[11 C]raclopride positron emission tomography study of dopamine-D2/3 receptor binding in patients with severe major depressive episodes before and after electroconvulsive therapy and compared to control subjects.

AIM: The aim of the study was to test: (i) if D2 /D3 binding in three functional subsections of striatum is different in patients with severe major depressive episodes than in controls; and (ii) if this difference is normalized after electroconvulsive therapy (ECT). METHODS: Nine inpatients were examined with positron emission tomography (PET) and the radioligand [11 C]raclopride before and after an average of 8.4 ECT sessions. Treatment response was assessed using the Montgomery-Åsberg Depression Rating Scale. Nine age- and sex-matched controls were examined twice with PET and [11 C]raclopride. RESULTS: [11 C]raclopride binding was significantly lower in all three subsections of striatum in patients compared to controls (Cohen's dz , 1.14-1.68; P = 0.003-0.027). Montgomery-Åsberg Depression Ratings decreased significantly after ECT (P < 0.001; Cohen's dz , 2.9). ECT had no statistically significant effect on [11 C]raclopride binding, although post-ECT binding estimates were more similar to those obtained in controls in all subsections of striatum. CONCLUSION: Using PET and [11 C]raclopride, we found support for the notion that severe major depressive episodes are associated with significantly lower dopamine D2 /D3 binding in all three subsections of striatum compared to controls. We noted no significant effect on D2 /D3 binding in the patient group after response to ECT.

Neuroleptic-induced deficit syndrome in bipolar disorder with psychosis.

Neuroleptics can induce not only physical adverse effects but also mental effects that produce deficit status in thought, affect, cognition, and behavior. This condition is known as neuroleptic-induced deficit syndrome (NIDS), which includes apathy, lack of initiative, anhedonia, indifference, blunted affect, and reduced insight into disease. Although this old concept now appears almost forgotten, neuroleptics, whether typical or atypical, can make depression or bipolar disorder resemble other more refractory conditions, readily leading to mistaken diagnosis and inappropriate treatment. The authors describe three cases of NIDS superimposed on depressive phase in bipolar disorder with psychosis, where the attending psychiatrist's failure to recognize NIDS prevented patients from receiving effective treatment and achieving remission. All cases achieved remission after reduction of neuroleptics and intensive therapy, including electroconvulsive therapy, for bipolar depression. The concept of NIDS was originally introduced for schizophrenia, and it has rarely been highlighted in other diseases. In recent years, however, atypical antipsychotics are being more often administered to patients with bipolar disorder. Psychiatrists, therefore, should also remember and exercise caution regarding NIDS in the pharmacotherapy of bipolar disorder with and without psychosis. The authors believe that the concept of NIDS needs to be reappraised in current psychiatry.

Effect of electroconvulsive therapy on 5-HT1A receptor binding in patients with depression: a PET study with [11C]WAY 100635.

In our previous positron emission tomography (PET) study, we demonstrated that ECT decreased dopamine D2 receptor in major depressive disorder (MDD). Although many animal studies have focused on the effect of ECT on serotonergic neurotransmission, no human study has directly examined the effect of ECT on brain serotonin [5-hydroxytryptamine (5-HT)] 1A receptors (5-HT1ARs). Using PET with [11C]WAY 100635, we aimed to evaluate the effect of ECT on 5-HT1ARs in patients with MDD. Nine patients underwent PET scans before and after a series of 6-7 bilateral ECTs. Region-of-interest analysis was performed based on the simplified reference tissue model. There were no significant changes in 5-HT1AR binding in patients between before and after ECT. ECT did not alter [11C]WAY 100635 binding even after recovery from depressive episode. Although the present finding does not exclude the involvement of brain 5-HT1A systems in the antidepressant action of ECT, it may indicate the involvement of other neurotransmission mechanisms.

Electroconvulsive therapy decreases dopamine D2receptor binding in the anterior cingulate in patients with depression: a controlled study using positron emission tomography with radioligand [¹¹C]FLB 457.

OBJECTIVE: Electroconvulsive therapy (ECT) has been confirmed as one of the most effective treatments in drug-resistant major depression. However, the mechanism of ECT is still poorly understood. Although several lines of studies have focused on its effect on dopamine neurotransmission, the effects of ECT on dopamine D(2) receptors in a living human brain have not been investigated. Using positron emission tomography (PET) scans with the radioligand [(11)C]FLB 457, we aimed to evaluate the effect of ECT on extrastriatal D(2) receptor binding in medicated patients with major depressive disorder (MDD). METHOD: Seven patients with a DSM-IV diagnosis of MDD underwent PET scans before and after a series of 6-7 treatments with bilateral ECT. Eleven healthy controls were scanned for comparison. All participants were scanned at the National Institute of Radiological Sciences, Chiba, Japan, between November 2000 and September 2005. The parametric images of [(11)C]FLB 457 binding were generated on the basis of a simplified reference tissue model. Voxel-based methods were used to assess the effect of ECT on D(2) receptor binding. RESULTS: There were no significant differences in D(2) receptor binding between patients with MDD and controls. All 7 patients showed clinical improvements in response to ECT treatment (P < .001). Significant changes in D(2) receptor binding, a mean of 25.2% reduction, were found in the right rostral anterior cingulate (AC) following ECT (P < .001). CONCLUSIONS: Electroconvulsive therapy decreased D(2) receptor binding in the rostral AC in MDD patients responding to ECT. Our finding suggests that one of the biologic mechanisms of ECT could be related to dopaminergic alteration in the rostral AC.

Genetic variation in brain-derived neurotrophic factor is associated with serotonin transporter but not serotonin-1A receptor availability in men.

BACKGROUND: The serotonergic system, including the serotonin transporter (5-HTT), which is the target of many antidepressants, seems to be influenced by brain-derived neurotrophic factor (BDNF). METHODS: Positron emission tomography (PET) was used to address, in 25 and 53 healthy volunteers, respectively, the possible association between six polymorphisms in the gene encoding BDNF and the availability of two proteins expressed by serotonergic neurons: the 5-HTT, measured with the radioligand [(11)C]MADAM, and the serotonin-1A (5-HT1A) receptor, measured with [(11)C]WAY-100635. RESULTS: Several single nucleotide polymorphisms were associated with [(11)C]MADAM binding potential (BP) in most brain regions, male carriers of the valine/valine genotype of the Val66Met polymorphism displaying higher availability. Effect sizes ranged from a 50% to a threefold increase. In contrast, there was no association for [(11)C]WAY-100635 BP. The observation that BDNF polymorphisms were associated with 5-HTT availability could be partly replicated in an independent population comprising nine male suicide attempters and nine matched control subjects, in which transporter availability had been measured with single photon emission computed tomography with (123)I-beta-CIT as ligand. CONCLUSIONS: Our results suggest that genetic variation in BDNF influences 5-HTT but not 5-HT1A receptor density in the human brain.

Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans.

The human serotonin transporter (5-HTT) gene is one of the most extensively studied in psychiatry. A functional polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) has been associated with several psychiatric disorders as well as anxiety-related personality traits. In search of a mechanistic understanding of the functional implications of 5-HTTLPR, the influence of this polymorphism on regional 5-HT1A receptor density has previously been examined in two positron emission tomography (PET) studies in humans, yielding, however, contradictory results. In the present study, 54 control subjects were examined with [11C]WAY 100635 PET and a battery of cognitive tests. Regional binding potential (BP) of [11C]WAY 100635 to 5-HT1A receptor was calculated for the dorsal raphe nuclei, the hippocampus, the anterior cingulate, the insula, the temporal cortex and the frontal cortex. The influence of 5-HTTLPR genotype on regional 5-HT1A BP and cognitive performance was investigated. No differences in 5-HT1A receptor density between carriers and non-carriers of the S allele were found. Thus, we could not replicate any of the previously reported associations between 5-HTTLPR and 5-HT1A density. There was, however, a highly significant association between 5-HTTLPR genotype and performance in Wisconsin Card Sorting Test; carriers of the S allele had a superior performance compared to the LL carriers. These observations suggest that functional implications of the 5-HTTLPR polymorphism are not likely to be mediated by differences in 5-HT1A expression levels and that other biomarkers must be considered for future investigations at phenotype level.

Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET.

Women and men differ in serotonin associated psychiatric conditions, such as depression, anxiety and suicide. Despite this, very few studies focus on sex differences in the serotonin system. Of the biomarkers in the serotonin system, serotonin(1A) (5-HT(1A)) receptor is implicated in depression, and anxiety and serotonin transporter (5-HTT) is a target for selective serotonin reuptake inhibitors, psychotropic drugs used in the treatment of these disorders. The objective of the present study was to study sex related differences in the 5-HT(1A) receptor and 5-HTT binding potentials (BP(ND)s) in healthy humans, in vivo. Positron emission tomography and selective radioligands [(11)C]WAY100635 and [(11)C]MADAM were used to evaluate binding potentials for 5-HT(1A) receptors (14 women and 14 men) and 5-HTT (8 women and 10 men). The binding potentials were estimated both on the level of anatomical regions and voxel wise, derived by the simplified reference tissue model and wavelet/Logan plot parametric image techniques respectively. Compared to men, women had significantly higher 5-HT(1A) receptor and lower 5-HTT binding potentials in a wide array of cortical and subcortical brain regions. In women, there was a positive correlation between 5-HT(1A) receptor and 5-HTT binding potentials for the region of hippocampus. Sex differences in 5-HT(1A) receptor and 5-HTT BP(ND) may reflect biological distinctions in the serotonin system contributing to sex differences in the prevalence of psychiatric disorders such as depression and anxiety. The result of the present study may help in understanding sex differences in drug treatment responses to drugs affecting the serotonin system.

Effects of the reference tissue setting on the parametric image of 11C-WAY 100635.

OBJECTIVES: C-WAY 100635 has been used widely in the PET research field to measure 5-HT1A receptors in the living human brain. Reference tissue model analysis, in which the cerebellum was used as the reference tissue, was employed in clinical studies. However, the reported binding potentials varied greatly among the reports. In this study, regions of interest (ROIs) of the cerebellum for C-WAY 100635 were determined in five different approaches for six healthy male volunteers, and the effects on binding potential parametric images were compared. METHODS: First, ROIs on the cerebellar cortex were decided based on information from magnetic resonance imaging (MRI), and then divided into upper and lower parts. They were then refined according to coregistered positron emission tomography (PET) image information, generating upper-refined and lower-refined parts. In a different approach, circular ROIs were decided upon, based on the PET images, and the areas under the curve (AUCs) of five ROIs were compared. Parametric images of binding potentials were calculated with the five ROIs as the reference, and compared with each other. RESULTS: The AUCs of the lower-refined parts were the lowest among the first four ROIs. The ratio of the AUCs between the upper part and lower-refined part was 1.54+/-0.17, that between the upper-refined part and lower-refined part was 1.27+/-0.21, that between the lower part and lower-refined part was 1.04+/-0.02, and that between the circular ROIs and lower-refined part was 1.01+/-0.04. The differences in AUCs among the five cerebellar parts led to significant differences in the binding potential parametric images. CONCLUSION: The binding potential parametric images of C-WAY100635 could vary significantly according to the different methods of establishing ROIs, using the cerebellum as the reference tissue, because radioactivity in the cerebellum for C-WAY100635 is very low.

In vivo drug action of tandospirone at 5-HT1A receptor examined using positron emission tomography and neuroendocrine response.

RATIONALE: Tandospirone is a selective 5-hydroxytryptamine (HT)(1A) receptor agonist and is clinically used as an anxiolytic in Japan. However, there are no data concerning the occupancy of these receptors by tandospirone in the living human brain. OBJECTIVES: The aim of this study was to assess the effect of tandospirone on in vivo 5-HT(1A) receptor binding of [(11)C]WAY 100635 using positron emission tomography (PET) and the neuroendocrine effect. METHODS: In the PET study, seven healthy volunteers were scanned three times following an oral dose of placebo or tandospirone (30 mg or 60 mg). The binding potential of [(11)C]WAY 100635 was estimated for six regions: prefrontal cortex, temporal cortex, anterior cingulate cortex, parietal cortex, hippocampus and dorsal raphe nucleus. In the neuroendocrine study, six volunteers received a single oral dose of tandospirone (60 mg) or placebo in a randomized double-blind, cross-over design, and then the plasma levels of growth hormone and cortisol and the body temperature were measured. RESULTS: Tandospirone (60 mg) induced a significant decrease in body temperature and an increase in the plasma concentration of growth hormone. However, there was no significant reduction of [(11)C]WAY 100635 binding following the administration of 30 mg or 60 mg tandospirone. CONCLUSION: Despite the significant effect on growth hormone and body temperature, a clinical dose of tandospirone had a negligible effect on [(11)C]WAY 100635 binding. This indicates that the agonist produces a pharmacological effect without measurable occupancy, and a new index other than occupancy will be required for the in vivo evaluation of agonists.