Treatment costs and clinical outcome for first episode schizophrenia patients: a 3-year follow-up of the Swedish "Parachute Project" and two comparison groups.

OBJECTIVE: To evaluate "need-specific treatment" of first episode schizophrenia syndrome patients. METHOD: Sixty-one consecutive first episode schizophrenia syndrome patients were followed over 3 years. They were compared with a Historical "treatment as usual" group (n = 41) and a Prospective group from a high quality social and biological psychiatry centre (n = 25). RESULTS: Symptomatic and functional outcome was significantly better compared with the Historical group and equal with the Prospective group. During the first year, the direct costs for in- and out-patient care per patient in the Parachute project were less than half of those in the Prospective group. CONCLUSION: The study confirms the feasibility, clinically and economically, with a large scale application of "need-specific treatments" for first episode psychotic patients.

One-year outcome in first episode psychosis patients in the Swedish Parachute project.

OBJECTIVE: Implementing a system designed to treat first episode psychotic (FEP) patients. METHOD: Every FEP patient (n=253) from a catchment area of 1.5 million inhabitants were asked to participate in this 5-year project. One historical (n=71) and one prospective (n=64) FEP group were used for comparisons. RESULTS: A total of 175 patients (69%) were followed up through the first year of treatment. Global Assessment of Functioning (GAF) values were significantly higher than in the historical comparison group but similar to the prospective group. Psychiatric in-patient care was lower as was prescription of neuroleptic medication. Satisfaction with care was generally high in the Parachute group. Access to a small overnight crisis home was associated with higher GAF. CONCLUSION: It is possible to successfully treat FEP patients with fewer in-patient days and less neuroleptic medication than is usually recommended, when combined with intensive psychosocial treatment and support.

D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia: a PET study.

OBJECTIVE: Quetiapine is a novel antipsychotic agent with many atypical features, including low D(2) and higher 5HT(2A) affinity in vitro, low propensity to induce extra-pyramidal side effects and minimal effects on prolactin levels. The purpose of this study was to investigate, using positron emission tomography (PET), the relationship between plasma concentrations of different doses of quetiapine and occupancy of D(2) and 5HT(2A) receptors in schizophrenic patients. METHODS: Five patients were treated with quetiapine (titrated to 750 or 450 mg/day) for 28 days, subsequently reduced weekly in a descending-dose schedule. Dopamine D(2) and 5HT(2A) occupancies were determined using [(11)C] raclopride and [(11)C] N-methylspiperone as ligands, respectively, and PET imaging. RESULTS: Mean D(2) receptor occupancies of 41 and 30% were observed at quetiapine doses of 750 and 450 mg/day. At lower dose levels no occupancy could be determined. Quetiapine induced a consistently higher degree of 5HT(2A) receptor occupancy, with mean occupancies of 74 and 57% at doses of 750 and 450 mg/day, respectively. No EPS emerged during the trial and most of the pre-trial EPS resolved during the study. CONCLUSIONS: In clinically effective doses, quetiapine induced low occupancy at D(2) receptors, which is consistent with atypical antipsychotics such as clozapine, and probably explains the lack of EPS observed in this trial. Correlations between receptor occupancy and plasma concentrations of quetiapine could not be calculated, although receptor occupancy increased with higher plasma concentrations for the 450 and 750 mg doses.

Tyrosine transport is regulated differently in patients with schizophrenia.

Previous PET studies of tyrosine transport have suggested that the transport of tyrosine from blood to brain compartment is not dependent on its plasma concentration in patients with schizophrenia. In order to examine this relationship, the transport constant (K1) of tyrosine was determined in five patients with schizophrenia and five normals. L-[1-11C]Tyrosine was injected i.v. and arterial blood samples were taken during PET scanning. The tyrosine transport was assessed during baseline conditions and after oral administration of L-tyrosine at a dose (175 mg/kg) that significantly elevated the plasma levels. K1 was determined from tracer kinetic modelling. The transport rate dropped in the normals after tyrosine loading, which is consistent with the prevailing notion that the brain transport system for neutral amino acids works close to saturation, whereas it was virtually unchanged in the schizophrenics. The results demonstrated that tyrosine transport was not saturated in the patients with schizophrenia and thus could lead to elevated brain concentrations of tyrosine.

CSF levels of HVA and 5-HIAA in drug-free schizophrenic patients and healthy controls: a prospective study focused on their predictive value for outcome in schizophrenia.

The CSF levels of HVA and 5-HIAA were determined in 90 drug-free DSM-III-R schizophrenic patients and 47 healthy control subjects, and their predictive value for 5-year outcome was evaluated. CSF was collected by lumbar puncture at index admission, and in 37 of the patients a second sample was drawn after approx. 7 weeks of neuroleptic treatment. Outcome was rated prospectively 5 years after index admission by means of the Strauss-Carpenter outcome scale. Schizophrenic patients had significantly lower levels of HVA in the CSF than the control group, but no difference was found for 5-HIAA. The CSF-amine metabolite levels were not correlated with age at admission, age at first symptoms or duration of the disorder. Neither HVA nor 5-HIAA correlated with the total outcome scores at a 1- and 5-year follow-up evaluation. First-admitted previously untreated patients with the poorest 5-year outcome had significantly lower HVA/5-HIAA quotients than those with a good outcome. Furthermore, patients still having a low HVA/5-HIAA quotient after treatment with neuroleptics had a poorer 5-year outcome than patients with an increased quotient. The data indicate that both HVA and 5-HIAA in the CSF, and especially their sensitivity to neuroleptic treatment, have a predictive value for the prognosis in schizophrenia.

N-[11C]methylspiperone PET, in contrast to [11C]raclopride, fails to detect D2 receptor occupancy by an atypical neuroleptic.

The occupancy of the atypical neuroleptic quetiapine (Seroquel) at the D2 dopamine receptor was investigated using the PET tracers [11C]raclopride and N-[11C]methylspiperone in a group of five schizophrenic patients. A steady-state treatment condition was ensured by dosing the patients with 750 mg quetiapine daily during 3 weeks followed by a period of tapering off the dose. For each patient, PET examinations were performed with both tracers at two of the following doses: 750, 450, 300 and/or 150 mg. As control, a group of six healthy untreated volunteers was investigated. The D2 binding potential in the putamen and the caudate nucleus was determined by using an evaluation method based on the method proposed by Patlak and Blasberg. The receptor occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing quetiapine dose (reaching 51% +/- 10% occupancy at the 750 mg dose) was detected with [11C]raclopride (P < 0.01), no such trend was apparent for N-[11C]methylspiperone (P > 0.09, maximal occupancy values were 2% +/- 3%, measured for the group of three patients on 450 mg). The study suggests that N-[11C]methylspiperone cannot be used for the assessment of D2 receptor occupancy induced by quetiapine. The result is discussed in terms of endogenous dopamine, tracer kinetics and equilibrium dissociation constants.

Relationships between social support, social coping and life events in the relapse of schizophrenic patients.

The vulnerability-stress model for schizophrenia posits that relapses are at least partly determined by interacting triggering and protecting psychosocial factors. This study examined social support and general coping style in 42 consecutively admitted DSM:III schizophrenic patients, who were followed prospectively for up to four years. In a second part of the study, a subgroup of the patients were interviewed using the Life Event and Difficulty Schedule 9 months after discharge or at relapse. Patients contented with low social integration had a higher relapse rate over four years than patients lacking of social provisions, but wanting more. We found an excess of life events three weeks before relapse compared to events reported in the non-relapsing group. Suggesting a buffering effect of social factors, time between life event and relapse was significantly extended among patients with a high availability of attachment and a coping strategy characterised of active support seeking.

Prenatal and neonatal risk factors for schizophrenia.

BACKGROUND: The present study examines the effects of independent, single pre- and perinatal risk factors and rates of obstetric complications upon the subsequent development of schizophrenia. METHOD: This study was based on prospectively recorded birth records of 107 cases (82 with schizophrenic disorders and 25 with other psychotic reactions) and 214 controls, individually matched by gender and time and place of birth. Variables univariately associated with significantly elevated risk were entered in a logistic regression model. RESULTS: A high non-optimality summary score (> or = 7 complications of 34 possible) was a significant risk estimate for the total index group (OR 4.58, 95% CI 1.74-12.03) and the 82 schizophrenic patients (OR 3.67, CI 1.30-10.36). Patients with 2-6 complications also had an increased, although lower, risk (OR 1.67, CI 1.02-2.75). A disproportionate birth weight for body length (OR 3.57, CI 1.77-7.19) and a small head circumference (OR 3.93, CI 1.32-11.71) were the strongest independent risk factors. CONCLUSIONS: A contribution of obstetric complications to the risk of schizophrenia was confirmed. Only aberrations in physical size remained as individual independent risk factors.

Electrodermal activity and social network as predictors of outcome of episodes in schizophrenia.

The predictive value of electrodermal activity and social network was examined among 48 consecutively admitted schizophrenic patients. The patients were followed from an initial admission, through hospital stay, discharge, follow-up (M = 31 months), and possible relapse. Outcome variables were the length of stay in the hospital at the key episode and time to relapse, defined as a marked exacerbation or return of schizophrenic symptoms requiring inpatient or expansion of outpatient treatment. Multivariate analyses showed that a psychosocial variable, the availability of attachment, was the only independent predictor of length of stay in the hospital. Age at admission was a strong predictor of time to relapse. Age interacted with both outcome and electrodermal activity, and young electrodermal nonresponders were found to have the shortest time to relapse. At the 1-year follow-up, a main relapse effect was found for patients with a low skin conductance level.

Symptoms at index admission as predictor for 1-5 year outcome in schizophrenia.

A total of 107 drug-free schizophrenic patients (76 males and 31 females) were consecutively admitted to an emergency ward and rated for psychotic symptoms by means of 32 items from the Comprehensive Psychopathological Rating Scale (CPRS). They were followed prospectively with ratings of social functioning by use of Strauss-Carpenter's outcome scale at 1, 3 and 5 years after index admission with the aim of determining possible early symptoms that are predictors of social outcome. In total, 59 of the patients were first admissions and had never been treated. At index admission, no difference was found in total CPRS scores between first-admission patients and chronic readmitted patients, or between male and female subjects. When subscales for positive symptoms (flights of ideas, feeling controlled, disrupted thoughts, auditory hallucinations, ideas of persecution) and negative symptoms (indecision, withdrawal, reduced speech, lack of appropriate emotions, slowness of movements) from the CPRS were applied, no relationship between the two subscales and outcome scores was found. However, in patients with a duration of the disorder of less than 24 months before index admission, high scores on both negative and positive subscales were significantly correlated with a poor 5-year outcome. No correlation was found in the group with a duration of illness of more than 24 months before index admission. It is concluded that symptoms at index admission have a predictive value for outcome in schizophrenic patients. Negative symptoms measured by use of a subscale of the CPRS have a predictive value for outcome up to 5 years after index admission, but high scores on both positive and negative symptoms are more strongly associated with a poor outcome. The duration of the symptoms before admission, as well as the kind of neuroleptic treatment given (clozapine vs. classical neuroleptics), seem to be important factors for prediction of outcome. Our data support the view that early negative symptoms in particular have a predictive value for the prognosis in schizophrenia for up to 5 years.

Schizophrenia and antipsychotic somatic treatment.

Schizophrenia typically affects individuals in early life and leads to long-term suffering at high cost to both the individual and the community. Structural, functional, and biochemical factors may play a role in the pathogenesis and perhaps the course, of schizophrenia. Although early research into the treatment of schizophrenia was not fruitful, the results of recent research, particularly the use of narcoleptics combined with new clinical appreciation of psychosocial factors in chronic psychotic disorders, give reason for hope and optimism.

Acid monoamine metabolites in the CSF of healthy controls punctured without preceding strict bedrest: a retrospective study.

Data were obtained from 46 healthy volunteers, 16 males and 30 females, lumbar punctured at the L4-5 level without strict bedrest prior to puncture. 18 ml of CSF was collected at the puncture, which was performed with a 0.9 mm diameter needle. Contradictory to previous reports, body height did not influence CSF 5-hydroxyindoleacetic acid (5-HIAA) or homovanillic acid (HVA). Age influenced HVA (but not 5-HIAA) in a curvilinear manner in male volunteers and the HVA/5-HIAA ratio in females. In contrast to previously reported correlations between 5-HIAA and HVA, a weak correlation was found, but only in females. In males, body weight related to 5-HIAA and atmospheric pressure to HVA, both in a positive direction. Our findings are largely contradictory to previous reports, a fact that might, hypothetically, be due to the absence of strict bedrest before puncture. The use of a comparatively wide needle (0.9 mm in diameter) and the amount of 18 ml CSF drawn might, taken together, make at least some contribution to an explanation.

A prospective 1-5 year outcome study in first-admitted and readmitted schizophrenic patients; relationship to heredity, premorbid adjustment, duration of disease and education level at index admission and neuroleptic treatment.

In a prospective outcome study, 120 DSM-III-R schizophrenic patients were followed for up to 5 years after index admission, when a comprehensive clinical and demographical examination was undertaken with the aim to find early prognostic factors for outcome. They were 86 males (72%) and 34 females (28%), and 66 (55%) were first-admitted and never before treated at index admission from a geographically defined area. Outcome was evaluated 1, 3 and 5 years after index admission by use of a Strauss-Carpenter outcome scale. At year five, 101 patients could be evaluated. Seven (7%) patients had committed suicide during the 5 years' follow-up period. 30% of the patients was considered to have a good, 14% a poor and 56% an intermediate outcome. It was found that 58% had not been in hospital during the last year, 27% were employed on the open market, 25% met friends regularly and 38% had no or only mild symptoms at the five years' follow-up evaluation. Females had a significantly better outcome than males. High education level and absence of premorbid deviant behaviour at index admission predicted a good outcome whereas problems in school (with friends and/or teachers) reported by relatives predicted poor outcome. No relationship was found between outcome and age at onset of the disorder and no gender difference in age at onset of the disorder. Patients with a family history of schizophrenia improved more between year one and five as compared with those without a family history, but heredity in itself was not an important factor for outcome. At 5 years after index admission, 40% of patients were on classical neuroleptics and 33% on clozapine whereas 19% were without medication. Of the total sample of 101 patients, 10% were drug-free and had a very good outcome at the 5 years' evaluation. The data indicate that there is a substantial subgroup of schizophrenic patients with a good prognosis and they can be characterized by female sex (even in a group without gender difference in age at onset), absence of premorbid deviant behaviour and a high education level at index admission.

Electrodermal activity as a predictor of social functioning in female schizophrenics.

Twenty-nine female schizophrenics and 20 female controls were presented with a series of moderately intense tones in a standard orienting habituation paradigm while skin conductance was monitored. Premorbid adjustment and symptoms were also rated, and the schizophrenics were observed 2 years later. The total schizophrenic group was divided into a good-outcome group and a poor-outcome group. Good social functioning outcome required both self-supporting ability in the job market and at least a minimal social life. The poor-outcome group had a significantly higher skin-conductance level and frequency of spontaneous skin-conductance fluctuations than the control group, whereas the few patients with good outcome did not differ from controls. These results are contrary to previous findings with a group of schizophrenic men in which poor social functioning was associated with low electrodermal activity. This discrepancy is discussed in terms of sex differences in schizophrenic disorder.

Interrater reliability of the Structured Clinical Interview for the Positive and Negative Syndrome Scale for schizophrenia.

The Swedish version of the Positive and Negative Syndrome Scale for schizophrenia (PANSS) has been tested and construct validity, internal reliability and interrater reliability have been demonstrated to be quite satisfactory. However, the interrater reliability of the negative symptoms was unsatisfactory low. In this study, the Swedish version of the Structured Clinical Interview for the PANSS has been tested. The interrater reliability is increased as compared with the inter-rater reliability achieved by means of the PANSS. As concerns the positive scale, the intraclass coefficients increased to 0.98-0.99 with the SCID-PANSS. For the negative scale, the intraclass coefficients increased to 0.83-0.90 with the SCID-PANSS, and for the general scale the increase was to 0.95-0.98 with the SCID-PANSS. It was also demonstrated that the interrater reliability is higher for the positive and the negative factors derived from the PANSS than for the positive and the negative scales.

Electrodermal orienting response, maternal age, and season of birth in schizophrenia.

Consistent with earlier research, male schizophrenic patients born during the season of excess risk for schizophrenia (January-April) showed significantly lower electrodermal responsivity than controls born during the season of excess risk, and patients and controls born during the season not associated with increased risk (May-December). No support for maternal age as an explanation for the season-of-birth effect was found.

Relationship between abnormal brainstem auditory-evoked potentials and subnormal CSF levels of HVA and 5-HIAA in first-episode schizophrenic patients.

Auditory brainstem-evoked responses (ABRs) were recorded and the CSF concentration of the amine metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in 39 drug-free schizophrenic patients. Twenty-four of the patients were first admissions and had never received antipsychotic medication. The ABRs were judged according to our normative data and the CSF concentrations of the amine metabolites were compared with those of 47 healthy volunteers. Clear-cut abnormal ABRs, identified as a lack of one or more peaks or abnormal peak latencies, were found in 15 patients. In controls and patients with normal ABRs, there was a significant positive correlation between the cerebrospinal fluid (CSF) levels of HVA and 5-HIAA; no such correlation was found in patients with abnormal ABRs. Schizophrenics with abnormal ABRs had significantly lower levels of HVA, but not 5-HIAA, in the CSF when compared with controls. Schizophrenic patients with normal ABRs (n = 24) did not differ from the controls with regard to the amine metabolites in CSF. A comparison of the CSF levels of HVA and 5-HIAA yielded no significant difference between patients with normal and those with abnormal ABRs. In contrast, when only first-episode, never-treated schizophrenics were considered, patients with abnormal ABRs (n = 10) had significantly lower levels of both HVA and 5-HIAA when compared with those having normal ABRs (n = 14). The results indicate an association between brainstem dysfunction and reduced central nervous dopaminergic and possibly also serotoninergic activity in schizophrenia.

A double-blind comparative multicentre study of remoxipride and haloperidol in schizophrenia.

In a double-blind multicentre study of parallel group design the efficacy and safety of remoxipride and haloperidol were compared in a total of 96 patients with acute episodes of schizophrenic or schizophreniform disorder according to DSM-III. There were 48 patients in each treatment group; 27 men and 21 women in the remoxipride group, 33 men and 15 women in the haloperidol group. The median duration of illness was 7 years in both groups. The mean daily dose was 437 mg for remoxipride and 10.6 mg for haloperidol during the last week of treatment. No statistically significant differences in total BPRS scores were found between remoxipride and haloperidol. The median total BPRS scores at the start of active treatment were 26 in the remoxipride and 27 in the haloperidol group; these were reduced to 16 and 12.5, respectively, at the last rating. According to Clinical Global Impression (CGI), 43% of patients in the remoxipride group and 68% of those in the haloperidol group improved much or very much during treatment. This difference was not statistically significant. Treatment-emergent extrapyramidal side effects such as akathisia, tremor, and rigidity occurred significantly more frequently in the haloperidol group; this group also made more frequent use of anticholinergic drugs. Neither of the trial drugs seriously affected laboratory or cardiovascular variables. It is concluded that remoxipride has an antipsychotic effect in a dose range of 150-600 mg per day comparable to that of haloperidol in doses up to 20 mg per day but with fewer extrapyramidal side effects.

Electrodermal nonresponding, premorbid adjustment, and symptomatology as predictors of long-term social functioning in schizophrenics.

The hypothesis that electrodermal nonresponsiveness to orienting stimuli delineates a core group of "Kraepelinian" type schizophrenics was tested by following up social functioning outcome over a 2-year period in 37 schizophrenics. Good social functioning outcome required both some self-supporting ability in the job market and a minimal social life. The prior assessments included monitoring of electrodermal responses to a series of moderately intense tones, ratings of reported and observed symptoms during an interview, and ratings of premorbid adjustment on the basis of an interview with a close relative. Electrodermal nonresponding, poor premorbid adjustment, and negative symptomatology predicted poor social functioning during the second follow-up year, but the relationship to nonresponding pertained exclusively to a group of 15 first-episode patients. Discriminant analysis showed that electrodermal nonresponding and symptoms were the only independent predictors of outcome.