Meyer JH. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 32: 86-102

Neurochemical Imaging Program in Mood Disorders, PET Centre, Centre for Addiction and Mental Health, Toronto, Ont.
Journal of psychiatry & neuroscience: JPN (Impact Factor: 5.86). 04/2007; 32(2):86-102.
Source: PubMed


This paper focuses on serotonin transporter 5-HTT imaging to investigate major depressive disorder (MDD) and antidepressant occupancy. Such investigations have only recently been possible as a result of major advances in ligand development. The state of the art method is [11C]DASB PET or [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) positron emission tomography. [11C]DASB is a breakthrough for brain imaging 5-HTT. Compared with previous radioligands, [11C]DASB offers both high selectivity and a favourable ratio of specific binding relative to free and nonspecific binding. These characteristics contribute to valid, reliable quantitation of the 5-HTT binding potential (BP). The 5-HTT BP can be viewed as an index of 5-HTT density in a medication free state, or unblocked 5-HTT density in a medication-treated state. During major depressive episodes with no other axis I comorbidity, either no difference in regional 5-HTT BP or a trend toward elevated 5-HTT BP is typically found. During major depressive episodes (of MDD) with more severe symptoms of pessimism (dysfunctional attitudes), regional 5-HTT BP is elevated. In subjects with major depressive episodes and comorbid axis I psychiatric illnesses, decreased regional 5-HTT BP is often reported. With selective serotonin reuptake inhibitor (SSRI) treatment at doses that distinguish from placebo in the treatment of major depressive episodes, 5-HTT occupancy is approximately 80%, and there is a strong relation between plasma level and occupancy that is not predictable based on affinity alone. Implications of 5-HTT imaging findings for understanding major depressive disorder and antidepressant treatment will be discussed.

5 Reads
  • Source
    • "In vivo imaging provides a noninvasive method for exploring SERT availability in subjects with major depressive disorder (MDD) and in individuals who have attempted suicide. However, previous in vivo imaging studies on SERT binding in patients with MDD have yielded contradictory results, which may be due to methodological differences, recruiting samples with mixed diagnoses or psychiatric comorbidity, or utilizing various radioligands with lower selective binding for SERT (Brust et al., 2006; Meyer, 2007), such as [(123)I]beta-CIT (2beta-carbomethoxy-3beta-(4-io- dophenyl)tropane) ([ 123 I]-β-CIT) in single-photon emission computed tomography (SPECT) or rel-(6R,10bS)-6-[4-(Methylsulfanyl) phenyl]-1,2,3,5,6,10b-hexahydropyrrolo[2,1-α]isoquinoline ([ 11 C] (+)McN5652) in positron emission tomography (PET). Although using highly-selective SERT radioligands, such as 2-([2-([dimethylamino]methyl )phenyl]thio)-5-(123)I-iodophenylamine ([ 123 I] ADAM) SPECT (Newberg et al., 2005 2012; Ho et al., 2013) and [(11) C] 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzoni- trile ([ 11 C]DASB) PET (Reimold et al., 2008; Selvaraj et al., 2011), have revealed diminished SERT binding in some brain regions in patients with MDD relative to healthy controls, other studies have reported no such difference (Meyer et al., 2004; Miller et al., 2013) or elevated SERT binding (Cannon et al., 2007) between subjects with MDD and controls using the same radioligand. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Much evidence supports the role of the serotonin transporter (SERT) in the pathophysiology and pharmacotherapy of major depressive disorder (MDD) and suicidal behaviors. In this study, we recruited 17 antidepressant-naïve patients with MDD and 17 age- and gender-matched healthy controls. SERT availability was measured in vivo with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) positron emission tomography (PET) imaging. The 21-item Hamilton Depression Rating Scale (HDRS) and Beck Scale for Suicide Ideation were used to assess the severity of depression and the intent of suicide ideation prior to PET imaging. All subjects with MDD were in a current state of depression with HDRS scores ≧ 18. Subjects who attempted suicide within two weeks of the study onset were recruited in the depressed suicidal group (n = 8). Subjects with MDD who denied any prior suicide attempt were recruited into the depressed non-suicidal group (n = 9). A significant reduction of SERT availability in the midbrain, thalamus, and striatum was noted in the MDD group relative to the control group (Bonferroni-adjusted p-value < 0.05). Moreover, this effect was more pronounced in depressed suicidal group compared to the control group (Bonferroni-adjusted p-value < 0.01). Relative to both depressed non-suicidal and control groups, the depressed suicidal group showed an increased prefrontal cortex (PFC)/midbrain SERT binding ratio (Bonferroni-adjusted p-value < 0.01). This study suggests an incongruent reduction of PFC SERT binding relative to midbrain might discriminate depressed suicide attempters from non-attempters in patients with MDD and may be involved in the pathophysiology of suicide behaviors. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 02/2015; 18(3). DOI:10.1093/ijnp/pyu065 · 4.01 Impact Factor
  • Source
    • "vermis and venous sinus) as 5-HTT-poor region. The cerebellar gray matter was chosen because it represents an optimal reference region for the quantification of the serotonin transporter with [11C]DASB [24], [25]. Regions of interest (ROI) for both radioligands were taken from an automated anatomical labeling-based (AAL) atlas [26] after normalization of BPND maps to standard MNI-space. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BackgroundThe brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) may impact on the in-vivo binding of important serotonergic structures such as the serotonin transporter (5-HTT) and the serotonin-1A (5-HT1A) receptor. Previous positron emission tomography (PET) studies on the association between Val66Met and 5-HTT and 5-HT1A binding potential (BPND) have demonstrated equivocal results.MethodsWe conducted an imaging genetics study investigating the effect of Val66Met genotype on 5-HTT or 5-HT1A BPND in 92 subjects. Forty-one subjects (25 healthy subjects and 16 depressive patients) underwent genotyping for Val66Met and PET imaging with the 5-HTT specific radioligand [11C]DASB. Additionally, in 51 healthy subjects Val66Met genotypes and 5-HT1A binding with the radioligand [carbonyl-11C]WAY-100635 were ascertained. Voxel-wise and region of interest-based analyses of variance were used to examine the influence of Val66Met on 5-HTT and 5-HT1A BPND.ResultsNo significant differences of 5-HTT nor 5-HT1A BPND between BDNF Val66Met genotype groups (val/val vs. met-carrier) were detected. There was no interaction between depression and Val66Met genotype status.ConclusionIn line with previous data, our work confirms an absent effect of BDNF Val66Met on two major serotonergic structures. These results could suggest that altered protein expression associated with genetic variants, might be compensated in vivo by several levels of unknown feedback mechanisms. In conclusion, Val66Met genotype status is not associated with changes of in-vivo binding of 5-HTT and 5-HT1A receptors in human subjects.
    PLoS ONE 09/2014; 9(9):e106810. DOI:10.1371/journal.pone.0106810 · 3.23 Impact Factor
  • Source
    • "In the present study, the low dose of vortioxetine, corresponding to approximately 50% occupancy of the 5-HT transporter, fully restored the stress-induced impairment of reversal learning. SSRIs generally require higher levels of 5-HT transporter occupancy to be active in both preclinical and clinical contexts (Meyer, 2007; Kreilgaard et al., 2008). Occupancy of the 5-HT transporter at clinically approved doses of vortioxetine is approximately 50% at 5 mg, 65% at 10 mg, and >80% at 20 mg (Areberg et al., 2012; Stenkrona et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.
    The International Journal of Neuropsychopharmacology 05/2014; 17(10). DOI:10.1017/S1461145714000571 · 4.01 Impact Factor
Show more


5 Reads
Available from