Key Points
Question
Is mania in bipolar disorder (BD) associated with dopamine transporter (DAT) density?
Findings
In this cross-sectional study of 26 individuals with BD (9 with current mania; 17 with recently remitted mania) and 21 healthy control individuals, patients with BD were observed to have lower DAT density in the striatum with more pronounced reduction in individuals with current mania and a negative correlation between DAT density and manic symptom severity.
Meaning
These 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.
This cross-sectional study including 26 patients with bipolar disorder and 21 healthy control individuals evaluates dopamine transporter density and severity of manic symptoms in patients with current mania and recently remitted mania.
Abstract
Importance
Although dopamine is implicated in the pathophysiology of bipolar disorder (BD), the precise alterations in the dopaminergic system remain unknown.
Objective
To 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 Participants
This 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 Measures
DAT 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.
Results
Of 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 Relevance
These 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.
Introduction
Mania is the hallmark of bipolar I disorder (BD), although depressive episodes are common. While the pathophysiology of BD is unknown, several lines of indirect clinical pharmacological evidence suggest that mania is associated with dopamine hyperactivity. For example, drugs that increase dopamine transmission, such as amphetamine, precipitate mania;1,2 fusaric acid, a dopamine hydroxylase inhibitor, worsens3 while alpha methyl para tyrosine, which blocks tyrosine hydroxylase, improves manic symptoms;4 and conventional5 as well as atypical antipsychotics have been found effective in treating acute mania6 and they share the property of blocking dopamine receptors. These observations support the hypothesis that dopamine hyperactivity is associated with the expression of manic symptoms; however, the precise neurochemical abnormalities in dopaminergic neurotransmission that underlie the manifestation of manic symptoms remain elusive. Positron emission tomography (PET) permits visualization of various aspects of dopamine transmission in humans. A previous PET study reported increased dopamine D2 receptors in patients with psychotic BD and schizophrenia but not in those with nonpsychotic BD compared with healthy control individuals.7 Another PET study found that dopamine synthesis and storage capacity as measured by [18F]dopa was higher in patients with BD with psychosis and those with schizophrenia compared with healthy control individuals, and this correlated with severity of psychotic symptoms, even after adjusting for severity of manic symptoms.8 These findings suggest that increased D2 receptor density and dopamine synthesis capacity are nonspecific markers of psychosis and not specific to BD. Consistent with these observations, we found no alterations in D2 receptor density as measured by [11C]-raclopride PET9 or dopamine synthesis and storage capacity measured with [18F]dopa uptake rate,10 nor correlation of these measures with severity of manic symptoms assessed with the Young Mania Rating Scale (YMRS) in drug-naive patients with acute nonpsychotic mania. While treatment with valproate monotherapy was not associated with changes in D2 receptor density,9 [18F]dopa uptake was noted to be significantly lower.10 These findings are consistent with the premise that antimanic treatments, such as valproate and antipsychotics, reduce dopaminergic transmission but likely through different mechanisms. If the dopamine synthesis and storage capacity and D2 receptors are not altered in patients with nonpsychotic mania, what other alterations in the dopaminergic system might be responsible for the presumed dopamine hyperactivity in mania? Dopamine transporters (DAT) play an important role in dopamine neurotransmission as extracellular dopamine levels in synaptic cleft are regulated by DAT.11 The striatum has a high density of DAT due to dopaminergic projections from the ventral tegmental area and the substantia nigra.12,13 Therefore, while it is conceivable that abnormalities in DAT could affect synaptic dopamine levels and contribute to dopaminergic hyperactivity in patients with mania, to our knowledge, no study to date has assessed DAT density in mania.
[11C]d-threo-methylphenidate (MP) binding in the human brain has been demonstrated to be reproducible, reversible, and specific for DAT, as it does not block serotonin transporter, making it an ideal ligand to estimate DAT density.14,15 In this study, we assessed striatal DAT density using PET with MP in patients with current mania and recently remitted mania and age- and sex-matched healthy control individuals. We hypothesized that patients with current mania but not those with not recently remitted mania would show lower MP binding in the striatum compared with healthy control individuals.
Methods
Participants
Patients with a diagnosis of DSM-IV BD with a current manic episode (n = 9) or who were recently treated for a manic episode (n = 17) with lithium or an anticonvulsant were recruited. The diagnosis of BD with current or most recent episode of mania was based on clinical interview and a Structured Clinical Interview for DSM-IV (SCID) diagnosis. Patients with recently remitted manic episodes were scanned as soon as possible after meeting the criteria for remission, which was defined as a score of 8 or less on both YMRS and the Hamilton Depression Rating Scale (HAM-D) 21-item scale. All patients were taking either a mood stabilizer or no medication prior to the PET scans. One patient had received quetiapine in addition to a mood stabilizer up to 1 month prior to the PET but no other patients had received any regular antipsychotic medications for at least 3 months prior to the PET. Patients with a history of comorbid substance or alcohol misuse or dependence within the previous 3 months or those with other current axis I or II diagnoses were excluded.
Healthy control participants were recruited through advertisements and screened using a SCID, nonpatient edition. They had no lifetime history of psychiatric illness or family history of mood disorders or schizophrenia in first-degree relatives. Written informed consent was obtained from all participants, and the study was approved by the ethics committee of the University of British Columbia.
PET Procedure
MP was synthesized as previously described.16 PET scans were performed on a CTI/Siemens ECAT 953B/31 tomograph (CTI/Siemens) operating in a 3-dimentional mode and presented in 31 image planes with 3.375-mm plane-to-plane separation. The transaxial reconstructed image resolution was 8.5 mm2, and the axial resolution was 6 mm. Participants were positioned supine in the gantry with the head centered in the field of view. A thermoplastic mask was molded to fit the participant’s head to minimize head movement. Following a 10-minute transmission scan, the emission scan started at the time of MP injection and lasted for 60 minutes. The scanning sequence consisted of 4 × 1–minute scans, 3 × 2–minute scans, 8 × 5–minute scans, and 1 × 10–minute scan.
Magnetic Resonance Imaging Procedure
An anatomical magnetic resonance imaging (MRI) image was obtained for each patient on a 3-T Philips Achieva scanner equipped with a head coil. T1-weighted images were obtained with a turbo field echo (T1-TFE) sequence with a repetition time of 6.5 milliseconds and a voxel size of 1.02 mm × 1.02 mm × 1.5 mm with an image size of 256 × 256 × 140 voxels. For each patient, head motion was minimized by placing foam padding within the coil.
Image Analysis
The dynamic PET data were used to produce parametric images of the MP nondisplaceable binding potential (BPND).17 The simplified reference tissue model18 was used with the occipital cortex as the reference region. All subsequent analyses were carried out using Statistical Parametric Mapping version 12 (SPM12) implemented in Matlab version 2018b (MathWorks).
Each participant’s parametric BPND image was coregistered to their own MR image using the mutual information algorithm available in SPM12. The MRI image was then normalized to the standard Montreal Neurological Institute (MNI) T1 template in SPM12. The normalization parameters were applied to the MRI-coregistered BPND images, and the resulting spatially normalized BPND images were used for subsequent statistical analysis. The normalized BPND images obtained for healthy control individuals were averaged and thresholded to produce a mask image containing only the left and right striatum. Given the relatively low PET spatial resolution available, we did not attempt to produce separate masks for the dorsal and ventral striatum.
Statistical Analysis
A full factorial statistical model was used to assess differences in BPND between healthy control individuals and patients with BD and between various subgroups using age as a covariate, as previous imaging studies have shown a significant association between age and DAT availability.19,20 We ran 4 contrasts of interest (healthy control individuals − [those with current mania + those with recently remitted mania], healthy control individuals − those with current mania, healthy control individuals − those with recently remitted mania, and individuals with recently remitted mania − those with current mania) in a search volume defined by a striatal mask encompassing 3686 voxels. We applied a small volume correction to allow for multiple comparisons within the volume searched. We applied the criterion P < .05, familywise error (FEW)–corrected, to determine the voxel level significance of local peak values. We also identified clusters of contiguous voxels satisfying the criterion P < .005 (uncorrected) for cluster inclusion. We applied a cluster-level criterion P < .05, FWE-corrected, to determine the significance of these clusters. In addition, the average value of BPND for all voxels within each significant cluster for each participant was extracted using the Marsbar tool and correlations between BPND values and the YMRS, HAM-D, or psychotic symptom scores on the Brief Psychiatric Rating Scale (BPRS) were computed using Spearman correlation coefficient ρ as the rating scale scores were not normally distributed.
Results
Demographic and Clinical Features
Of 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. Full clinical and demographic features of the study participants are shown in Table 1. There was no statistically significant difference in age (mean [SD; range], 39.2 [17.9; 18-65 years]; 37.0 [14.1; 18-60] years; and 37.8 [13.9; 20-60 years; F = 0.067; P = .94) or sex (male = 5 [55.6%], 7 [41.2%], 8 [38.1%]; χ2 = 0.81; P = .67) between 9 patients with current mania, 17 with recently remitted mania, and 21 healthy control individuals, respectively.
Table 1. Demographic and Clinical Data.
| BD manic (n = 9) | BD euthymic (n = 17) | Control (n = 21) | |
|---|---|---|---|
| Age, mean (SD), y | 39.2 (17.9) | 37.0 (14.1) | 37.8 (13.9) |
| Female, No. (%) | 4 (44.4) | 10 (58.8) | 13 (61.9) |
| Male, No. (%) | 5 (55.6) | 7 (41.2) | 8 (38.1) |
| Duration of manic episode, mean (SD), wk | 6.04 (7.45) | 7.49 (8.06) | NA |
| Duration of remission from mania, mean (SD), wk | NA | 7.18 (4.6) | NA |
| Duration of illness, mean (SD), y | 4.46 (4.33) | 17.1 (13.8) | NA |
| Mania with psychosis, No. (%) | 2 (22.2) | 5 (29.4) | NA |
| Previous depressive episodes, mean (SD) | 1.62 (1.06) | 5.33 (6.33) | NA |
| Previous manic episodes, mean (SD) | 0.33 (0.5) | 9.44 (12.9) | NA |
| Lifetime comorbidities | |||
| Anxiety disorders, No. (%) | 5 (55.5) | 2 (11.8) | NA |
| Substance use disorders, No. (%) | 4 (44.4) | 4 (23.5) | NA |
| YMRS, mean (SD) | 21.22 (5.87) | 1.69 (2.27) | 0.70 (1.36) |
| Current treatment | |||
| Lithium, No. (%) | 2 (22.2) | 6 (35.0) | NA |
| Dose, mean (SD), mg/d) | 900 (0) | 960 (134) | NA |
| Valproate, No. (%) | 2 (22.2) | 9 (52.9) | NA |
| Dose, mean (SD), mg/d | 938 (88.4) | 1000 (331) | NA |
| Lamotrigine, No. (%) | 1 (11.1) | 1 (5.9) | NA |
| Dose, mean (SD), mg/d) | 50 (0) | 300 (0) | NA |
| Clonazepam, No. (%) | 1 (11.1) | NA | NA |
| Dose, mean (SD), mg/d | 3 (0) | NA | NA |
| Topiramate, No. (%) | NA | 1 (5.9) | NA |
| Dose, mean (SD), mg/d | NA | 200 (0) | NA |
| Carbamazepine, No. (%) | NA | 2 (11.8) | NA |
| Dose, mean (SD), mg/d | NA | 700 (141) | NA |
Abbreviations: BD, bipolar disorder; NA, not applicable; YMRS, Young Mania Rating Scale.
DAT Density
Table 2 shows areas of significant differences in MP BPND between different groups. The reduction in BPND reached stringent voxel level significance (FEW-corrected P < .05) at the peaks in each of the significant clusters in all 4 of the contrasts of interest.
Table 2. Areas of Significant Differences in [11C]d-Threo-Methylphenidate Nondisplaceable Binding Potential (BPND) Between Groupsa.
| Voxels in cluster, kE | MNI coordinates for peak significant voxels (FWE-corrected P < .05) | t Value | Voxel significance (P, FWE corrected) | Brain regions included in the clusters | Cluster significance (P, FWE corrected) |
|---|---|---|---|---|---|
| Areas where patients with bipolar disorder had lower BPND compared with healthy control individuals | |||||
| 608 | −8, 12, −12 | 4.97 | .007 | Left caudate | <.001 |
| −12, 12, −8 | 4.33 | .01 | Left putamen | ||
| 587 | 32, −14, 2 | 5.66 | .001 | Right putamen; right nucleus accumbens | <.001 |
| Areas where patients with current mania had lower BPND compared with healthy control individuals | |||||
| 705 | 30, −12, 2 | 5.72 | .001 | Right putamen | <.001 |
| 28, 0, 0 | 4.76 | .01 | Right nucleus accumbens | ||
| 28, −4, 6 | 4.43 | .03 | Right caudate | ||
| 632 | −14, 8, −14 | 4.21 | .02 | Left nucleus accumbens | <.001 |
| −16, 10, −10 | 4.09 | .02 | Left putamen; left caudate | ||
| Areas where patients with remitted mania had lower BPND compared with healthy control individuals | |||||
| 393 | −12, 18, −2 | 4.37 | .04 | Left caudate; left putamen | .001 |
| Areas where patients with current mania had lower BPND compared with patients with recently remitted mania | |||||
| 388 | 28, −10, 0 | 4.47 | .006 | Right putamen | .001 |
| 28, −4, 0 | 4.27 | .01 | Right nucleus accumbens; right caudate | ||
| 380 | −28, −18, −2 | 4.43 | .006 | Left putamen; left nucleus accumbens; left caudate | .001 |
Abbreviations: FWE, familywise error; MNI, Montreal Neurological Institute.
The cluster and voxel threshold significance was set at FWE-corrected P < .05, and a striatum mask was applied to determine significances using small volume corrections.
Patients With BD vs Healthy Control Individuals
BPND values for MP were significantly lower in patients with BD (both with current mania and recently remitted mania) compared with healthy control individuals as indicated by 2 significant clusters of voxels in the striatum (Figure 1A; Table 2); further, the reduction in BPND reached stringent voxel level significance (FWE-corrected P < .05) at the peaks of each of these 2 significant clusters. The cluster in the right striatum (FWE-corrected P < .001) included 587 voxels and embraced right putamen and right nucleus accumbens while the cluster in the left striatum (FWE-corrected P < .001) had 608 voxels and included left caudate and left putamen. The mean reduction in binding was 22% in the cluster in the right striatum and 24% in the cluster in the left striatum.
Figure 1. Areas in Striatum Where [11C]d-Threo-Methylphenidate Nondisplaceable Binding Potential Was Significantly Lower.
The mean BPND values in these clusters were significantly lower in patients with current mania compared with those with recently remitted mania (right striatum: mean [SD] BPND = 0.78 [0.08] vs 1.29 [0.11]; P < .001; left striatum: mean [SD] BPND = 0.78 [0.11] vs 1.13 [0.08]; P < .001, respectively).
Patients With Current Mania vs Those With Recently Remitted Mania vs Healthy Control Individuals
Both patients with current mania and those with recently remitted mania had significantly lower MP BPND compared with healthy control individuals (Table 2). Reduction in MP BPND in patients with current mania was more spatially extensive and included putamen, caudate, and nucleus accumbens on both sides; reductions in binding were 45% and 42% in patients with current mania in these clusters in the right and left striatum, respectively. However, the reduction in MP BPND in patients with recently remitted mania was confined to a cluster that included left putamen and left caudate only, as the BPND values in the right striatum in this group were not significantly different from those of healthy control individuals.
Patients With Current Mania vs Those With Recently Remitted Mania
Compared with patients with recently remitted mania, those with current mania had significantly lower MP BPND in both the right and left striatal regions (Table 2; Figure 1B). The significant cluster in the right striatum included 388 voxels and embraced right putamen, right nucleus accumbens, and right caudate, while the cluster in the left striatum had 380 voxels and also included left putamen, nucleus accumbens, and caudate. The MP BPND was 40% and 37% lower in patients with current mania in these clusters in the right and left striatum, respectively, compared with patients with recently remitted mania.
Association With Clinical Scores and Mood Stabilizers
Since the distribution of YMRS scores was bimodal in patients, we performed Spearman correlation tests separately for patients with current mania and those with remitted mania for the clusters that were significantly different between patients and control individuals. A significant negative correlation was observed between YMRS scores and BPND values in the right striatal cluster both in patients with current mania (ρ = −0.93; 95% CI, −0.99 to −0.69; P < .001) and patients with recently remitted mania (ρ = −0.64; 95% CI, −0.86 to −0.23; P = .005) (Figure 2A). Although the correlations were also negative for the left striatal cluster, they were not significant either for those with current mania (ρ = −0.62; 95% CI, −0.91 to 0.08; P = .07) or those with recently remitted mania (ρ = −0.06; 95% CI, −0.53 to 0.43; P = .81) (Figure 2B).
Figure 2. Correlation of [11C]d-Threo-Methylphenidate (MP) Nondisplaceable Binding Potential and Young Mania Rating Scale (YMRS) Scores in Patients With Bipolar Disorder.
There was no significant correlation between BPND values and HAM-D scores (right striatum: ρ = 0.01; P = .95; left striatum: ρ = 0.09; P = .67) or BPRS psychosis symptom scores (right striatum: ρ = −0.35; P = .08; left striatum: ρ = −0.29; P = .15). Similarly, in the cluster that was significantly different between patients with remitted mania and healthy control individuals, there was no significant correlation between YMRS scores and BPND values (ρ = −0.26; P = .11). The mean (SD) DAT BPND values were significantly higher in patients who were taking a mood stabilizer vs those who were not (right striatum: 1.17 [0.24] vs 0.87 [0.23]; P = .04; left striatum: 1.06 [0.17] vs 0.82 [0.16]; P = .02).
Discussion
To our knowledge, this is the first study to investigate MP binding potential in patients with BD with current mania and recently remitted mania. The results showed that patients with BD had a lower MP BPND in the right putamen and nucleus accumbens as well as left putamen and caudate. The reduction in MP BPND was more extensive in patients with current mania and included right putamen, nucleus accumbens, and caudate as well as the left putamen, nucleus accumbens, and caudate compared not only with healthy control individuals but also patients with recently remitted mania. Further, there were significant negative correlations between YMRS scores and MP binding in the clusters in the right but not in the left striatum. The reduction in MP BPND in patients with recently remitted mania was evident only in the left putamen and caudate compared with healthy control individuals.
The lower MP BPND in patients with current mania and with recently remitted mania compared with healthy control individuals suggests that BD and in particular mania may be associated with reduced DAT density. However, since mania may be associated with increased synaptic dopamine levels, it is conceivable that reduced MP BPND observed in the study participants is a result of increased endogenous synaptic dopamine occupying more DAT sites, thus leaving fewer sites for occupation by MP. However, this is unlikely, as MP has high affinity for DAT and studies suggest that estimates of DAT density as measured by MP BPND are not affected by the endogenous dopamine levels.21 Alternatively, since a number of patients in this study had been taking lithium or an anticonvulsant mood stabilizer prior to the PET scans, the possibility that reduced DAT availability was due to the effect of medication cannot be ruled out.
However, patients who were taking a mood stabilizer had a higher DAT binding in our study compared with those who were not taking any mood stabilizer. This is consistent with 2 preclinical studies22,23 that reported increased DAT binding following long-term treatment with lithium. Similarly, valproate has been reported to increase DAT gene expression in various preclinical models.24,25 Thus, lower DAT binding in patients with current and recently remitted mania is unlikely to be due to the effects of lithium or valproate, as they are expected to increase or normalize and not reduce DAT density.
Our study showed that the reduction in DAT density was more extensive embracing both right and left striatum, including nucleus accumbens, in patients with current mania compared with healthy control individuals as well as patients with remitted mania while the reduction in DAT density in patients with remitted mania was confined mainly to left caudate and left putamen compared with healthy control individuals. Further, the YMRS scores correlated with DAT density in the right striatum but not in the left striatum. These findings suggest that DAT density in the right striatum may be associated with mood state such that lower DAT density is associated with more severe manic symptoms and higher DAT density is associated with fewer or no manic symptoms. Further, the fact that there was no significant correlation between YMRS scores and DAT density in the cluster that was different between patients with remitted mania and healthy control individuals suggests that perhaps DAT density in the right caudate, putamen, nucleus accumbens, and left nucleus accumbens is more critical to the expression of manic symptoms than DAT density in the left caudate and putamen.
While no previous study to our knowledge assessed DAT density in patients with current or recently remitted mania, 2 previous studies that used single photon emission computed tomography to assess DAT in patients with euthymic BD that included mostly bipolar II disorder reported increased DAT in striatal regions.26,27 Further, 2 studies that assessed DAT in patients with a current depressive episode that included some patients with bipolar II disorder also reported increased DAT in the right and left putamen and left caudate regions.28,29 Taken together, the findings of these studies and those of our study suggest that DAT may be lower in patients with current mania, approximately normal in those with euthymia, and higher in those with depression. Based on this, it might be tempting to speculate a critical role for DAT across mood states in BD; however, it must be acknowledged that these findings are based on cross-sectional and not longitudinal studies. Further, a small PET study of patients with both bipolar I and bipolar II disorder, which included 6 patients with depression and 5 with euthymia, reported no difference in DAT binding between patients with euthymia vs those with depression and found an overall reduction in DAT in patients with BD compared with healthy control individuals.30 While the possibility of type I and type II errors due to the small sample size in this study30 might explain the discrepancy in findings, further studies with larger sample sizes that include patients with depression, mania, and euthymia or longitudinal studies of patients in various phases are needed to confirm the role of varying DAT density in pathophysiology of BD.
Patients with current mania were observed to have reduced DAT density amounting to 42% and 45% compared with healthy control individuals and 37% and 40% compared with patients with recently remitted mania in the left and right striatum, respectively. These findings are consistent with the dopamine hyperactivity hypothesis of mania, as reduced DAT is expected to result in increased synaptic dopamine levels with a subsequent increase in dopamine transmission. This is consistent with animal models of mania, which showed that reduced DAT expression is associated with a wide range of manialike behaviors.31 The findings are also in line with known pharmacological effects of current antimanic treatments, which reduce dopamine transmission through blockade of dopamine D2 receptors, reduction in rate of dopamine synthesis, or reduction in dopamine D2 receptor density. Reduced DAT does not appear to be associated with psychotic symptoms, as we found no correlation between psychotic symptoms and DAT BPND. This is consistent with a meta-analysis32 that found no changes in striatal DAT density in patients with schizophrenia.
Limitations
Limitations of our study include its cross-sectional design as opposed to a within-subject longitudinal design, smaller sample size, lack of a drug-naive sample, and assessment of DAT binding in striatal areas. The groups were not matched for smoking status or menstrual cycle, which may be associated with quantification of DAT binding.33 Further, the distribution volumes of current PET ligands, including MP coupled with the low resolution of this scanner, render it unsuitable to ascertain DAT availability in most extrastriatal regions.
Conclusions
To the best of our knowledge, this is the first PET study that assessed dopaminergic transmission in a clinically representative sample of patients with current and recently remitted mania. The strengths of the study lie in its use of the MP, which is highly specific for DAT; adjustment for age, which is known to be associated with MP binding; and recruitment of patients with both current and recently remitted mania.
The findings from this study indicate that mania was associated with reduced DAT availability, signifying abnormal presynaptic dopaminergic neurocircuitry in patients with mania. This has implications in furthering our understanding of neurobiology of BD and discovering novel therapies that target DAT. Future research in this area needs to focus on ascertaining how DAT density is altered across depression, mania, and euthymia to understand the role of DAT in pathophysiology of BD. Pharmacological challenge paradigms that alter dopamine transmission combined with PET might provide further insights into the role of dopamine in BD.
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