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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Smooth pursuit eye movement is a visual tracking reflex evoked by a smoothly moving target, usually elicited by stimuli presented on a computer monitor. The aim of the smooth pursuit reflex is to maintain the image of the moving target on the fovea, the region of the retina with the highest density of photoreceptors. The neural pathways involved in generating smooth pursuit are a complex network from the cortical visual pathways through to the brainstem ocular motor nuclei (III, IV, and VI), and consequently, an alteration in smooth pursuit performance may not in itself shed light on the actual nature of the dysfunction.

Components of smooth pursuit which are quantified include gain in the open and closed loops, as well as rates and amplitudes for both intrusive and anticipatory saccades (fast eye movements). Closed loop gain is an index of temporal synchrony of the eye and the target during pursuit, and is estimated as the ratio of the respective velocities. Open loop gain is the average acceleration during the initiation of pursuit, in the first 100ms. During this period there is no visual feedback and so the movement is solely a result of visual motion signal input. Spontaneous saccades can occur during smooth pursuit: these can either be anticipatory saccades that facilitate movement towards the target, such as reflexive visually guided saccades; or intrusive saccades, which interrupt the smooth tracking of the target, such as catch-up saccades, back-up saccades, and memory-guided saccades.

What is the evidence for eye movement dysfunction in people with bipolar disorder?

Moderate to low quality evidence suggests reaction time and error rates in antisaccade tasks are increased, and accuracy is decreased in people with bipolar disorder compared to controls. People with major depression also show increased reaction time and error rates, with no differences in accuracy. On predictive tasks, people with bipolar disorder perform similarly to controls, while people with major depression show reduced accuracy and increased correction rates. On smooth pursuit tasks, both people with bipolar disorder and depression show less pursuit gain and more initial eye accelerations and catch-up saccades. On fixation tasks, people with bipolar disorder showed more inhibition error than controls.

December 2021

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fMRI measures blood flow to determine activation and deactivation of the specific brain regions associated with particular tasks.

What is the evidence for fMRI findings in people with bipolar disorder?

Compared to controls, moderate quality evidence finds decreased activation in adults with bipolar disorder in the inferior frontal gyrus during cognitive and emotion tasks, and during a mania phase. There were also decreases in the lingual gyrus during cognitive tasks and euthymia, and in the putamen during cognitive tasks. There were increases in activation in the medial temporal lobe, putamen, pallidum, and caudate during cognitive tasks.

In children and adolescents with bipolar disorder, there was decreased activation in the right ventrolateral prefrontal cortex, right dorsolateral prefrontal cortex, right superior frontal gyrus, right dorsal cingulate cortex, and right dorsal striatum compared to age-matched controls. There was increased activation in the right amygdala, right limbic lobe, right parahippocampal gyrus, right medial prefrontal cortex, right subgenual cingulate cortex, right somatosensory association cortex, left ventral striatum, left ventrolateral prefrontal cortex, left cerebellum, left lentiform nucleus, putamen, and lateral globus pallidus.

There was increased activation in children with a parent with bipolar disorder in the right dorsolateral prefrontal cortex, right insula, right inferior parietal lobule, and left cerebellum compared to age-matched controls. Compared to children and adolescents with a parent with bipolar disorder, there was decreased activation in children and adolescents with bipolar disorder in the right dorsolateral prefrontal cortex, right insula, and left cerebellum.

Moderate to low quality evidence suggests more hypoactivation in the putamen of people with bipolar disorder than in the putamen of people with major depressive disorder, post-traumatic stress disorder, or an anxiety disorder. There were similar levels of hypoactivation across diagnoses in the prefrontal/insula and the inferior parietal clusters and similar levels of hyperactivation in the left amygdala/parahippocampal gyrus, the left thalamus, and the perigenual/dorsal anterior cingulate cortex.

During facial affect processing tasks

Compared to controls, moderate quality evidence suggests decreased activation in people with bipolar disorder in the bilateral ventrolateral prefrontal cortex, and increased activation in bilateral parahippocampal gyrus (including the amygdala), left putamen and left pulvinar. With fear-face stimuli, people with bipolar disorder showed decreased activation in bilateral inferior frontal gyri and the left anterior cingulated gyrus, and increased activation in the left parahippocampal gyrus, left putamen, and left pulvinar thalamus. With happy-face stimuli, people with bipolar disorder showed decreased activation in the right anterior cingulated gyrus and increased activation in bilateral caudate and the left parahippocampal gyrus.

Compared to age-matched controls, moderate to low quality evidence suggests decreased activation in children or adolescents in the left middle occipital gyrus, and the right inferior frontal gyrus, with increased activity in the right amygdala, right parahippocampal gyrus, left inferior frontal gyrus, and left putamen.

Compared to adults with bipolar disorder, moderate to low quality evidence suggests increased activation in children or adolescents with bipolar disorder in the right amygdala.

Compared to people with major depression, moderate quality evidence suggests decreased activation in people with bipolar disorder in the dorsal anterior cingulate gyrus, and increased activation in the parahippocampal gyrus (including the amygdala), bilateral ventral anterior cingulate gyri, and left pulvinar.

Compared to people with schizophrenia moderate quality evidence suggests decreased activation in people with bipolar disorder in bilateral occipital cunei, and increased activation in the left thalamus pulvinar.

During cognitive control tasks (perceived task difficulty and effort)

Compared to controls, moderate quality evidence suggests decreased activation in people with bipolar disorder in the right inferior frontal gyrus, the right caudate nucleus, the right angular gyrus, the left inferior temporal gyrus, the left inferior frontal gyrus and the left posterior cingulate gyrus. There was also increased activation in the left precentral, left superior frontal, and the right superior temporal gyrus of patients.

During executive functioning tasks

Compared to controls, moderate quality evidence suggests reduced activation in the striatum, supplementary motor area, precentral gyrus, left cerebral hemisphere, and left cerebellum and more activation in the left gyrus rectus and right middle temporal gyrus. During euthymia there was reduced activation in the striatum, left supplementary motor area, and right inferior parietal gyrus, and more activation in the left gyrus rectus, and right middle and superior temporal lobe. People with bipolar I disorder showed hypoactivation in the putamen, insula, amygdala, supplementary motor area, and left caudate nucleus, and hyperactivation the right superior temporal lobe and left superior frontal gyrus.

During response inhibition tasks

Compared to controls, moderate quality evidence suggests decreased activation in the right inferior frontal gyrus, left lentiform nucleus, left precuneus, and left postcentral gyrus, with no evidence of increased activation. During euthymia, patients showed decreased activation in the striatum, left supplementary motor area, right anterior cingulate cortex, left lentiform nucleus/putamen, right inferior frontal gyrus, left inferior parietal lobule, right inferior parietal lobule, and the left precuneus. Euthymic patients showed increased activation in the left superior temporal gyrus, right middle frontal gyrus, and in rostral parts of the right inferior frontal gyrus. During mania, patients showed decreased activation in the right inferior frontal gyrus, left medial frontal gyrus, and the anterior cingulate cortex, and increased activation in the right insula and bilateral basal ganglia

During attention tasks

Compared to age-matched controls, moderate quality evidence suggests decreased activation in children and adolescents with bipolar disorder in the right anterior cingulate cortex, right limbic areas (including the amygdala), right dorsolateral prefrontal cortex, right lentiform nucleus and right globus pallidus. Increased activation was found in the right middle frontal gyrus, left insula, and bilateral ventrolateral prefrontal cortex of patients.

During working memory tasks

Compared to controls, moderate quality evidence suggests decreased activation in the left precentral gyrus and left cerebellum, and increased activation in the left gyrus rectus, and right middle and superior temporal lobe. People with bipolar disorder in the euthymic state showed hypoactivation in the left precuneus, right inferior occipital gyrus, and dorsolateral prefrontal cortex, and hyperactivation in the left ventromedial prefrontal cortex and right superior temporal gyrus.

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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