Ing-Marie Wieselgren

D2 and 5HT2A 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.

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.

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.

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.

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.

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.

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.

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.