The results from the present study vary considerably between the two sections utilizing differing methodologies. This is despite the fact that both studies were carried out by the same group on the same scanner with bipolar patients coming from the same patient pool. This strongly suggests that the methodology used to determine choline concentrations can considerably alter the results. In the first part of the study we found that both the lithium-treated and valproate-treated patients had significantly reduced Cho/Cr peak ratios compared to controls. This is similar to the findings from one previous study which also suggested that there may be a trend towards decreased choline in grey matter [28
]. This study was a frontal lobe study that measured metabolite concentrations in a 1.5 T scanner in bipolar type I patients hospitalized for manic (n = 9) or mixed (n = 8) states. In this study most patients were being treated with valproate and an atypical antipsychotic.
These findings, however, differ from those in the second part of the present study in which we found no differences in choline concentrations between valproate-treated patients and controls in either frontal or temporal lobes. This second part of the study was much better controlled in terms of the patients receiving valproate monotherapy, only including bipolar Type I patients, and in using an external choline solution to accurately quantify choline concentrations. This finding of a lack of change is also in keeping with most previous studies. Several studies which have also previously measured metabolite concentrations with 1.5 T scanners also found no changes. These include a study of the hippocampus in 15 euthymic bipolar type 1 patients, of whom 10 were taking either lithium or valproate [19
], a study of basal ganglia in 8 rapid cycling patients on lithium [22
], a study of the anterior cingulate in 10 bipolar children [23
], and a study in frontal lobes of 23 euthymic bipolar patients of whom 13 were on lithium [25
]. Several other studies have examined metabolite ratios, mostly in patients on lithium, and those also found no changes in choline concentrations [20
]. In a study using metabolite ratios in bipolar children who were off medication for at least one week there was also no change in choline concentrations [24
]. In a double-blind placebo-controlled human volunteer study before and after one week of lithium administration we also found no changes in cholinein 10 volunteers [30
], which is similar to a patient study which compared 7 patients on lithium to 6 non-lithium treated controls and in which no differences were seen [29
In contrast, animal studies have suggested that lithium may increase brain choline concentrations, and in lithium-treated patients it also increases the accumulation of choline within erythrocytes [4
]. Nonetheless, 1
H-MRS studies in patients examining this possibility is mixed. To date 6 studies have suggested some support for this [13
], but in none of these studies were metabolite concentrations measured, and most of the studies measured choline/creatine ratios [14
], the other one measuring metabolite intensity/tissue volume [13
]. The first study to examine brain choline in basal ganglia studied only 4 patients, all of whom were on lithium [18
]. Another study examined 19 euthymic inpatients and found increased choline/creatine ratios in basal ganglia, but only 10 of these patients were receiving lithium [17
]. The third study to report an increase in this ratio (in this case in the left subcortical region) was in a mixed group of patients receiving a wide range of medications [16
]. Two other studies have reported increased choline concentrations, but only in limited circumstances. In one study in 11 bipolar children patients were examined before and after lithium administration [14
]. There were no significant findings before or after lithium administration, although there was a trend towards increased choline/creatine ratios in the patients before lithium treatment. This latter finding does not suggest that in patients lithium significantly alters the choline/creatine ratio. The final study examined 15 euthymic males who were on either lithium or valproate [13
]. This study found that thalamic choline concentrations, determined by measuring metabolite intensity/tissue volume ratios, were significantly increased only if the right and left hemisphere were compared separately, but not if they were compared together.
It is also conceivable that both lithium and valproate may increase Choline concentrations, but that the differences were not large enough for us to detect, or that without lithium or valproate treatment patients would have lower Choline concentrations. The cross-sectional nature of this study does not allow this to be examined. It is also important to recognize other limitations of the present study. Firstly, these MRS studies are not pre- and post-treatments, so may not accurately reflect changes that occur in individual patients. Secondly, part of the study used a ratio-method to assess choline concentrations, the limitations of which are increasingly clear (particularly since creatine concentrations may be altered by medication [37
]). Thirdly, the sizes of all groups are small and it therefore possible that a larger study may have been fully powered to identify differences between groups. Fourthly, several patients in the first study (but not the second study) were on other drugs which may have affected the results of this study. Fifthly, we have not determined if age affects the results, and in the first part the groups were not all matched for age. In addition, the voxel locations were not the same in both studies due to the reasons discussed in the methodology section. Nonetheless, despite these limitations we believe the results add significantly to the literature in this under-researched area.
We conclude that, taking all current evidence together including the findings from the present study, it is unlikely that either lithium or valproate significantly alter brain choline concentrations. However, given the large differences in patients populations, medications received, and MRS methodologies it is difficult to directly compare all these studies. In addition, the methodology used to measure choline concentrations can significantly alter the results. Future MRS studies in bipolar patients should, therefore, examine metabolite concentrations rather than a ratio of choline compared to other metabolites.