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 schizophrenia?

Moderate quality evidence suggests no significant differences in brain pH between people with schizophrenia and controls. Lower quality evidence is unclear of changes in lactate concentrations.

October 2020

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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.

October 2020

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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.

October 2020

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Dopamine is a neurotransmitter that is important for emotional and cognitive processing in the brain, particularly rewarding and pleasurable stimuli or experiences. Alterations of the dopamine system have been suggested in schizophrenia. This may be assessed as changes in levels of dopamine or its metabolites, or as changes in levels or activity of the mechanical components of the dopamine system, such as the receptors that receive dopamine, or the transporters that remove it.

What is the evidence for dopamine?

Moderate quality evidence suggests elevated striatal dopamine synthesis and release capacities and increased synaptic dopamine levels in people with schizophrenia compared to controls. The finding for dopamine synthesis was apparent in treatment-responsive and treatment-naive patients, but not in treatment-resistant patients. There were no differences in dopamine D2/3 receptor or transporter availability. Within-group variability was similar in patient and control groups for dopamine synthesis and release capacities, but there was greater variability in synaptic dopamine levels, and in dopamine D2/3 receptor and transporter availability in the patient groups.

Moderate to low quality evidence suggests an association between dopamine receptor occupancy and clinical improvement on the PANSS following treatment with antipsychotic medications. Greatest D2 receptor occupancy occurs with haloperidol (91.9%), then risperidone, olanzapine, clozapine, quetiapine, aripiprazole, ziprasidone, and then amisulpride (85%).

October 2020

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The endocannabinoid system is an endogenous biological system that regulates functions including cognition, sleep, energy metabolism, and inflammation. It modulates different neurotransmitter systems in the brain, including dopamine, glutamate, and GABA using two major lipid-based mediators, anandamide and arachidonoyl-sn-glycerol, that act through type one and type two cannabinoid receptors.

Exogenous cannabinoids, such as delta-9-tetrahydrocannabinol (THC), the main psychoactive components of cannabis, and cannabidiol (CBD), impact on the endocannabinoid system. While disturbance of the endocannabinoid system after cannabis consumption has been associated with increased risk of psychotic illness, CBD alone has shown anti-inflammatory and antipsychotic properties.

What is the evidence on endocannabinoids in schizophrenia?

Moderate to high quality evidence finds a large effect of higher concentrations of anandamide in the cerebrospinal fluid of patients, a medium-sized effect of higher concentrations of anandamide in the blood of patients, and a medium-sized effect of higher expression of type one cannabinoid receptors on peripheral immune cells of patients. There were insufficient usable data for a meta-analysis on type two cannabinoid receptors, and authors report mixed findings.

Increased severity of positive and negative symptoms was associated with decreased anandamide levels in cerebrospinal fluid and increased expression of type one and two cannabinoid receptors in peripheral blood mononuclear cells.

Poor cognitive performance was associated with decreased anandamide levels in serum and cerebrospinal fluid, increased expression of type one and two cannabinoid receptors in peripheral blood mononuclear cells, decreased expression of endocannabinoid system-synthesizing enzymes in peripheral blood mononuclear cells, and increased expression of endocannabinoid system-degrading enzymes in peripheral blood mononuclear cells.

October 2020

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GABA (gamma-aminobutyric acid) is the most important inhibitor of neurotransmitters in the central nervous system and is often dysfunctional in people with mood disorders. It has also been investigated in people with schizophrenia. GABA can be measured via peripheral levels in plasma, via central levels in cerebrospinal fluid, and in brain regions using magnetic resonance spectroscopy (MRS). Possible GABA dysfunction has led to interest in GABA-acting medications as possible adjunctive treatments for schizophrenia, such as baclofen, progabide, and sodium valproate.

What is the evidence for GABA?

Moderate quality evidence finds no differences in GABA levels in the medial frontal cortex, parietal/occipital cortex, and the striatum of the basal ganglia of people with schizophrenia compared to controls, as measured by MRS.

October 2020

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Hormones are chemical messengers secreted by the endocrine glands. Hormones travel through the bloodstream to tissues and organs, and control most of the body’s major systems including heart rate, metabolism, mood, sexual function, and growth and development.

Neuroactive steroids, including testosterone, dehydroepiandrosterone and its sulphide ester, are important for brain development as they influence synaptic connectivity and neuronal differentiation. Thyroid hormones also play a role in neurodevelopmental processes, such as differentiation of neural cells, synaptogenesis, and myelination.

Prolactin is involved in many biological functions including reproduction, pregnancy and lactation, and growth and development. Body weight is regulated by anorexigenic or appetite suppressing hormones (e.g. insulin, leptin, peptide YY, and cholecystokinin) and orexigenic or appetite stimulating hormones (e.g. neuropeptide Y, orexins, agouti-related peptide, galanin, and ghrelin).

Melatonin is involved in various biological functions including sleep regulation, circadian rhythm, immune modulation, reproduction, anti-inflammation, antioxidant, and energy metabolism. Oxytocin and vasopressin are released through the posterior pituitary gland where they regulate a range of physiological functions. They are also released in the central nervous system, influencing neurophysiological processes and behaviours, including feeding, anxiety, aggression, social recognition, and the stress/fear response to social stimuli.

What is the evidence for hormonal changes in people with schizophrenia?

Moderate quality evidence found a medium to large increase in dehydroepiandrosterone-sulfate levels in people with schizophrenia compared to controls, with testosterone elevated only in first-episode psychosis patients and in patients during an acute relapse. There were no differences in dehydroepiandrosterone levels between patients and controls.

Moderate to high quality evidence finds a small increase in thyroid-stimulating hormone in people with multi-episode schizophrenia compared to controls, with no differences in triiodothyronine or thyroxine. In people with first-episode psychosis who were drug-naïve, there was a small decrease in thyroid-stimulating hormone and a medium-sized decrease in total triiodothyronine. There was also a medium-sized increase in free thyroxine in first-episode patients.

Moderate quality evidence found a large increase in prolactin levels in antipsychotic-naïve males with schizophrenia and a medium-sized increase in antipsychotic-naïve females with schizophrenia. There was a small to medium-sized increase in leptin, particularly in chronic patients taking the second generation antipsychotics olanzapine and clozapine. There was a small to medium-sized increase in insulin levels and a trend effect of lower leptin levels in first-episode psychosis compared to controls; these effects were both significant in subgroup analyses of antipsychotic-naïve patients. The severity of negative symptoms was associated with an increased effect size for insulin. There may also be reduced adiponectin levels in patients taking clozapine or olanzapine, but no differences in other patients, including first-episode patients. There were also no differences in ghrelin, orexin, resistin, and visfatin in first-episode psychosis.

Moderate to low quality evidence finds a large decrease in oxytocin in blood serum, and a medium-sized increase in oxytocin in cerebrospinal fluid of people with schizophrenia. There were no differences in oxytocin in blood plasma. There was decreased vasopressin in blood plasma of patients with schizophrenia, with no differences in cerebrospinal fluid.

Moderate quality evidence finds reduced midnight melatonin plasma levels in people with schizophrenia compared to controls.

Unfortunately we found no systematic review specifically assessing estrogen levels in people with schizophrenia.

January 2022

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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. HPA activity can be measured by basal cortisol and ACTH levels in an unstressed or resting state. HPA activity can also be measured after a stressful stimulus (chemical or psychological). There is evidence that the HPA axis may be dysfunctional in a number of mental disorders, including schizophrenia.

What is the evidence on HPA axis functioning?

Moderate to high quality evidence suggests a small to medium-sized increase in blood cortisol levels in people with first-episode psychosis. There was a small overall increase in morning (≤10am) cortisol levels, a lower cortisol awakening response (high quality evidence), and a lower cortisol psychological stress response (moderate to low quality evidence) in people with schizophrenia compared to controls. Moderate to low quality evidence suggests increased cortisol levels are related to increased symptom severity.

There was also a lower cortisol awakening response in people with first-episode psychosis compared to controls (high quality evidence), with no differences in salivary basal cortisol levels (moderate quality evidence). For people with subclinical psychotic symptoms, there was no difference in the cortisol awakening response compared to controls (high quality evidence), but increased salivary basal cortisol levels were found (moderate quality evidence).

October 2020

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This topic summarises the available evidence on markers of earlier infection (antibodies) in adults with schizophrenia. Please also see the infectious agents as risk factors topic.

The Herpesviridae are a family of viruses which cause latent, recurring, and sometimes lifelong infections. These include Herpes simplex virus (HHV1 & 2) which causes oral and/or genital herpes; the Varicella Zoster Virus (VZV,HHV3) which causes chicken pox, shingles and rarely, encephalitis; the Epstein-Barr Virus (EBV, HHV4) and Cytomegalovirus (CMV, HHV5) which cause neurological complications; and the Herpes lymphotropic virus (HHV6), which causes roseola (skin rash and fever).

Borna Disease Virus (BDV) is the key causative component of Borna disease, a neurological syndrome primarily affecting animals (particularly horses, cattle, sheep, dogs and cats). However, human infection with BDV has been linked to some psychiatric illnesses through its neurological interactions.

Human Endogenous Retroviruses (HERVs) are fragments of ancient viral infections that became embedded within the germ cells (sperm and eggs), and are passed on to subsequent generations, making up a large proportion of the human genome. HERVs are proposed to have involvement in some autoimmune diseases.

The Human T-lymphotropic virus Type I (HTLV-1) is a human retrovirus that integrates into immune cells and is associated with an increased risk of developing cancers such as adult T-cell leukemia, myeloma, and lymphoma.

The Chlamydiaceae family of bacteria can cause a range of infections in humans, including chlamydia and trachoma (Chlyamydia trachomysis) and pneumonia (Chlamydophila pneumonia, Chlamydophila psittaci).

Toxoplasma gondii is a parasitic protozoa, hosted by domestic cats and other warm-blooded animals including humans. Toxoplasma gondii infection is usually of minor consequence to an adult but can have serious implications for a foetus.

What is the evidence for infectious agents in people with schizophrenia?

Moderate to high quality evidence suggests higher levels of markers for Human Herpesvirus-2 (small effect); Borna Disease Virus (small to medium effect); Human Endogenous Retroviruses (HERV-W: large effect); Chlamydophila pneumoniae and Chlamydophila psittaci (large effects); and Toxoplasma gondii (small to medium effect).

Moderate quality evidence indicates a medium-sized increase in antibodies to Toxoplasma gondii in people with recent-onset schizophrenia, and a small increase in antibodies to Toxoplasma gondii prior to illness onset.

October 2020

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Inflammation is caused by the immune system’s response to pathogens or tissue damage. Key cells in the innate (immediate) immune response are known as cytokines, including interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), transforming growth factors (TGF), and chemokines. C-reactive proteins, autoantibodies, and lymphocytes are also involved in the immune system response.

What is the evidence for inflammatory and immunological changes?

For cytokines levels in serum or plasma, moderate to high quality evidence found a large increase in IL-1β, a large decrease in IFN-γ, medium-sized increases in MCP-1, eotaxin-1, and IL-8, and small increases in MIP-1β, IL-6, TNF-α, and sIL-2r. There were no differences in IL-2, IL-4, IL-10, MIP-1α, fractalkine or IP-10. In cerebrospinal fluid, there were medium to large increases in IL-6 and IL-8, a large decrease in sIL-2r (from moderate to low quality evidence), and no differences in IL-1β, IL-1α, IL-2, IL-6R, MIP-1α, MCP-2, sTNFR2, TGF-β1 or TGF-β2. In patients with acute symptoms, moderate to high quality evidence found medium-sized increases in IL-6, IL-8, TGF-β, IL-1ra, and sIL-2r, and small increases in IFN-γ, IL-1β, and TNF-α. There were small to medium-sized decreases in IL-10 and IL-4, and no differences in IL-2. After treatment for acute symptoms, there were reductions in IL-1β, IL-6, sIL-6r, TNF-α and IFN-γ, and a small increase in sIL-2r. There were no differences post-treatment in IL-12, IL-2, IL-17, TGF-β, IL-10, or IL-4. In first-episode psychosis patients, moderate to high quality evidence found large increases in IL-1β, IL-6, and sIL-2r, medium-sized increases in TGF-β and MCP-1, and small increases in TNF-α, IL-1ra, IL-12, IFN-γ, and IL-10. There was a medium-sized decrease in IL-4, and no differences in IL-2, IL-8, IL-17 or IL-18. After treatment for first-episode psychosis, there were reductions in IL-1β, IL-6 and IL-4. In antipsychotic-naïve patients, moderate to high quality evidence found medium-sized increases in IFN-y, IL-17, IL-6, sIL-2r, TGF-β, and TNF-α. There were no differences in IL-10, IL-1β, IL-2, IL-4, or IL-8. After treatment, moderate to low quality evidence found medium-sized reductions in IL-2 and IL-6; there may also be reductions in IL-1β, IFN-y, and IL-17. In people at high-risk of psychosis (clinical or genetic), there was a small increase in IL-6 and a medium-sized decrease in IL-1β.

For autoantibodies in serum or plasma, moderate to high quality evidence found a medium-sized increase in cardiolipin IgM and a small increase in cardiolipin IgG. There were increases in N-methyl-D-aspartate, nerve growth factor, antinuclear antibodies, DNA, dopamine receptor, gliadin IgA, heat shock protein 60, lupus anticoagulant, rheumatoid factor, smith, thyroglobulin, thyroid microsomal, and tissue transglutaminase. Moderate to low quality evidence also finds increases in cold agglutinin, histone/anti-histone IgG, nucleoprotein, phospholipid, and serotonin. Moderate quality evidence found an increase in anti-gliadin IgG and IgA (medium-sized effects), anti-TTG2 IgA (large effects) and other wheat protein antibodies (small effects for anti-gluten, anti-wheat and non-specified anti-gliadin). In cerebrospinal fluid, moderate to low quality evidence found medium-sized increases in IgG ratio and a medium-sized decrease in IgG/albumin ratio, with no differences in CSF IgG or IgG index. In first-episode psychosis patients, moderate quality evidence found increases in cardiolipin IgG and N-methyl-D-aspartate.

For leukocytes levels in schizophrenia patients’ serum or plasma, moderate to high quality evidence finds medium-sized increases in total white blood cell count, monocytes, and neutrophils in people with schizophrenia or first-episode psychosis compared to controls, and medium-sized increases in neutrophil-to-lymphocyte and monocyte-lymphocyte ratios. There was a medium-sized decrease in T-lymphocytes (CD3 percentage) in stable medicated patients. In antipsychotic-naïve patients, there was a medium-sized decrease in T-lymphocytes (CD3 percentage), a medium to large increase in T-lymphocytes (CD3), a large increase in T-helper lymphocytes (CD4), and a medium-sized increase in T-helper/suppressor lymphocyte ratio (CD4/CD8). In patients with acute symptoms, there was a medium-sized decreases in T-lymphocytes (CD3 percentage), increases in total white blood cell count, T-helper lymphocytes (CD4 percentage), natural killer cells (CD56 absolute), and an increase in T-helper / suppressor lymphocyte ratio (CD4/CD8) Moderate to low quality evidence also found a large increase in natural killer cells (CD56 percentage) and no differences in total lymphocyte count. After treatment, moderate to high quality evidence finds a medium-sized increase in T-suppressor/cytotoxic lymphocytes (CD8 percentage), natural killer cells (CD56 absolute), and T-lymphocytes (CD3 percentage), a small to medium effect of increased T-suppressor/cytotoxic lymphocytes (CD8 absolute), and a small effect of decreased T-helper/suppressor lymphocyte ratio (CD4/CD8).

For C-reactive protein levels in serum or plasma, moderate to high quality evidence finds a medium-sized increase in patients. This effect was largest in those who were drug-naïve or drug-free, in those on first than second generation antipsychotics, and in those with more severe positive symptoms.

For tryptophan catabolites, there was a medium-sized increase in kynurenic acid in people with schizophrenia, particularly in cerebrospinal fluid, brain tissue, in older patients, in medicated patients, and in male patients. There was also a medium to large increase in kynurenine in the CSF of patients compared to controls.

For translocator protein levels in serum or plasma, moderate quality evidence found a small to medium-sized increase in people with schizophrenia when measured using binding potential, but not when measured using volume of distribution. There was also a large increase in homocysteine levels in first-episode patients.

October 2020

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