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The aim of this chapter is to provide an overview of various perspectives of the aberrant immune system in bipolar disorder (BD) in light of the search for new therapy options. The chapter follows the macrophage-T cell theory of mood disorders formulated in the 1990’s, and the theory was founded on high serum levels of pro-inflammatory and T cell regulating cytokines in mood disorder patients. Besides higher levels of pro-inflammatory cytokines depending on the episodic activity of the disorder, BD patients also show a higher prevalence of auto-immune diseases and minor numerical T cell deficiencies. These minor T cell deficiencies go together with a proneness of T helper subsets (such as Th17 cells) to overreact, for T regulatory cells to be deficient, and for monocytes/macrophages to react pro-inflammatory. These various aberrant immune reactions are thought to have their effect on BD illness progression, via alterations in the tryptophan catabolism and via dysfunction of glial cells, such as the microglia and oligodendrocytes. Therapeutic immune interventions in BD have thus far mainly been focused on non-steroidal anti-inflammatory drugs (NSAID), omega-3-fatty acids and N- acetylcysteine (NAC). More recently, scientific attention has been directed to the gut-brain-axis, with emphasis on increased intestinal permeability of immune stimulants and microbiome disturbances driving the inflammatory dysregulation. Based on the research that is becoming more extensive and global, this field seems promising for potential treatment options in this severe mental illness.

Background: The clinical effects of smartphone-based interventions for bipolar disorder (BD) have yet to be established. Objectives: To examine the efficacy of smartphone-based interventions in BD and how the included studies reported user-engagement indicators. Methods: We conducted a systematic search on January 24, 2022, in PubMed, Scopus, Embase, APA PsycINFO, and Web of Science. We used random-effects meta-analysis to calculate the standardized difference (Hedges’ g) in pre-post change scores between smartphone intervention and control conditions. The study was pre-registered with PROSPERO (CRD42021226668). Results: The literature search identified 6034 studies. Thirteen articles fulfilled the selection criteria. We included seven RCTs and performed meta-analyses comparing the pre-post change in depressive and (hypo)manic symptom severity, functioning, quality of life, and perceived stress between smartphone interventions and control conditions. There was significant heterogeneity among studies and no meta-analysis reached statistical significance. Results were also inconclusive regarding affective relapses and psychiatric readmissions. All studies reported positive user-engagement indicators. Conclusion: We did not find evidence to support that smartphone interventions may reduce the severity of depressive or manic symptoms in BD. The high heterogeneity of studies supports the need for expert consensus to establish ideally how studies should be designed and the use of more sensitive outcomes, such as affective relapses and psychiatric hospitalizations, as well as the quantification of mood instability. The ISBD Big Data Task Force provides preliminary recommendations to reduce the heterogeneity and achieve more valid evidence in the field.

Schizophrenia and bipolar disorder are severe mental disorders, both placing a significant burden on individuals’ wellbeing and global health generally. The complex interaction of multiple mechanisms, underlying these disorders, still needs further elucidation. Increased activation of components of the immune system may be involved, including alterations in intestinal permeability and the gut microbiome. Probiotics, defined as living microorganisms conferring health benefits to the host when administered in adequate amounts, may have some supportive therapeutic effect in psychiatric disorders. The authors in this chapter provide an overview of this emerging research field and summarize both the published microbiome studies in schizophrenia and bipolar disorder and the current clinical research using probiotic supplementation in patients diagnosed with these disorders. The current data indicate that there are differences in the microbiome in schizophrenia and bipolar disorder patients as compared with healthy controls. Part of these differences may be induced by medication use, others by smoking and other lifestyle factors. Correlations between microbiome quantification and symptom severity have been observed in cross-sectional studies, but unfortunately, there are nor replicated findings so far. Probiotic supplementation was shown not only to alleviate gastrointestinal complaints but also reduce symptom severity, rehospitalization rates, and cognitive improvement in some studies. Replication of improvement of cognition is needed. In conclusion, differences in microbiome have been shown in both SCZ and bipolar disorder in comparison to healthy controls. Evidence that probiotics can improve psychiatric functioning is still very limited.

The aim of this chapter is to provide an overview of various perspectives of the aberrant immune system in bipolar disorder (BD) in light of the search for new therapy options. The chapter follows the macrophage-T cell theory of mood disorders formulated in the 1990’s, and the theory was founded on high serum levels of pro-inflammatory and T cell regulating cytokines in mood disorder patients. Besides higher levels of pro-inflammatory cytokines depending on the episodic activity of the disorder, BD patients also show a higher prevalence of auto-immune diseases and minor numerical T cell deficiencies. These minor T cell deficiencies go together with a proneness of T helper subsets (such as Th17 cells) to overreact, for T regulatory cells to be deficient, and for monocytes/macrophages to react pro-inflammatory. These various aberrant immune reactions are thought to have their effect on BD illness progression, via alterations in the tryptophan catabolism and via dysfunction of glial cells, such as the microglia and oligodendrocytes. Therapeutic immune interventions in BD have thus far mainly been focused on non-steroidal anti-inflammatory drugs (NSAID), omega-3-fatty acids and N- acetylcysteine (NAC). More recently, scientific attention has been directed to the gut-brain-axis, with emphasis on increased intestinal permeability of immune stimulants and microbiome disturbances driving the inflammatory dysregulation. Based on the research that is becoming more extensive and global, this field seems promising for potential treatment options in this severe mental illness.