Lithium, the gold standard drug for bipolar disorder: analysis of current clinical studies.

Lithium is the gold standard drug in the treatment of bipolar disorder. Despite increasing scientific interest, relatively few patients with bipolar disorder receive lithium therapy. Lithium is the only drug that is effective in the prophylaxis of manic, depressive, and suicidal symptoms. Lithium therapy is also associated with a variety of adverse drug reactions and the need for therapeutic drug monitoring. Numerous studies have focussed on the efficacy and safety of both lithium-monotherapy and lithium-add-on therapy. The aim of this study is to provide a systematic overview of clinical studies on lithium therapy for bipolar disorder from the last 7 years and to present a critical analysis of these studies. The results provide an up-to-date overview of the efficacy, tolerability, and safety of lithium therapy for bipolar disorder and thus improve the pharmacotherapy of bipolar disorder. A total of 59 studies were analysed using various analysis parameters. The studies were also categorised into different subgroups. These are lithium-monotherapy, lithium vs. placebo/drug, and lithium + adjunctive therapy. The majority of the studies (N = 20) had a duration of only 3-8 weeks. Only 13 studies lasted for > 40 weeks. Lithium was superior to aripiprazole, valproic acid, and quetiapine in terms of improving manic symptoms. Lithium therapy resulted in a lower relapse rate compared to valproic acid therapy. Lithium was more neuroprotectively effective than quetiapine. Fourteen of the 22 add-on therapies to lithium showed a predominantly positive effect on the treatment outcome compared to lithium-monotherapy. Only the add-on therapy with sertraline led to a higher rate of study discontinuations than lithium-monotherapy. Lithium is a safe and effective treatment option for children. However, risperidone and quetiapine were superior to lithium in some aspects, which is why these drugs should be considered as an alternative treatment option for children. Collectively, current clinical studies highlight the relevance of lithium in the treatment of bipolar disorder.

Airainer M ，Seifert R 《-》

Systematic Review and Network Meta-Analysis: Efficacy and Safety of Antipsychotics vs Antiepileptics or Lithium for Acute Mania in Children and Adolescents.

To compare second-generation antipsychotics (SGAs) and mood stabilizers (MSs) in youth with a bipolar disorder type I (BD-I) manic/mixed episode. A systematic PubMed/Embase/PsycInfo literature search until December 31, 2023, for randomized trials of SGAs or MSs in patients ≤18 years of age with BD-I manic/mixed episode was conducted. The study included a network meta-analysis comparing treatments regarding mania symptoms and mania response (co-primary outcomes), and secondary efficacy and tolerability outcomes. Eighteen studies (n = 2844, mean age = 11.74, female participants = 48.0%, mean study duration = 5.4 weeks) comparing 6 SGAs (aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone) and 4 MSs (lithium, oxcarbazepine, topiramate, and valproate) were meta-analyzed. All 6 SGAs outperformed placebo in reducing manic symptomatology, including risperidone (standardized mean difference [SMD] = -1.18, 95% CI = -0.92, -1.45, Confidence in Network Meta-Analysis [CINeMA] = moderate confidence), olanzapine (SMD = -0.77, 95% CI = -0.36, -1.18, low confidence), aripiprazole (SMD = -0.67, 95% CI = -0.33, -1.01, moderate confidence), quetiapine (SMD = -0.60, 95% CI = -0.32, -0.87, high confidence), asenapine (SMD = -0.54, 95% CI = -0.19, -0.89, moderate confidence), and ziprasidone (SMD = -0.43, 95% CI = -0.17, 0.70, low confidence), whereas no mood stabilizer outperformed placebo. Concerning mania response, risperidone (Risk ratio [RR] = 2.58, 95% CI = 1.88, 3.54, low confidence), olanzapine (RR = 2.42, 95% CI = 1.33, 3.54, very low confidence), aripiprazole (RR = 2.05, 95% CI = 1.44, 2.92, low confidence), quetiapine (RR = 1.89, 95% CI = 1.45n 2.47, moderate confidence), asenapine (RR = 1.81, 95% CI = 1.28, 2.55, very low confidence) and lithium (RR = 1.35, 95% CI = 1.00, 1.83, p = .049, very low confidence) outperformed placebo, without superiority of other MSs vs placebo. Individually, risperidone was more efficacious in reducing manic symptomatology than all other comparators, except olanzapine and topiramate, yet with low/very low confidence, and was associated with increased prolactin and glucose. Pooled together, SGAs outperformed both placebo and MSs for mania symptom reduction (SMD = -0.68, 95% CI = -0.86, -0.51 and SMD = -0.61, 95% CI = -0.82, -0.40, moderate confidence), and mania response (RR = 1.85, 95% CI = 1.53, 2.24 and RR = 1.65, 95% CI = 1.33, 2.04, moderate confidence) without differences between MSs and placebo. There were no significant treatment-placebo differences for all-cause discontinuation, whereas lithium, ziprasidone, and oxcarbazepine were associated with more adverse event-related drop-outs than placebo. Most SGAs were associated with more sedation, weight gain, and metabolic issues vs placebo and MSs. SGAs were more efficacious than placebo and MSs in treating acute mania symptoms, however, their use must be carefully weighed against important side effects.

Vita G ，Nöhles VB ，Ostuzzi G ，Barbui C ，Tedeschi F ，Heuer FH ，Keller A ，DelBello MP ，Welge JA ，Blom TJ ，Kowatch RA ，Correll CU ... -  《-》

Real-world effectiveness of pharmacological maintenance treatment of bipolar depression: a within-subject analysis in a Swedish nationwide cohort.

Long-term add-on antidepressant use for bipolar depression remains controversial. This study aimed to investigate primarily the association between psychopharmacological treatments and hospitalisation (ie, hospital admission) for bipolar depression, and secondarily the association between psychopharmacological treatments and hospitalisation for bipolar mania and somatic reasons in a registry-based national Swedish cohort. In this within-subject analysis, people diagnosed with bipolar disorder were identified from Swedish nationwide registers of inpatient and specialised outpatient care, sickness absence, and disability pension between Jan 1, 2006, and Dec 31, 2021. Data for hospitalisations, and antidepressant, antipsychotic, and mood stabiliser medication use were also retrieved from national databases. Treatment periods were modelled using the PRE2DUP method. Data were analysed with a within-individual design with stratified Cox Regression models, to eliminate selection bias when calculating adjusted hazard ratios (aHRs) and 95% CIs. The main outcome was hospitalisation due to depression and secondary outcomes were mania-related and somatic hospitalisations to address the risk-benefit ratio of antidepressant treatment. The reference was non-use of antidepressant, antipsychotic, and mood stabiliser medications. We also did head-to-head comparisons (ie, comparing different drug use periods within the same individual against each other) between medications to obtain results on comparative effectiveness while minimising confounding by indication. Ethnicity data were not available. People with related lived experience were involved in the research and writing process. The study cohort included 105 495 individuals (mean age 44·2 years, SD 18·8; 65 607 [62·2%] women and 39 888 [37·8%] men). In medication class-based analyses, a higher risk of depression-related hospitalisation was associated with the use of antidepressant only (aHR 1·25, 95% CI 1·16-1·34), antipsychotic only (1·39, 1·24-1·55), antidepressant-antipsychotic combination (1·28, 1·18-1·39), and antipsychotic-mood stabiliser combination treatment (1·13, 1·03-1·24). By contrast, use of mood stabilisers only (0·89, 0·81-0·98) was associated with lower risk. For specific monotherapies, only lithium was associated with lower depression-related hospitalisation risk (0·75, 0·67-0·85). No specific antidepressant monotherapy was associated with reduced depression-related hospitalisation, while several antidepressants and antipsychotics were related to an increased risk. In head-to-head comparisons, lithium monotherapy was associated with a superior outcome compared with antidepressant monotherapy (0·59, 0·51-0·68), antipsychotic monotherapy (0·54, 0·44-0·66), lamotrigine monotherapy (0·69, 0·53-0·91), and quetiapine monotherapy (0·54, 0·41-0·71). Lithium was associated with the lowest risk of somatic hospitalisation (0·86, 0·80-0·93) when compared with non-use of antidepressants, antipsychotics, and mood stabilisers. Finally, antidepressant-only treatment (1·22, 1·03-1·44) was associated with increased risk of mania-related hospitalisation and other monotherapies and combinations were associated with a lower risk. Since medications are typically started when depressive symptoms re-emerge, all treatments might appear less effective than they actually are when the reference is non-use of medication. Lithium was the only specific monotherapy with significantly reduced risk of depression-related hospitalisations when compared with non-use of antidepressants, antipsychotics, and mood stabilisers, and with more than 30% lower risk than any antidepressant, any antipsychotic, quetiapine, or lamotrigine monotherapy in the head-to-head analysis. Lithium was also associated with the lowest risk of somatic hospitalisation. Our findings supported the use of lithium as the mainstay of treatment in bipolar disorder. The Swedish Research Council for Health, Working Life and Welfare, FORTE (grant number 2021-01079).

Ermis C ，Taipale H ，Tanskanen A ，Vieta E ，Correll CU ，Mittendorfer-Rutz E ，Tiihonen J ... -  《-》

Factors that influence participation in physical activity for people with bipolar disorder: a synthesis of qualitative evidence.

Mental health problems contribute significantly to the overall disease burden worldwide and are major causes of disability, suicide, and ischaemic heart disease. People with bipolar disorder report lower levels of physical activity than the general population, and are at greater risk of chronic health conditions including cardiovascular disease and obesity. These contribute to poor health outcomes. Physical activity has the potential to improve quality of life and physical and mental well-being. To identify the factors that influence participation in physical activity for people diagnosed with bipolar disorder from the perspectives of service users, carers, service providers, and practitioners to help inform the design and implementation of interventions that promote physical activity. We searched MEDLINE, PsycINFO, and eight other databases to March 2021. We also contacted experts in the field, searched the grey literature, and carried out reference checking and citation searching to identify additional studies. There were no language restrictions. We included qualitative studies and mixed-methods studies with an identifiable qualitative component. We included studies that focused on the experiences and attitudes of service users, carers, service providers, and healthcare professionals towards physical activity for bipolar disorder. We extracted data using a data extraction form designed for this review. We assessed methodological limitations using a list of predefined questions. We used the "best fit" framework synthesis based on a revised version of the Health Belief Model to analyse and present the evidence. We assessed methodological limitations using the CASP Qualitative Checklist. We used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) guidance to assess our confidence in each finding. We examined each finding to identify factors to inform the practice of health and care professionals and the design and development of physical activity interventions for people with bipolar disorder. We included 12 studies involving a total of 592 participants (422 participants who contributed qualitative data to an online survey, 170 participants in qualitative research studies). Most studies explored the views and experiences of physical activity of people with experience of bipolar disorder. A number of studies also reported on personal experiences of physical activity components of lifestyle interventions. One study included views from family carers and clinicians. The majority of studies were from high-income countries, with only one study conducted in a middle-income country. Most participants were described as stable and had been living with a diagnosis of bipolar disorder for a number of years. We downgraded our confidence in several of the findings from high confidence to moderate or low confidence, as some findings were based on only small amounts of data, and the findings were based on studies from only a few countries, questioning the relevance of these findings to other settings. We also had very few perspectives of family members, other carers, or health professionals supporting people with bipolar disorder. The studies did not include any findings from service providers about their perspectives on supporting this aspect of care. There were a number of factors that limited people's ability to undertake physical activity. Shame and stigma about one's physical appearance and mental health diagnosis were discussed. Some people felt their sporting skills/competencies had been lost when they left school. Those who had been able to maintain exercise through the transition into adulthood appeared to be more likely to include physical activity in their regular routine. Physical health limits and comorbid health conditions limited activity. This included bipolar medication, being overweight, smoking, alcohol use, poor diet and sleep, and these barriers were linked to negative coping skills. Practical problems included affordability, accessibility, transport links, and the weather. Workplace or health schemes that offered discounts were viewed positively. The lack of opportunity for exercise within inpatient mental health settings was a problem. Facilitating factors included being psychologically stable and ready to adopt new lifestyle behaviours. There were positive benefits of being active outdoors and connecting with nature. Achieving balance, rhythm, and routine helped to support mood management. Fitting physical activity into a regular routine despite fluctuating mood or motivation appeared to be beneficial if practised at the right intensity and pace. Over- or under-exercising could be counterproductive and accelerate depressive or manic moods. Physical activity also helped to provide a structure to people's daily routines and could lead to other positive lifestyle benefits. Monitoring physical or other activities could be an effective way to identify potential triggers or early warning signs. Technology was helpful for some. People who had researched bipolar disorder and had developed a better understanding of the condition showed greater confidence in managing their care or providing care to others. Social support from friends/family or health professionals was an enabling factor, as was finding the right type of exercise, which for many people was walking. Other benefits included making social connections, weight loss, improved quality of life, and better mood regulation. Few people had been told of the benefits of physical activity. Better education and training of health professionals could support a more holistic approach to physical and mental well-being. Involving mental health professionals in the multidisciplinary delivery of physical activity interventions could be beneficial and improve care. Clear guidelines could help people to initiate and incorporate lifestyle changes. There is very little research focusing on factors that influence participation in physical activity in bipolar disorder. The studies we identified suggest that men and women with bipolar disorder face a range of obstacles and challenges to being active. The evidence also suggests that there are effective ways to promote managed physical activity. The research highlighted the important role that health and care settings, and professionals, can play in assessing individuals' physical health needs and how healthy lifestyles may be promoted. Based on these findings, we have provided a summary of key elements to consider for developing physical activity interventions for bipolar disorder.

McCartan CJ ，Yap J ，Best P ，Breedvelt J ，Breslin G ，Firth J ，Tully MA ，Webb P ，White C ，Gilbody S ，Churchill R ，Davidson G ... -  《Cochrane Database of Systematic Reviews》

Comparative efficacy, safety, and tolerability of pharmacotherapies for acute mania in adults: a systematic review and network meta-analysis of randomized controlled trials.

The aim of this study was to provide evidence-based recommendations regarding the efficacy, safety, and tolerability of currently used pharmacological treatments for adults with acute bipolar mania. To achieve this, we conducted a systematic review and network meta-analysis (NMA) using R software and related packages. We searched primary clinical databases until February 2023 for reports of randomized controlled trials of drug treatments and adjunctive therapies for adults with acute bipolar mania, with outcomes including efficacy (mean change from baseline to endpoint in mania rating scores), safety (clinically significant adverse events from baseline to end of treatment), and tolerability (the proportion of patients who completed the whole trial to the planned endpoint). A total of 113 studies were included in our analysis, in which 23,491 participants (50.38% males; mean age = 38.6 years; mean study duration = 3.39 weeks; mean manic baseline score = 29.37) were randomly allocated to one of 51 monotherapies, adjunctive treatments, or placebo. Our results showed that tamoxifen (mean difference, -22.31 [-25.97, -18.63], N = 2, n1 = 43, n2 = 39) and tamoxifen+ lithium or valproate (LIT/VAL) (-16.37 [-22.55, -10.25], N = 1, n1 = 20, n2 = 20) had the best and second-best clinical efficacy in adults with acute bipolar mania over the placebo. Furthermore, olanzapine, paliperidone, quetiapine, ziprasidone, risperidone, divalproex, and haloperidol were significantly better tolerated than placebo. Combination therapies of antipsychotics and LIT/VAL appeared to be more effective than their corresponding monotherapies. While pharmacotherapies were associated with specific common adverse events, we found no evidence of increased incidence of headache or depression events compared to the placebo. Overall, our NMAs provided important insights into the effectiveness, safety, and tolerability of pharmacological treatments for acute bipolar mania and can help guide treatment decisions for clinicians.

Huang W ，He S ，Liu M ，Xu J ... -  《-》