The influence of successful prophylactic drug treatment on cognitive dysfunction in bipolar disorders

Background:  Cognitive variables such as negative self-evaluations have been discussed as vulnerability factors for depressive syndromes. In the context of bipolar disorders dysfunctional cognitive structures have received little interest as these patients seem to be less disturbed during the euthymic interval than patients with major depression.
Methods:  In the present study, the self-esteem of remitted patients with DSM-III-R diagnosis of major depression (n=20), bipolar disorder (n=20) and healthy controls (n=20) was measured with the Frankfurt Self-concept Scale (FSKN).
Results:  1) Statistical analysis by analysis of variance (ANOVA) showed no significant differences as to age, sex, etc. between the psychiatric groups. The clinical groups showed lower self-esteem ratings in comparison to healthy controls. 2) Four groups (T1–T4) of remitted patients with bipolar disorders (20 in each group) were successfully maintained on mood stabilizers (lithium or carbamazepine) and classified by the duration of their episode-free period. T1 included those who were episode-free for only the week before discharge from hospital. T2 were symptom-free for <30 months. T3 were episode-free for >30 months and <60 months. T4 were episode-free for >60 months. The comparison of their FSKN self-esteem ratings by ANOVA suggests that self-esteem improves during successful prophylactic treatment. A posteriori contrasts indicate a normalized self-esteem after a bipolar episode-free period of at least 47 months.
Conclusions:  Dysfunctional cognitions can be demonstrated in unipolar as well as in bipolar patients. Successful episode-preventive medication with mood stabilizers seems to counteract lowered self-esteem. Adjunctive cognitive therapy might help to optimize the long-term course of bipolar disorder.     

The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s

Objectives: The aim of the study was to assess the prophylactic effect of long-term lithium administration in patients with bipolar mood disorders entering treatment in the 1970s and 1980s at the outpatient clinic of the Department of Psychiatry, University of Medical Sciences, Poznan, Poland. Methods: The clinical characteristics of two groups of patients before and during lithium therapy were compared, namely, the 60 bipolar patients who entered lithium prophylaxis in the 1970s and 49 patients who entered in the 1980s. Both groups received the drug over a 10-year period. Results: The patients who entered lithium in the 1970s had fewer previous episodes of depression and more of mania than the patients who entered the therapy in the 1980s, although the total number of affective episodes was similar in both groups. The overall prophylactic efficacy of lithium over a 10-year period of administration was similar in both groups, except for a trend towards a greater number of depressive episodes in the first year of lithium prophylaxis in the 1980s group. The excellent lithium responders constituted 35% of the 1970s patients and 27% of those in the 1980s group. The 1970s patients were maintained on a higher level of serum lithium compared to the patients in the 1980s group and had more lithium-induced side effects. Conclusions: A decrease in lithium prophylactic efficacy in consecutive decades was not observed. Small differences between the bipolar patients entering lithium therapy in the 2 decades were observed in terms of the previous history of illness and during the course of lithium administration.     

Discontinuing lithium maintenance treatment in bipolar disorders: risks and implications

Objective: To review research findings on clinical effects of discontinuing lithium maintenance treatment.
Methods: Data from studies reported since 1970 plus our recent findings were updated.
Results: Discontinuing lithium maintenance treatment led to marked increases of early affective morbidity and suicidal risk. Gradual discontinuation markedly reduced early recurrences of mania or depression, did so more in bipolar II than I disorder patients, and also tended to reduce suicidal risk. Similar effects were found in pregnant and nonpregnant women after lithium discontinuation. Long-term retreatment with lithium following discontinuation was only slightly less effective than in initial trials.
Conclusions: Recurrences increased sharply soon after discontinuing lithium, but were markedly limited and not merely delayed, by slow discontinuation. Similar reactions may follow discontinuation of other drugs, evidently as responses to long-term pharmacodynamic adaptations. Discontinuing treatment is not equivalent to not-treating. Post-discontinuation relapse risk has implications for the design, management, and interpretation of protocols involving discontinuation of long-term treatments that should be considered in both clinical management and research.     

The increasing use of anticonvulsants in prophylactic treatment of bipolar disorder

The medical records of patients with bipolar disorders who received prophylactic drug treatments during three time periods from January 1983 to December 1984, January 1988 to December 1989, and from January 1993 to December 1994, were reviewed retrospectively. The percentage of lithium monotherapy sharply decreased from 96% (51/53) in the first study period to 51.9% (83/160) in the third study period. Carbamazepine monotherapy and combination of lithium and carbamazepine increased from 3.8% in the first study period to 45.6% in the third study period. These results suggest that anticonvulsants may become one of the major drug treatment strategies for bipolar disorder in the future.     

奥卡西平和碳酸锂治疗双相障碍躁狂发作患者的对照研究

目的：比较奥卡西平和碳酸锂治疗双相障碍躁狂发作的疗效和安全性。方法：70例双相障碍躁狂发作患者随机分为奥卡西平组和碳酸锂组各35例,分别给予奥卡西平和碳酸锂治疗8周。以Bech-Rafaelsen躁狂量表（BRMS）、临床疗效总评量表-病情严重程度（CGI-SI）以及治疗中出现的症状量表（TESS）评定疗效及不良反应。结果：两组治疗后BRMS、CGI-SI评分均较治疗前显著下降（P〈0.05或P〈0.01）;两组间比较差异无统计学意义（P〉0.05）;两组不良反应均为轻度。结论：奥卡西平治疗双相障碍躁狂发作的疗效与碳酸锂相当,不良反应轻。     

Cognitive effects of atypical antipsychotics: focus on bipolar spectrum disorders

Abstract:  Studies examining cognitive dysfunction in bipolar disorder have documented neuropsychologic impairment in some patients. Recollection memory, attention, and visual information processing may be particularly impaired in patients with bipolar illness. Cognitive impairment appears to worsen with illness progression, and may have a significant impact on function. Pharmacotherapy to treat bipolar disorder including lithium, anticonvulsants, antidepressants, and atypical antipsychotics may have varying effects on cognitive functioning. Treatment with atypical antipsychotics has been associated with improvement in various cognitive measures in patients with schizophrenia, and the little data available in patients with bipolar disorder suggest the potential for similar benefits. Studies to determine if current treatments for bipolar disorder can prevent, delay, or even improve cognitive dysfunction are needed.     

Maintenance treatment in bipolar disorder: a reassessment of lithium as the first choice

Objective:  In consideration of the declining use of lithium over the past several decades, this review focuses on three topics to argue for lithium's status as first choice as the maintenance treatment of bipolar disorder.
Methods:  This review (i) describes success rates for patients assigned to lithium and those assigned to placebo in early (1973–1976) and recent (2000–2003) trials, as well as those assigned to alternative mood stabilizers versus placebo; (ii) summarizes the results of studies that compared lithium to alternative mood stabilizers by the degree of weight gain during maintenance therapy; and (iii) reviews evidence that lithium exhibits unique antisuicidal properties.
Results:  Differing success rates in early and more recent maintenance trials strongly suggest a cohort effect in which the lithium responders are relatively unavailable for recent maintenance trials. Moreover, among mood stabilizers studied in randomized trials, lithium appears least likely to cause substantial weight gain, and a considerable literature has developed to suggest that lithium has antisuicidal effects that extend beyond its benefits in relapse prevention.
Conclusion:  The evidence reviewed here strongly supports the consideration of lithium when prophylactic treatment is first begun for a bipolar patient.     

Effects of lamotrigine and lithium on body weight during maintenance treatment of bipolar I disorder

OBJECTIVE: The effect of lamotrigine maintenance therapy on body weight was assessed retrospectively in analyses of data from two double-blind, placebo- and lithium-controlled, 18-month studies in patients with bipolar I disorder (n = 227 for lamotrigine, 190 for placebo, 166 for lithium). METHODS: Endpoints included mean change in weight, the percentage of patients with > or = 7% change (increase, decrease, fluctuation) in weight, and the percentage of patients with weight-related adverse events during double-blind treatment. RESULTS: Mean weight remained stable during maintenance therapy with lamotrigine. In a mixed-model repeated-measures analysis, mean changes in weight (kg) at week 52 were -1.2 with lamotrigine, +0.2 with placebo, and +2.2 with lithium [estimated difference (95% CI) lamotrigine minus placebo = -1.3 (-3.6, 0.9), p = 0.237; lithium minus placebo = +2.0 (-0.3, 4.4), p = 0.094; lithium minus lamotrigine = +3.4 (1.4, 5.4), p < 0.001]. Analyses were truncated at week 52 because of the high incidence of missing data at later time points. The percentages of patients with a >/=7% weight gain, during randomized treatment, were 10.9%, 7.6% and 11.8% for the lamotrigine, placebo, and lithium groups, respectively. The percentages of patients with a > or = 7% weight loss, during randomized treatment, were 12.1%, 11.5%, and 5.1% for the lamotrigine, placebo, and lithium groups, respectively. The percentage of patients with a > or = 7% weight loss did not significantly differ between lamotrigine and placebo but was significantly higher with lamotrigine than lithium. The incidences of > or = 7% weight changes and of weight changes reported as adverse events were comparable between active treatments and placebo. CONCLUSION: Lamotrigine was associated with stable body weight during 1 year of treatment and was comparable to placebo in mean weight change, incidence of clinically significant weight change, and incidence of weight changes reported as adverse events in patients with bipolar disorder. Lithium was associated with weight gain, but the magnitude of lithium-associated weight gain was lower in the current analysis than in previous studies.     

Obesity and the three‐year longitudinal course of bipolar disorder

Goldstein BI, Liu S‐Min, Schaffer A, Sala R, Blanco C. Obesity and the three‐year longitudinal course of bipolar disorder.
Bipolar Disord 2013: 00: 000–000. © 2013 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd. Objectives: Despite substantial cross‐sectional evidence that obesity is associated with an increased medical and psychiatric burden in bipolar disorder (BD), few longitudinal studies have examined this topic. Methods: Subjects with BD (n = 1600) who completed both Wave 1 and Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions were included. Analyses examined the association between obesity at Wave 1, and the subsequent course of BD, and of psychiatric and medical comorbidities, between Wave 1 and Wave 2. Results: BD subjects with obesity (n = 506; 29.43%), compared to BD subjects without obesity (n = 1094; 70.57%) were significantly more likely to have a major depressive episode and to receive counseling for depression during follow‐up, more likely to report a lifetime suicide attempt, and less likely to develop new‐onset alcohol use disorders. These differences were no longer significant, however, after controlling for baseline demographic variables. No significant differences in new episodes or treatment of mania/hypomania were observed. After controlling for demographic variables, obese subjects remained significantly more likely to report any new‐onset medical condition [odds ratio (OR) = 2.32, 95% confidence interval (CI): 1.63–3.30], new‐onset hypertension (OR = 1.81, 95% CI: 1.16–2.82) and arthritis (OR = 1.64, 95% CI: 1.07–2.52). Obese subjects were significantly more likely to report physician‐diagnosed diabetes (OR = 6.98, 95% CI: 4.27–11.40) and hyperlipidemia (OR = 2.32, 95% CI: 1.63–3.30) (assessed in Wave 2 only). The incidence of heart attacks was doubled among obese subjects, although this difference was not statistically significant. Conclusions: The association between obesity and increased prospective depressive burden appears to be explained by baseline demographic variables. By contrast, obesity independently predicts the accumulation of medical conditions among adults with BD. Treatment of obesity could potentially mitigate the psychiatric and medical burden of BD.     

Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment

Hajek T, Cullis J, Novak T, Kopecek M, Höschl C, Blagdon R, O’Donovan C, Bauer M, Young L T, MacQueen G, Alda M. Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment.
Bipolar Disord 2012: 14: 261–270. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Hippocampal volume decrease associated with illness burden is among the most replicated findings in unipolar depression. The absence of hippocampal volume changes in most studies of individuals with bipolar disorder (BD) may reflect neuroprotective effects of lithium (Li). Methods: We recruited 17 BD patients from specialized Li clinics, with at least two years of regularly monitored Li treatment (Li group), and compared them to 12 BD participants with < 3 months of lifetime Li exposure and no Li treatment within two years prior to the scanning (non‐Li group) and 11 healthy controls. All BD patients had at least 10 years of illness and five episodes. We also recruited 13 Li‐naïve, young BD participants (15–30 years of age) and 18 sex‐ and age‐matched healthy controls. We compared hippocampal volumes obtained from 1.5‐T magnetic resonance imaging (MRI) scans using optimized voxel‐based morphometry with small volume correction. Results: The non‐Li group had smaller left hippocampal volumes than controls (corrected p < 0.05), with a trend for lower volumes than the Li group (corrected p < 0.1), which did not differ from controls. Young, Li‐naïve BD patients close to the typical age of onset had comparable hippocampal volumes to controls. Conclusions: Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li‐naïve BD patients, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.