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Clinical Trial
. 2022 Aug 4;25(7):534-544.
doi: 10.1093/ijnp/pyac001.

Serotonin 1A Receptor Binding of [11C]CUMI-101 in Bipolar Depression Quantified Using Positron Emission Tomography: Relationship to Psychopathology and Antidepressant Response

Martin J Lan  1   2 , Francesca Zanderigo  1   2 , Spiro P Pantazatos  1   2 , M Elizabeth Sublette  1   2 , Jeffrey Miller  1   2 , R Todd Ogden  1   2 , J John Mann  1   2   3
Affiliations
Clinical Trial

Serotonin 1A Receptor Binding of [11C]CUMI-101 in Bipolar Depression Quantified Using Positron Emission Tomography: Relationship to Psychopathology and Antidepressant Response

Martin J Lan et al. Int J Neuropsychopharmacol. .

Abstract

Background: The pathophysiology of bipolar disorder (BD) remains largely unknown despite it causing significant disability and suicide risk. Serotonin signaling may play a role in the pathophysiology, but direct evidence for this is lacking. Treatment of the depressed phase of the disorder is limited. Previous studies have indicated that positron emission tomography (PET) imaging of the serotonin 1A receptor (5HT1AR) may predict antidepressant response.

Methods: A total of 20 participants with BD in a current major depressive episode and 16 healthy volunteers had PET imaging with [11C]CUMI-101, employing a metabolite-corrected input function for quantification of binding potential to the 5HT1AR. Bipolar participants then received an open-labeled, 6-week clinical trial with a selective serotonin reuptake inhibitor (SSRI) in addition to their mood stabilizer. Clinical ratings were obtained at baseline and during SSRI treatment.

Results: Pretreatment binding potential (BPF) of [11C]CUMI-101 was associated with a number of pretreatment clinical variables within BD participants. Within the raphe nucleus, it was inversely associated with the baseline Montgomery Åsberg Rating Scale (P = .026), the Beck Depression Inventory score (P = .0023), and the Buss Durkee Hostility Index (P = .0058), a measure of lifetime aggression. A secondary analysis found [11C]CUMI-101 BPF was higher in bipolar participants compared with healthy volunteers (P = .00275). [11C]CUMI-101 BPF did not differ between SSRI responders and non-responders (P = .907) to treatment and did not predict antidepressant response (P = .580). Voxel-wise analyses confirmed the results obtained in regions of interest analyses.

Conclusions: A disturbance of serotonin system function is associated with both the diagnosis of BD and its severity of depression. Pretreatment 5HT1AR binding did not predict SSRI antidepressant outcome.The study was listed on clinicaltrials.gov with identifier NCT02473250.

Keywords: Antidepressant; bipolar disorder; positron emission tomography; selective serotonin reuptake inhibitor; serotonin.

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Figures

Figure 1.
Figure 1.
BPF values of [11C]CUMI-101 had an inverse association with both a self-reported severity of depression severity as measured by the Beck Depression Inventory (A,B), and the Buss Durkee Hostility Score, a self-reported assessment of lifetime hostility (C,D). (A,C) BPF values within the raphe nucleus region of interest. (B,D) BPF values within a representative region where the serotonin 1A receptors are post synaptic, the hippocampus.
Figure 2.
Figure 2.
BPF values of [11C]CUMI-101 were higher in bipolar disorder (BD) participants (n = 20) compared with healthy volunteers (HVs) (n = 16) in the raphe nucleus (RN) as well as regions where the serotonin 1A receptors are post synaptic. Abbreviations: ACN, anterior cingulate cortex; AMY, amygdala; BD, bipolar disorder participants; CIN, cingulate; DOR, dorsolateral prefronal cortex; HIP, hippocampus; HV, healthy volunteer; INS, insula; MED, medial prefrontal cortex; OCC, occipital lobe; ORB, orbital cortex; PAR, parietal lobe; PHG, parahippocampal gyrus; TEM, temporal lobe. The horizontal bar represents the mean value.
Figure 3.
Figure 3.
Clinical antidepressant response to 6-week open label SSRI treatment for bipolar depression when added to a mood stabilizer. Abbreviations: MADRS, Montgomery Åsberg Depression Rating Scale. Mean values are plotted and error bars indicate standard deviations.
Figure 4.
Figure 4.
Pretreatment BPF values of [11C]CUMI-101 did not differ between responders (n = 7) and non-responders (n = 13) to selective serotonin reuptake inhibitor treatment. (A) BPF values within the raphe nucleus region of interest. (B) BPF values within a representative region where the 5HT1ARs are post synaptic, the hippocampus. Abbreviations: ACN, anterior cingulate cortex; AMY, amygdala; CIN, cingulate; DOR, dorsolateral prefronal cortex; HIP, hippocampus; INS, insula; MED, medial prefrontal cortex; OCC, occipital lobe; ORB, orbital cortex; PAR, parietal lobe; PHG, parahippocampal gyrus; TEM, temporal lobe. The horizontal bar represents the mean value.
Figure 5.
Figure 5.
Results from whole-brain, voxel-wise analyses of BPF values of [11C]CUMI-101 with clinical variables. (A) BPF of [11C]CUMI-101 was higher in bipolar participants (n = 20) compared with healthy volunteers (n = 16). (B) BPF of [11C]CUMI-101 was inversely associated with Beck Depression Inventory (n = 19) within the bipolar group. BPF of [11C]CUMI-101 was inversely associated with Buss Durkee Hostility Inventory (n = 16). The clusters of significant association between BPF of [11C]CUMI-101 and these clinical variables had overlapping regional distribution.
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