Dual-isotope SPECT imaging of striatal dopamine: a comparative study between never-treated and haloperidol-treated first-episode schizophrenic patients.

The aim of this dual-isotope SPECT imaging study was to evaluate striatal dopamine transporter (DAT) and D2 receptor availability in first-episode never-treated and haloperidol-treated schizophrenic patients and whether the availability is associated with psychopathology. Twenty-four inpatients with a first acute schizophrenic episode were enrolled in the study; 12 of these patients were treated with haloperidol for 2 weeks before dual-isotope SPECT was performed, whereas the other 12 patients underwent the SPECT evaluation directly after enrollment. Twelve healthy control persons were also recruited and evaluated with the dual-isotope SPECT protocol. Psychopathology was assessed by the Positive and Negative Syndrome Scale and other scales. D2-radioligand binding did not differ between drug-naïve patients and the control group but was significantly lower in the haloperidol-treated group. DAT availability was also significantly lower in the haloperidol patients than in the other two groups and differed significantly between drug-naïve, positive-syndrome-type patients and healthy controls. The data obtained with the new dual-isotope SPECT technique reveal a direct effect of haloperidol at the D2 and DAT receptor level.

Structural brain alterations in subjects at high-risk of psychosis: a voxel-based morphometric study.

Forty Untreated high-risk (HR) individuals for psychosis and 75 healthy control subjects (HC) matched for age, gender, handedness and educational level were investigated by structural MRI. HR subjects were recruited at the Early Detection and Intervention Centre for Mental Crises (FETZ) of the Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Germany. Measurements of gray matter volumes were performed by voxel-based morphometry using SPM5. The sample of HR subjects showed GM volume reductions in frontal, lateral temporal and medial temporal regions compared to the healthy control group. These regions are compatible with structural findings in the clinically apparent disease of schizophrenia.

Dual-isotope SPECT imaging of striatal dopamine: first episode, drug naïve schizophrenic patients.

OBJECTIVE: The aim of this investigation was to evaluate the usefulness of a dual-isotope SPECT technique to assess simultaneously striatal dopamine binding structures - presynaptic dopamine transporter (DAT) and postsynaptic dopamine D(2) receptor - in first-episode, drug-naive schizophrenic patients compared to healthy control persons. Additionally, relations between radioligand binding to DAT and D(2) and positive symptoms were assessed. METHODS: Twenty acutely ill inpatients suffering from a first acute schizophrenic episode and 12 healthy control persons participated in the study. Patients were naïve with respect to neuroleptic or antidepressant medication. A dual-isotope SPECT protocol was performed using combined application of [99mTc]TRODAT-1 and [123I]IBZM. On the day of SPECT, psychopathology was assessed in the patient group by PANSS rating. RESULTS: In the patient but not in the healthy control group there was a significant correlation between DAT and D(2) receptor availability. Patients with predominant positive symptoms (n=12) had a significantly higher DAT availability compared to the healthy control group. An inverse correlation between DAT and D(2) availability and the extent of "delusions", "conceptual disorganization", and "hallucinatory behaviour" could be demonstrated. DISCUSSION: The data obtained with this dual-isotope SPECT technique show a change in interaction between striatal DAT and D(2) receptor in first-episode, never-treated schizophrenic patients. Additionally, an association between dopamine transmission and the core symptoms of the acute psychotic syndrome was found.

The role of dopamine for the pathophysiology of schizophrenia.

Since decades, experimental approaches and clinical experience have suggested a dopaminergic system's dysregulation playing an important role within the pathophysiology of schizophrenia. This paper summarizes the actual standard of knowledge of the physiological fundamentals and hypothesized dysbalances of the dopamine (DA) system with respect to schizophrenia including interaction with other neurotransmitter systems (glutamate, GABA). The assumed functional role of DA with respect to physiological and illness-associated cognitive performance, especially working memory, reward, and motivation, as it was assessed by fMRI studies, is presented. A third focus concentrates on giving a short survey of SPECT and PET studies measuring the amount of the striatal and extrastriatal DA, the striatal and extrastriatal dopamine D2 receptor, and the dopamine transporter (DAT) comparing first-episode, drug-naïve, treated, and relapsing schizophrenic patients and healthy control persons.

Striatal dopamine transporter availability is associated with the productive psychotic state in first episode, drug-naive schizophrenic patients.

OBJECTIVE: Supposing a "hyperdopaminergic State" associated at least with acute psychotic illness phases in schizophrenia, a direct relationship between striatal dopamine metabolism and the core psychopathological symptoms rarely can be provided. Recently, a new SPECT ligand to the presynaptic dopamine transporter (DAT) was introduced. Association of DAT availability and the acute psychotic syndrome is now demonstrated in a large cohort of first episode, never treated schizophrenic patients. METHODS: Twenty-eight inpatients suffering from a first acute exacerbation of schizophrenia and 12 healthy control subjects underwent SPECT scanning with the new radioligand [(99m)Tc]TRODAT-1. On the day of SPECT, psychopathology was assessed using specific scales including PANSS. RESULTS: There was no significant difference in [(99m)Tc]TRODAT-1 specific binding to the striatal DAT comparing both groups. The extend of hallucinations was significantly inversely correlated with DAT availability in patients with a predominantly positive syndrome type. DISCUSSION: Our data support evidence that differences in presynaptic dopaminergic activity in schizophrenic patients are associated with the extend of the acute psychotic syndrome. [(99m)Tc]TRODAT-1 seems to be a useful agent for in vivo assessment of a psychopathological association with dopamine metabolism.

The striatal dopamine transporter in first-episode, drug-naive schizophrenic patients: evaluation by the new SPECT-ligand[99mTc]TRODAT-1.

Following the current hypothesis that acute schizophrenic psychotic illness is associated with a striatal 'hyperdopaminergic state', presynaptic integrity and dopamine transporter (DAT) density in first-episode, neuroleptic-naive schizophrenic patients was measured by single-photon-emission-tomography (SPECT) and compared with that in healthy control subjects. A new SPECT-ligand for assessment of the striatal DAT, the Technetium-99m-labelled tropane TRODAT-1 ([99mTc]TRODAT-1), was used. Ten inpatients suffering from a first acute schizophrenic episode and 10 age- and sex-matched healthy control subjects underwent SPECT with [99mTc]TRODAT-1. On the day of SPECT, psychopathological ratings were performed with the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and Schedule for Assessment of Negative Symptoms (SANS). Patients had not previously received any neuroleptic or antidepressant medication. Mean specific TRODAT-1 binding in the striatum did not differ significantly between the patient and the age- and sex-matched control group (1.25 vs. 1.28). Variance was significantly higher in the patient group. The data obtained with the new ligand in first-episode, drug-naive schizophrenic patients are in line with the PET results from the group of Laakso et al. in a comparable patient sample. [99mTc]TRODAT-1 seems to be a valuable new SPECT-ligand in the evaluation of the presynaptic site of the striatal dopaminergic synapse in schizophrenia.

Striatal dopamine D2 receptor binding of risperidone in schizophrenic patients as assessed by 123I-iodobenzamide SPECT: a comparative study with olanzapine.

The aim of this investigation was to compare the degree of striatal dopamine-(D2) receptor blockade by two atypical antipsychotic drugs, risperidone and olanzapine. The percentage of D2 receptor occupancy during treatment was calculated by comparing the results of 123I-iodobenzamide SPECT with those from healthy control subjects. Twenty inpatients suffering from schizophrenia or schizoaffective psychosis according to DSM IV/ICD-10 criteria were treated with clinically recommended doses of risperidone and compared with 13 inpatients treated with up to 20 mg olanzapine. Neuroleptic dose and D2 receptor blockade correlated strongly for both risperidone (Pearson r = -0.86, p = 0.0001) and olanzapine (Pearson r = -0.77, p = 0.002). There was no significant difference between the D2 receptor occupancy of the two substances when given in the clinically recommended dose range (unpaired t-test, t = -0.112, p = 0.911).

D2 receptor occupancy under recommended and high doses of olanzapine: an iodine-123-iodobenzamide SPECT study.

The aim of this study was to compare the degree of striatal dopamine D2 receptor availability in patients treated with recommended (5-20 mg, mean dose 11.9 +/- 6.3 mg daily) and higher doses (25-40 mg, mean 32.1 +/- 5.6 mg daily) of the novel antipsychotic drug olanzapine by means of [123I] IBZM Single photon emission computed tomography (SPECT). The results were compared to those of a group of 10 untreated, healthy, age- and sex-matched controls. The degree of dopamine D2 receptor occupancy in the patient group was correlated with the presence of extrapyramidal symptoms (EPS). A total of 20 patients who met the DSM III R criteria for schizophrenia or schizoaffective disorder received a clinically effective antipsychotic monotherapy with olanzapine. The mean daily dose of olanzapine ranged from 0.05-0.6 mg/kg body weight. The dopamine D2 receptor binding was reduced in all patients treated with olanzapine. Specific IBZM binding expressed as the [STR-BKG]/BKG ratio ranged from 0.13-0.61 (healthy controls 0.95). The D2 receptor availability revealed an exponential dose-response relationship (r = - 0.85, p < 0.001). The frequency of EPS induced by olanzapine was considerably lower. Only one patient, treated with 40 mg olanzapine, suffered from severe EPS symptoms and had to be given biperiden. There were no significant differences in the presence of EPS symptoms between patients with recommended doses and those with higher doses of olanzapine.

Principles for the conduct of non-drug clinical studies*.

Synopsis The World Medical Association's Declaration of Helsinki outlines the principles for the conduct of drug and non-drug clinical studies. The key difference between drug and non-drug biomedical research is to be seen in the fact that for non-drugs, the potential benefits, hazards and discomforts for the volunteer enrolled in a clinical study cannot be weighed against advantages of improving current diagnostic or therapeutic methods. The principles reflected in the Guidelines for Good Clinical Practice for Trials on Medicinal Products in the European Community, issued by the Commission of the European Communities in substantial parts also apply for trials on non-medicinal products. Specifically this is true with regard to the requirements for the privacy, integrity, and well-being of volunteers subjected to research, and fully informing them about the risks and benefits potentially associated with the use of a test product. Skin care products are the most prominent group of non-drug products for which clinical studies are conducted. Using these products, the key differences between executing the principles in a non-drug and a drug clinical study are highlighted.