.01). The results indicate that, during the early course, schizophrenia patients still show relatively poor outcomes, although a small number of schizophrenia patients enter into complete remission. Over time, many schizophrenia patients fluctuate between severe disability and moderate disability rather than always showing severe disability. Schizophrenia patients tend to recover more slowly then other psychotic patients. Differences between schizophrenia patients and other psychotic patients in clinical course over time may be larger than differences at any single followup.

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 t 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.

Assessment of Enduring Deficit and Negative Symptom Subtypes in Schizophrenia

The clinical importance of subtypes based on enduring deficit or negative symptoms was examined in a group of schizophrenic patients who were assessed twice over a 1-year period. Subgroups of patients with high levels of enduring negative or deficit symptoms, based on the Scale for the Assessment of Negative Symptoms and the Quality of Life Scale, had a poorer prognosis and were consistently worse in social adjustment, quality of life, and thought disorder over the year than were patients with less severe negative symptoms. Subtypes based on Andreasen's negative schizophrenia classification and on enduring thought disorder were only weakly related to other symptoms and social adjustment. Social-skill deficits were weakly related to the enduring negative symptom subtype and Andreasen's negative schizophrenia. The results suggest that enduring negative and deficit symptoms may be associated with a poor outcome in schizophrenia, including more severe positive symptoms, lower levels of social adjustment, and a poorer quality of life.

Premorbid sociosexual functioning and long-term outcome in schizophrenia.

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

Dr. Carpenter and Associates Reply

Dr. Carpenter and Associates Reply

Outcome and familial psychopathology in schizophrenia.

We examine whether the variation in outcome in schizophrenia is associated with differences in familial psychopathology. We begin with a methodologically oriented review of the large number of previous studies that have addressed this question. Although some trends are evident, the findings are variable. Most of the studies have important methodologic limitations. We then examine the relationship between short-term outcome and four dimensions of long-term outcome in 253 DSM-III schizophrenics and psychiatric illness in their 723 first-degree relatives. No relationship is found between any dimension of outcome in schizophrenics and risk in their relatives for schizophrenia, all nonaffective psychoses, bipolar illness, or anxiety disorder. A marital outcome of divorce was strongly associated with a family history of alcoholism. Good long-term marital, residential, and occupational outcomes were positively correlated with the risk for unipolar illness in relatives. These results do not support the hypothesis that poor outcome schizophrenia is the "genetic" form of the disorder. However, they are compatible with the hypothesis that the liability to affective illness may influence outcome in schizophrenia.

Characteristics of very poor outcome schizophrenia.

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