An examination on cognitive functioning following a first episode of mania in people treated with lithium and quetiapine monotherapy: a 12-month follow-up study
AffiliationCentre for Youth Mental Health
Document TypePhD thesis
Access StatusOnly available to University of Melbourne staff and students, login required
© 2016 Dr. Rothanthe Georgiou
Cognitive impairments that persist during remission in bipolar disorder have received intensive investigation over the past couple of decades. Nevertheless, the onset and extent of cognitive deficits that occur either prior to, or following, a first episode of mania (FEM), and the trajectory of cognitive functioning in the early stages of illness remain unclear. Moreover, the effect of treatment medication on cognitive functioning in people with bipolar disorder warrants systematic investigation. Specifically, lithium carbonate and quetiapine fumurate have shown to be effective in the treatment of mania and bipolar depression and are both postulated to have neuroprotective properties. The aims of this research program were to: (i) examine cognitive functioning in people following FEM; (ii) assess cognitive changes following FEM over a 12-month period; and (iii) compare the effects of lithium and quetiapine monotherapy on cognitive functioning over the same 12-months. A systematic review of all peer-reviewed studies on cognitive functioning in people with FEM during both the acute and remission phases of the illness was conducted. This involved a systematic search of the literature from three electronic databases from 1980 to 2014. The search identified seven studies on cognitive functioning in people with FEM. The limited studies in the acute phase focussed only on aspects of executive functioning, with findings of impairment in cognitive flexibility, but not in response inhibition or verbal fluency. Although deficits in several cognitive domains were identified during the remission phase, the findings between studies were largely inconsistent. Nevertheless, the most consistent finding during remission was a deficit in working memory, and that verbal fluency and nonverbal memory were not affected. The systematic review highlighted the need for further studies and clarification on the extent of cognitive impairment following FEM, and assisted in the formation of the hypotheses of the empirical studies. For the empirical studies, a total of 61 participants with FEM randomised to lithium or quetiapine monotherapy, and 21 demographically matched healthy controls (HCs) were recruited. FEM participants and HCs were compared on cognitive functioning using an extensive cognitive battery over a 12-month follow-up period. FEM participants were assessed on cognitive functioning at baseline, 3-months, and 12-months, whereas, cognitive functioning of HCs was assessed at baseline and 12-months. The cognitive assessment included measurements of processing speed, attention, sustained attention, verbal learning and memory, nonverbal memory, working memory, verbal fluency, executive functioning, and intelligence. The first empirical study involved a cross-sectional analysis comparing cognitive functioning in FEM participants following stabilisation relative to HCs. Although the groups were matched in age, sex and premorbid intelligence, the findings revealed that FEM participants had significantly lower full-scale IQ (FSIQ) and education level than HCs. However, the difference between groups in FSIQ was no longer significant after controlling for premorbid intelligence. FEM participants displayed cognitive deficits of medium to large effect in processing speed, verbal learning and memory, and working memory compared to HCs. There were no significant differences between groups on other measures of cognition after controlling for FSIQ, education and premorbid intelligence. The second empirical paper involved a longitudinal analysis that assessed the trajectory of cognitive functioning in the FEM participants relative to HCs over 12-months. The findings revealed a significant group by time interaction in one measure of processing speed (Trail Making Test – Part A), and immediate verbal recall (Rey Auditory Verbal Learning Test – trial 1), with a significant improvement observed in the FEM group relative to HCs over time. On the contrary, a significant group by time interaction was observed in a processing speed measure of focussed reaction time (CogstateTM Detection), with FEM participants showing a slower performance relative to HCs over time. A significant group by time interaction was also observed in one aspect of executive functioning - effortful inhibitory control (Stroop effect), revealing that HCs improved in performance over 12-months, whereas the FEM participants did not. There were no other group by time interactions for other measures of cognition. The final empirical study was a randomised-controlled trial, which examined the effects of lithium and quetiapine monotherapy in people following FEM over a 12-month period. The results showed a significant group by time interaction in phonemic verbal fluency, with an improved performance in lithium-treated participants compared to quetiapine-treated participants over time. There were no other significant group by time interactions after controlling for multiple comparisons. In conclusion, the findings from this research program revealed that FEM participants had poorer global intelligence relative to HCs, as well as impairments in some but not all cognitive domains following stabilisation from FEM. There appears to be stability in cognitive functioning for most domains over the 12-month period following FEM. However, an improvement was observed in immediate verbal memory and one measure of processing speed over time in FEM participants relative to HCs, although FEM participants performed slower over time on a simple processing speed test of focused reaction time. In addition, there may be a developmental arrest in effortful inhibitory control, as HCs showed an improvement in this function over the 12-month period that was not evident in the FEM group. There were no significant differences between lithium-treated and quetiapine-treated participants on most cognitive domains, apart from phonemic verbal fluency, in which lithium-treated participants showed a significant improvement relative to quetiapine-treated participants over the 12-month period. These findings suggest that neuroprotective properties of lithium may benefit aspects of cognitive functioning when commenced in the early stages of illness. The presence of cognitive deficits in FEM signifies that cognitive changes may occur very early in the illness course. The findings from this research program did not provide evidence for a progressive deterioration in cognitive functioning following FEM, although more rigorous longitudinal studies involving subgroup analysis are warranted. Future studies should examine the relationship between brain abnormalities and cognitive functioning in people following FEM, as well as assess the effects of lithium and quetiapine monotherapy on clinical and neuroanatomical changes over time.
Keywordscognition; trajectory; mania; bipolar disorder; depression
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