Maintenance of an adequate pH balance in all tissues and organs is important for good health. Decreased levels of brain pH are associated with increased levels of lactate, and vise versa. Lactate is an acidic source of fuel that is constantly generated and consumed in the brain. An imbalance in pH, particularly a shift toward high acidity, is associated with numerous physical and mental disorders.

What is the evidence for brain pH and lactate in people with bipolar disorder?

Moderate to low quality evidence suggests increased brain lactate levels in people with bipolar disorder compared to controls.

Low quality evidence is unclear of pH differences.

December 2021

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Cellular calcium concentrations are potentially disrupted in bipolar disorder. Intracellular calcium has a fundamental role in neuronal excitation, transmitter synthesis and release, and synaptic function and plasticity, and disruptions to these functions can affect mood. Cellular calcium levels may be altered by lithium and other psychotropic drugs.

What is the evidence for calcium alterations in people with bipolar disorder?

Moderate to high quality evidence suggests a medium-sized effect of increased intracellular calcium in people with bipolar disorder compared to controls. This effect was apparent in platelets and lymphocytes, in patients with mania or depression symptoms but not during euthymia, and in drug naïve and drug free patients.

December 2021

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The electron transport chain involves a series of complexes that transfer electrons from donors to acceptors via reduction-oxidation reactions. Complex I is the first and largest enzyme in the electron transport chain, while complex IV is the last enzyme in the chain. Both of these complexes have been found to be altered in psychiatric disorders. The remaining complexes have been studied to a lesser degree.

What is the evidence for complex I and IV alterations in people with bipolar disorder?

Moderate quality evidence suggests small to medium-sized effects of lower complex I levels in bipolar disorder in subunits NDUFS1 in the cerebellum, striatum, and frontal cortex, with complex I subunit NDUFS7 also reduced in the frontal cortex. There were no significant changes in complex IV levels.

December 2021

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Pending enough primary studies, we invite reviews on this topic to be conducted. Alternatively, we will endeavour to conduct our own review to fill this gap in the Library.

December 2021

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Gamma-aminobutyric acid (GABA) is one of the most important inhibitors of neurotransmitters in the central nervous system. GABA is thought to be dysfunctional in people with depression and other affective disorders, with reduced levels found in human postmortem studies. GABA can also be measured via peripheral levels in plasma, via central levels in cerebrospinal fluid, and in particular brain regions using proton magnetic resonance spectroscopy.

What is the evidence for changes in GABA levels in people with bipolar disorder?

Moderate to high quality evidence shows a medium-sized effect of reduced levels of GABA in plasma of people with bipolar disorder during a depression phase when compared to controls without bipolar disorder. Moderate quality evidence also suggests a medium-sized effect of reduced levels of GABA in plasma during a euthymic phase. There were no differences in GABA levels between bipolar disorder and controls when GABA was measured in cerebrospinal fluid or with magnetic resonance spectroscopy.

Compared to people with unipolar depression, people with bipolar depression showed higher GABA levels in cerebrospinal fluid, with no differences in plasma levels.

December 2021

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Gut microbiota involves a dynamic community of microorganisms that inhabits the human body, and changes in response to intrinsic and extrinsic factors. This community includes bacteria, archaea, microbial eukaryotes, fungi, and viruses, and so it is critical in maintaining healthy physiology, Disruption to it has been shown to have a pivotal role across a range of medical conditions including inflammatory bowel disease, metabolic diseases, cancer, and chronic pulmonary diseases.

Studies are now investigating how the gut microbiota can influence the brain. The mechanisms by which intestinal microorganisms could be linked to emotional and cognitive functions of the brain are not fully understood, but they are thought to include the vagus nerve, gut hormone signalling, the immune system, tryptophanmetabolism, and microbial metabolites such as short-chain fatty acids.

What is the evidence for changes in gut microbiota in people with bipolar disorder?

High quality evidence finds increased proxy biomarkers of gut-microbial diversity (gut dysbiosis), in particular antibodies against bacterial endotoxins and sCD14, in people with bipolar disorder relative to controls. Lower quality evidence finds the proxy biomarker zonula may also be increased in bipolar disorder. There was overall reduced gut biodiversity in medicated versus non-medicated patients.

Moderate to low quality evidence finds the family Ruminococcaceae, genus Faecalibacterium, and species Faecalibacterium prausnitzii may be reduced in bipolar disorder, while genera Bacteroides or Bacteroides-Prevotella group species may be elevated compared to controls.

December 2021

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Homocysteine is a sulphur-containing amino acid that is derived from the diet. As folate is needed to metabolise homocysteine, and vitamin B12 helps keep homocysteine levels low, people who are deficient in these vitamins may have increased levels of homocysteine. Homocysteine is involved in a large number of processes in the central nervous system, including alteration in glutamatergic neurotransmission which has been implicated in many psychiatric disorders. Increased homocysteine can also promote vasulotoxic effects which contribute to a range of medical disorders, including cardiovascular disease; a common comorbid condition in people with bipolar disorder.

What is the evidence for changes in homocysteine in people with bipolar disorder?

High quality evidence suggests a large effect of increased homocysteine in people with bipolar disorder during a mania phase, and a small effect during euthymia when compared to controls without bipolar disorder. The effect during euthymia was not influenced by age or sex, and there were insufficient studies to assess the effect of age or sex during mania.

Only one study assessed homocysteine levels during bipolar depression, and found no differences between people with bipolar disorder and controls.

December 2021

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Stress is defined as a threat to the body’s ability to regulate internal processes following exposure to an adverse event. People adapt physiologically and behaviourally in response to stress in order to re-establish internal balance. The biological response to stress is mediated through the HPA axis and the sympathetic nervous system. This is achieved through the release of cortisol and adrenocorticotropin hormone (ACTH). Altered HPA axis activity can result in prolonged exposure to cortisol or ACTH which can be detrimental to physical and psychological health.

What is the evidence for HPA axis anomalies?

High quality evidence suggests a small to medium-sized increase in awakening and post-dexamethasone cortisol levels in people with bipolar disorders compared to controls. Moderate to high quality evidence suggests morning, nighttime and 12-24hour cortisol levels may also be increased. The manic phase of the illness was associated with the largest effect sizes, while the use of antipsychotics was associated smaller effect sizes. Radioimmunoassay method of measurement and older age were associated with trend effects for larger effect sizes.

Moderate quality evidence suggests ACTH, but not corticotropin-releasing hormone, is also increased in people with bipolar disorder.

There were no differences in morning cortisol levels between people with bipolar disorder or schizophrenia.

December 2021

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Several markers of infectious agents have been investigated in people with mental disorders due to their neurological interactions. Any association between these agents and risk of subsequent bipolar disorder remains unclear.

Infectious agents include Toxoplasma gondii and Borna Disease Virus. Toxoplasma gondii is a parasitic protozoa usually hosted by domestic cats and other warm-blooded animals, including humans. Borna Disease Virus is the key causative component of Borna disease, a neurological syndrome primarily affecting animals, but sometimes humans.

What is the evidence for markers of infectious agents in people with bipolar disorder?

Moderate to high quality evidence suggests a small effect of increased markers for Borna disease virus and for Toxoplasma gondii in people with bipolar disorder compared to controls. Increases in Toxoplasma gondii antibodies were particularly apparent in people with bipolar disorder who were under 40 years of age. There were no differences in herpes viruses antibodies between patients and controls.

December 2021

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Inflammation is caused by the immune system’s response to pathogens or tissue damage. The immune system is the body’s first line of defence and predominantly uses proteins called cytokines that are secreted by immune cells and act to allow cell-to-cell communication. Cytokines include interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), transforming growth factors (TGF), adipokines, and chemokines. C-reactive protein (CRP) is released by the body during inflammation, with increased CRP suggestive of infection and chronic inflammatory conditions such as cardiovascular disease, diabetes, and metabolic dysfunction.

What is the evidence for inflammation and immune system anomalies in bipolar disorder?

Moderate to high quality evidence found medium to large increases in CRP levels in people with bipolar disorder during a manic phase, and medium-sized increases during a depressive phase, when compared to controls. These effects were increased slightly in studies that matched controls for age and body mass index (in depression only), in studies of drug-free patients (in depression only) and in studies using serum rather than plasma measures (in mania only). These effects were not related to symptom severity but were decreased slightly after resolution of the index mood episode.

Moderate quality evidence found IL-8, monocyte-chemoattractant protein-1 (MCP-1), eotaxin-1, and interferon-γ-induced protein 10 (IP-10) were elevated in people with bipolar disorder compared to controls. The elevated levels of IL-8 and MCP-1 appeared only during the depressive phase, while the elevated levels of IP-10 were present only during euthymia. The analysis of eotaxin-1 levels was mainly based on studies of euthymic patients. Small to medium-sized increases were also found in IL-4, IL-6, IL-10. sIL-2R, sIL-6R, TNF-a and sTNFR1 in serum or plasma of people with bipolar disorder. No differences were found in IL-2, IFN-y, C-C motif ligand 2, or IL-1β in serum or plasma. However, small increases were found in IL-1β in cerebrospinal fluid of patients. In separate assessment of acutely ill patients, there were medium to large increases in blood IL-1RA, sIL-2R, IL-6, and TNF-α, with no increases in sIL-6R or IL-10. In chronic patients during euthymia, there were small to medium-sized increases in sIL-2R, sIL-6R, IL-4, sTNF-R1, IL-1β, IL-6, and IL-10, with no increases in IL-2, TNF-α, or IFN-γ.

Moderate to high quality evidence found medium-sized increases in neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) levels in people with bipolar disorder, particularly during a manic phase. Increasing age and male gender were associated with larger effect sizes for NLR but not for PLR. There were small to medium-sized reductions in tryptophan, kynurenine, xanthurenic acid, and kynurenic acid. However, increased kynurenic acid was found in cerebrospinal fluid. The kynurenic acid to kynurenine ratio and the kynurenic acid to quinolinic acid ratio were reduced in bipolar disorder. People in a manic episode had the greatest reductions in tryptophan, while kynurenic acid levels were more reduced in a depressive phase. There were similar reductions in kynurenine in depression and mania phases. Finally, adiponectin levels were significantly higher in bipolar patients during euthymia but may be lower than controls during depression.

December 2021

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