Lower striatal dopamine transporter binding in neuroleptic-naive schizophrenic patients is not related to antipsychotic treatment but it suggests an illness trait.

INTRODUCTION: Drug induced parkinsonism (DIP) is directly related to dopamine D2 receptor blockade. However, there are many references describing parkinsonian signs (PS) in naive-patients. In our previous study, we observed lower DAT binding in a group of first-episode schizophrenic patients after short-term treatment with risperidone, compared with age-matched healthy controls. AIM: To clarify if DAT decrease could be an illness trait, excluding the effect of antipsychotics on DAT availability, and to determine whether DAT availability before treatment with antipsychotics may predict subsequent development of PS. MATERIALS AND METHODS: A new series of 20 neuroleptic-naive schizophrenic patients and 15 healthy subjects was recruited. SPECT with [(123)I] FP-CIT (DaTSCAN(R)) was performed before starting antipsychotics and after 4 weeks of treatment. PS and psychopathological status were assessed by the Simpson-Angus (SAS), CGI and PANSS scales. Quantitative analyses of SPECTs were performed using ROIs placed in the caudate, putamen and occipital cortex. RESULTS: Schizophrenic patients showed lower DAT binding compared with the healthy subjects at baseline (p<0.001) and after a 4-week-treatment period (p=0.001). Six out of eight schizophrenic patients of the DIP group were symptomatic for PS at baseline, in comparison to two out of 12 in the NoDIP group. Nonetheless, no differences were observed on DAT between DIP and NoDIP, neither at baseline (p=0.360) nor at endpoint (p=0.984). Finally, no differences between baseline-endpoint DAT binding were observed, neither in the DIP group (p=0.767) nor in the NoDIP group (p=0.093). CONCLUSION: Our new series of first-episode naive-schizophrenic patients (1) points out DAT dysfunction as an illness trait due to the significantly lower DAT binding in schizophrenic patients in comparison to healthy subjects; (2) supports the results of other authors who describe PS in never-treated patients; (3) confirms that [(123)I] FP-CIT does not allow us to predict which patients will develop parkinsonism due to the lack of differences between DIP and NoDIP patients; and (4) confirms a null effect of antipsychotics on DAT due to the lack of differences in [(123)I] FP-CIT before and after a 4-week-treatment period.

Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics.

INTRODUCTION: Impaired dopamine transporter (DAT) function may be involved in antipsychotic (AP)-induced extrapyramidal symptoms (EPS). A polymorphism involving a variable number of tandem repeats (VNTR) has been described in the DAT gene (SLC6A3). OBJECTIVE: We studied whether the SLC6A3 VNTR polymorphism is a risk or protection factor for AP-induced EPS. We also investigated the relationship between the polymorphism and DAT availability in the schizophrenic patient's brain. METHODS: Sixty-one patients receiving AP therapy participated in the EPS study. Of these, thirty-two cases presented EPS (Simpson-Angus >3) and twenty-nine without EPS (Simpson-Angus < or =3). The DAT expression was studied in fifteen AP-naive patients by [(123)I] FP-CIT SPECT. RESULTS: No significant differences were observed for the more common alleles ((*)9R and (*)10R) or for genotype frequencies between patients with EPS and those without EPS. The frequency of the (*)9R and (*)10R alleles was similar to that described in other European populations. There were no significant differences in striatal DAT binding among the three major VNTR genotype groups. CONCLUSIONS: Our results suggest that the VNTR polymorphism did not influence AP-induced EPS and did not affect DAT gene expression or protein function.

Decreased striatal dopamine transporter binding assessed with [123I] FP-CIT in first-episode schizophrenic patients with and without short-term antipsychotic-induced parkinsonism.

RATIONALE: Drug-induced parkinsonism (DIP) is one of the main causes of treatment drop-out in schizophrenic patients causing a high incidence of relapse that leads patients to a bad clinical prognosis. The dopaminergic nigrostriatal pathway is involved in the movement control, so the study of the dopamine transporter (DAT) could be of great value to determine its implication in the appearance of DIP. OBJECTIVE: The goal of the study is to determine the striatal DAT binding assessed with [(123)I] FP-CIT SPECT in first-episode neuroleptic-naive schizophrenic in-patients with DIP after short-term antipsychotic treatment. METHOD: The [(123)I] FP-CIT binding ratios of ten schizophrenic in-patients who developed DIP during the first 4-week period of risperidone treatment (6+/-2 mg/day) were compared with ten schizophrenic in-patients treated with the same doses of risperidone and who do not developed DIP and with ten age-matched healthy subjects. Quantitative analyses of SPECTs were performed using regions of interest located in caudate, putamen and occipital cortex. Parkinsonism was assessed by the Simpson-Angus Scale and the psychopathological status by the Clinical General Impression and Positive and Negative Syndrome Scales. RESULTS: Whole striatal [(123)I] FP-CIT binding ratios were significantly lower in patients with and without DIP than in healthy subjects (p<0.001). This was also observed in whole putamen (p<0.001) and caudate nucleus (p<0.001). Females showed higher whole striatal [(123)I] FP-CIT binding ratios than males (p<0.05). No differences in psychopathological scales were observed between patients with and without DIP. CONCLUSION: Our first-episode schizophrenic patients with and without DIP after short-term risperidone treatment have a decreased striatal DAT binding assessed with [(123)I] FP-CIT. This alteration could be related to the schizophrenic disease or may be secondary to the antipsychotic treatment.

Frontal cerebral perfusion after antidepressant drug treatment versus ECT in elderly patients with major depression: a 12-month follow-up control study.

BACKGROUND: Little is known about the evolution of brain perfusion alterations in patients with major depression, and still less about the changes in functional neuroimage produced by different antidepressant biological treatments. METHOD: Between January 2001 and December 2003, long-term follow-up frontal brain perfusion was compared in 2 subgroups of elderly patients (>or= 60 years) treated for severe unipolar major depression (DSM-IV): one subgroup of 16 patients administered electroconvulsive therapy, and another of 26 patients receiving pharmacologic treatment. All patients were remitters. A medication-free brain single photon emission computed tomography was performed in baseline conditions and after a minimum period of 12 months of euthymia. Twenty-eight age- and sex-matched healthy controls were also assessed. RESULTS: No significant differences were found between the 2 subgroups in frontal uptake ratios after a 12-month follow-up period of euthymia. During the acute episode, patients presented significant anterior hypofrontality; 12 months later the hypofrontality had disappeared. CONCLUSION: The long-term evolution of frontal perfusion in elderly major depressives who respond to antidepressant biological treatment is essentially the same in those who receive electroconvulsive therapy and in those who receive medication.

Normalization of frontal cerebral perfusion in remitted elderly major depression: a 12-month follow-up SPECT study.

We examined global and regional cerebral blood flow abnormalities in a group of unmedicated nondemented elderly late-onset unipolar major depressed patients in acute depression and in remission (after a 12-month follow-up period). 35 somatic treatment remitter patients over the age of 60 years and 20 sex-, age-, and vascular risk factor-matched healthy controls were imaged with single photon emission computed tomography, using technetium-99m hexamethylpropylene amine oxime as a tracer. In depression, the depressed group had significantly lower uptake in the left anterior frontal region than the control group. In remission, the left frontal cerebral perfusion abnormalities disappeared, and there were no significant differences in uptake between controls and patients. No significant correlations were found between baseline clinical characteristics of patients and their regional cerebral perfusion at baseline or after a 12-month follow-up. These findings are consistent with the hypothesis that certain neuroanatomic regions of the central nervous system may be functionally and reversibly involved in unipolar major depression, particularly in the late-onset subgroup.

Prognostic value of frontal functional neuroimaging in late-onset severe major depression.

BACKGROUND: There is growing evidence of a relationship between frontal neuroimaging and neuropsychological abnormalities and the physiopathology and course of late-onset major depression. AIMS: To assess acute antidepressant response in late-onset major depression in relation to baseline frontal perfusion ratios. METHOD: A 99mTc HMPAO single photon emission computed tomographic brain scan was performed in medication-free patients with late-onset major depression, who were then included in a 12-week antidepressant treatment regimen. Logistic regression was used to define a predictive model of non-remission. RESULTS: A total of 47 patients completed the study, 34 of whom were classed as remitters and 13 as non-remitters. The variable left anterior fronto-cerebellar perfusion ratio had a global predictive power of 87%. Analysing this variable together with the baseline variables age of onset and duration of index episode, the predictive power of the model rose to 94%. CONCLUSIONS: Our study suggests that a specific frontal functioning could predict the acute antidepressant response in late-onset severe major depression.