Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study.

BACKGROUND: Neuroprotective effects of lithium (Li) have been well documented in tissue cultures and animal models, whereas human data continue to be limited. Previous studies investigating the association between Li treatment and brain N-acetylaspartate (NAA), a putative neuronal marker, showed mixed results because of methodological heterogeneity. METHODS: To investigate the effects of Li on prefrontal cortex NAA levels, we compared patients with bipolar disorder from specialized Li clinics in Berlin and Halifax with at least 2 years of ongoing Li treatment (Li group), patients with lifetime Li exposure of less than 3 months more than 2 years ago (non-Li group) and healthy controls. Participants in both patient groups had at least 10 years of illness and 5 episodes. We measured left prefrontal NAA levels using 1.5-T magnetic resonance spectroscopy. RESULTS: We enrolled 27 participants in the Li, 16 in the non-Li and 21 in the healthy control groups. The non-Li group had lower prefrontal NAA levels than the Li group (t41 = -3.44, corrected p < 0.01) or control participants (t35 = -2.91, corrected p < 0.05), who did not differ from the Li group (t46 = -0.14, p = 0.89). The same pattern of prefrontal NAA differences was replicated in both sites. In addition, there was a negative correlation between prefrontal NAA and duration of illness in the non-Li group (r = -0.60, p = 0.019) but not in the Li group (r = 0.07, p = 0.74). LIMITATIONS: Study limitations include the crosssectional design and exposure to other medications. CONCLUSION: Whereas patients with bipolar disorder, substantial illness burden and limited lifetime Li exposure had significantly lower prefrontal NAA levels than controls, Li-treated patients with similar illness burden showed prefrontal NAA levels comparable to those of healthy controls. These findings provide indirect support for neuroprotective effects of Li and for negative effects of illness burden on prefrontal NAA levels in patients with bipolar disorder.

Prophylactic lithium treatment and cognitive performance in patients with a long history of bipolar illness: no simple answers in complex disease-treatment interplay.

Cognitive impairment in patients with bipolar disorder (BD) is not restricted to symptomatic phases. It is also present in euthymia. There is evidence of differences in the brain's structure between bipolar patients and healthy individuals, as well as changes over time in patients. Lithium constitutes the gold standard in long-term prophylactic treatment. Appropriate therapy that prevents new episodes improves the disease's course and reduces the frequency of harmful outcomes. Interestingly, preclinical data suggest that lithium has a (additional) neuroprotective effect. There is limited data on its related effects in humans and even less on its long-term application. In this multi-center cross-sectional study from the International Group for the Study of Lithium-treated Patients (IGSLi), we compared three groups: bipolar patients without long-term lithium treatment (non-Li group; <3 months cumulative lithium exposure, ≥24 months ago), bipolar patients with long-term lithium treatment (Li group, ongoing treatment ≥24 months), and healthy subjects (controls). Strict inclusion and exclusion criteria were defined; the inclusion criteria for patients were diagnosis of BD types I or II, duration of illness ≥10 years, ≥5 episodes in patient's history and a euthymic mood state. Neurocognitive functioning was assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the California Verbal Learning Test (CVLT), and a visual backward masking (VBM) task. A total of 142 subjects were included, 31 in the non-Li and 58 in the Li group, as well as 53 healthy controls. Treated patients with long-standing BD and controls did not differ significantly in overall cognitive functioning and verbal learning, recall, and recognition; regardless of whether lithium had been part of the treatment. Patients, however, demonstrated poorer early visual information processing than healthy controls, with the lithium-treated patients performing worse than those without. Our data suggest that bipolar patients with a long illness history and effective prophylactic treatment do not reveal significantly impaired general cognitive functioning or verbal learning and memory. However, they are worse at processing early visual information. Accompanying volumetric and spectroscopic data suggest cell loss in patients not treated with lithium that may be counterbalanced by long-term lithium treatment.