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.

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.

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.

Clinical epidemiologic first-episode psychosis: 1-year outcome and predictors.

OBJECTIVE: To describe 1-year outcome in a large clinical epidemiologic sample of first-episode psychosis and its predictors. METHOD: A total of 301 patients with first-episode psychosis from four healthcare sectors in Norway and Denmark receiving common assessments and standardized treatment were evaluated at baseline, at 3 months, and at 1 year. RESULTS: Substantial clinical and social improvements occurred within the first 3 months. At 1-year 66% were in remission, 11% in relapse, and 23% continuously psychotic. Female gender and better premorbid functioning were predictive of less severe negative symptoms. Shorter DUP was predictive for shorter time to remission, stable remission, less severe positive symptoms, and better social functioning. Female gender, better premorbid social functioning and more education also contributed to a better social functioning. CONCLUSION: This first-episode sample, being well treated, may be typical of the early course of schizophrenia in contemporary centers.

Positive symptoms and duration of illness predict functional laterality and attention modulation in schizophrenia.

OBJECTIVE: Dichotic listening (DL) performance in schizophrenia, reflecting hemispheric asymmetry and the functional integrity of the left temporal lobe, can vary with clinical characteristics. Previous studies have not taken the co-linearity of clinical variables into account. The aim of the present study was to evaluate the roles of positive symptoms and duration of illness in DL through Structural Equation Modeling (SEM), thus allowing for complex relationships between the variables. METHOD: We pooled patients from four previous DL studies to create a heterogeneous group of 129 schizophrenic patients, all tested with a consonant-vowel syllables DL procedure that included attentional instructions. RESULTS: A model where positive symptoms predicted a laterality component and duration of illness predicted an attention component in DL was confirmed. CONCLUSION: Positive symptoms predicted reduced functional laterality, suggesting involvement of left temporal lobe language processing. Duration of illness predicted impaired attention modulation, possibly reflecting the involvement of frontotemporal networks.

Neuropsychological test profiles in schizophrenia and non-psychotic depression.

OBJECTIVE: The study examined to what degree schizophrenia is characterized by a neuropsychological (NP) test profile specific in shape and level compared with depression and normal functioning. METHOD: Fifty-three patients with schizophrenia, 45 with non-psychotic depression, and 50 normals were assessed with a comprehensive NP test battery and clinical instruments. NP test scores were factor analyzed into seven composite scores. RESULTS: Schizophrenia patients performed significantly below normals across all seven composite scores, whereas depression patients were impaired in two. Verbal memory was most impaired. Sixty-two percent of schizophrenia patients were moderately or severely impaired, the corresponding figure for depression was 28%. Impairment was moderately associated with IQ level and clinical symptom load in schizophrenia, but not in depression. CONCLUSION: Schizophrenia is characterized by deficits across a wide range of NP functions. Thirty-eight percent of the patients are within normal limits. A mild and limited NP disturbance is apparent in depression.

Cortisol level predicts executive and memory function in depression, symptom level predicts psychomotor speed.

OBJECTIVE: On a group level depression is related to hypercortisolism and to psychomotor retardation, executive dysfunction and memory impairment. However, intra-group heterogeneity is substantial. Why some are impaired while others remain in the normal range, is not clear. The present study aims at discerning the relative contribution of present symptom severity and hypercortisolism to impairment in the three domains of cognition. METHOD: Morning saliva cortisol was measured in 26 subjects with recurrent major depression prior to a neuropsychological examination with tests known to be sensitive to cognitive impairment in depression. RESULTS: Cortisol level correlated with executive dysfunction and post-encoding memory deficits, but not with processing speed. Depression level correlated with processing speed. These patterns remained significant after controlling for confounders through partial correlations. CONCLUSION: The association between cortisol and cognition is not an artifact of psychiatric symptom load. High level of saliva cortisol is associated with aspects of cognition that can be dissociated from psychomotor retardation, which is dependent on symptom load.

Reducing the duration of untreated first-episode psychosis -- effects on baseline social functioning and quality of life.

OBJECTIVE: Long duration of untreated psychosis (DUP) is associated with poorer outcome. The TIPS study demonstrated that DUP can be reduced through early detection (ED). As quality of life (QoL) is associated with DUP it is expected that reduction of DUP leads to better QoL. METHOD: Consecutive first-episode patients with a DSM-IV diagnosis of non-organic, non-affective psychosis were included, 281 patients gave informed consent and 263 completed a full evaluation of QoL. RESULTS: There were no differences in subjective QoL between ED and No-ED groups attributable to reduction in DUP. There were significant bivariate differences in frequency of family and social contacts in favor of the ED group, but multivariate analyses indicated that these differences were based on differences in sample characteristics. CONCLUSION: Deterioration in QoL may precede overt symptom formation. Focus on functional loss in ED educational campaigns may identify risk subjects earlier in the course of the disorder.

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.

Cognitive remediation for adolescents with early onset psychosis: a 1-year follow-up study.

OBJECTIVE: To investigate the long-term effects of a cognitive remediation programme for adolescents with early onset psychosis. METHOD: Twenty-five subjects (cognitive remediation, n=14; control, n=11) were assessed on cognitive, clinical and psychosocial measures 1 year after discharge. All patients had received a psychoeducational programme, while the experimental group received the addition of a 30-h cognitive remediation programme. RESULTS: A significant overall improvement for eight of 10 cognitive and three of four outcome measures was found. After controlling for IQ, there was a differential improvement in early visual information processing (P<0.05) in favour of the remediation group. No other between-group differences were found. CONCLUSION: The remediation programme may have a favourable long-term effect for early visual information processing. Improved cognitive functioning in both groups may be caused by beneficial elements in the psychoeducational programme. Because the study may be underpowered, the results should be interpreted with caution.

General psychopathology is more important for executive functioning than diagnosis.

OBJECTIVE: Impaired executive functioning (EF) has often been reported in patients with major depression or schizophrenia. We hypothesize that the variance in EF is more affected by level of general psychopathology than by diagnosis. METHOD: Forty-three patients with major depression and 47 with schizophrenia were included. EF was measured with Wisconsin Card Sorting Test, Stroop Colour Word Test, Paced Auditory Serial Addition Test, Digits Backwards and Controlled Oral Word Association Test. The level of general psychopathology was measured with Brief Psychiatric Rating Scale - Expanded and Positive and Negative Syndrome Scale, the General psychopathology subscale. RESULTS: The level of general psychopathology predicted more of the variance in EF than diagnosis. In multivariate analyses, the effect of general psychopathology on EF was more robust for adjustment for diagnosis than vice versa. CONCLUSION: Future research on cognitive functioning in psychiatric patients should include level of general psychopathology to avoid overemphasising effects of diagnoses.

A controlled randomized treatment study: the effects of a cognitive remediation program on adolescents with early onset psychosis.

OBJECTIVE: To examine if a cognitive remediation program could be a positive supplement to a psychoeducational treatment program for adolescents with early onset psychosis. METHOD: Twenty-six subjects, randomly assigned to cognitive remediation (n = 14) or control group (n = 12), were assessed on cognitive, clinical, psychosocial and behavioural measures. RESULTS: No significant between-group differences in pre- and post-treatment scores were found. This may be due to low statistical power. Exploratory within-group analyses showed that the training group improved on five of the 10 cognitive, and three of the five functioning outcome measures, while the control group improved on three of the cognitive, and one functioning outcome variable. CONCLUSION: Based on these results we cannot conclude that the addition of this cognitive remediation program, yields better results than psychoeducation alone. However, within-group analyses indicate that on specific cognitive functions, as well as on some functioning outcome measures, the remediation program may have a positive effect.

Attention profile in schizophrenia compared with depression: differential effects of processing speed, selective attention and vigilance.

OBJECTIVE: The aim of the study is to investigate whether subjects with schizophrenia and major depression display attention deficits for different reasons. METHOD: Subjects with schizophrenia (n = 53), recurrent major depression (n = 50) and normal controls (n = 50) were administered with 11 measures of processing speed, selective attention and vigilance. Indices of basal speed, speeded attention, non-speeded attention and vigilance were computed. RESULTS: Both clinical groups were impaired on all chronometric tests. The schizophrenic subjects were also more impaired on speeded attention compared with basal processing speed. Only the schizophrenics were impaired on the non-speeded measures of selective attention. Compared with the schizophrenics, the depressives showed a decrement in vigilance. CONCLUSION: Reduced performance on attention tests in major depression is because of a non-specific speed reduction and loss of vigilance consistent with lack of effort. In addition to generally impaired processing speed, the schizophrenic subjects exposed a deficit in selective attention, indicating executive dysfunction.

Methodological pitfalls in early detection studies - the NAPE Lecture 2002. Nordic Association for Psychiatric Epidemiology.

OBJECTIVE: To identify and discuss methodological pitfalls that may help explain why many questions around early detection (ED) and duration of untreated psychosis (DUP) are still unsolved. METHOD: This paper concentrates on pitfalls in the following areas: sampling, measurement and data analyses. RESULTS: The main problems seem to be: SAMPLING: Referral bias, exclusion of patients, patient refusal, and patients lost to follow-up. MEASUREMENT: Reliability, which is particularly cogent for multisite investigations, and validity, which includes: Start of illness, start of psychosis, diagnoses, start of treatment, the relationship between ED and DUP and choice of outcome measures. Data Analyses: Overlooking threshold effects of DUP, improper control for baseline scores, and lack of control for confounders. CONCLUSION: Methodological pitfalls may bias ED studies. Several pitfalls are unavoidable, but proper design and quality assurance can reduce their impact. Researchers ought to identify the pitfalls, and to estimate and discuss their influence.

Neurocognitive dimensions characterising patients with first-episode psychosis.

BACKGROUND: Assessment of neurocognitive dysfunction in schizophrenia is hampered by the multitude of tests used in the literature. AIMS: We aimed to identify the main dimensions of an assessment battery for patients with first-episode psychosis and to estimate the relationship between dimension scores and gender, age, education, diagnosis and symptoms. METHOD: Eight frequently used neuropsychological tests were used. We tested 219 patients 3 months after start of therapy or at remission, whichever occurred first. RESULTS: We identified five dimensions: working memory (WM); verbal learning (VL); executive function (EF); impulsivity (im); and motor speed (MS). Significant findings were that the MS score was higher for men, and the WM and VL scores were correlated with years of education. CONCLUSIONS: Neurocognitive function in first-episode psychosis is described by at least five independent dimensions.

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.

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.