Serotonin transporter occupancy of high-dose selective serotonin reuptake inhibitors during major depressive disorder measured with [11C]DASB positron emission tomography

Voineskos, Aristotle N.; Wilson, Alan A.; Boovariwala, Anahita; Sagrati, Sandra; Houle, Sylvain; Rusjan, Pablo; Sokolov, Stephen T.H.; Spencer, Edgar P.; Ginovart, Nathalie; Meyer, Jeffrey H.

doi:10.1007/s00213-007-0806-z

Cited by 65 publications

(47 citation statements)

References 28 publications

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“…Imaging techniques such as positron emission tomography (PET) and single-photon emissioncomputed tomography (SPECT) allow in vivo labeling of SERT in the brain, which can be used to study their occupancy. Till date, several imaging studies measured SERT occupancy after short or prolonged treatment with SSRIs (Klein et al, 2006(Klein et al, , 2007Voineskos et al, 2007;Parsey et al, 2006;Takano et al, 2006;Catafau et al, 2006;Herold et al, 2006;Cavanagh et al, 2006;Erlandsson et al, 2005;Suhara et al, 2003;Kent et al, 2002;Meyer et al, 2001bMeyer et al, , 2004Hiltunen et al, 1998). Particularly, Meyer et al (2004) showed 60-80% SERT occupancy after standard clinical doses of SSRIs, and demonstrated curvilinear doseresponse relationships for SERT occupancy by SSRIs.…”

Section: Introductionmentioning

confidence: 99%

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Evidence Why Paroxetine Dose Escalation is Not Effective in Major Depressive Disorder: A Randomized Controlled Trial With Assessment of Serotonin Transporter Occupancy

Ruhé

Booij

Weert

et al. 2008

Neuropsychopharmacol

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Dose escalation is often used in depressed patients who fail to respond to standard doses of selective serotonin reuptake inhibitors, but clinical efficacy is equivocal. We aimed to reassess the efficacy of paroxetine dose escalation and quantify whether paroxetine dose escalation increases occupancy of the serotonin transporter (SERT) more than placebo dose escalation in a randomized controlled trial. We recruited 107 nonpsychotic, unipolar depressed outpatients (18-70 years; Hamilton Depression Rating Scale (HDRS(17)) >18) from primary care and psychiatric outpatient departments. After 6 weeks, open-label paroxetine 20 mg per day (T0), nonresponding patients (HDRS(17) decrease <50%; n=60) were randomized to double-blind paroxetine (30-50 mg per day as tolerable) or placebo dose escalation (paroxetine 20 mg per day+placebo). Patients were followed until 6 weeks after randomization (T1). Forty-nine patients, drug free at study entry, underwent single-photon emission-computed tomography (SPECT) scanning before treatment and were scanned repeatedly at T0 and T1. Paroxetine serum concentrations and SERT occupancy were determined at T0 and T1 (n=32). We terminated the dose-escalation trial after an interim analysis. Thirty nonresponding patients were randomized to paroxetine (46.7+/-5.5 mg per day), 27 to placebo dose escalation. Response rates were 10/30 (33.3%) and 10/27 (37.0%), respectively. Repeated measurement analyses showed no significant effect for treatment (p=0.88, exceeding a priori stopping rules for futility (p>0.5)). Overall dropout was higher for placebo (26.7%) than paroxetine (3.3%; p=0.03). Paroxetine dose escalation increased paroxetine serum concentrations (p<0.001). SPECT measurements (12 patients randomized to paroxetine (46.9+/-4.8 mg) and 14 to placebo dose escalation) showed no significant increase of midbrain SERT occupancy (2.5+/-26.4%, paroxetine; 3.1+/-25.8% placebo; p=0.687) nor in diencephalon (p=0.529). Paroxetine dose escalation in depressed patients has no clinical benefit over placebo dose escalation. This is explained by the absence of significant increases of SERT occupancy by paroxetine dose escalation, despite increased paroxetine serum concentrations (ISRCTN44111488).

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Section: Introductionmentioning

confidence: 99%

“…Particularly, Meyer et al (2004) showed 60-80% SERT occupancy after standard clinical doses of SSRIs, and demonstrated curvilinear doseresponse relationships for SERT occupancy by SSRIs. However, high doses of SSRIs were rarely studied (Voineskos et al, 2007), and dose escalation was never studied.…”

Section: Introductionmentioning

confidence: 99%

Evidence Why Paroxetine Dose Escalation is Not Effective in Major Depressive Disorder: A Randomized Controlled Trial With Assessment of Serotonin Transporter Occupancy

Ruhé

Booij

Weert

et al. 2008

Neuropsychopharmacol

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“…In our view, PET studies with the radioligands that are currently available for assessing serotonergic functions in the living human brain have failed to provide conclusive evidence for aberrant serotonergic mechanisms in depressive disorders. We have noted, however, that receptor occupancy of serotonin transporters can be assessed reliably by PET with [ 11 C]DASB or [ 11 C]McNeil 5652 (Voineskos et al 2007;. Perhaps studies of receptor occupancy before and during antidepressant therapies can provide a means of determining whether treatment-resistance stems from inadequate receptor blockade.…”

Section: Recent Pet Studies Of Serotonin In Depressive Disordersmentioning

confidence: 99%

Challenges for PET Neuroimaging of Depressive Disorders

Smith¹,

Miller²

2010

Neuroimaging

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“…This is based on studies reporting lower plasma availability of the serotonin (5-HT) precursor tryptophan for uptake into the brain, reduced cerebrospinal fluid concentration of the 5-HT metabolite 5-hydroxyindoleacetic (5-HIAA) and decreased platelet 5-HT uptake in depressed patients, suggesting diminished brain 5-HT uptake and metabolism (Maes and Meltzer 1995;Neumeister et al 2004). The level of 5-HT in the synaptic cleft is mainly regulated by the 5-HT transporter (5-HTT), which is targeted by most antidepressants (Meyer et al 2004;Suhara et al 2003;Voineskos et al 2007). Interestingly, the human 5-HTT gene, located on chromosome 17q11.1-q12 (Lesch et al 1994), contains a 5-HTT-linked polymorphic region (5-HTTLPR) with two functional variants: the short (s) form and the long (l) form (Greenberg et al 1999;.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of 5-HTTLPR genotypes on mood, memory, and attention bias following acute tryptophan depletion and stress exposure

Firk

Markus

2008

Psychopharmacology

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Rationale Polymorphisms of the serotonin transporter gene (5-HTTLPR) may be associated with increased vulnerability to acute tryptophan depletion (ATD) and depression vulnerability especially following stressful life events. Objective The aim of the present study was to investigate the effects of ATD in subjects with different 5-HTTLPR profiles before and after stress exposure on affective and cognitive-attentional changes. Materials and methods Eighteen subjects with homozygotic short alleles (S′/S′) and 17 subjects with homozygotic long alleles (L′/L′) of the 5-HTTLPR participated in a double-blind, placebo-controlled, crossover design to measure the effects of ATD on mood, memory, and attention before and after acute stress exposure. Results ATD lowered mood in all subjects independent of genotype. In S′/S′ genotypes, mild acute stress increased depressive mood and in L′/L′ genotypes increased feelings of vigor. Furthermore, S′/S′ genotypes differed from L′/L′ genotypes on measures of attention independent of treatment and memory following ATD. Conclusions Polymorphisms of the 5-HTTLPR differentially affect responses to mild stress and ATD, suggesting greater vulnerability of S′/S′ carriers to serotonergic manipulations and supporting increased depression vulnerability.

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Serotonin transporter occupancy of high-dose selective serotonin reuptake inhibitors during major depressive disorder measured with [11C]DASB positron emission tomography

Abstract: Significantly greater 5-HTT blockade at high dose provides a rationale for raising the dose from the minimum therapeutic dose in specific clinical circumstances. It is likely that 15% unoccupied 5-HTT remains, which should be addressed in future drug development.

Cited by 65 publications

References 28 publications

Evidence Why Paroxetine Dose Escalation is Not Effective in Major Depressive Disorder: A Randomized Controlled Trial With Assessment of Serotonin Transporter Occupancy

Evidence Why Paroxetine Dose Escalation is Not Effective in Major Depressive Disorder: A Randomized Controlled Trial With Assessment of Serotonin Transporter Occupancy

Challenges for PET Neuroimaging of Depressive Disorders

Differential effects of 5-HTTLPR genotypes on mood, memory, and attention bias following acute tryptophan depletion and stress exposure

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