The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

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Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

Despite its virtually universal acceptance as the gold standard in treating bipolar disorder, prescription rates for lithium have been decreasing recently. Although this observation is multifactorial, one obvious potential contributor is the side effect and toxicity burden associated with lithium. Additionally, side effect concerns assuredly play some role in lithium nonadherence. This paper summarizes the knowledge base on side effects and toxicity and suggests optimal management of these problems. Thirst and excessive urination, nausea and diarrhea and tremor are rather common side effects that are typically no more than annoying even though they are rather prevalent. A simple set of management strategies that involve the timing of the lithium dose, minimizing lithium levels within the therapeutic range and, in some situations, the prescription of side effect antidotes will minimize the side effect burden for patients. In contrast, weight gain and cognitive impairment from lithium tend to be more distressing to patients, more difficult to manage and more likely to be associated with lithium nonadherence. Lithium has adverse effects on the kidneys, thyroid gland and parathyroid glands, necessitating monitoring of these organ functions through periodic blood tests. In most cases, lithium-associated renal effects are relatively mild. A small but measurable percentage of lithium-treated patients will show progressive renal impairment. Infrequently, lithium will need to be discontinued because of the progressive renal insufficiency. Lithium-induced hypothyroidism is relatively common but easily diagnosed and treated. Hyperparathyroidism from lithium is a relatively more recently recognized phenomenon.

https://link.springer.com/content/pdf/10.1186%2Fs40345-016-0068-y.pdf

Lithium side effects and toxicity: prevalence and management strategies.

Bipolar disorder (BD) is strongly associated with immune dysfunction. Replicated epidemiological studies have demonstrated that BD has high rates of inflammatory medical comorbidities, including autoimmune disorders, chronic infections, cardiovascular disease and metabolic disorders. Cytokine studies have demonstrated that BD is associated with chronic low-grade inflammation with further increases in pro-inflammatory cytokine levels during mood episodes. Several mechanisms have been identified to explain the bidirectional relationship between BD and immune dysfunction. Key mechanisms include cytokine-induced monoamine changes, increased oxidative stress, pathological microglial over-activation, hypothalamic-pituitary-adrenal (HPA) axis over-activation, alterations of the microbiome-gut-brain axis and sleep-related immune changes. The inflammatory-mood pathway presents several potential novel targets in the treatment of BD. Several proof-of-concept clinical trials have shown a positive effect of anti-inflammatory agents in the treatment of BD; however, further research is needed to determine the clinical utility of these treatments. Immune dysfunction is likely to only play a role in a subset of BD patients and as such, future clinical trials should also strive to identify which specific group(s) of BD patients may benefit from anti-inflammatory treatments.

https://www.mdpi.com/2076-3425/7/11/144/pdf

Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

OBJECTIVE: Inflammation has been implicated in the risk, pathophysiology, and progression of mood disorders and, as such, has become a target of interest in the treatment of bipolar disorder (BD). Therefore, the objective of the current qualitative and quantitative review was to determine the overall antidepressant effect of adjunctive anti-inflammatory agents in the treatment of bipolar depression. METHODS: Completed and ongoing clinical trials of anti-inflammatory agents for BD published prior to 15 May 15 2015 were identified through searching the PubMed, Embase, PsychINFO, and Clinicaltrials.gov databases. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with standard therapy alone. RESULTS: Ten RCTs were identified for qualitative review. Eight RCTs (n = 312) assessing adjunctive nonsteroidal anti-inflammatory drugs (n = 53), omega-3 polyunsaturated fatty acids (n = 140), N-acetylcysteine (n = 76), and pioglitazone (n = 44) in the treatment of BD met the inclusion criteria for quantitative analysis. The overall effect size of adjunctive anti-inflammatory agents on depressive symptoms was -0.40 (95% confidence interval -0.14 to -0.65, p = 0.002), indicative of a moderate and statistically significant antidepressant effect. The heterogeneity of the pooled sample was low (I² = 14%, p = 0.32). No manic/hypomanic induction or significant treatment-emergent adverse events were reported. CONCLUSIONS: Overall, a moderate antidepressant effect was observed for adjunctive anti-inflammatory agents compared with conventional therapy alone in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.

Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.

Bipolar Disorder and Inflammation.

Objectives
The aim of the present study was to assess the effect of aspirin on lithium-related sexual dysfunction in men with stable bipolar affective disorder (BAD).

Methods
In a randomized, double-blind, placebo-controlled study, 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240 mg/day) or placebo for six weeks. The International Index for Erectile Function (IIEF) was used to assess sexual symptoms at baseline, Week 3, and Week 6. Depressive and mania symptoms and plasma lithium concentrations were assessed at baseline and Week 6. Side effects were assessed using a checklist.

Results
Thirty patients (15/group) completed the study. Baseline and endpoint lithium concentrations and mania and depressive symptoms did not differ significantly between the two groups. Significant effects of time × treatment interaction were observed for total score [Greenhouse–Geisser: F(1.410,39.466) = 6.084, p = 0.010] and erectile function [Greenhouse–Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total (63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline, p-values = 0.002 and 0.001, respectively). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change [χ2(1) = 10.800, p = 0.001]. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups.

Conclusion
Aspirin effectively improves lithium-related sexual dysfunction in men with stable BAD.

Morteza Emami-Parsa

Papers

Aspirin for treatment of lithium-associated sexual dysfunction in men: randomized double-blind placebo-controlled study.