Matthäus Willeit

[123I]-β-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder

Abstract Background: Numerous findings indicate alterations in brain serotonin systems in seasonal affective disorder (SAD). [ 123 I]-2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane ([ 123 I]-β-CIT) labels serotonin transporters (5-HTTs) in the midbrain. We performed a [ 123 I]-β-CIT single photon emission computer tomography (SPECT) study under the hypothesis of lower [ 123 I]-β-CIT binding reflecting reduced central 5-HTT availability in depressed SAD patients. Methods: Depressed SAD patients and healthy control subjects were investigated using [ 123 I]-β-CIT SPECT 4 hours and again 24 hours after tracer injection. Subjects had either never used psychotropic medication or had been drug-free for at least 6 months prior to the investigation. Specific-to-nondisplaceable partition coefficient (V 3 ′′) was calculated for the thalamus-hypothalamus and the midbrain-pons; the cerebellum served as a reference region. Results: Patients showed a reduction in V 3 ′′ in thalamus-hypothalamus (2.41 ± 0.3 vs. 2.84 ± 0.4; p = .026) 24 hours post tracer injection (p.i.). No difference between patients and control subjects was found in midbrain-pons (1.31 ± 0.2 vs. 1.42 ± 0.2; p = .39). No differences were detected in the SPECT acquisitions 4 hours p.i. Conclusions: Depressed SAD patients showed lower specific-to-nondisplaceable [ 123 I]-β-CIT binding in the region of interest (ROI) thalamus-hypothalamus. The small size of the midbrain-pons ROI may have contributed to the failure to show a difference in this ROI as well. Similar to reduced midbrain 5-HTT availability in nonseasonal depression, depression in SAD seems to be associated with reduced 5-HTT availability to the thalamus-hypothalamus.

The Formation of Abnormal Associations in Schizophrenia: Neural and Behavioral Evidence

It is hypothesized that due to an abnormal functioning of the reward system patients with schizophrenia form context-inappropriate associations. It has been shown that the dopamine target regions, especially the ventral striatum, are critical in the formation of reward associations. We wanted to examine how the ventral striatum responds as patients learn reward-related associations and how this neural response is linked to objective and subjective behavioral measures. Functional magnetic resonance imaging (fMRI) Blood oxygen level dependent (BOLD) responses were examined using aversive Pavlovian learning in 13 medicated patients with schizophrenia and 13 matched healthy controls. Colored circles served as conditioned stimulus (CS+) while a loud, individually adjusted, noise served as the unconditioned stimulus. Circles of another color served as neutral comparators (CS−). Subjective indices were assessed by a post-scan self-report, and galvanic skin responses (GSR) were used as objective measures of associative learning. fMRI data were analyzed using a random effects model in SPM2. Patients showed inappropriately strong activations in the ventral striatum in response to the neutral stimulus (CS−) as compared to the healthy controls. Consistent with this neural evidence of aberrant learning, patients also showed evidence of abnormal learning by self-report and as indexed by GSR. The main finding here is that patients with schizophrenia, when exposed to neutral stimuli in a threatening situation, show an abnormal pattern of learning. The aberrant activations and response are consistent with the idea that patients aberrantly assign motivational salience to neutral stimuli, and this process may be one of the aberrations that predisposes them to psychosis.

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism

BACKGROUND A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.

First human evidence of d-amphetamine induced displacement of a D2/3 agonist radioligand: A [11C]-(+)-PHNO positron emission tomography study

Imaging the competition between D2/3 radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D2 receptor exists in a high (D2high) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D2high only. [11C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D2/3 agonist radioligand for positron emission tomography (PET) imaging in humans. Since [11C]-(+)-PHNO is expected to bind preferentially to D2high, it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d-amphetamine and one after placebo. [11C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [11C]-(+)-PHNO BPs in caudate (−13.2%), putamen (−20.8%), and ventral striatum (−24.9%), but not in globus pallidus (−6.5%). d-Amphetamine-induced displacement correlated with serum d-amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D2/3 agonist radioligand in humans. [11C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D2/3 antagonist radioligands.

Receptor and Transporter Imaging Studies in Schizophrenia, Depression, Bulimia and Tourette's Disorder—Implications for Psychopharmacology-

Summary: Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourettes disorder. Striatal D2 and 5-HTIA receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naive or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D2 receptor occupancy rates and antipsychotic efficacy has been found. The measurement of S-HTIA receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HTIA receptor binding potential in schizophrenia. β-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age-and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [124I]/β-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the β-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourettes disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naïve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drugnaive TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.

Lithium in drinking water and suicide mortality

BACKGROUND There is some evidence that natural levels of lithium in drinking water may have a protective effect on suicide mortality. AIMS To evaluate the association between local lithium levels in drinking water and suicide mortality at district level in Austria. METHOD A nationwide sample of 6460 lithium measurements was examined for association with suicide rates per 100,000 population and suicide standardised mortality ratios across all 99 Austrian districts. Multivariate regression models were adjusted for well-known socioeconomic factors known to influence suicide mortality in Austria (population density, per capita income, proportion of Roman Catholics, as well as the availability of mental health service providers). Sensitivity analyses and weighted least squares regression were used to challenge the robustness of the results. RESULTS The overall suicide rate (R(2) = 0.15, β = -0.39, t = -4.14, P = 0.000073) as well as the suicide mortality ratio (R(2) = 0.17, β = -0.41, t = -4.38, P = 0.000030) were inversely associated with lithium levels in drinking water and remained significant after sensitivity analyses and adjustment for socioeconomic factors. CONCLUSIONS In replicating and extending previous results, this study provides strong evidence that geographic regions with higher natural lithium concentrations in drinking water are associated with lower suicide mortality rates.

Imaging the effects of genetic polymorphisms on radioligand binding in the living human brain: A review on genetic neuroreceptor imaging of monoaminergic systems in psychiatry

Imaging genetics is a research field that describes the impact of genetic risk variants on brain structure and function. While magnetic resonance based imaging techniques are able to provide complex information on a system level, positron emission tomography (PET) and single photon emission computer tomography (SPECT) allow for determination of distribution and density of single receptor molecules in the human brain. Major psychiatric disorders are highly heritable, and have been associated with a dysregulation in brain dopamine and serotonin systems. Understanding the role of genetic polymorphisms within these neurotransmitter systems on brain phenotype is essential. This review tries to cover the literature on the impact of gene variants implicated in psychiatric disorders on serotonin, dopamine, and MAO-A radioligand binding in living humans. The majority of PET and SPECT studies investigated the role of polymorphisms within genes coding for the serotonin and dopamine transporters, the serotonin 1A receptor, and the dopamine D2 receptor on G protein coupled receptors or transporter proteins critically involved in serotonin or dopamine neurotransmission. Other studies investigated the impact of variants in genes for monoamine oxidase-A (MAO-A) or brain derived neurotrophic factor on monoamine transporters, receptors, or MAO-A activity. Two main findings in healthy subjects emerge from the current literature: one is an increased binding of the selective ligand [(11)C]DASB to serotonin transporters in subjects homozygous for the triallelic 5-HTTLPR LA allele. The other one is decreased binding of the radioligand [(11)C]raclopride to dopamine D2 receptors in D2 Taq1 A1 allele carriers. Other findings reported are highly interesting but require independent replication.

Enhanced Serotonin Transporter Function during Depression in Seasonal Affective Disorder

Decreased synaptic serotonin during depressive episodes is a central element of the monoamine hypothesis of depression. The serotonin transporter (5-HTT, SERT) is a key molecule for the control of synaptic serotonin levels. Here we aimed to detect state-related alterations in the efficiency of 5-HTT-mediated inward and outward transport in platelets of drug-free depressed patients suffering from seasonal affective disorder (SAD). 5-HTT turnover rate, a measure for the number of inward transport events per minute, and tyramine-induced, 5-HTT-mediated outward transport were assessed at baseline, after 4 weeks of bright light therapy, and in summer using a case–control design in a consecutive sample of 73 drug-free depressed patients with SAD and 70 nonseasonal healthy controls. Patients were drug-naive or medication-free for at least 6 months prior to study inclusion, females patients were studied in the follicular phase of the menstrual cycle. All participants were genotyped for a 5-HTT-promoter polymorphism (5-HTTLPR) to assess the influence of this polymorphism on 5-HTT parameters. Efficiency of 5-HTT-mediated inward (p=0.014) and outward (p=0.003) transport was enhanced in depressed patients. Both measures normalized toward control levels after therapy and in natural summer remission. Changes in outward transport showed a clear correlation with treatment response (ρ=0.421, p=0.001). Changes in inward transport were mediated by changes in 5-HTT transport efficiency rather than affinity or density. 5-HTTLPR was not associated with any of the 5-HTT parameters. In sum, we conclude that the 5-HTT is in a hyperfunctional state during depression in SAD and normalizes after light therapy and in natural summer remission.

Actigraphy in Patients with Seasonal Affective Disorder and Healthy Control Subjects Treated with Light Therapy

BACKGROUND Abnormalities of the circadian rest-activity cycle are hypothesized to accompany the clinical picture of seasonal affective disorder (SAD). The purpose of this study was to investigate if bright light therapy (BLT) is able to reverse these disturbances. METHODS Seventeen SAD outpatients and 17 sex- and age-matched healthy control subjects were treated with BLT administered in the morning for 4 weeks. Activity levels were measured with wrist actigraphy. RESULTS SAD patients had 33% lower total (p = .031) and 43% lower daylight activity (p = .006) in week 1 compared with control subjects. The relative amplitude of the sleep-wake cycle was attenuated by 6% in patients (p = .025); they were phase delayed by 55 minutes (p = .023) and had significantly lower sleep efficiency (p = .030). Total (p = .002) and daylight activity (p = .001) increased after 4 weeks of treatment in SAD patients. Moreover, BLT led to increase of relative amplitude (p = .005), advance of delayed rhythms (p = .036), and improved sleep efficiency (p = .011) in patients. Intradaily stability, measuring the strength of coupling of the rhythm to external zeitgebers, increased by 9% both in patients and healthy control subjects (p = .032). CONCLUSIONS Treatment with BLT normalizes disturbed activity patterns and restores circadian rhythms in SAD patients. BLT might also stabilize the circadian rhythm in nondepressed individuals during the fall-winter season.

Seasonal variation of availability of serotonin transporter binding sites in healthy female subjects as measured by [123I]-2β-carbomethoxy-3β- (4-iodophenyl)tropane and single photon emission computed tomography

BACKGROUND Previous studies have indicated annual variations in central and peripheral serotonergic activity. In the present study we studied five women in summer and six women in winter and evaluated possible differences in availability of brain serotonin transporters between summer and winter. METHODS We employed the single photon emission computed tomography ligand [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I] beta-CIT) to visualize binding to the serotonin transporter site in the human thalamus/hypothalamus midbrain area in vivo. Brain imaging studies were performed in one group between May and August and in the other between November and December. RESULTS We found significant differences in displaceable [123I] beta-CIT binding in the region corresponding to thalamus/hypothalamus between the summer group and the winter group (1.9 +/- 0.3 vs. 1.4 +/- 0.2, respectively; p < .01). CONCLUSIONS The results of the present study suggest reduced brain serotonin transporter availability in winter. This finding further substantiates evidence of seasonal variations in brain serotonergic function.