A Positron Emission Tomography Study of Dopamine Transporter Density in Patients With Bipolar Disorder With Current Mania and Those With Recently Remitted Mania

Abstract

ImportanceAlthough dopamine is implicated in the pathophysiology of bipolar disorder (BD), the precise alterations in the dopaminergic system remain unknown.ObjectiveTo assess dopamine transporter (DAT) density in the striatum in patients with BD with current and recently remitted mania in comparison to healthy control individuals and its correlation with severity of manic symptoms.Design, Setting, and ParticipantsThis cross-sectional study conducted in a tertiary care referral center for mood disorders in Vancouver, British Columbia, Canada, recruited 26 patients with BD (9 with current mania; 17 with recently remitted mania) and 21 matched healthy control individuals. DAT density was measured using positron emission tomography with [11C]d-threo-methylphenidate (MP). The differences between the groups in nondisplaceable binding potential (BPND) for DAT was assessed using statistical parametric mapping. The study was conducted from November 2001 to February 2007 and the data were analyzed from November 2020 to December 2021.Main Outcomes and MeasuresDAT density as indexed by BPND for MP across groups; manic symptom severity as measured with the Young Mania Rating Scale (YMRS) and correlated with BPND values in patients with BD.ResultsOf 47 total participants (mean [SD] age, 37.8 [14.4] years), 27 (57.4%) were female; 26 individuals had BD (9 with current mania and 17 with recently remitted mania) and there were 21 healthy control individuals. MP BPND was significantly lower in patients with BD in the right putamen and nucleus accumbens (mean reduction [MR] = 22%; cluster level familywise error [FWE]–corrected P < .001) as well as left putamen and caudate (MR = 24%; cluster level FWE–corrected P < .001). The reduction in BPND was more extensive and pronounced in patients with current mania, while patients with recently remitted mania had lower BPND in the left striatum but not the right. There was a significant negative correlation between YMRS scores and MP BPND in the right striatum in patients with current mania (ρ = −0.93; 95% CI, −0.99 to −0.69; P < .001) and those with recently remitted mania (ρ = 0.64; 95% CI, −0.86 to −0.23; P = .005) but not in the left striatum in either group.Conclusions and RelevanceThese findings indicate that mania was associated with reduced DAT density and remitted mania was associated with DAT levels that approximated those present in individuals without BD. These results have potential implications for drug development for mania.

Application of Antipsychotic Drugs in Mood Disorders

“…They considered striatal dopaminergic D2/D3 receptor availability, explaining elevated dopaminergic neurotransmission in mania, and an increase in striatal dopamine transporter (DAT), elucidating lowered dopaminergic function in depression. The latter finding was corroborated in a recent study by Yatham et al [ 89 ], showing reduced DAT in the right putamen and nucleus accumbens during an acute manic episode, suggesting dopaminergic overactivity. Therefore, the therapeutic action in mania, as well as the prevention of manic episodes in bipolar disorder, can be connected with the anti-dopaminergic activity, mainly by blocking D2 receptors, which manifests in all three generations of antipsychotic drugs.…”

Parkinsonism in bipolar disorder: a clinical-neuroimaging study

“…The dopamine hypothesis of bipolar disorder (BD) has been proposed based on the similarity between behavioral changes induced by amphetamine administration and manic symptoms, as well as the effects of antidopaminergic medications on manic symptoms. Although dopaminergic neuroimaging studies have revealed various abnormalities in BD, there are also many inconsistencies in the findings across studies [36,37]. Some studies have reported that striatal dopamine transporter (DAT) activity is decreased only in the manic state of BD [36,37], while others have reported a decrease also in euthymia [20].…”

“…Although dopaminergic neuroimaging studies have revealed various abnormalities in BD, there are also many inconsistencies in the findings across studies [36,37]. Some studies have reported that striatal dopamine transporter (DAT) activity is decreased only in the manic state of BD [36,37], while others have reported a decrease also in euthymia [20]. The present study found that most BD patients with parkinsonism had reduced striatal DAT activity, and there was a trend of correlation between striatal DAT activity and the severity of parkinsonism.…”

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…A significant effect on VGSCs is also reported for the bias-ligand aripiprazole [ 568 ]. Concerning the dopaminergic presynaptic mechanism, DAT has also been implicated for its potential involvement in antipsychotics’ response despite the fact that its role in schizophrenia pathophysiology is still elusive partly due to methodological limitations both at clinical and preclinical levels [ 5 , 569 , 570 , 571 ]. Beyond intracellular dopamine D2-directly mediated signaling, dopamine-dependent trans-synaptic mechanisms have emerged, unveiling antipsychotics’ impact on the expression and functions of molecules belonging to different neurotransmitter systems.…”