Depression as a Prodromal Symptom of Neurodegenerative Diseases.

Neurodegenerative diseases can manifest as psychiatric symptoms in the prodromal phase, before the onset of core symptoms such as neurological, motor, and cognitive symptoms. Positron emission tomography (PET) has made it possible to detect the pathology of some neurodegenerative diseases in vivo. Many studies have indicated that depression is a preclinical symptom of neurodegenerative diseases. Approximately 10% of non-demented participants with depression developed Alzheimer's disease (AD) during the follow-up period. The prevalence of depression/dysphoria was 42.9% in the preclinical stage of dementia with Lewy bodies. Depression was present in 33.3% of patients with preclinical behavioral-variant frontotemporal lobar degeneration. Approximately 10% of patients had a history of depression at the time of diagnosis with Parkinson's disease. PET studies have revealed the pathology of neurodegenerative diseases in some cases of geriatric depression. Increased brain amyloid-beta deposition in late-onset depression is a possible reflection of prodromal AD. The severity of depression was significantly associated with greater inferior temporal tau and marginally associated with greater entorhinal cortex tau, and depression was associated with significantly greater mean cortical tau deposition. Thus, the presence of depression as a preclinical/prodromal symptom of neurodegenerative diseases has been demonstrated by epidemiological, pathological, and biomarker studies. A growing body of evidence from PET studies indicates that some cases of geriatric depression have pathologies of degenerative neurological disease. In the future, it is expected that PET will be utilized as an imaging biomarker for diagnosis of psychiatric disorders and development of new therapeutic agents.

Effect of DL-Methylephedrine on Dopamine Transporter Using Positron Emission Tomography With [18F]FE-PE2I.

Rationale: Since ephedrine has a dopamine transporter (DAT) inhibitory effect similar to amphetamine, dl-methylephedrine, a derivative of ephedrine, is considered to have the characteristics of a central nervous system stimulant due to the DAT inhibitory effect. For example, the World Anti-Doping Agency categorizes dl-methylephedrine as a stimulant in the prohibited list for competitions. Assuming to have the same effect as ephedrine, the urinary concentration of dl-methylephedrine is regulated below 10 µg/mL, as is ephedrine. However, the extent to which dl-methylephedrine affects brain function is not yet fully understood. Objectives: The purpose of this study was to evaluate DAT occupancy by a single oral administration of a daily dose of dl-methylephedrine using positron emission tomography (PET) with [18F]FE-PE2I to characterize its stimulatory effect on the central nervous system. Methods: Nine healthy male volunteers were enrolled in the study. The experiments were designed as a placebo-controlled randomized double-blind crossover comparative study. After the first PET scan in a drug-free state, the second and third PET scans were performed with randomized dosing at 60 mg of dl-methylephedrine or placebo. The plasma and urine concentrations of dl-methylephedrine were measured just before and after the PET scans, respectively. Results: Mean urine and plasma concentrations of dl-methylephedrine were 13.9 µg/mL and 215.2 ng/mL, respectively. Mean DAT occupancy in the caudate was 4.4% for dl-methylephedrine and 1.2% for placebo. Mean DAT occupancy in the putamen was 3.6% for dl-methylephedrine and 0.5% for placebo. There was no significant difference of DAT occupancies between the groups. Conclusion: In this study, the urinary concentration of dl-methylephedrine (13.9 µg/mL) was higher than the prohibited reference value (10.0 µg/mL), and there was no significant difference in DAT occupancy between dl-methylephedrine and placebo. These findings suggest that a clinical daily dose of dl-methylephedrine may exceed the doping regulation value according to urine concentration; however, it was considered that at least the central excitatory effect mediated by DAT inhibition was not observed at the daily dose of dl-methylephedrine.

A positron emission tomography study of the serotonin1B receptor effect of electroconvulsive therapy for severe major depressive episodes.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for depressive disorders, although its molecular mechanism of action is unknown. The serotonin 1B (5-HT1B) receptor is a potential target for treatment of depression and low 5-HT1B receptor binding in limbic regions has been reported in previous positron emission tomography (PET) studies of depression. METHODS: The objective of this longitudinal PET study was to examine the effect of ECT for depression on 5-HT1B receptor binding. Fifteen hospitalized patients with major depressive episodes were examined with PET and the 5-HT1B receptor selective radioligand [11C]AZ10419369, before and after ECT. Fifteen controls matched for age and sex were examined. Limbic regions with previously reported low 5-HT1B receptor binding in depression and a dorsal brain stem region were selected. RESULTS: Thirteen patients completed the study according to protocol. Eleven out of thirteen patients responded to ECT. 5-HT1B receptor binding in hippocampus increased with 30 % after ECT (p=0.021). Using linear mixed effects modelling, we observed increases in 5-HT1B receptor binding following ECT with a moderate to large effect size, which did not differ significantly between regions. In an exploratory analysis, strong correlations between changes in 5-HT1B receptor binding and agitation scores on the Hamilton Depression Rating Scale after ECT were observed. LIMITATIONS: Albeit representative of a PET study, the sample size is still small and there are potential confounding effects of medication. CONCLUSIONS: Increased 5-HT1B receptor binding was observed following ECT for depression, corresponding to previous findings of increased 5-HT1B receptor binding in hippocampus after rapid acting ketamine for treatment resistant depression.

Multi-Atlas MRI-Based Striatum Segmentation for 123I-FP-CIT SPECT (DAT-SPECT) Compared With the Bolt Method and SPECT-Atlas-Based Segmentation Method Toward the Accurate Diagnosis of Parkinson's Disease/Syndrome.

Aims: This study aimed to analyze the performance of multi-atlas MRI-based parcellation for 123I-FP-CIT SPECT (DAT-SPECT) in healthy volunteers. The proposed method was compared with the SPECT-atlas-based and Bolt methods. 18F-FE-PE2I-PET (DAT-PET) was used as a reference. Methods: Thirty healthy subjects underwent DAT-SPECT, DAT-PET, and 3D-T1WI-MRI. We calculated the striatum uptake ratio (SUR/SBR), caudate uptake ratio (CUR), and putamen uptake ratio (PUR) for DAT-SPECT using the multi-atlas MRI-based method, SPECT-atlas-based method, and Bolt method. In the multi-atlas MRI-based method, the cerebellum, occipital cortex, and whole-brain were used as reference regions. The correlation of age with DAT-SPECT activity and the correlations of SUR/SBR, CUR, and PUR between DAT-SPECT and DAT-PET were calculated by each of the three methods. Results: The correlation between age and SUR/SBR for DAT-SPECT based on the multi-atlas MRI-based method was comparable to that based on the SPECT-atlas-based method (r = -0.441 to -0.496 vs. -0.488). The highest correlation between DAT-SPECT and DAT-PET was observed using the multi-atlas MRI-based method with the occipital lobe defined as the reference region compared with the SPECT-atlas-based and Bolt methods (SUR, CUR, and PUR: 0.687, 0.723, and 0.676 vs. 0.698, 0.660, and 0.616 vs. 0.655). Conclusion: Multi-atlas MRI-based parcellation with the occipital lobe defined as the reference region was at least comparable to the clinical methods.

Striatal Dopamine D2 Receptor Occupancy Induced by Daily Application of Blonanserin Transdermal Patches: Phase II Study in Japanese Patients With Schizophrenia.

BACKGROUND: Transdermal antipsychotic patch formulations offer potential benefits, including improved adherence. This study investigated the striatal dopamine D2 receptor occupancy with daily blonanserin transdermal patch application. METHODS: This open-label, phase II study enrolled 18 Japanese outpatients (20 to <65 years) with schizophrenia (DSM-IV-TR criteria; total Positive and Negative Syndrome Scale score <120 at screening) treated with blonanserin 8-mg or 16-mg tablets. Patients continued tablets for 2-4 weeks at their current dose and were then assigned to once-daily blonanserin patches (10/20/40/60/80 mg daily) for 2-4 weeks based on the oral dose. [11C]raclopride positron emission tomography scanning determined blonanserin striatal dopamine D2 receptor occupancy (primary endpoint). Secondary endpoints included assessment of receptor occupancy by dose, changes in Positive and Negative Syndrome Scale and Clinical Global Impressions-Severity of Illness-Severity scores, patient attitudes towards adherence, and patch adhesiveness. RESULTS: Of 18 patients who started the blonanserin tablet treatment period, 14 patients completed treatment. Mean D2 receptor occupancy for blonanserin tablets 8 mg/d (59.2%, n = 5) and 16 mg/d (66.3%, n = 9) was within the values for blonanserin patches: 10 mg/d (33.3%, n = 3), 20 mg/d (29.9%, n = 2), 40 mg/d (61.2%, n = 3), 60 mg/d (59.0%, n = 3), and 80 mg/d (69.9%, n = 3). Occupancy generally increased with increasing blonanserin dose for both formulations with the half maximal receptor occupancy for tablets and patches associated with doses of 6.9 mg/d and 31.9 mg/d, respectively. Diurnal variability in occupancy was lower during transdermal patch treatment than during tablet treatment. Blonanserin transdermal patches were well tolerated with no major safety concerns. CONCLUSIONS: Blonanserin patches (40/80 mg/d) have lower diurnal variability in occupancy than blonanserin tablets (8/16 mg/d), and patches at doses of 40 mg/d and 80 mg/d appear to be a suitable alternative for blonanserin tablets at doses of 8 mg/d and 16 mg/d, respectively. Blonanserin patches represent a potential new treatment option for patients with schizophrenia. TRIAL REGISTRY: JAPIC Clinical Trials Information registry (www.clinicaltrials.jp; JapicCTI-No: JapicCTI-121914).

Evaluation of dopamine D3 receptor occupancy by blonanserin using [11C]-(+)-PHNO in schizophrenia patients.

RATIONALE: Unlike other antipsychotics, our previous positron emission tomography (PET) study demonstrated that a single dose of blonanserin occupied dopamine D3 as well as dopamine D2 receptors in healthy subjects. However, there has been no study concerning the continued use of blonanserin. OBJECTIVES: We examined D2 and D3 receptor occupancies in patients with schizophrenia who had been treated with blonanserin. METHODS: Thirteen patients with schizophrenia participated. PET examinations were performed on patients treated with clinical dosage of blonanserin or olanzapine alone. A crossover design was used in which seven patients switched drugs after the first scan, and PET examinations were conducted again. D2 and D3 receptor occupancies were evaluated by [11C]-(+)-PHNO. We used nondisplaceable binding potential (BPND) of 6 healthy subjects which we previously reported as baseline. To consider the effect of upregulation of D3 receptor by continued use of antipsychotics, D3 receptor occupancy by blonanserin in seven subjects who completed 2 PET scans were re-analyzed by using BPND of olanzapine condition as baseline. RESULTS: Average occupancy by olanzapine (10.8 ± 6.0 mg/day) was as follows: caudate 32.8 ± 18.3%, putamen 26.3 ± 18.2%, globus pallidus - 33.7 ± 34.9%, substantia nigra - 112.8 ± 90.7%. Average occupancy by blonanserin (12.8 ± 5.6 mg/day) was as follows: caudate 61.0 ± 8.3%, putamen 55.5 ± 9.5%, globus pallidus 48.9 ± 12.4%, substantia nigra 34.0 ± 20.6%. EC50 was 0.30 ng/mL for D2 receptor for caudate and putamen (df = 19, p < 0.0001) and 0.70 ng/mL for D3 receptor for globus pallidus and substantia nigra (df = 19, p < 0.0001). EC50 for D3 receptor of blonanserin changed to 0.22 ng/mL (df = 13, p = 0.0041) when we used BPND of olanzapine condition as baseline. CONCLUSIONS: Our study confirmed that blonanserin occupied both D2 and D3 receptors in patients with schizophrenia.

Electroconvulsive therapy decreases striatal dopamine transporter binding in patients with depression: A positron emission tomography study with [18F]FE-PE2I.

Electroconvulsive therapy (ECT) is an effective treatment for major depression. Previous studies suggested that dopaminergic neurotransmission plays a crucial role in the mechanism of the action of ECT. Since dopamine transporters (DAT) regulate extracellular dopamine concentration, DAT represents an interesting target for the study of the mechanism of action of ECT. Eight inpatients (7 patients with major depressive disorder and 1 patient with bipolar disorder with a DSM-IV diagnosis) received a series of 7-15(11.3±5.2) bilateral ECT sessions.The severity of symptoms was assessed using the 21-item Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression-Severity (CGI-S). All patients were examined with [18F]FE-PE2I positron emission tomography (PET) at pre-ECT, after the 10th ECT, and at post-ECT. Striatal DAT-binding potential (BPND) of all patients was reduced, with an average change ratio of DAT-BPND of -13.1±5.6%. In the 2 cases with 15 ECT sessions, the ratio change of DAT-BPND after the 15th ECT was larger than that after the 10th ECT. Also, HDRS and CGI-S were reduced. These results indicate that the dopamine nervous system is part of themechanism of action of ECT.

Low dopamine transporter binding in the nucleus accumbens in geriatric patients with severe depression.

AIM: Dysfunction of dopaminergic neurons in the central nervous system is considered to be related to major depressive disorder (MDD). Especially, MDD in geriatric patients is characterized by anhedonia, which is assumed to be associated with reduced dopamine neurotransmission in the reward system. Dopamine transporter (DAT) is considered to reflect the function of the dopamine nerve system. However, previous DAT imaging studies using single photon emission computed tomography or positron emission tomography (PET) have shown inconsistent results. The radioligand [18 F]FE-PE2I for PET enables more precise evaluation of DAT availability. Hence, we aimed to evaluate the DAT availability in geriatric patients with MDD using [18 F]FE-PE2I. METHODS: Eleven geriatric patients with severe MDD and 27 healthy controls underwent PET with [18 F]FE-PE2I, which has high affinity and selectivity for DAT. Binding potentials (BPND ) in the striatum (caudate and putamen), nucleus accumbens (NAc), and substantia nigra were calculated. BPND values were compared between MDD patients and healthy controls. RESULTS: MDD patients showed significantly lower DAT BPND in the NAc (P = 0.009), and there was a trend of lower BPND in the putamen (P = 0.032) compared to controls. CONCLUSION: We found low DAT in the NAc and putamen in geriatric patients with severe MDD, which could be related to dysregulation of the reward system.

Comparison of Dopamine D3 and D2 Receptor Occupancies by a Single Dose of Blonanserin in Healthy Subjects: A Positron Emission Tomography Study With [11C]-(+)-PHNO.

Background: Blockade of D3 receptor, a member of the dopamine D2-like receptor family, has been suggested as a possible medication for schizophrenia. Blonanserin has high affinity in vitro for D3 as well as D2 receptors. We investigated whether a single dose of 12 mg blonanserin, which was within the daily clinical dose range (i.e., 8-24 mg) for the treatment of schizophrenia, occupies D3 as well as D2 receptors in healthy subjects. Methods: Six healthy males (mean 35.7±7.6 years) received 2 positron emission tomography scans, the first prior to taking blonanserin, and the second 2 hours after the administration of a single dose of 12 mg blonanserin. Dopamine receptor occupancies by blonanserin were evaluated by [11C]-(+)-PHNO. Results: Occupancy of each region by 12 mg blonanserin was: caudate (range 64.3%-81.5%; mean±SD, 74.3±5.6%), putamen (range 60.4%-84.3%; mean±SD, 73.3%±8.2%), ventral striatum (range 40.1%-88.2%; mean±SD, 60.8%±17.1%), globus pallidus (range 65.8%-87.6%; mean±SD, 75.7%±8.6%), and substantia nigra (range 56.0%-88.7%; mean±SD, 72.4%±11.0%). Correlation analysis between plasma concentration of blonanserin and receptor occupancy in D2-rich (caudate and putamen) and D3-rich (globus pallidus and substantia nigra) regions showed that EC50 for D2-rich region was 0.39 ng/mL (r=0.43) and EC50 for D3-rich region was 0.40 ng/mL (r=0.79). Conclusions: A single dose of 12 mg blonanserin occupied D3 receptor to the same degree as D2 receptor in vivo. Our results were consistent with previous studies that reported that some of the pharmacological effect of blonanserin is mediated via D3 receptor antagonism.

Effect of apolipoprotein E phenotype on the association of plasma amyloid ß and amyloid positron emission tomography imaging in Japan.

INTRODUCTION: The plasma concentration of beta-amyloid (Aß) has been considered another biomarker of Alzheimer's disease and was reportedly associated with cortical Aß accumulation. METHODS: We analyzed 28 subjects with apolipoprotein E4 (ApoE4; E4 group) and 89 subjects without ApoE4 (non-E4 group) to determine the association between cortical Aß accumulation by standard uptake value ratio with [18F]florbetapir positron emission tomography and plasma Aß1-40 and Aß1-42. RESULTS: Aß1-42/Aß1-40 correlated significantly with mean regional [18F]florbetapir standard uptake value ratio in the non-E4 group (R2 = 0.06, P = .02) but not in the E4 group, and receiver operating characteristic curve analysis for Aß1-42/Aß1-40 in the non-E4 group showed sensitivity (92.9%) and specificity (45.9%) with a cutoff value of 0.150 for Aß positivity. DISCUSSION: We verified that the correlation between Aß1-42/Aß1-40 and Aß accumulation differed according to ApoE phenotype. The high sensitivity of plasma Aß1-42/Aß1-40 for Aß positivity in non-E4 subjects indicated a possible role of plasma Aß1-42/Aß1-40 as a screening biomarker before amyloid positron emission tomography in clinical settings.

Time-course of serotonin transporter occupancy by single dose of three SSRIs in human brain: A positron emission tomography study with [(11)C]DASB.

Sixteen healthy volunteers were enrolled and divided into four groups according to the single administration of 10mg or 20mg escitalopram, 50mg sertraline, or 20mg paroxetine. Four positron emission tomography scans with [(11)C]DASB were performed on each subject, the first prior to taking the drug, followed by the others at 4, 24, and 48h after. Serotonin transporter occupancies of the drugs at each time point were calculated. All drugs showed maximum occupancy at 4h after dosing and then decreasing occupancies with time. Escitalopram and sertraline showed high occupancies of 69.1-77.9% at 4h, remaining at 52.8-57.8% after 48h. On the other hand, paroxetine showed relatively low occupancy of 44.6%, then decreasing to 10.3% at 48h. Escitalopram (both 10mg and 20mg) and sertraline (50mg) showed high and sustained occupancy. Paroxetine (20mg) showed relatively low and rapidly decreasing occupancy, possibly due to the low plasma concentration by single dosing schedule. Applying the reported concentration of multiple dosing, 20mg paroxetine will induce over 80% occupancy. The present study suggested that these drugs and doses would be sufficient for the treatment of depression.

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.

Comparison of imaging biomarkers for Alzheimer's disease: amyloid imaging with [18F]florbetapir positron emission tomography and magnetic resonance imaging voxel-based analysis for entorhinal cortex atrophy.

OBJECTIVE: We compared amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) in subjects clinically diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI), and older healthy controls (OHC) in order to test how these imaging biomarkers represent cognitive decline in AD. METHODS: Fifteen OHC, 19 patients with MCI, and 19 patients with AD were examined by [(18)F]florbetapir PET to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI and the voxel-based specific regional analysis system for AD to calculate z-score as the degree of entorhinal cortex atrophy, and by mini-mental state examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive component--Japanese version (ADAS-Jcog) for cognitive functions. RESULTS: Both cutoff values for measuring AD-like levels of amyloid (1.099 for SUVR) and entorhinal cortex atrophy (1.60 for z-score) were well differentially diagnosed and clinically defined AD from OHC (84.2% for SUVR and 86.7% for z-score). Subgroup analysis based on beta-amyloid positivity revealed that z-score significantly correlated with MMSE (r = -0.626, p < 0.01) and ADAS-Jcog (r = 0.691, p < 0.01) only among subjects with beta-amyloid. CONCLUSIONS: This is the first study to compare [(18)F]florbetapir PET and MRI voxel-based analysis of entorhinal cortex atrophy for AD. Both [(18)F]florbetapir PET and MRI detected changes in AD compared with OHC. Considering that entorhinal cortex atrophy correlated well with cognitive decline only among subjects with beta-amyloid, [18F]florbetapir PET makes it possible to detect AD pathology in the early stage, whereas MRI morphometry for subjects with beta-amyloid provides a good biomarker to assess the severity of AD in the later stage.

A case of Alzheimer's disease following mild traumatic brain injury.

OBJECTIVE: To report a case of Alzheimer's disease (AD) following mild traumatic brain injury (TBI). METHOD: Case report. RESULTS: We report the time course of AD following mild TBI with evidence of AD pathology. A patient complained of minor memory disturbance 6 months after TBI and was diagnosed with mild cognitive impairment 1.5 years after TBI, and she was finally diagnosed as probable AD 4 years after TBI. Amyloid PET revealed brain accumulation of beta-amyloid at a pathological AD level. CONCLUSION: Our case well illustrated how TBI can accelerate the AD process. Clinicians should carefully follow up patients with persistent cognitive impairment after TBI.

Amyloid imaging with [(18)F]florbetapir in geriatric depression: early-onset versus late-onset.

BACKGROUND: We examined patients with mild cognitive impairment (MCI) with a history of geriatric depression (GD) and healthy controls (HC) to evaluate the effect of beta-amyloid (Aß) pathology on the pathology of GD by using [(18)F]florbetapir PET. METHODS: Thirty-three elderly patients (76.7 ± 4.2 years) and 22 healthy controls (HC; 72.0 ± 4.5 years, average ± SD) were examined by [(18)F]florbetapir positron emission tomography (PET) to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI to determine the degree of atrophy, by Mini-Mental State Examination for cognitive functions, and by Geriatric Depression Scale for the severity of depression, and by Clinical Dementia Rating for activity of daily living (ADL). The cut-off value of 1.08 for SUVR was defined as Aß-positive. RESULTS: Of the patients and HC, 39.4% and 27.3%, respectively, were beta-amyloid-positive. The onset age of GD was significantly correlated with SUVR (r = 0.44, p < 0.01). Compared to patients without Aß (GD-Aß), patients with Aß (GD + Aß) did not differ in terms of age, cognitive function, severity of depression and ADL, and brain atrophy. GD + Aß had significantly older average ± SD age at onset of GD (73.6 ± 7.1 versus 58.7 ± 17.8, p < 0.01) and significantly shorter average ± SD time between onset of GD and PET scan day (3.1 ± 5.2 years versus 18.1 ± 18.6 years, p < 0.001) than GD-Aß. CONCLUSIONS: Our results showed that the rate of Aß positivity was higher in late-onset GD and that onset-age was associated with SUVR, suggesting that the later the onset of GD, the more Aß pathology affected its onset.

Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB.

Tramadol is used for the treatment of pain, and it is generally believed to activate the µ-opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [11C]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50 mg and 50.2% at 100 mg. The estimated median effective dose (ED50) of tramadol was 98.1 mg, and the plasma concentration was 0.33 µg/ml 2 h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400 mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs).

Age-related decline in dopamine transporter in human brain using PET with a new radioligand [¹8F]FE-PE2I.

OBJECTIVE: Dopamine transporter (DAT) density is considered as a marker of pre-synaptic function. Numerous neuroimaging studies have consistently demonstrated an age-related decrease in DAT density in normal human brain. However, the precise degree of the regional decline is not yet clear. The purpose of this study was to evaluate the effect of the normal aging process on DAT densities in human-specific brain regions including the substantia nigra and thalamus using positron emission tomography (PET) with [(18)F]FE-PE2I, a new PET radioligand with high affinity and selectivity for DAT. METHODS: Thirty-six healthy volunteers ranging in age from 22 to 80 years were scanned with PET employing [(18)F]FE-PE2I for measuring DAT densities. Region of interest (ROI)-based analysis was used, and ROIs were manually defined for the caudate, putamen, substantia nigra, thalamus, and cerebellar cortex. DAT binding was quantified using a simplified reference tissue model, and the cerebellum was used as reference region. Estimations of binding potential in the caudate, putamen, substantia nigra, and thalamus were individually regressed according to age using simple regression analysis. Estimates of DAT loss per decade were obtained using the values from the regression slopes. RESULTS: There were 7.6, 7.7, and 3.4% per-decade declines in DAT in the caudate, putamen, and substantia nigra, respectively. By contrast, there was no age-related decline of DAT in the thalamus. CONCLUSIONS: [(18)F]FE-PE2I allowed reliable quantification of DAT, not only in the caudate and putamen but also in the substantia nigra. From the results, we demonstrated the age-related decline in the caudate and putamen as reported in previous studies, and additionally for those in the substantia nigra for the first time.

In vivo activity of modafinil on dopamine transporter measured with positron emission tomography and [¹8F]FE-PE2I.

Modafinil, a wake-promoting drug used to treat narcolepsy, is a dopamine transporter inhibitor and is said to have very low abuse liability; this, however, is still up for debate. We conducted a dopamine transporter (DAT) occupancy study with modafinil (200 or 300 mg) in ten healthy volunteers using positron emission tomography (PET) with [¹8F]FE-PE2I, a new PET radioligand with high affinity and selectivity for the dopamine transporter, to characterize its relation to abuse liability. Mean striatal DAT occupancies were 51.4% at 200 mg and 56.9% at 300 mg. There was a significant correlation between occupancy and plasma concentration, indicating dose dependency of DAT inhibition by modafinil in the striatum, and especially in the nucleus accumbens. This study showed that DAT occupancy by modafinil was close to that of methylphenidate, indicating that modafinil may be near the same level as methylphenidate in relation to abuse liability in terms of dopaminergic transmission.

Effect of mazindol on extracellular dopamine concentration in human brain measured by PET.

RATIONALE: Mazindol, an appetite suppressant, inhibits the reuptake of dopamine in the synaptic cleft. It has been considered that mazindol might enhance dopamine transmission in the human brain. However, there has been no study that investigated the extracellular dopamine concentration in vivo. OBJECTIVE: Using positron emission tomography (PET), we aimed to measure the effect of mazindol on the extracellular dopamine concentration and to evaluate how mazindol affects the dopamine system in the healthy human brain. METHODS: Eleven healthy individuals (six males, five females, age 30.9 ± 4.9 years) were enrolled in this study. Each participant was scanned with [(11)C]raclopride on 1 day without any medicine as baseline condition, and on another day with mazindol as drug condition. In the drug condition, participants took mazindol 0.5 mg (N = 5) or 1.5 mg (N = 6) 2 h before the PET scan. Plasma concentrations of mazindol were measured before the injection of [(11)C]raclopride, and urine concentrations of mazindol were measured after the scan. RESULTS: After taking mazindol, the calculated decrease in binding potential (ΔBP) in the striatum was 1.74 % for 0.5 mg and 8.14 for 1.5 mg, and the correlation with the blood concentration of mazindol was significant (P = 0.0016, R (2) = 0.69). ΔBP was not significantly correlated with the urine concentration of mazindol (P = 0.84, R (2) = 0.005). CONCLUSIONS: Mazindol increased the extracellular concentration of dopamine in the human brain, and its effect was dose dependent. A single administration of mazindol, even at usual dosage, elevated dopamine concentration similarly to other addictive drugs, suggesting that the risk of dependence may increase with the mazindol dose.