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

Willeit, Matthäus; Praschak-Rieder, Nicole; Neumeister, Alexander; Pirker, Walter; Asenbaum, S.; Vitouch, Oliver; Tauscher, Johannes; Hilger, Eva; Stastny, J.; Brücke, Thomas; Kasper, Siegfried

doi:10.1016/s0006-3223(99)00293-0

Cited by 171 publications

(85 citation statements)

References 38 publications

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“…Only van der Wee et al (2004) (2003) also included OCD patients with comorbid depressive symptomatology. It is known that depression influences the SERT status (Malison et al, 1998;Willeit et al, 2000). The studies also varied as to their control subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical studies in psychiatric research using b-CIT and SPECT have shown increased SERT availability in acutely abstinent cocaine-dependent patients (diencephalon and brainstem; Jacobsen et al, 2000) and in OCD patients (midbrain-pons;Pogarell et al, 2003), whereas reduced SERT status has been revealed in patients with major depression (brainstem; Malison et al, 1998), alcoholism (brainstem; Heinz et al, 1998b), seasonal affective disorder (thalamus-hypothalamus; Willeit et al, 2000), bulimia (thalamus-hypothalamus; Tauscher et al, 2001), and OCD (midbrain-brainstem; Stengler-Wenzke et al, 2004). Thus, the only two studies to ever demonstrate specific serotonergic abnormities in patients with OCD to date were, as previously mentioned, that of Pogarell et al (2003), which showed a 25% increase in SERTs in the midbrain-pons area and that of Stengler-Wenzke et al (2004), which revealed a significantly reduced SERT availability in the midbrain and brainstem.…”

Section: Introductionmentioning

confidence: 99%

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[123I]-β-CIT SPECT Imaging Shows Reduced Thalamus–Hypothalamus Serotonin Transporter Availability in 24 Drug-Free Obsessive-Compulsive Checkers

Zitterl

Aigner

Stompe

et al. 2006

Neuropsychopharmacol

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Numerous findings indicate alterations in brain serotonin systems in obsessive-compulsive disorder (OCD). We investigated the in vivo availability of thalamus-hypothalamus serotonin transporters (SERT) in patients with DSM-IV OCD who displayed prominent behavioral checking compulsions (OC-checkers). Four hours after injection of [ 123 I]-2b-carbomethoxy-3b-(4-iodophenyl)tropane ([ 123 I]-b-CIT), single photon emission computed tomography (SPECT) scans were performed in 24 medication-free non-depressed OC-checkers and 24 age-and gender-matched healthy controls. For quantification of brain serotonin transporter availability, a ratio of specific to non-displaceable [ 123 I]-b-CIT brain binding was used (V 00 3 ¼ (thalamus and hypothalamusÀcerebellum)/cerebellum). Drug-free nondepressed OC-checkers showed an 18% reduced brain serotonin transporter availability in the thalamus and hypothalamus, as compared with healthy control subjects (1.3870.19 vs 1.6970.21; po0.001). There was a strong negative correlation between severity of OC symptomatology (Y-BOCS scores) and SERT availability (r ¼ À0.80; po0.001). Moreover, we found a significant positive correlation between illness duration and serotonin transporter availability (r ¼ 0.43; po0.05). This first report of significantly reduced [ 123 I]-b-CIT binding in the thalamus-hypothalamus region in OC-checkers suggests reduced brain serotonin transporter availability, which is more pronounced with increased severity of OC symptomatology and short duration of illness. The results provide direct evidence for an involvement of the serotonergic system in the pathophysiology of OCD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

[123I]-β-CIT SPECT Imaging Shows Reduced Thalamus–Hypothalamus Serotonin Transporter Availability in 24 Drug-Free Obsessive-Compulsive Checkers

Zitterl

Aigner

Stompe

et al. 2006

Neuropsychopharmacol

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“…Using [ 123 I]b-CIT and SPECT, we have previously shown decreased midbrain 5-HTT availability in depressed patients with SAD (Willeit et al, 2000). It is unclear whether 5-HTT B max data acquired in platelets can be expected to reflect the situation in the CNS (Malison et al, 1998;Rausch et al, 2005).…”

Section: -Htt Function In Sadmentioning

confidence: 99%

“…Brain imaging techniques (positron emission tomography or single photon computed tomography, SPECT) allow for measurement of 5-HTT availability in the living human brain. While some studies suggest reductions in CNS 5-HTT availability in seasonal (Willeit et al, 2000) and nonseasonal depression (Malison et al, 1998;Parsey et al, 2006;Staley et al, 2006), recent studies failed to find altered 5-HTT binding (Meyer et al, 2004). An important limitation of current brain imaging techniques is that they are confined to quantification of 5-HTT binding sites but do not allow for functional assessments of transport processes.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Serotonin Transporter Function during Depression in Seasonal Affective Disorder

Willeit

Sitte

Thierry

et al. 2007

Neuropsychopharmacol

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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 tyramineinduced, 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 ¼ 0.014) and outward (p ¼ 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 (r ¼ 0.421, p ¼ 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.

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“…Up to this point, the development of SPECT or PET imaging agents targeting SERT binding sites has relied on four different core structures, 5-iodo-nitroquipazine [21][22][23], tropanes [24][25][26], (+)-McN5652 [27][28][29][30][31] and biphenylthiols [32][33][34][35][36][37][38][39][40]. Biphenylthiol derivatives, [ 123 I] IDAM (1) [41] and [ 123 I]ADAM (2) [39,42], have been evaluated as potential agents for SPECT because there are several unique benefits associated with using this core structure (Table 1).…”

Section: Introductionmentioning

confidence: 99%

5-Chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new serotonin transporter ligand

Oya

Choi

Kung

et al. 2007

Nuclear Medicine and Biology

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Two novel ligands with a 4′-substitution on the phenyl ring B of biphenylthiol: 5-chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine, 7, and 2-(2′-((dimethylamino) methyl)-4′-methoxyphenylthio)-5-iodobenzenamine, 8, were prepared and tested as potential serotonin transporter (SERT) imaging agents. The new ligands displayed extremely high binding affinities to SERT (K i = 0.22 ± 0.09 and 0.11 ± 0.04 nM, respectively), with very low binding affinities to dopamine and norepinephrine transporters (K i > 1, 000 nM). The corresponding [ 125 I]7 and [ 125 I] 8 were successfully prepared from the tri-n-butyltin derivatives. They showed good brain uptakes and prolonged retention after iv injection in rats (brain uptake was 1.77 and 0.98 %dose/g for [ 125 I] 7 and 0.92 and 0.29 %dose/g for [ 125 I]8 at 2 and 120 minutes, respectively). Significantly, [ 125 I]7 showed excellent uptake and prolonged retention in the hypothalamus, where the SERT concentration is the highest. The hypothalamus/cerebellum ratios (target to background ratios) were 4.24, 7.10, 8.24 and 12.6 at 2, 4, 6 and 12 hours, respectively. The hypothalamus/cerebellum ratios for [ 125 I]8 were 3.97, 5.57 and 5.06 at 1, 2 and 4 hours, respectively. Adding the 4′-iodo-group to the phenyl ring B of 7 appeared to reduce the rate of clearance from the brain, and the kinetics favored uptake and retention in the hypothalamus. The localization of [ 125 I]7 in the hypothalamus region in the brain of rats could be blocked by pretreatment with (+)McN5652, escitalopram and ADAM (2), all selective serotonin transporter ligands (at 2 mg/Kg dose, iv, 5 min pretreatment). Ex vivo autoradiograms of rat brain sections (at 4 hr after iv injection of [ 125 I]7) showed intense labeling in regions of the brain known to have high SERT density. The excellent selective uptake and retention in the hypothalamus region suggests that [ 123 I]7 is a potential lead compound for developing new imaging agents targeting SERT binding sites with single photon emission computed tomography (SPECT).

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

Cited by 171 publications

References 38 publications

[123I]-β-CIT SPECT Imaging Shows Reduced Thalamus–Hypothalamus Serotonin Transporter Availability in 24 Drug-Free Obsessive-Compulsive Checkers

[123I]-β-CIT SPECT Imaging Shows Reduced Thalamus–Hypothalamus Serotonin Transporter Availability in 24 Drug-Free Obsessive-Compulsive Checkers

Enhanced Serotonin Transporter Function during Depression in Seasonal Affective Disorder

5-Chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new serotonin transporter ligand

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