Does active psychosis cause neurobiological pathology? A critical review of the neurotoxicity hypothesis.

BACKGROUND: Since the neurotoxicity hypothesis was launched in 1991, it has generated a great deal of interest and given rise to several studies investigating the validity of the hypothesis that being psychotic has a toxic effect on the brain. The toxicity argument is used to justify early treatment. This review attempts to assess the studies that have addressed the question: Does an active psychosis, indexed by the duration of untreated psychosis (DUP), cause neurobiological pathology? METHOD: The validity of the hypothesis has been studied primarily by correlation analyses that assess whether there are significant correlations between DUP and changes in neurocognitive functioning or brain structure. In this review, relevant reports were identified by a literature survey. RESULTS: Of the 35 studies (33 papers) evaluated, six neurocognitive studies supported the hypothesis and 16 did not. Eight morphology studies supported the hypothesis and five did not. In general, the studies that did not support the neurotoxicity hypothesis were larger in size and had more adequate designs (longitudinal) than those that supported the hypothesis. CONCLUSIONS: Overall, there is limited empirical evidence for the neurotoxicity hypothesis in the studies reviewed. However, it is possible that there is a threshold value for a toxic effect of psychosis, rather than a linear relationship between DUP and a neurotoxic effect, and that several of the studies evaluated did not have a long enough DUP to detect a toxic effect of active psychosis.

Early detection of psychosis: positive effects on 5-year outcome.

BACKGROUND: During the last decades we have seen a new focus on early treatment of psychosis. Several reviews have shown that duration of untreated psychosis (DUP) is correlated to better outcome. However, it is still unknown whether early treatment will lead to a better long-term outcome. This study reports the effects of reducing DUP on 5-year course and outcome. METHOD: During 1997-2000 a total of 281 consecutive patients aged >17 years with first episode non-affective psychosis were recruited, of which 192 participated in the 5-year follow-up. A comprehensive early detection (ED) programme with public information campaigns and low-threshold psychosis detection teams was established in one healthcare area (ED-area), but not in a comparable area (no-ED area). Both areas ran equivalent treatment programmes during the first 2 years and need-adapted treatment thereafter. RESULTS: At the start of treatment, ED-patients had shorter DUP and less symptoms than no-ED-patients. There were no significant differences in treatment (psychotherapy and medication) for the 5 years. Mixed-effects modelling showed better scores for the ED group on the Positive and Negative Syndrome Scale negative, depressive and cognitive factors and for global assessment of functioning for social functioning at 5-year follow-up. The ED group also had more contacts with friends. Regression analysis did not find that these differences could be explained by confounders. CONCLUSIONS: Early treatment had positive effects on clinical and functional status at 5-year follow-up in first episode psychosis.

Early identification of non-remission in first-episode psychosis in a two-year outcome study.

OBJECTIVE: To identify predictors of non-remission in first-episode, non-affective psychosis. METHOD: During 4 years, we recruited 301 patients consecutively. Information about first remission at 3 months was available for 299 and at 2 years for 293 cases. Symptomatic and social outcomes were assessed at 3 months, 1 and 2 years. RESULTS: One hundred and twenty-nine patients (43%) remained psychotic at 3 months and 48 patients (16.4%) remained psychotic over 2 years. When we compared premorbid and baseline data for the three groups, the non-remitted (n = 48), remitted for <6 months (n = 38) and for more than 6 months (n = 207), duration of untreated psychosis (DUP) was the only variable that significantly differentiated the groups (median DUP: 25.5, 14.4 and 6.0 weeks, respectively). Three months univariate predictors of non-remission were being single, longer DUP, core schizophrenia, and less excitative and more negative symptoms at baseline. Two-year predictors were younger age, being single and male, deteriorating premorbid social functioning, longer DUP and core schizophrenia. In multivariate analyses DUP, negative and excitative symptoms predicted non-remission at 3 months, but only DUP predicted at 2 years. CONCLUSION: Long DUP predicted both 3 month and 2-year non-remission rates in first-episode psychosis.

A 2-year follow-up of involuntary admission's influence upon adherence and outcome in first-episode psychosis.

OBJECTIVE: To see, if voluntary admission for treatment in first-episode psychosis results in better adherence to treatment and more favourable outcome than involuntary admission. METHOD: We compared consecutively first-admitted, hospitalised patients from a voluntary (n = 91) with an involuntary (n = 126) group as to psychopathology and functioning using Positive and Negative Syndrome Scale and Global Assessment of Functioning Scales at baseline, after 3 months and at 2 year follow-up. Moreover, duration of supportive psychotherapy, medication and number of hospitalisations during the 2 years were measured. RESULTS: More women than men were admitted involuntarily. Voluntary patients had less psychopathology and better functioning than involuntary patients at baseline. No significant difference as to duration of psychotherapy and medication between groups was found. No significant difference was found as to psychopathology and functioning between voluntarily and involuntarily admitted patients at follow-up. CONCLUSION: Legal admission status per se did not seem to influence treatment adherence and outcome.

Are multi family groups appropriate for patients with first episode psychosis? A 5-year naturalistic follow-up study.

OBJECTIVE: To compare outcome over 5 years for patients who participated in multi family groups (MFGs) to those who refused or were not offered participation. METHOD: Of 301 first episode psychotic patients aged 15-65 years, 147 participated in MFGs. Outcome was measured by drop-out rates, positive and negative syndrome scale (PANSS) symptom scores, and duration of psychotic episodes during the follow-up period. RESULTS: Multi family group participants had a significantly lower drop-out rates at 5-year follow-up than patients who did not participate. However, the MFG participants had significantly less improvement in PANSS positive and excitative symptoms and had significantly longer duration of psychotic symptoms during the follow-up period. CONCLUSION: Multi family groups appear to increase the chance of retaining patients in a follow-up study, but adjustment of the programme may be necessary with first episode psychosis patients to meet their needs better.

Measuring quality of life in first-episode psychosis.

Quality of life (QoL) measures are increasingly recognized as necessary parts of outcome assessments in psychosis. The present paper is a comprehensive study of patients with first-episode psychosis where QoL is measured by the commonly used Lehman Quality of Life Interview (L-QoLI). The aim is to examine if the L-QoLI maintain its original structure when used in a group of patients with first-episode psychosis, and to investigate what determines global subjective QoL with a specific emphasis on premorbid adjustment, duration of untreated psychosis (DUP) and clinical symptoms. The study indicates that the psychometric properties of the L-QoLI do not change significantly when used in first-episode samples. The patients report subjective and objective QoL in the fair to good range, with only a moderate association between the objective and subjective measures. Poor global satisfaction is predicted by being single, abusing drugs, being depressed, having a diagnosis of psychotic affective disorder, having poor premorbid social adjustment and DUP over 10 weeks. The study supports the notion that patients with first-episode psychosis construct QoL in the same way as other groups, and that longer durations of compromised function at this stage produces poor satisfaction with life rather than a downward readjustment of expectations.

Neuropsychological deficits in adolescent-onset schizophrenia compared with attention deficit hyperactivity disorder.

OBJECTIVE: Impaired neuropsychological performance involving abstraction-flexibility, memory, motor function, and attention has frequently been reported in schizophrenia as well as in attention deficit hyperactivity disorder (ADHD). This study represents an attempt to compare groups of adolescents with schizophrenia and ADHD on a comprehensive neuropsychological test battery. Such a comparison affords the opportunity to ascertain differences in the degree, profile, and specificity of impairments. METHOD: The performance of 19 adolescents with schizophrenia, 20 adolescents with ADHD, and 30 normal adolescents on a broad battery of cognitive tests was compared. RESULTS: The schizophrenic group showed the most pronounced deficits on tests of abstraction, visual memory, and motor function in comparison with the subjects with ADHD, while the ADHD subjects had the most pronounced deficits on measures of attention, verbal memory, and learning. CONCLUSIONS: The subjects with schizophrenia appeared to have a more general pattern of brain dysfunction, whereas the impairment of the ADHD subjects seemed to be relatively specific to tests associated with frontal lobe function.

Backward-masking deficit in adolescents with schizophrenic disorders or attention deficit hyperactivity disorder.

OBJECTIVE: Backward masking is a cognitive task that involves the earliest phases of visual information processing. Disrupted task performance caused by a visual mask has been found repeatedly in schizophrenic patients; however, the specificity to schizophrenia of deficits in backward masking has received only limited study. METHOD: In this study 20 patients with early-onset schizophrenic disorders were compared to 20 adolescents with attention deficit hyperactivity disorder (ADHD) and 30 normal adolescents on a two-digit identification task in three backward-masking conditions: no mask, a short stimulus interval (33.0 msec), and a long stimulus interval (49.5 msec). RESULTS: The performance of the two groups of patients was similar, and both groups showed a statistically significant masking deficit after the long stimulus interval and a nearly significant deficit after the short stimulus interval in comparison with the normal subjects. CONCLUSIONS: Increased vulnerability to the masking stimulus was confirmed in schizophrenic subjects, but it is not specific to schizophrenia and is not accounted for by psychotic symptoms alone, since the subjects with ADHD performed similarly.

Contrasts in memory functions between adolescents with schizophrenia or ADHD.

Previous research on memory and schizophrenia has relied on a limited number of global memory measures instead of a comprehensive assessment of various memory components. In addition, little effort has been directed at examining memory functioning in patients with early-onset schizophrenia. Published research often lacks a relevant neuropsychiatric comparison group to control for attention difficulties. Patients with Attention Deficit Hyperactivity Disorder (ADHD) were included in the present study for this purpose. To our knowledge, a direct comparison of the two patient groups on memory functions has never been made. In the present study, both adolescents with schizophrenia and adolescents with ADHD were compared on a comprehensive memory test battery. Nineteen adolescents with schizophrenia were compared to 20 ADHD adolescents and 30 normally functioning adolescents on measures of working memory and long-term episodic memory, including tests of verbal and visual memory, free recall and recognition memory. The performance of the adolescents with schizophrenia was impaired as compared to the normal group on most of the memory measures. They performed significantly more poorly than the adolescents with ADHD on the visual memory tests. The ADHD group scored more impaired than the schizophrenia group on working memory tests with focus on distractibility. The findings suggest a general memory deficit among adolescents with schizophrenia related to both verbal and visual material. Impairment on the measures of visual memory is specific to schizophrenia and does not characterise the ADHD subjects.

Distractibility and recall capability in schizophrenics. A 4 year longitudinal study of stability in cognitive performance.

Longitudinal study is a well suited, but so far not much used, research strategy to elucidate which cognitive deficits are markers of vulnerability and which are symptom-linked states in schizophrenia. In the present study, 14 schizophrenics, eight non-psychotic psychiatric controls and 20 normals were assessed on recall performance and distractibility twice, at an interval of 4 years. The method was a digit-span test with neutral and distractor condition strings. Results showed that schizophrenics, primarily non-paranoid schizophrenics, were inferior to normals with respect to short-term recall at both instances of assessment, a finding which indicates recall deficiency to be a vulnerability-linked factor in this sub-group of schizophrenics. Paranoid schizophrenics performed better on the distractor strings than on the matched neutral strings at the first assessment, but not at the second. Non-paranoid schizophrenics, as well as the control groups, showed a relatively stable pattern of performance with respect to distractibility. How distracting stimuli are dealt with may thus be a symptom-linked factor in schizophrenia, since most of the paranoid schizophrenics changed symptomatology from the first to the second assessment. The present data cannot, however, be used to draw a definite conclusion on this point.

Covert visual attention in patients with early-onset schizophrenia.

The aim of the present study is to examine attentional costs (inhibition) in covert visual attention in a group of acutely ill adolescents with schizophrenia without long histories of neuroleptic treatment. Variations in reaction time were analyzed for possible age and sex differences. Adolescents with schizophrenia (n = 19) were compared to a group of ADHD subjects (n = 20) and a group of normally functioning adolescents (n = 30) on a measure of covert visual attention. The results support a hypothesis of abnormally rapid disengagement (reduced costs) in male adolescents with schizophrenia. Such an abnormality has also been found in adults with chronic schizophrenia. Whether this holds true for both sexes of adolescents with schizophrenia or is restricted to male subjects cannot be answered with certainty due to the small number of females with schizophrenia in our sample. Our findings indicate, however, that there are some general sex differences and some specific sex differences related to covert visual attention in adolescents with schizophrenia.

Memory functioning in chronic and non-chronic schizophrenics, affectively disturbed patients and normal controls.

Memory impairment has been reported among schizophrenics in several studies. There are a number of uncertainties in interpreting such deficits. The present study examined short- and long-term verbal memory in schizophrenic patients (n = 30), affectively distributed patients (n = 18) and normal controls (n = 18). Schizophrenics showed a significant decrease in memory test performance, compared with both normal controls and other psychiatric patients. Chronic schizophrenics seem to be characterized by qualitatively different memory functioning compared with non-chronic subjects. In a free recall task chronic subjects showed significantly decreased performance for the initial (primacy) and final (recency) items. Memory functioning was not correlated with performance on the Wisconsin Card Sorting Test. This could indicate a selective cognitive dysfunction of an amnesic nature in chronic schizophrenics.

Honig's model of working memory and brain activation: an fMRI study.

The present study investigated changes in neuronal activation with fMRI related to Honig's model of working memory, which is much less studied compared with other working memory models. In contrast to other studies which have applied recognition procedures, the primary aim with the present study was to examine brain activation when subjects had to continuously recall and forget items held in working memory. The results showed that the mid-ventrolateral frontal cortex was particularly activated in the left hemisphere, whereas the mid-dorsolateral frontal cortex was particularly activated in the right hemisphere during execution of the working memory task. The findings are discussed in relation to process- and domain-specific accounts of working memory.

The effect of distraction on focal attention in paranoid and non-paranoid schizophrenic patients compared to normals and non-psychotic psychiatric patients.

Previous research comparing the performance of schizophrenics and normals in neutral and distractor conditions has indicated that schizophrenics are more vulnerable to distraction. The present study was designed to clarify whether schizophrenics are more distractible than normals and non-psychotic psychiatric patients when the distractor conditions are matched with the neutral conditions for discriminating power and to determine whether paranoid and non-paranoid paranoid schizophrenics, eight non-psychotic psychiatric patients, and 20 normals were tested using neutral and distractor digit-span tests. The results do not support the hypothesis of a differential deviation in all schizophrenics with respect to distractibility. However, significant differences were found between paranoid and non-paranoid schizophrenics; the paranoid, in contrast to the non-paranoid schizophrenics, did not appear to be vulnerable to distraction under the conditions of this experiment.

A review of longitudinal studies of cognitive functions in schizophrenia patients.

Even though the idea that schizophrenia is a neurobehavioral syndrome has become a mainstream position, there is no consensus on the precise nature of the cognitive and neuropsychological impairment. Research on cognitive dysfunctions in schizophrenia has been directed toward discriminating stable dysfunctions (traits) from symptom-linked (state) deficits. A longitudinal study design is the only one that can provide answers to the question of the stability of psychological functions. This article reviews 15 studies with a followup of at least a year. The main conclusion drawn from these studies is that after the onset of schizophrenia, cognitive deficits are relatively stable over long periods. No support for a decline in cognitive functions is found. Thus, schizophrenia does not appear to be a degenerative process, but rather a static encephalopathy. Whether or not the cognitive deficits found in schizophrenia can be remediated is still an open question that needs to be examined.

Auditory laterality and selective attention: normal performance in patients with early-onset schizophrenia.

In this study, auditory laterality and selective attention were examined in patients with early-onset schizophrenia using a dichotic listening (DL) test. Deficient performance on this test has repeatedly been found in adult patients with chronic schizophrenia, indicating abnormalities in left hemisphere function. The hypothesis in the present study was that subjects with early-onset schizophrenia manifest deficits in DL test performance similar to adult chronic patients. A group of 19 patients with early-onset schizophrenia were compared with a group of 20 adolescents with attention-deficit hyperactivity disorder and a group of 30 normal adolescents. Results indicated no significant differences between the three groups on any of the measures. Alternative hypotheses are put forth to explain the findings, among them that deficits in DL performance may be secondary to long-time illness and/or drug treatment, and that these deficits may become apparent only after interaction with maturational neurodevelopmental changes during adolescence.

Backward-masking performance in chronic and nonchronic schizophrenics, affectively disturbed patients, and normal control subjects.

There is ample evidence that schizophrenics exhibit a backward masking deficit. To what extent other psychotic patients are susceptible to visual masking is still an open question. Likewise, differences between subgroups of schizophrenics have to be further explored. In the present study a computerized backward masking task was applied to 30 schizophrenics, 18 affectives and 20 normals. Results confirmed previous findings of a performance deficit in the schizophrenics. However, affectively disturbed patients performed even poorer than the schizophrenics. The most outstanding finding when the group of schizophrenics was split into different subgroups was the significant differences that appeared between chronic and nonchronic patients. The latter group (n = 8) performed as well as the normals, while the chronic schizophrenics (n = 22) showed evidence of a performance deficit comparable to the affectives.

Stability in cognitive dysfunctions in schizophrenic patients.

The purpose of the present study was to classify cognitive dysfunctions in schizophrenic subjects according to a trait/state model. A sample of 15 patients was examined on 10 different cognitive measures in two distinctly different phases: an acute psychotic state and partial remission. To determine the degree of dysfunction at the two stages of illness, the schizophrenic patients were also compared to 14 non-psychiatric controls. Six of the 10 measures examined can be classified as cognitive deficits in schizophrenics. Four measures are possibly trait-dependent components: two backward masking scores and two long-term memory measures. A short-term memory measure is the only one that can be classified as an episode-linked factor. The other cognitive deficits found can be characterized as mediating vulnerability factors, i.e. they are more prominent in the acute psychotic state, but do not completely disappear during remission states.

Fully recovered schizophrenics: a retrospective study of some premorbid and treatment factors.

The present study is an exploratory, retrospective examination of 10 schizophrenics who have fully recovered. The subjects were recruited through an inquiry to approximately 100 clinical psychologists and psychiatrists working in two mental hospitals in the Oslo area. These (previous) patients did not fulfill the criteria of a schizophrenia diagnosis at the time but had done so earlier. Further, they had not been admitted to a mental hospital during the last 3 years, had psychosocial functioning that could be called "normal, or nearly normal," and were not on neuroleptic drugs or were on only a low-dose level. The principal questions that were asked were: Do schizophrenics who fully recover have anything in common with respect to premorbid adjustment, family interaction, hospitalization, or treatment? Further, is psychotherapy an absolute precondition for full recovery? These questions were examined using a semistructured interview. The results showed that the age of debut of illness averaged 20 years and most of the patients had a fairly good premorbid psychosocial adjustment. Problematic nurturance during childhood was a factor in many of the interviews. Eight patients had been in psychotherapy and attached great importance to it. Religious belief and psychological support from the spouse were also considered important for recovery. The sample includes three "star cases," one of which is presented thoroughly.

"Full recovery" from schizophrenia in the long term: a ten-year follow-up of eight former schizophrenic patients.

The present study reports longitudinal data on individuals who ten years ago were fully recovered from a previously diagnosed schizophrenia. Seven out of ten subjects consented and were reexamined at the present follow-up, and data on an eighth subject was secured elsewhere. A semistructured interview was used to examine psychosocial functioning of the subjects in the follow-up period. Out of the six subjects with a confirmed diagnosis of schizophrenia, only three subjects were still fully recovered; one had a deteriorating course and two had a fluctuating course of illness. The results from the study indicate that recovery from schizophrenia may take the form of time-limited remissions for half of the reexamined subjects when strict criteria for full recovery are used. Protective factors such as willpower, a (partly) intact capacity for object attachment, and a supportive family may be important prerequisites for recovery. Two different courses of schizophrenia are illustrated by cases.