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In a pragmatic trial involving older persons with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole was better than augmentation with bupropion or a switch to bupropion.

Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimer's disease, although no benefits were obtained from short-term treatment. To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI). Forty-five participants with aMCI were randomised to receive lithium (0.25-0.5 mmol/l) (n = 24) or placebo (n = 21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (Aβ(42)), total tau (T-tau), phosphorylated-tau) (P-tau). NCT01055392. Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P = 0.03) and better perform-ance on the cognitive subscale of the Alzheimer's Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%. The present data support the notion that lithium has disease-modifying properties with potential clinical implications in the prevention of Alzheimer's disease.

ABSTRACT Objective: To assess the efficacy and tolerability of quetiapine in Chinese patients hospitalized with acute bipolar mania. Methods: This was a 4-week, multicenter, randomized, double-blind, lithium-controlled, parallel-group study. Secondary endpoints in the primary analysis were: response rate (≥ 50% decrease from baseline in YMRS total score) and remission rate as defined using 3 criteria: YMRS total score ≤ 12, YMRS total score ≤ 12 + MADRS total score ≤ 8, and YMRS total score ≤ 8. Other measures included: change from baseline at Day 28 in YMRS, PANSS, and MADRS total score. Adverse event (AE) data were collected throughout the study. Results: 73 (94.8%) quetiapine and 62 (80.5%) lithium patients completed the study. Mean (SD) quetiapine doses for the ITT population and responders were 648.2 (111.84) mg/dayand 637.5 (118.78) mg/day, respectively, while mean lithium concentrations for the ITT population and responders were 0.80 (0.28) mmol/L and 0.80 (0.22) mmol/L, respectively. Of patients who responded to quetiapine at Day 28, 88.3% were receiving 600-800 mg/day. At Day 28 YMRS response rate was significantly greater with quetiapine than lithium (77.9% vs. 59.7%, p = 0.0132), and remission rates using the 3 criteria were significantly greater with quetiapine than lithium: YMRS total score ≤ 12 (70.1% vs. 48.1%, p = 0.0071), YMRS ≤ 12 + MADRS ≤ 8 (70.1% vs. 48.1%; p = 0.0071), and YMRS ≤ 8 (51.9% vs. 32.5%; p = 0.0147). Significant decreases were observed in PANSS, YMRS, and MADRS total scores for both groups. The most common AEs experienced by patients receiving quetiapine were constipation, dizziness, diarrhea, alanine aminotransferase increase, palpitations, aspartate aminotransferase increase, pharyngolaryngeal pain, upper respiratory tract infection and dry mouth. In patients receiving lithium, the most common AEs were nausea (16.9%), constipation (13.0%), vomiting (13.0%), nasopharyngitis (11.7%), dizziness (6.5%), diarrhea (6.5%), and upper respiratory tract infection (6.5%). Conclusion: Quetiapine was shown to be clinically effective in patients with acute bipolar mania. There were side effects with quetiapine similar to those reported in other studies that included other ethnic populations of patients.

To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.

Controversy exists over antidepressant use in bipolar II depression. To compare the safety and effectiveness of antidepressantv.mood stabiliser monotherapy for bipolar type II major depressive episodes. Randomised, double-blind, parallel-group, 12-week comparison of venlafaxine (n= 65)v.lithium (n= 64) monotherapy in adult out-patients (trial registration numberNCT00602537). Primary outcome - venlafaxine produced a greater response rate (67.7%)v lithium (34.4%,P<0.001). Secondary outcomes - venlafaxine produced a greater remission rate (58.5%v 28.1%,P<0.001); greater decline in depression symptom scores over time (β = -5.32, s.e. = 1.16, χ(2)= 21.19,P<0.001); greater reduction in global severity scores over time (β = -1.05, s.e. = 0.22, w(2)= 22.33,P<0.001); and greater improvement in global change scores (β = -1.31, s.e. = 0.32, χ(2)= 16.95,P<0.001) relative to lithium. No statistically significant or clinically meaningful differences in hypomanic symptoms were observed between treatments. These findings suggest that short-term venlafaxine monotherapy may provide effective antidepressant treatment for bipolar II depression without a statistically significant increase in hypomanic symptoms relative to lithium.

Disruptions in the limbic system, and in emotion regulation circuitry that supports affect modulation, have been reported during acute manic episodes of bipolar disorder (BD). The impact of pharmacological treatment on these deficits, especially in youth, remains poorly characterized. 107 youths with acute manic or mixed episodes of bipolar I disorder and 60 group-matched healthy controls were recruited. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. Task-based fMRI studies were performed using an identical pairs continuous performance task (CPT-IP) at pre-treatment baseline and post-treatment weeks one and six. Region of interest analyses focused on the limbic system and ventral PFC - basal ganglia - thalamocortical loop structures known to be involved in emotion regulation. Changes in regional activation were compared between the two treatment groups, and pretreatment regional activation was used to predict treatment outcome. Mania treatment scores improved more rapidly in the quetiapine than lithium treated group, as did significant normalization of neural activation toward that of healthy individuals in left amygdala (p = 0.007), right putamen (p < 0.001), and right globus pallidus (p = 0.003). Activation changes in the right putamen were correlated with reduction of mania symptoms. The limbic and emotion regulation system activation at baseline and week one predicted treatment outcome in youth with bipolar disorder with significant accuracy (up to 87.5%). Our findings document more rapid functional brain changes associated with quetiapine than lithium treatment in youth with bipolar disorder, with most notable changes in the limbic system and emotion regulation circuitry. Pretreatment alterations in these regions predicted treatment response. These findings advance understanding of regional brain alterations in youth with bipolar disorder, and show that fMRI data can predict treatment outcome before it can be determined clinically, highlighting the potential utility of fMRI biomarkers for early prediction of treatment outcomes in bipolar disorder.Clinical Trials Registration: Name: Multimodal Neuroimaging of Treatment Effects in Adolescent Mania. URL: https://clinicaltrials.gov/. Registration number: NCT00893581

Whereas some prior data had suggested a large increase in the risk of cardiac malformations among offspring of women using lithium in early pregnancy, this analysis using a large Medicaid database showed more modest increases in the risk of these complications. In the early 1970s, results from the International Register of Lithium Babies evaluating infants born to mothers who were treated with lithium early in pregnancy 1 , 2 suggested a risk of Ebstein’s anomaly, a right ventricular outflow tract obstruction defect, that was increased by a factor of 400 (on the basis of two cases associated with lithium exposure) and a risk of overall cardiac defects that was increased by a factor of 5. 3 By 1979, the final report included data on 225 infants born to lithium-exposed women; 18 infants had congenital cardiac defects (8%), including 6 with Ebstein’s anomaly (3%). 4 On . . .

We summarize evidence supporting contemporary pharmacological treatment of phases of BD, including: mania, depression, and long-term recurrences, emphasizing findings from randomized, controlled trials (RCTs). Effective treatment of acute or dysphoric mania is provided by modern antipsychotics, some anticonvulsants (divalproex and carbamazepine), and lithium salts. Treatment of BD-depression remains unsatisfactory but includes some modern antipsychotics (particularly lurasidone, olanzapine + fluoxetine, and quetiapine) and the anticonvulsant lamotrigine; value and safety of antidepressants remain controversial. Long-term prophylactic treatment relies on lithium, off-label use of valproate, and growing use of modern antipsychotics. Lithium has unique evidence of antisuicide effects. Methods of evaluating treatments for BD rely heavily on meta-analysis, which is convenient but with important limitations. Underdeveloped treatment for BD-depression may reflect an assumption that effects of antidepressants are similar in BD as in unipolar major depressive disorder. Effective prophylaxis of BD is limited by the efficacy of available treatments and incomplete adherence owing to adverse effects, costs, and lack of ongoing symptoms. Long-term treatment of BD also is limited by access to, and support of expert, comprehensive clinical programs. Pursuit of improved, rationally designed pharmacological treatments for BD, as for most psychiatric disorders, is fundamentally limited by lack of coherent pathophysiology or etiology.