Epigenetics of neurodegenerative diseases

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https://en.wikipedia.org/wiki/Epigenetics_of_neurodegenerative_diseases 

Para-sagittal MRI of the head in a patient with benign familial macrocephaly

Neurodegenerative diseases are a heterogeneous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased signal transduction and in some cases even neuronal death. Peripheral nervous system diseases may be further categorized by the type of nerve cell (motor, sensory, or both) affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.

Neurodengenerative diseases of motor neurons can cause degeneration of motor neurons involved in voluntary muscle control such as muscle contraction and relaxation. This article will cover the epigenetics and treatment of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). See the Motor Neuron Fact Sheet for details regarding other motor neuron diseases. Neurodegenerative diseases of the central nervous system can affect the brain and spinal cord. This article will cover the epigenetics and treatment of Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). These diseases are characterized by chronic and progressive neuronal dysfunction, sometimes leading to behavioral abnormalities (as with PD), and, ultimately, neuronal death, resulting in dementia.

Neurodegenerative diseases of sensory neurons can cause degeneration of sensory neurons involved in transmitting sensory information such as hearing and seeing. The main group of sensory neuron diseases are hereditary sensory and autonomic neuropathies (HSAN) such as HSAN I, HSAN II, and Charcot-Marie-Tooth Type 2B (CMT2B). Though some sensory neuron diseases are recognized as neurodegenerative, epigenetic factors have not yet been clarified in the molecular pathology.

Epigenetics and epigenetic drugs

The nucleus of a human cell showing the location of euchromatin

The term epigenetics refers to three levels of gene regulation: (1) DNA methylation, (2) histone modifications, and (3) non-coding RNA (ncRNA) function. Briefly, histone-mediated transcriptional control occurs by the wrapping of DNA around a histone core. This DNA-histone structure is called a nucleosome; the more tightly the DNA is bound by the nucleosome, and the more tightly a string of nucleosomes are compressed among each other, the greater the repressive effect on transcription of genes in the DNA sequences near or wrapped around the histones, and vice versa (i.e. looser DNA binding and relaxed compaction leads to a comparatively derepressed state, resulting in facultative heterochromatin or, even further derepressed, euchromatin). At its most repressive state, involving many folds into itself and other scaffolding proteins, DNA-histone structures form constitutive heterochromatin. This chromatin structure is mediated by these three levels of gene regulation. The most relevant epigenetic modifications to treatment of neurodegenerative diseases are DNA methylation and histone protein modifications via methylation or acetylation.

• In mammals, methylation occurs on DNA and histone proteins. DNA methylation occurs on the cytosine of CpG dinucleotides in the genomic sequence, and protein methylation occurs on the amino termini of the core histone proteins – most commonly on lysine residues. CpG refers to a dinucleotide composed of a cytosine deoxynucleotide immediately adjacent to a guanine deoxynucleotide. A cluster of CpG dinucleotides clustered together is called a CpG island, and in mammals, these CpG islands are one of the major classes of gene promoters, onto or around which transcription factors may bind and transcription can begin. Methylation of CpG dinucleotides and/or islands within gene promoters is associated with transcriptional repression via interference of transcription factor binding and recruitment of transcriptional repressors with methyl binding domains. Methylation of intragenic regions is associated with increased transcription. The group of enzymes responsible for addition of methyl groups to DNA are called DNA methyltransferases (DNMTs). The enzyme responsible for removal of methyl group are called DNA demethylases. The effects of histone methylation are residue dependent (e.g. which amino acid on which histone tail is methylated) therefore the resulting transcriptional activity and chromatin regulation can vary. The enzymes responsible for the addition of methyl groups to histones are called histone methyltransferases (HMTs). The enzymes responsible for the removal of methyl groups from histone are histone demethylases.
• Acetylation occurs on the lysine residues found at the amino N-terminal of histone tails. Histone acetylation is most commonly associated with relaxed chromatin, transcriptional derepression, and thus actively transcribed genes. Histone acetyltransferases (HATs) are enzymes responsible for the addition of acetyl groups, and histone deacetylases (HDACs) are enzymes responsible for the removal of acetyl groups. Therefore, the addition or removal of an acetyl group to a histone can alter the expression of nearby genes. The majority of drugs being investigated are inhibitors of proteins that remove acetyl from histones or histone deacetylases (HDACs).
• Briefly, ncRNAs are involved in signaling cascades with epigenetic marking enzymes such as HMTs, and/or with RNA interference(RNAi) machinery. Frequently these signaling cascades result in epigenetic repression (for one example, see X-chromosome inactivation), though there are some cases in which the opposite is true. For example, BACE1-AS ncRNA expression is upregulated in Alzheimer's disease patients and results in increased stability of BACE1 – the mRNA precursor to an enzyme involved in Alzheimer's disease.

Epigenetic drugs target the proteins responsible for modifications on DNA or histone. Current epigenetic drugs include but are not limited to: HDAC inhibitors (HDACi), HAT modulators, DNA methyltransferase inhibitors, and histone demethylase inhibitors. The majority of epigenetic drugs tested for use against neurodegenerative diseases are HDAC inhibitors; however, some DNMT inhibitors have been tested as well. While the majority of epigenetic drug treatments have been conducted in mouse models, some experiments have been performed on human cells as well as in human drug trials (see table below). There are inherent risks in using epigenetic drugs as therapies for neurodegenerative disorders as some epigenetic drugs (e.g. HDACis such as sodium butyrate) are non-specific in their targets, which leaves potential for off-target epigenetic marks causing unwanted epigenetic modifications.

Epigenetic Drugs

Function	Classification	Drug	ALS	AD	HD	PD	SMA
DNA-methylation inhibitor	chemical analogue of cytidine	Azathioprine		M (ny)		M (ny)
HDAC inhibitor (small molecule)	benzamide	M344					MC 19
	fatty acid	Sodium butyrate		M (y) 5, 6, 7 ; H (ny)	D (y) 11	M (y) 14; R (y) 15; D (y) 16, 18; H (ny)	MC 20; M (y) 21; H (ny)
		Sodium phenylbutyrate	M (y) 1; H (y) 2	M (y) 8; H (ny)	H (ys) 12		MC 20; H (v) 21, 22
		Valproic acid	M (y) 2; H (ni) 3	M (y) 9; H (ny)	D (y) 11	R (y) 17; H (ny)	MC 23, 24; M (y) 25; H (v) 26, 27, 28, 29
	hydroxamic acid	Trichostatin A	M (y) 4; H (ny)	M (y) 10; H (ny)	MC 13; D (y) 11		M (y) 30, 31; H (ny)
		Vorinostat (suberanilohydroxamic acid-SAHA)		M (y) 9; H (ny)	MC 13; D (y) 11	D (y) 18	MC 32, 33; M (y) 34; H (ny)

Disease: amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Huntington's disease (HD), spinal muscular atrophy (SMA), Parkinson's disease (PD)

Tested on: mouse (M), only mouse cells (MC), human (H), Drosophila (D), rat (R)

Successful treatment: yes (y), yes but with side effects (ys), not yet (ny), variable (v), no improvement (ni)

Neurodegenerative diseases of motor neurons

Amyotrophic lateral sclerosis (ALS)

Main article: Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a motor neuron disease that involves neurogeneration. All skeletal muscles in the body are controlled by motor neurons that communicate signals from the brain to the muscle through a neuromuscular junction. When the motor neurons degenerate, the muscles no longer receive signals from the brain and begin to waste away. ALS is characterized by stiff muscles, muscle twitching, and progressive muscle weakness from muscle wasting. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first, usually the limbs. As the disease progresses most patients are unable to walk or use their arms and eventually develop difficulty speaking, swallowing and breathing. Most patients retain cognitive function and sensory neurons are generally unaffected. Patients are often diagnosed after the age of 40 and the median survival time from onset to death is around 3–4 years. In the final stages, patients can lose voluntary control of eye muscles and often die of respiratory failure or pneumonia as a result of degeneration of the motor neurons and muscles required for breathing. Currently there is no cure for ALS, only treatments that may prolong life.

Genetics and underlying causes

To date, multiple genes and proteins have been implicated in ALS. One of the common themes between many of these genes and their causative mutations is the presence of protein aggregates in motor neurons. Other common molecular features in ALS patients are altered RNA metabolism and general histone hypoacetylation.

Chromosome 21

SOD1

The SOD1 gene on chromosome 21 that codes for the superoxide dismutase protein is associated with 2% of cases and is believed to be transmitted in an autosomal dominant manner. Many different mutations in SOD1 have been documented in ALS patients with varying degrees of progressiveness. SOD1 protein is responsible for destroying naturally occurring, but harmful superoxide radicals produced by the mitochondria. Most of the SOD1 mutations associated with ALS are gain-of-function mutations in which the protein retains its enzymatic activity, but aggregate in motor neurons causing toxicity. Normal SOD protein is also implicated in other cases of ALS due to potentially cellular stress. An ALS mouse model through gain-of-function mutations in SOD1 has been developed.

c9orf72

A gene called c9orf72 was found to have a hexanucleotide repeat in the non-coding region of the gene in association with ALS and ALS-FTD. These hexanucleotide repeats may be present in up 40% of familial ALS cases and 10% of sporadic cases. C9orf72 likely functions as a guanine exchange factor for a small GTPase, but this is likely not related to the underlying cause of ALS. The hexanucleotide repeats are likely causing cellular toxicity after they are spliced out of the c9orf72 mRNA transcripts and accumulate in the nuclei of affected cells.

UBQLN2

The UBQLN2 gene encodes the protein ubiquilin 2 which is responsible for controlling the degradation of ubiquitinated proteins in the cell. Mutations in UBQLN2 interfere with protein degradation resulting in neurodegeneration through abnormal protein aggregation. This form of ALS is X chromosome-linked and dominantly inherited and can also be associated with dementia.

Epigenetic treatment with HDAC inhibitors

ALS patients and mouse models show general histone hypoacetylation that can ultimately trigger apoptosis of cells. In experiments with mice, HDAC inhibitors counteract this hypoacetylation, reactivate aberrantly down-regulated genes, and counteract apoptosis initiation. Furthermore, HDAC inhibitors are known to prevent SOD1 protein aggregates in vitro.

Sodium phenylbutyrate

Sodium phenylbutyrate treatment in a SOD1 mouse model of ALS showed improved motor performance and coordination, decreased neural atrophy and neural loss, and increased weight gain. Release of pro-apoptotic factors was also abrogated as well as a general increase in histone acetylation. A human trial using phenylbuturate in ALS patients showed some increase in histone acetylation, but the study did not report whether ALS symptoms improved with treatment.

Valproic scid

Valproic acid in mice studies restored histone acetylation levels, increased levels of pro-survival factors, and mice showed improved motor performance. However, while the drug delayed the onset of ALS, it did not increase lifespan or prevent denervation. Human trials of valproic acid in ALS patients did not improve survival or slow progression.

Trichostatin A

Trichostatin A trials in mouse ALS models restored histone acetylation in spinal neurons, decreased axon demyelination, and increased survival of mice.

Spinal muscular atrophy (SMA)

Main article: Spinal muscular atrophy

Alpha motor neurons are derived from the basal plate (basal lamina).

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by mutations in the SMN1 gene. Symptoms vary greatly with each subset of SMA and the stage of the disease. General symptoms include overall muscle weakness and poor muscle tone including extremities and respiratory muscles leading to difficulty walking, breathing, and feeding. Depending on the type of SMA, the disease can present itself from infancy through adulthood. As SMN protein generally promotes the survival of motor neurons, mutations in SMN1 results in slow degeneration motor neurons leading to progressive system-wide muscle wasting. Specifically, over time, decreased levels of SMN protein results in gradual death of the alpha motor neurons in the anterior horn of the spinal cord and brain. Muscles depend on connections to motor neurons and the central nervous system to stimulate muscle maintenance and therefore degeneration of motor neurons and subsequent denervation of muscles lead to loss of muscle control and muscle atrophy. The muscles of the lower extremities are often affected first followed by upper extremities and sometimes the muscles of respiration and mastication. In general, proximal muscle is always affected more than distal muscle.

Genetic cause

Spinal muscular atrophy is linked to genetic mutations in the SMN1 (Survival of Motor Neuron 1) gene. The SMN protein is widely expressed in neurons and serves many functions within neurons including spliceosome construction, mRNA axon transport, neurite outgrowth during development, and neuromuscular junction formation. The causal function loss in SMA is currently unknown.

SMN1 is located in a telomeric region of human chromosome 5 and also contains SMN2 in a centromeric region. SMN1 and SMN2 are nearly identical except for a single nucleotide change in SMN2 resulting in an alternative splicing site where intron 6 meets exon 8. This single base pair change leads to only 10–20% of SMN2 transcripts resulting in fully functional SMN protein and 80–90% of transcripts leading to a truncated protein that is rapidly degraded. Most SMA patients have 2 or more copies of the SMN2 gene with more copies resulting in a decrease in disease severity. Most SMA patients have either point mutations or a deletion in exon 7 often leading to a protein product similar to the truncated and degraded version of the SMN2 protein. In SMA patients this small amount of functional SMN2 protein product allows for some neurons to survive.

Epigenetic treatment through SMN2 gene activation

Although SMA is not caused by an epigenetic mechanism, therapeutic drugs that target epigenetic marks may provide SMA patients with some relief, halting or even reversing the progression of the disease. As SMA patients with higher copy numbers of the SMN2 gene have less severe symptoms, researchers predicted that epigenetic drugs that increased SMN2 mRNA expression would increase the amount of functional SMN protein in neurons leading to a reduction in SMA symptoms. Histone deacetylase (HDAC) inhibitors are the main compounds that have been tested to increase SMN2 mRNA expression. Inhibiting HDACs would allow for hyperacetylation of the SMN2 gene loci theoretically resulting in an increase in SMN2 expression. Many of these HDAC inhibitors (HDACi) are first tested in mouse models of SMA created through a variety of mutations in the mouse SMN1 gene. If the mice show improvement and the drug does not cause very many side effects or toxicity, the drug may be used in human clinical trials. Human trials with all of the below HDAC inhibitors are extremely variable and often impacted by the patient's exact SMA subtype.

Quisinostat (JNJ-26481585)

Quisinostat is effective at low doses resulting in some improved neuromuscular function in mouse model of SMA, but survival was not increased. No human trials have been conducted.

Sodium butyrate

Sodium butyrate was the first HDAC inhibitor tested in SMA mouse models. It prolonged SMA mouse life span by 35% and showed increased levels of SMN protein in spinal cord tissue. However, sodium butyrate has not been used in human trials to date.

Sodium phenylbutyrate

Sodium phenylbutyrate increases SMN2 full length mRNA transcripts in cell culture but drug application must be repeated in order to maintain results. Human trials show mixed results with one study showing increased SMA transcript levels in blood and improved motor function, but a larger trial showing no effects on disease progression or motor function.

Valproic acid

Valproic acid added to cells from SMA patients increased SMN2 mRNA and protein levels and that the drug directly activates SMN2 promoter. In a SMA mouse model, valproic acid was added to the drinking water and restored motor neuron density and increased motor neuron number over a period of 8 months. Human trials are extremely variable showing increased SMN2 levels and increased muscle strength in some trials and absolutely no effects in other trials.

M344

M344 is a benzamide that shows promising results in fibroblast cell culture and increases level of splicing factors known to modulate SMN2 transcripts, but the drug was determined toxic and research has not progressed to in vivo testing.

Trichostatin A

Trichostatin A treatment shows promising results in mice. In one study, Trichostatin A combined with extra nourishment in early onset mouse SMA models resulted in improved motor function and survival and delays progressive denervation of muscles. A second study in a SMA mouse model showed increased SMN2 transcripts with daily injections. No human trials have been conducted.

Vorinostat (SAHA)

Vorinostat is a second generation inhibitor that is fairly non-toxic and found to be effective in cell culture at low concentrations and increases histone acetylation at the SMN2 promoter. In a SMA mouse model, SAHA treatment resulted in weight gain, increased SMN2 transcripts levels in muscles and spinal cord, and motor neuron loss and denervation were halted. No human trials have been conducted.

Myasthenia gravis

Myasthenia gravis is an autoimmune disease affecting synapses at the neuromuscular junction, whereby antibodies produced primarily in the thymus gland by B-cells associate with postsynaptic nicotinic acetylcholine receptors (AChR), along with other NMJ post-synaptic receptors (MuSK-R and low-density lipoprotein receptor). These antibodies include acetylcholine receptor antibodies, MuSK antibodies, and low-density lipoprotein receptor related protein 4 antibodies (LRP4-Ab). Antibody binding to their respective receptors causes the destruction of those receptors, leading to a reduction in the number of postsynaptic acetylcholinergic receptors and a reduction in overall acetylcholine transport. Disease symptoms include muscular weakness that fatigues due to overuse, but improves with rest. Hallmark symptoms due to muscular weakness include ptosis, double vision, dysphagia, as well as aberrant speech.

Myasthenia gravis is a relatively rare disease, occurring in about 3–30 individuals per 100,000, but has been rising over the past couple decades. There exists two variations of myasthenia gravis with respect to age and gender demographics: early-onset myasthenia gravis, which has a higher incidence among females, and late-onset myasthenia gravis, which has a higher incidence among males.

Epigenetic factors

There has been extensive research on the genetic basis of myasthenia gravis, however evidence does not suggest that it is an inherited disease. There has also been extensive research on the epigenetic contribution to myasthenia gravis. DNA methylation and noncoding RNA, such as miRNA (micro RNA) and long noncoding RNA (lncRNA), are epigenetic factors that play a significant role in increasing the likelihood of acquiring myasthenia gravis. In addition, the thymus is a key organ in the immune response that is often negatively affected by abnormal miRNA expression and DNA methylation.

miRNA

Micro RNA (miRNA) are single-stranded non-coding RNAs that bind their target mRNAs. From there, they can regulate gene expression by inhibiting translation or degrading the mRNA strand, oftentimes in B-cells and T-cells of the immunological process. With respect to myasthenia gravis, abnormal miRNA function is associated with immunoregulatory pathogenesis, and each miRNA has its own unique downstream effects.

The thymus is an important endocrine organ implicated in myasthenia gravis. In normal, healthy development, the thymus shrinks in size over time. In those with thymus-associated myasthenia gravis there are correlations with thymomas in late-onset myasthenia gravis as well as thymic hyperplasia with germinal centers in early-onset myasthenia gravis, and each of these conditions can be attributed partly to irregular miRNA function. In late-onset myasthenia gravis subjects, it was shown that miRNA-12a-5p expression was increased in thymoma-associated myasthenia gravis. MiRNA-12a-5p inhibits expression of the gene FoxP3, a gene known to be associated with normal thymus development and whose alteration is attributed to thymomas. Additionally, an association between thymoma-associated myasthenia gravis and decreased miR-376a/miR-376c expression was found. Autoimmune regulation is known to be downregulated in thymoma-associated myasthenia gravis, and in thymus cells with downregulated autoimmune regulation there was simultaneous downregulation in miR-376a, miR-376c, and miRNA-12a-5p expression. In early-onset myasthenia gravis patients, 61 miRNA's were found to be either significantly downregulated or upregulated. The most downregulated miRNA was found to be miR-7-5p, whose target gene is CCL21. CCL21 is known to aberrantly recruit B-cells in the thymus of early-onset myasthenia gravis patients, and was found to be highly expressed in early-onset myasthenia gravis patients, potentially explaining the abnormally large amounts of B cells found in thymic hyperplasia.

Aside from miRNA's corresponding to altered thymus function, there are other several key miRNA's that are correlated with myasthenia gravis. MiR-15 cluster (miR-15a, miR-15b, and miR-15c) was shown to be associated with autoimmunity, in that its downregulation increased CXCL10 expression, a target gene involved in T-cell signaling. CXCL10 expression was also shown to be increased in the thymus of myasthenia gravis patients. Additionally, miR-146 was found to be upregulated in myasthenia gravis patients. In these patients with upregulated miR-146, there was a concurrent increase in proteins that correspond to a wide array of immune responses, specifically TLR4, CD40, and CD80.

DNA methylation

DNA methylation is the epigenetic process by which methyl groups are added to either adenine or cytosine bases, which results in the repression of that sequence when cytosine methylation occurs. DNA methylation was found to be a factor in increasing the likelihood of acquiring myasthenia gravis, albeit this topic has not been widely researched. Research in China has identified the gene CTLA-4 (cytotoxic T lymphocyte antigen-4) as being highly methylated in myasthenia gravis patients compared to control groups throughout the entire span of the disease. The CTLA-4 gene produces an antigen of the same name that is presented on killer T-cells and allows for the suppression of the immune response. Methylation of this gene represses production of the antigen CTLA-4—a pattern seen in a significant majority of myasthenia gravis patients—and can explain the elevated immune response seen in myasthenia gravis. Furthermore, myasthenia gravis patients with thymic abnormalities (approximately 10–20% of all myasthenia gravis patients) had even higher levels of CTLA-4 methylation than other myasthenia gravis patients. It is not extensively researched why certain genes are hypermethylated in these cases, but information on myasthenia gravis largely points to upregulation of the DNA methyltransferase genes DNMT1, DNMT3A, and DNMT3B in patients with myasthenia gravis.

In addition to CTLA-4 methylation, hypermethylation of the growth hormone secretagogue receptor gene was seen in patients with thymoma-associated late-onset myasthenia gravis. Growth hormone secretagogue receptor hypermethylation is detected in a wide variety of cancers, however only recently has been correlated with the development of thymoma-associated myasthenia gravis. Although it is seen in approximately 1/4 of thymoma-associated myasthenia gravis subjects, it is not a reliable biomarker for the disease, and its relevance to disease progression is not well known.

Long ncRNA

Long ncRNA (lncRNA) are a second type of non-coding RNA that are key post-transcriptional modifiers of protein-coding gene expression. These also play a significant role in myasthenia gravis. Their aberrant regulation can cause differential expression in downstream genes. For instance, the differential expression of lncRNA interferon gamma antisense RNA negatively regulates the expression of HLA-DRB and HLA-DOB, two genes implicated in the body's autoimmune response by differentiating endogenous and foreign proteins. As seen in myasthenia gravis patients with downregulated lethal (let)-7 lncRNA, it was also found that the level of let-7 lncRNA was negatively correlated with levels of interleukin (IL)-10, a gene responsible for inhibiting cytokine secretion/activation, antigen presentation, and macrophage activity, but also for exhibiting anti-tumor effects. Therefore, the negative correlation between let-7 lncRNA and IL-10 levels and its specific effects on myasthenia gravis development are ambiguous.

In addition to aberrant regulation of downstream target genes, lncRNA also affect expression by acting as competing endogenous RNA (ceRNA). The competing endogenous RNA theory states that transcripts sharing common miRNA binding sites can compete to bind these identical miRNAs, and in this way lncRNAs can bind miRNAs, regulating their downstream binding activity and affecting their function. In the case of myasthenia gravis, the lncRNA small nucleolar RNA host gene (SNHG) 16 regulates the expression of IL-10 by adsorbing let-7c-5p, a miRNA that commonly associates with IL-10, as a competing endogenous RNA.

Epigenetic treatments

Diagnosis of myasthenia gravis, individual prognosis, and the level of treatment needed can be determined by detecting the amounts of circulating miRNA.

Immunosuppressants represent a large category in clinical studies for myasthenia gravis treatment, as they reduce the hyperactive immunological response in T-cells presenting acetylcholine receptor-binding antigens. By overexpressing miR-146, studies show that patients with early-onset myasthenia gravis can have antigen-specific suppressive effects. This has implications in reducing the immune response of myasthenia gravis patients and improving prognosis. Likewise, miR-155 is proven to be correlated with myasthenia gravis-associated thymic inflammation and immune response. Research is being conducted whereas repression of miR-155 could reduce these aberrant effects. Lastly, the miRNA's miR-150-5p and miR-21-5p are consistently shown to be elevated in myasthenia gravis patients with acetylcholinergic receptor antibodies (in contrast to the MuSK-binding variant of myasthenia gravis), therefore these two miRNA's are reliable biomarkers in detecting this variant of myasthenia gravis.

Neurodegenerative diseases of the central nervous system

Alzheimer's disease (AD)

Main article: Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly. The disease is characterized behaviorally by chronic and progressive decline in cognitive function, beginning with short-term memory loss, and neurologically by buildup of misfolded tau protein and associated neurofibrillary tangles, and by amyloid-beta senile plaques amyloid-beta senile plaques. Several genetic factors have been identified as contributing to AD, including mutations to the amyloid precursor protein (APP) and presenilins 1 and 2 genes, and familial inheritance of apolipoprotein E allele epsilon 4. In addition to these common factors, there are a number of other genes that have shown altered expression in Alzheimer's disease, some of which are associated with epigenetic factors.

Epigenetic factors

Brain-derived neurotrophic factor

ncRNA

ncRNA that is encoded antisense from an intron within the beta-amyloid cleaving enzyme gene, BACE1, is involved in AD. This ncRNA, BACE1-AS (for antisense), which overlaps exon 6 of BACE1, is involved in increasing the stability of the BACE1 mRNA transcript. As that gene's name suggests, BACE1 is an enzymatic protein that cleaves the amyloid precursor protein into the insoluble amyloid beta form, which then aggregates into senile plaques. With increased stability of BACE1 mRNA resulting from BACE1-AS, more BACE1 mRNA is available for translation into BACE1 protein.

miRNA

factors have not consistently been shown to play a role in progression of AD. miRNAs are involved in post-transcriptional gene silencing via inhibiting translation or involvement in RNAi pathways. Some studies have shown upregulation of miRNA-146a, which differentially regulates neuroimmune-related Interleukin-1R associated kinases IRAK1 and IRAK2 expression, in human AD brain, while other studies have shown upregulation or downregulation of miRNA-9 in brain.

DNA methylation

In Alzheimer's disease cases, global DNA hypomethylation and gene-specific hypermethylation has been observed, though findings have varied between studies, especially in studies of human brains. Hypothetically, global hypomethylation should be associated with global increases in transcription, since CpG islands are most prevalent in gene promoters; gene-specific hypermethylation, however, would indicate that these hypermethylated genes are repressed by the methylation marks. Generally, repressive hypermethylation of genes related to learning and memory has been observed in conjunction with derepressive hypomethylation of neuroinflammatory genes and genes related to pathological expression of Alzheimer's disease. Reduced methylation has been found in the long-term memory-associated temporal neocortex neurons in monozygotic twins with Alzheimer's disease compared to the healthy twin. Global hypomethylation of CpG dinucleotides has also been observed in hippocampus and in entorhinal cortex layer II of human AD patients, both of which are susceptible to AD pathology. These results, found by probing with immunoassays, have been challenged by studies that interrogate DNA sequence by bisulfite sequencing, a CpG transformation technique which is sensitive to CpG methylation status, in which global hypomethylation has been observed.

COX-2

At the individual gene level, hypomethylation and thus derepression of COX-2 occurs, inhibition of which reduces inflammation and pain, and hypermethylation of BDNF, a neurotrophic factor important for long-term memory.^[85] Expression of CREB, an activity-dependent transcription factor involved in regulating BDNF among many other genes, has also been shown to be hypermethylated, and thus repressed, in AD brains, further reducing BDNF transcription. Furthermore, synaptophysin (SYP), the major synaptic vesicle protein-encoding gene, has been shown to be hypermethylated and thus repressed, and transcription factor NF-κB, which is involved in immune signaling, has been shown to be hypomethylated and thus derepressed. Taken together, these results have elucidated a role for dysregulation of genes involved in learning and memory and synaptic transmission, as well as with immune response.

Hypomethylation

has been observed in promoters of presenilin 1, GSK3beta, which phosphorylates tau protein, and BACE1, an enzyme that cleaves APP into the amyloid-beta form, which in turn aggregates into insoluble senile plaques. Repressive hypermethylation caused by amyloid-beta has been observed at the promoter of NEP, the gene for neprilysin, which is the major amyloid-beta clearing enzyme in the brain. This repression of NEP could result in a feed-forward buildup of senile plaques; combined with the observed increase in AD brains of BACE1-AS and corresponding increases in BACE1 protein and amyloid beta, multiple levels of epigenetic regulation may be involved in controlling amyloid-beta formation, clearance or aggregation, and senile plaque deposition. There may be some effect of age in levels of DNA methylation at specific gene promoters, as one study found greater levels of methylation at APP promoters in AD patients up to 70 years old, but lower levels of methylation in patients greater than 70 years old. Studies on differential DNA methylation in human AD brains remain largely inconclusive possibly owing to the high degree of variability between individuals and to the numerous combinations of factors that may lead to AD.

Histone marks

Acetylation of lysine residues on histone tails is typically associated with transcriptional activation, whereas deacetylation is associated with transcriptional repression. There are few studies investigating specific histone marks in AD. These studies have elucidated a decrease in acetylation of lysines 18 and 23 on N-terminal tails of histone 3 (H3K18 and H3K23, respectively) and increases in HDAC2 in AD brains - both marks related to transcriptional repression. Age-related cognitive decline has been associated with deregulation of H4K12 acetylation, a cognitive effect that was restored in mice by induction of this mark.

Treatments

Treatment for prevention or management of Alzheimer's disease has proven troublesome since the disease is chronic and progressive, and many epigenetic drugs act globally and not in a gene-specific manner. As with other potential treatments to prevent or ameliorate symptoms of AD, these therapies do not work to cure, but only ameliorate symptoms of the disease temporarily, underscoring the chronic, progressive nature of AD, and the variability of methylation in AD brains.

Folate and other B vitamins

B vitamins are involved in the metabolic pathway that leads to SAM production. SAM is the donor of the methyl group utilized by DNA methyltransferases (DNMTs) to methylate CpGs. Using animal models, Fuso et al. have demonstrated restoration of methylation at previously hypomethylated promoters of presenilin 1, BACE1 and APP – a hypothetically stable epigenetic modification that should repress those genes and slow the progression of AD. Dietary SAM supplementation has also been shown to reduce oxidative stress and delay buildup of neurological hallmarks of AD such as amyloid beta and phosphorylated tau protein in transgenic AD mice.

AZA

Khan and colleagues have demonstrated a potential role for neuroglobinin attenuating amyloid-related neurotoxicity. 5-aza-2' deoxycitidine (AZA, or decitabine), a DNMT inhibitor, has shown some evidence for regulating neuroglobin expression, though this finding has not been tested in AD models.

Histone-directed treatments

Though studies of histone marks in AD brains are few in number, several studies have looked at the effects of HDACis in treatment of Alzheimer's disease. Class I and II HDAC inhibitors such as trichostatin A, vorinostat, and sodium butyrate, and Class III HDACis, such as nicotinamide, have been effective at treating symptoms in animal models of AD. While promising as a therapeutic in animal models, studies on the long-term efficacy of HDACis and human trials have yet to be conducted.

Sodium butyrate

Sodium butyrate is a class I and II HDACi and has been shown to recover learning and memory after 4 weeks, decrease phosphorylated tau protein, and restore dendritic spine density in the hippocampus of AD transgenic mice. Histone acetylation resulting from diffuse sodium butyrate application is especially prevalent in the hippocampus, and genes involved in learning and memory showed increased acetylation in AD mice treated with this drug.

Trichostatin A

Trichostatin A is also a class I and II HDACi that rescues fear learning in a fear conditioning paradigm in transgenic AD mice to wild type levels via acetylation on histone 4 lysine tails.

Vorinostat

Vorinostat is a class I and II HDACi that has been shown to be especially effective at inhibiting HDAC2 and restoring memory functions in non-AD models of learning deficits. One study showed vorinostat is effective at reversing contextual memory deficits in transgenic AD mice.

Huntington's (HD)

Main article: Huntington's disease

This is a transverse section of the striatum from a structural MR image. The striatum, in red, includes the caudate nucleus (top), the putamen (right), and, when including the term 'corpus' striatum, the globus pallidus (lower left).

Huntington's disease (HD) is an inherited disorder that causes progressive degeneration of neurons within the cerebral cortex and striatum of the brain resulting in loss of motor functions (involuntary muscle contractions), decline in cognitive ability (eventually resulting in dementia), and changes in behavior.

Genetics and underlying causes

Huntington's is caused by an autosomal dominant mutation expanding the number of glutamine codon repeats (CAG) within the Huntingtin gene (Htt). The Htt gene encodes for the huntingtin protein which plays a role in normal development but its exact function remains unknown. The length of this CAG repeat correlates with the age-of-onset of the disease. The average person without Huntington's has less than 36 CAG repeats present within the Htt gene. When this repeat length exceeds 36, the onset of neuronal degradation and the physical symptoms of Huntington's can range from as early as 5 years of age (CAG repeat > 70) to as late as 80 years of age (CAG repeat < 39).

This CAG expansion results in mRNA downregulation of specific genes, decreased histone acetylation, and increased histone methylation. The exact mechanism of how this repeat causes gene dysregulation is unknown, but epigenome modification may play a role. For early-onset Huntington's (ages 5–15), both transgenic mice and mouse striatal cell lines show brain specific histone H3 hypoacetylation and decreased histone association at specific downregulated genes within the striatum (namely Bdnf, Cnr1, Drd2 – dopamine 2 receptor, and Penk1 – preproenkephalin). For both late- and early-onset Huntington's, the H3 and H4 core histones associated with these downregulated genes in Htt mutants have hypoacetylation (decreased acetylation) compared to wild-type Htt. This hypoacetylation is sufficient to cause tighter chromatin packing and mRNA downregulation.

Along with H3 hypoacetylation, both human patients and mice with the mutant Htt have increased levels of histone H3 lysine 9 trimethylation. This increase in H3-K9 trimethylation is linked to an increased expression of the methyltransferase ESET/SETDB1 (ERG-associated protein with SET domain (ESET)), which targets and trimethylates H3-K9 residues. It is proposed that this hypermethylation may account for the onset of specific gene repression in Htt mutants.

HDAC inhibitors

Huntington patients and both mouse and Drosophila models show histone H3 and H4 hypoacetylation. There are currently no treatments for the disease but numerous HDAC inhibitors have been tested and shown to reverse the certain symptoms caused by the Htt mutation.

• Sodium butyrate

Sodium butyrate treatment slowed neuronal degeneration in Drosophila models. Sodium butyrate treatment also increased histone H3 acetylation and normalized mRNA levels for mutant Htt downregulated genes.

• Valproic acid

Valproic acid treatment increased mutant Htt H3 and H4 acetylation levels comparable to wild-type Htt in Drosophila models.

• Sodium phenylbutyrate

Sodium phenylbutyrate phase II human trials with 12 to 15 g/day showed restored mRNA levels of Htt mutant repressed genes but also had adverse side effects such as nausea, headaches, and gain instability. Phenylbutyrate has also been shown to increase histone acetylation, decrease histone methylation, increase survival rate, and decrease the rate of neuronal degradation in Htt mutant mouse models.

• Trichostatin A

Trichostatin A (TSA) treatment increased mutant Htt H3 and H4 acetylation levels comparable to wild-type Htt in Drosophila models. TSA treatment has also been shown to increase alpha-tubulin lysine 40 acetylation in mouse striatal cells and increase intracellular transport of BDNF, a brain-derived neurotrophic factor that function in nerve growth and maintenance within the brain.

• Vorinostat (SAHA)

Vorinostat treatment slowed photoreceptor degeneration and improved longevity of adult Htt mutant Drosophila. Like TSA, SAHA treatment increased alpha-tubulin lysine 40 acetylation in mouse striatal cells and also increased intracellular transport of BDNF.

Parkinson's disease (PD)

Main article: Parkinson's disease

Lewy bodies

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra by causes unknown. Several genes and environmental factors (e.g. pesticide exposure) may play a role in onset of PD. Hallmarks include mutations to the alpha-synuclein gene, SNCA, as well as PARK2, PINK1, UCHL1, DJ1, and LRRK2 genes, and fibrillar accumulation of Lewy bodies from misfolded alpha-synuclein. Symptoms are most noticeably manifested in disorders of movement, including shaking, rigidity, deficits in making controlled movements, and slow and difficult walking. The late stages of the disease result in dementia and depression. Levodopa and dopaminergic therapy may ameliorate symptoms, though there is no treatment to halt progression of the disease.

Epigenetic factors

ncRNA

Reductions of miR-133b correlated to decreased numbers of dopaminergic neurons in the midbrain of PD patients. miR-132, meanwhile, is negatively correlated with dopaminergic neuron differentiation in the midbrain. miR-7 and miR-153 act to reduce alpha-synuclein levels (a hallmark of PD) but are reduced in PD brain.

DNA methylation

Neurons of PD patients show hypomethylation of tumor necrosis factor (TNF) alpha encoding sequence, overexpression of which leads to apoptosis of neurons. Cerebrospinal fluid of PD patients also shows elevated TNF alpha. Research indicates there may be a link between DNA methylation and SNCA expression. Furthermore, human and mouse models have shown reduction of nuclear DNMT1 levels in PD subjects, resulting in hypomethylated states associated with transcriptional repression.

Histone marks

alpha-synuclein, the protein encoded by SNCA, can associate with histones and prevent their acetylation in concert with the HDACs HDAC1 and Sirt2. Furthermore, it has been demonstrated that alpha-synuclein binds histone 3 and inhibits its acetylation in Drosophila. Dopamine depletion in Parkinson's disease is associated with repressive histone modifications, including reduced H3K4me3, and lower levels of H3 and H4 lysine acetylation after levodopa therapy (a common treatment of PD).

Treatments

Epigenetic treatments tested in models of PD are few, though some promising research has been conducted. Most treatments investigated thus far are directed at histone modifications and analysis of their roles in mediating alpha-synuclein expression and activity. Pesticides and paraquat increase histone acetylation, producing neurotoxic effects similar to those seen in PD, such as apoptosis of dopaminergic cells. Despite this, treatment with HDACis seems to have a neuroprotective effect.

Sodium butyrate

Several studies using different animal models have demonstrated that sodium butyrate may be effective in reducing alpha-synuclein-related neurotoxicity. In Drosophila, sodium butyrate improved locomotor impairment and reduced early mortality rates.

Valproic acid

In an inducible rat model of PD, valproic acid had a neuroprotective effect by preventing translocation of alpha-synuclein into cell nuclei.

Vorinostat

In an alpha-synuclein overexpressing Drosophila model of PD, vorinostat (as well as sodium butyrate) reduced alpha-synuclein-mediated neurotoxicity.

siRNA inhibition of SIRT2

Treatment with SIRT2 inhibiting siRNA leads to reduced alpha-synuclein neurotoxicity AK-1 or AGK-2.

Multiple sclerosis

Multiple sclerosis (MS) is a demyelinating neurodegenerative disease that does not have a confirmed cause, but is widely considered to be an autoimmune disease in nature. It is indicated by demyelination of the nerves of the brain and spinal cord. Its symptoms are unique in nature and vary, but include those that have degenerative effects in the eyes and limbs. These can present themselves as numbness or atrophy, shock like sensations, paralysis, as well as lack of coordination or tremors, within the extremities. Within the eye, multiple sclerosis can cause blurriness, double vision, pain, or vision loss. Multiple sclerosis effects can be presented throughout other realms of the body, but is largely characterized by these main symptoms. Some of these can include loss of sexual or excretory function and epilepsy. While there are a few subcategories of multiple sclerosis, in most instances, the disease afflicts in a relapsing nature, where relapses of symptoms might not occur for extended periods of time, yielding more to the uncertainty of the disease. There is no known cure for MS, but measures can be taken post relapse to regain loss of function and the symptoms can be mitigated via therapeutic or medicinal means.

Epigenetic factors

Because of the outside factors that precede multiple sclerosis and the heritability typically occurring within the mother, it is thought to have an epigenetic cause. Some factors that may increase the incidence of MS are smoking, vitamin deficiency, and a history of some viral infections—which are factors that can induce epigenetic change.

Human leukocyte antigen-DRB1*15 allele

Human leukocyte antigen-DRB1*15 haplotype is a potential risk factor of MS. Because of the increased likelihood of the mother's human leukocyte antigen-DRB1*15 allele being passed onto their children, this contributes to the instances of MS being more prevalent from the mother. HLA-DRB1 is thought to be regulated via epigenetic means. The correlation of MS and this allele is speculated to be due to the presence of hypomethylation in the CpG island of HLA-DRB1, and those that carry the allele tend to exhibit this hypomethylation. HLA-DRB1 exon 2 is a particular region where evidence has shown that methylation is shown to be important in regulation. Research has furthered the evidence that variation in HLA-DRB1 DMR, which is a mechanism that is methylation regulated, that in turn regulates increased HLA-DRB1 expression, displays an increased risk for MS, and the exhibition of the disease.

miRNA

Higher levels of expression of specific types of miRNA are often seen in the brain of those afflicted, showing an association of these types of miRNA and MS. Higher expression of miR-155 and miR-326 is often associated with CD4+T cell differentiation, and with this differentiation, instances of autoimmune encephalitis occur, which is the link with which it is thought that smoking can induce epigenetic changes that increase susceptibility to MS. Higher expression levels of miR-18b, miR-493, miR-599, and miR-96 are often seen in patients diagnosed with MS. miR-145 detection appears to be a promising future diagnostic tool due to its high specificity of 90% and sensitivity of 89.5% in whole blood testing due to its capability of distinguishing healthy patients versus those with MS. A symptom associated with MS patients is white matter lesions in the brain, and these lesions when biopsied showed higher expression of miR-155, miR-326 and miR-34a. These are especially notable due to the fact that overexpression of these miRNA's cause downregulation of CD47, leading to myelin phagocytosis, because of CD47's role of inhibiting macrophage activity.

DNA methylation

MS patients can be identified through observation of abnormal DNA methylation patterns in genes responsible for inflammation and myelination factor expression. Methylation occurs in the genomic region, CpG island, and is imperative in regulation of transcription. A methylated CpG region typically is the mechanism that will silence a gene, whereas a hypomethylated region is able to induce transcription. Using methylation inhibitors it has been shown that allowing higher proliferation of T cells can be achieved by preventing silencing. Abnormalities in methylation patterns increase the generation of CD4+T auto reactive. Hypomethylation of CpG regions of the PAD2 gene, a regulator of MBP which in turn regulates myelin, is also associated with higher instances of MS. This hypomethylation leads to overexpression of the PAD2 gene. These patterns have been observed in the white matter of patients with MS. While methylation is an indicator of MS, its effects are more specialized to location in MS, for example, where these patterns are observed in white matter.

Histone modifications

Association of abnormal histone modification in MS patients can be found in lesions located in the brain, with most instances of this being observed in patients over time and in lesions located in the frontal lobe. Higher instance of histone acetylation can be seen in patients afflicted over time, but this is counteracted by lower instances of histone acetylation in lesions found on the brain early in the course of the disease. The mechanisms by which histone modifications work in the progression of MS are unconfirmed, but changes in acetylation are often associated with the disease.

Treatments

HDAC inhibitors

Trichostatin

Positive responses were observed in animal trials utilizing this HDAC inhibitor, associated with mediation of inflammatory pathways and thus resulting in lower instances of inflammatory responses in the brain. It was also shown to be effective in decreasing levels of disability when the mice were in a relapsing stage of MS. Trichostatin's mediation of symptoms is not well known but is thought to work in increasing acetylation at the H3 and H4 histones in CD4+T cells where MS patients often display differences in acetylation levels at these histones that control patients do not.

Vorinostat

Animal trials were utilized along with the testing of human myeloid dendritic cells. Not much is known about the mechanisms of vorinostat; however regulation of Th1/Th17 cytokine expression, which are responsible for inducing inflammation, were observed, thereby decreasing instances of inflammation and demyelination. Decreased patterns of T cell proliferation were also observed, similar to how trichostatin mediates disease symptoms.

Valpropic acid

Valpropic acid has been shown to have positive results in animal trials, in the mitigation of the disease by regulating the severity and duration of MS. Its mechanism is decreasing the presentation of miRNA. Its mechanism for such has been observed in rats by shifting Th1 and Th17 to Th2 (responsible for inducing inflammation), thereby downregulating miRNA expression in inflammatory cytokines, tumor mediating mechanisms, and the spine. This is another instance in which T cell expression regulation is present, by preventing proliferation through interference of its pathway, similar to trichostatin and vorinostat. Another effect of VPA is its prevention of macrophage and lymphocyte proliferation in the spinal cords of MS rats. Currently, no HDAC inhibitors are in use for the mitigation of symptoms in MS patients; however, some are in pre-clinical trials at this time.

Mental disorder

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Mental_disorder

 

Mental disorder
Other names	Mental breakdown, mental disability, mental disease, mental health condition, mental illness, nervous breakdown, psychiatric disability, psychiatric disorder, psychological disability, psychological disorder
Specialty	Psychiatry, clinical psychology
Symptoms	Agitation, anxiety, depression, mania, paranoia, psychosis
Complications	Cognitive impairment, social problems, suicide
Types	Anxiety disorders, eating disorders, mood disorders, personality disorders, psychotic disorders, substance use disorders
Causes	Genetic and environmental factors
Treatment	Psychotherapy and medications
Medication	Antidepressants, antipsychotics, anxiolytics, mood stabilizers, stimulants
Frequency	18% per year (United States)

A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is also characterized by a clinically significant disturbance in an individual's cognition, emotional regulation, or behavior, often in a social context. Such disturbances may occur as single episodes, may be persistent, or may be relapsing–remitting. There are many different types of mental disorders, with signs and symptoms that vary widely between specific disorders. A mental disorder is one aspect of mental health.

The causes of mental disorders are often unclear. Theories incorporate findings from a range of fields. Disorders may be associated with particular regions or functions of the brain. Disorders are usually diagnosed or assessed by a mental health professional, such as a clinical psychologist, psychiatrist, psychiatric nurse, or clinical social worker, using various methods such as psychometric tests, but often relying on observation and questioning. Cultural and religious beliefs, as well as social norms, should be taken into account when making a diagnosis.

Services for mental disorders are usually based in psychiatric hospitals, outpatient clinics, or in the community, Treatments are provided by mental health professionals. Common treatment options are psychotherapy or psychiatric medication, while lifestyle changes, social interventions, peer support, and self-help are also options. In a minority of cases, there may be involuntary detention or treatment. Prevention programs have been shown to reduce depression.

In 2019, common mental disorders around the globe include: depression, which affects about 264 million people; dementia, which affects about 50 million; bipolar disorder, which affects about 45 million; and schizophrenia and other psychoses, which affect about 20 million people. Neurodevelopmental disorders include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability, of which onset occurs early in the developmental period. Stigma and discrimination can add to the suffering and disability associated with mental disorders, leading to various social movements attempting to increase understanding and challenge social exclusion.

Definition

"Nervous breakdown" redirects here. For other uses, see Nervous breakdown (disambiguation).

The definition and classification of mental disorders are key issues for researchers as well as service providers and those who may be diagnosed. For a mental state to be classified as a disorder, it generally needs to cause dysfunction. Most international clinical documents use the term mental "disorder", while "illness" is also common. It has been noted that using the term "mental" (i.e., of the mind) is not necessarily meant to imply separateness from the brain or body.

According to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), published in 1994, a mental disorder is a psychological syndrome or pattern that is associated with distress (e.g., via a painful symptom), disability (impairment in one or more important areas of functioning), increased risk of death, or causes a significant loss of autonomy; however, it excludes normal responses such as the grief from loss of a loved one and also excludes deviant behavior for political, religious, or societal reasons not arising from a dysfunction in the individual.

DSM-IV predicates the definition with caveats, stating that, as in the case with many medical terms, mental disorder "lacks a consistent operational definition that covers all situations", noting that different levels of abstraction can be used for medical definitions, including pathology, symptomology, deviance from a normal range, or etiology, and that the same is true for mental disorders, so that sometimes one type of definition is appropriate and sometimes another, depending on the situation.

In 2013, the American Psychiatric Association (APA) redefined mental disorders in the DSM-5 as "a syndrome characterized by clinically significant disturbance in an individual's cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning." The final draft of ICD-11 contains a very similar definition.

The terms "mental breakdown" or "nervous breakdown" may be used by the general population to mean a mental disorder. The terms "nervous breakdown" and "mental breakdown" have not been formally defined through a medical diagnostic system such as the DSM-5 or ICD-10 and are nearly absent from scientific literature regarding mental illness. Although "nervous breakdown" is not rigorously defined, surveys of laypersons suggest that the term refers to a specific acute time-limited reactive disorder involving symptoms such as anxiety or depression, usually precipitated by external stressors. Many health experts today refer to a nervous breakdown as a mental health crisis.

Nervous illness

In addition to the concept of mental disorder, some people have argued for a return to the old-fashioned concept of nervous illness. In How Everyone Became Depressed: The Rise and Fall of the Nervous Breakdown (2013), Edward Shorter, a professor of psychiatry and the history of medicine, says:

About half of them are depressed. Or at least that is the diagnosis that they got when they were put on antidepressants. ... They go to work but they are unhappy and uncomfortable; they are somewhat anxious; they are tired; they have various physical pains—and they tend to obsess about the whole business. There is a term for what they have, and it is a good old-fashioned term that has gone out of use. They have nerves or a nervous illness. It is an illness not just of mind or brain, but a disorder of the entire body. ... We have a package here of five symptoms—mild depression, some anxiety, fatigue, somatic pains, and obsessive thinking. ... We have had nervous illness for centuries. When you are too nervous to function ... it is a nervous breakdown. But that term has vanished from medicine, although not from the way we speak.... The nervous patients of yesteryear are the depressives of today. That is the bad news.... There is a deeper illness that drives depression and the symptoms of mood. We can call this deeper illness something else, or invent a neologism, but we need to get the discussion off depression and onto this deeper disorder in the brain and body. That is the point.

— Edward Shorter, Faculty of Medicine, the University of Toronto

In eliminating the nervous breakdown, psychiatry has come close to having its own nervous breakdown.

— David Healy, MD, FRCPsych, Professor of Psychiatry, University of Cardiff, Wales

"Nervous breakdown" is a pseudo-medical term to describe a wealth of stress-related feelings and they are often made worse by the belief that there is a real phenomenon called "nervous breakdown".

— Richard E. Vatz, co-author of explication of views of Thomas Szasz in "Thomas Szasz: Primary Values and Major Contentions"

Nerves stand at the core of common mental illness, no matter how much we try to forget them.

— Peter J. Tyrer, FMedSci, Professor of Community Psychiatry, Imperial College, London

Classifications

Main article: Classification of mental disorders

There are currently two widely established systems that classify mental disorders:

• ICD-11 Chapter 06: Mental, behavioural or neurodevelopmental disorders, part of the International Classification of Diseases produced by the WHO (in effect since 1 January 2022).
• Diagnostic and Statistical Manual of Mental Disorders (DSM-5) produced by the APA since 1952.

Both of these list categories of disorder and provide standardized criteria for diagnosis. They have deliberately converged their codes in recent revisions so that the manuals are often broadly comparable, although significant differences remain. Other classification schemes may be used in non-western cultures, for example, the Chinese Classification of Mental Disorders, and other manuals may be used by those of alternative theoretical persuasions, such as the Psychodynamic Diagnostic Manual. In general, mental disorders are classified separately from neurological disorders, learning disabilities or intellectual disability.

Unlike the DSM and ICD, some approaches are not based on identifying distinct categories of disorder using dichotomous symptom profiles intended to separate the abnormal from the normal. There is significant scientific debate about the relative merits of categorical versus such non-categorical (or hybrid) schemes, also known as continuum or dimensional models. A spectrum approach may incorporate elements of both.

In the scientific and academic literature on the definition or classification of mental disorder, one extreme argues that it is entirely a matter of value judgements (including of what is normal) while another proposes that it is or could be entirely objective and scientific (including by reference to statistical norms). Common hybrid views argue that the concept of mental disorder is objective even if only a "fuzzy prototype" that can never be precisely defined, or conversely that the concept always involves a mixture of scientific facts and subjective value judgments. Although the diagnostic categories are referred to as 'disorders', they are presented as medical diseases, but are not validated in the same way as most medical diagnoses. Some neurologists argue that classification will only be reliable and valid when based on neurobiological features rather than clinical interview, while others suggest that the differing ideological and practical perspectives need to be better integrated.

The DSM and ICD approach remains under attack both because of the implied causality model and because some researchers believe it better to aim at underlying brain differences which can precede symptoms by many years.

Dimensional models

The high degree of comorbidity between disorders in categorical models such as the DSM and ICD have led some to propose dimensional models. Studying comorbidity between disorders have demonstrated two latent (unobserved) factors or dimensions in the structure of mental disorders that are thought to possibly reflect etiological processes. These two dimensions reflect a distinction between internalizing disorders, such as mood or anxiety symptoms, and externalizing disorders such as behavioral or substance use symptoms. A single general factor of psychopathology, similar to the g factor for intelligence, has been empirically supported. The p factor model supports the internalizing-externalizing distinction, but also supports the formation of a third dimension of thought disorders such as schizophrenia. Biological evidence also supports the validity of the internalizing-externalizing structure of mental disorders, with twin and adoption studies supporting heritable factors for externalizing and internalizing disorders. A leading dimensional model is the Hierarchical Taxonomy of Psychopathology.

Disorders

See also: List of mental disorders as defined by the DSM and ICD

There are many different categories of mental disorder, and many different facets of human behavior and personality that can become disordered.

Anxiety disorders

Main article: Anxiety disorder

An anxiety disorder is anxiety or fear that interferes with normal functioning may be classified as an anxiety disorder. Commonly recognized categories include specific phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive–compulsive disorder and post-traumatic stress disorder.

Mood disorders

Main article: Mood disorder

Other affective (emotion/mood) processes can also become disordered. Mood disorder involving unusually intense and sustained sadness, melancholia, or despair is known as major depression (also known as unipolar or clinical depression). Milder, but still prolonged depression, can be diagnosed as dysthymia. Bipolar disorder (also known as manic depression) involves abnormally "high" or pressured mood states, known as mania or hypomania, alternating with normal or depressed moods. The extent to which unipolar and bipolar mood phenomena represent distinct categories of disorder, or mix and merge along a dimension or spectrum of mood, is subject to some scientific debate.

Psychotic disorders

Main article: Psychotic disorder

Patterns of belief, language use and perception of reality can become dysregulated (e.g., delusions, thought disorder, hallucinations). Psychotic disorders in this domain include schizophrenia, and delusional disorder. Schizoaffective disorder is a category used for individuals showing aspects of both schizophrenia and affective disorders. Schizotypy is a category used for individuals showing some of the characteristics associated with schizophrenia, but without meeting cutoff criteria.

Personality disorders

Main article: Personality disorder

Personality—the fundamental characteristics of a person that influence thoughts and behaviors across situations and time—may be considered disordered if judged to be abnormally rigid and maladaptive. Although treated separately by some, the commonly used categorical schemes include them as mental disorders, albeit on a separate axis II in the case of the DSM-IV. A number of different personality disorders are listed, including those sometimes classed as eccentric, such as paranoid, schizoid and schizotypal personality disorders; types that have described as dramatic or emotional, such as antisocial, borderline, histrionic or narcissistic personality disorders; and those sometimes classed as fear-related, such as anxious-avoidant, dependent, or obsessive–compulsive personality disorders. Personality disorders, in general, are defined as emerging in childhood, or at least by adolescence or early adulthood. The ICD also has a category for enduring personality change after a catastrophic experience or psychiatric illness. If an inability to sufficiently adjust to life circumstances begins within three months of a particular event or situation, and ends within six months after the stressor stops or is eliminated, it may instead be classed as an adjustment disorder. There is an emerging consensus that personality disorders, similar to personality traits in general, incorporate a mixture of acute dysfunctional behaviors that may resolve in short periods, and maladaptive temperamental traits that are more enduring. Furthermore, there are also non-categorical schemes that rate all individuals via a profile of different dimensions of personality without a symptom-based cutoff from normal personality variation, for example through schemes based on dimensional models.

Neurodevelopmental disorders

Main article: Neurodevelopmental disorder

Neurodevelopmental disorders is a group of mental disorder that affect the central nervous system, such as the brain and spinal cord. These disorders can appear in early childhood. They can even persist into adulthood. A few of the common ones are attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disabilities, motor disorders, and communication disorders among others. Some causes can contribute to these disorders like genetic factors (genetics, family medical history), environmental factors (excessive stress, exposure to neurotoxins, pollution, viral infections, and bacterial infections), physical factors (traumatic brain injury, illness), and prenatal factors (birth defects, exposure to drugs during pregnancy, low birth weight). Neurodevelopmental disorders can be managed with behavioral therapy, applied behavior analysis (ABA), educational interventions, specific medications, and other such treatments.

Approximately 8 in 10 people with autism suffer from a mental health problem in their lifetime, in comparison to 1 in 4 of the general population that suffers from a mental health problem in their lifetimes.

Eating disorders

Main article: Eating disorder

An eating disorder is a serious mental health condition that involves an unhealthy relationship with food and body image. They can cause severe physical and psychological problems. Eating disorders involve disproportionate concern in matters of food and weight. Categories of disorder in this area include anorexia nervosa, bulimia nervosa, exercise bulimia or binge eating disorder.

Sleep disorders

Main article: Sleep disorder

Sleep disorders are associated with disruption to normal sleep patterns. A common sleep disorder is insomnia, which is described as difficulty falling and/or staying asleep. Other sleep disorders include narcolepsy, sleep apnea, REM sleep behavior disorder, chronic sleep deprivation, and restless leg syndrome.

Narcolepsy is a condition of extreme tendencies to fall asleep whenever and wherever. People with narcolepsy feel refreshed after their random sleep, but eventually get sleepy again. Narcolepsy diagnosis requires an overnight stay at a sleep center for analysis, during which doctors ask for a detailed sleep history and sleep records. Doctors also use actigraphs and polysomnography. Doctors will do a multiple sleep latency test, which measures how long it takes a person to fall asleep.

Sleep apnea, when breathing repeatedly stops and starts during sleep, can be a serious sleep disorder. Three types of sleep apnea include obstructive sleep apnea, central sleep apnea, and complex sleep apnea. Sleep apnea can be diagnosed at home or with polysomnography at a sleep center. An ear, nose, and throat doctor may further help with the sleeping habits.

Sexuality related

Sexual disorders include dyspareunia and various kinds of paraphilia (sexual arousal to objects, situations, or individuals that are considered abnormal or harmful to the person or others). Sexual dysfunction is common among psychiatric patients, yet the specific impact of psychopathology independent of factors like psychotropic substances or somatic symptom disorders, remains unclear.

A systematic review explored the prevalence of sexual dysfunction in psychiatric patients free from psychotropic medications and somatic diseases. The review included 24 studies with 1,199 participants and identified high rates of sexual dysfunction across various psychiatric disorders. Reported prevalence ranged from 45%-93% for depressive disorders, 33%-75% for anxiety disorders, 25%-81% for obsessive–compulsive disorder (OCD), and 25% for schizophrenia. Sexual desire was frequently impaired in depressive disorders, PTSD, and schizophrenia, while OCD and anxiety disorders were associated with difficulties during the orgasm phase.

The findings emphasize the importance of addressing sexual health in psychiatric care through psychoeducation, sexual history assessments, and targeted interventions. This highlights the significant impact of psychopathology on sexual functioning.

Other

Impulse control disorders: People who are abnormally unable to resist certain urges or impulses that could be harmful to themselves or others, may be classified as having an impulse control disorder, and disorders such as kleptomania (stealing) or pyromania (fire-setting). Various behavioral addictions, such as gambling addiction, may be classed as a disorder. Obsessive–compulsive disorder can sometimes involve an inability to resist certain acts but is classed separately as being primarily an anxiety disorder.

Substance use disorders: This disorder refers to the use of drugs (legal or illegal, including alcohol) that persists despite significant problems or harm related to its use. Substance dependence and substance abuse fall under this umbrella category in the DSM. Substance use disorder may be due to a pattern of compulsive and repetitive use of a drug that results in tolerance to its effects and withdrawal symptoms when use is reduced or stopped.

Dissociative disorders: People with severe disturbances of their self-identity, memory, and general awareness of themselves and their surroundings may be classified as having these types of disorders, including depersonalization derealization disorder or dissociative identity disorder (which was previously referred to as multiple personality disorder or "split personality").

Cognitive disorders: These affect cognitive abilities, including learning and memory. This category includes delirium and mild and major neurocognitive disorder (previously termed dementia).

Somatoform disorders may be diagnosed when there are problems that appear to originate in the body that are thought to be manifestations of a mental disorder. This includes somatization disorder and conversion disorder. There are also disorders of how a person perceives their body, such as body dysmorphic disorder. Neurasthenia is an old diagnosis involving somatic complaints as well as fatigue and low spirits/depression, which is officially recognized by the ICD-10 but no longer by the DSM-IV.

Factitious disorders are diagnosed where symptoms are thought to be reported for personal gain. Symptoms are often deliberately produced or feigned, and may relate to either symptoms in the individual or in someone close to them, particularly people they care for.

There are attempts to introduce a category of relational disorder, where the diagnosis is of a relationship rather than on any one individual in that relationship. The relationship may be between children and their parents, between couples, or others. There already exists, under the category of psychosis, a diagnosis of shared psychotic disorder where two or more individuals share a particular delusion because of their close relationship with each other.

There are a number of uncommon psychiatric syndromes, which are often named after the person who first described them, such as Capgras syndrome, De Clerambault syndrome, Othello syndrome, Ganser syndrome, Cotard delusion, and Ekbom syndrome, and additional disorders such as the Couvade syndrome and Geschwind syndrome.

Signs and symptoms

Course

The onset of psychiatric disorders usually occurs from childhood to early adulthood. Impulse-control disorders and a few anxiety disorders tend to appear in childhood. Some other anxiety disorders, substance disorders, and mood disorders emerge later in the mid-teens. Symptoms of schizophrenia typically manifest from late adolescence to early twenties.

The likely course and outcome of mental disorders vary and are dependent on numerous factors related to the disorder itself, the individual as a whole, and the social environment. Some disorders may last a brief period of time, while others may be long-term in nature.

All disorders can have a varied course. Long-term international studies of schizophrenia have found that over a half of individuals recover in terms of symptoms, and around a fifth to a third in terms of symptoms and functioning, with many requiring no medication. While some have serious difficulties and support needs for many years, "late" recovery is still plausible. The World Health Organization (WHO) concluded that the long-term studies' findings converged with others in "relieving patients, carers and clinicians of the chronicity paradigm which dominated thinking throughout much of the 20th century."

A follow-up study by Tohen and coworkers revealed that around half of people initially diagnosed with bipolar disorder achieve symptomatic recovery (no longer meeting criteria for the diagnosis) within six weeks, and nearly all achieve it within two years, with nearly half regaining their prior occupational and residential status in that period. Less than half go on to experience a new episode of mania or major depression within the next two years.

Disability

Disorder	Disability-adjusted life years
Major depressive disorder	65.5 million
Alcohol-use disorder	23.7 million
Schizophrenia	16.8 million
Bipolar disorder	14.4 million
Other drug-use disorders	8.4 million
Panic disorder	7.0 million
Obsessive–compulsive disorder	5.1 million
Primary insomnia	3.6 million
Post-traumatic stress disorder	3.5 million

Some disorders may be very limited in their functional effects, while others may involve substantial disability and support needs. In this context, the terms psychiatric disability and psychological disability are sometimes used instead of mental disorder. The degree of ability or disability may vary over time and across different life domains. Furthermore, psychiatric disability has been linked to institutionalization, discrimination and social exclusion as well as to the inherent effects of disorders. Alternatively, functioning may be affected by the stress of having to hide a condition in work or school, etc., by adverse effects of medications or other substances, or by mismatches between illness-related variations and demands for regularity.

It is also the case that, while often being characterized in purely negative terms, some mental traits or states labeled as psychiatric disabilities can also involve above-average creativity, non-conformity, goal-striving, meticulousness, or empathy. In addition, the public perception of the level of disability associated with mental disorders can change.

Nevertheless, internationally, people report equal or greater disability from commonly occurring mental conditions than from commonly occurring physical conditions, particularly in their social roles and personal relationships. The proportion with access to professional help for mental disorders is far lower, however, even among those assessed as having a severe psychiatric disability. Disability in this context may or may not involve such things as:

• Basic activities of daily living. Including looking after the self (health care, grooming, dressing, shopping, cooking etc.) or looking after accommodation (chores, DIY tasks, etc.)
• Interpersonal relationships. Including communication skills, ability to form relationships and sustain them, ability to leave the home or mix in crowds or particular settings
• Occupational functioning. Ability to acquire an employment and hold it, cognitive and social skills required for the job, dealing with workplace culture, or studying as a student.

In terms of total disability-adjusted life years (DALYs), which is an estimate of how many years of life are lost due to premature death or to being in a state of poor health and disability, psychiatric disabilities rank amongst the most disabling conditions. Unipolar (also known as Major) depressive disorder is the third leading cause of disability worldwide, of any condition mental or physical, accounting for 65.5 million years lost. The first systematic description of global disability arising in youth, in 2011, found that among 10- to 24-year-olds nearly half of all disability (current and as estimated to continue) was due to psychiatric disabilities, including substance use disorders and conditions involving self-harm. Second to this were accidental injuries (mainly traffic collisions) accounting for 12 percent of disability, followed by communicable diseases at 10 percent. The psychiatric disabilities associated with most disabilities in high-income countries were unipolar major depression (20%) and alcohol use disorder (11%). In the eastern Mediterranean region, it was unipolar major depression (12%) and schizophrenia (7%), and in Africa it was unipolar major depression (7%) and bipolar disorder (5%).

Suicide, which is often attributed to some underlying mental disorder, is a leading cause of death among teenagers and adults under 35. There are an estimated 10 to 20 million non-fatal attempted suicides every year worldwide.

Risk factors

Main article: Causes of mental disorders

The predominant view as of 2018 is that genetic, psychological, and environmental factors all contribute to the development or progression of mental disorders. Different risk factors may be present at different ages, with risk occurring as early as during prenatal period.

Genetics

Main article: Psychiatric genetics

A number of psychiatric disorders are linked to a family history (including depression, narcissistic personality disorder and anxiety). Twin studies have also revealed a very high heritability for many mental disorders (especially autism and schizophrenia). Although researchers have been looking for decades for clear linkages between genetics and mental disorders, that work has not yielded specific genetic biomarkers yet that might lead to better diagnosis and better treatments.

Statistical research looking at eleven disorders found widespread assortative mating between people with mental illness. That means that individuals with one of these disorders were two to three times more likely than the general population to have a partner with a mental disorder. Sometimes people seemed to have preferred partners with the same mental illness. Thus, people with schizophrenia or ADHD are seven times more likely to have affected partners with the same disorder. This is even more pronounced for people with Autism spectrum disorders who are 10 times more likely to have a spouse with the same disorder.

Environment

Main article: Brain health and pollution

The prevalence of mental illness is higher in more economically unequal countries.

During the prenatal stage, factors like unwanted pregnancy, lack of adaptation to pregnancy or substance use during pregnancy increases the risk of developing a mental disorder. Maternal stress and birth complications including prematurity and infections have also been implicated in increasing susceptibility for mental illness. Infants neglected or not provided optimal nutrition have a higher risk of developing cognitive impairment.

Social influences have also been found to be important, including abuse, neglect, bullying, social stress, traumatic events, and other negative or overwhelming life experiences. Aspects of the wider community have also been implicated, including employment problems, socioeconomic inequality, lack of social cohesion, problems linked to migration, and features of particular societies and cultures. The specific risks and pathways to particular disorders are less clear, however.

Nutrition also plays a role in mental disorders.

In schizophrenia and psychosis, risk factors include migration and discrimination, childhood trauma, bereavement or separation in families, recreational use of drugs, and urbanicity.

In anxiety, risk factors may include parenting factors including parental rejection, lack of parental warmth, high hostility, harsh discipline, high maternal negative affect, anxious childrearing, modelling of dysfunctional and drug-abusing behavior, and child abuse (emotional, physical and sexual). Adults with imbalance work to life are at higher risk for developing anxiety.

For bipolar disorder, stress (such as childhood adversity) is not a specific cause, but does place genetically and biologically vulnerable individuals at risk for a more severe course of illness.

Drug use

Mental disorders are associated with drug use including: cannabis, alcohol and caffeine, use of which appears to promote anxiety. For psychosis and schizophrenia, usage of a number of drugs has been associated with development of the disorder, including cannabis, cocaine, and amphetamines. There has been debate regarding the relationship between usage of cannabis and bipolar disorder. Cannabis has also been associated with depression. Adolescents are at increased risk for tobacco, alcohol and drug use; Peer pressure is the main reason why adolescents start using substances. At this age, the use of substances could be detrimental to the development of the brain and place them at higher risk of developing a mental disorder.

Chronic disease

People living with chronic conditions like HIV and diabetes are at higher risk of developing a mental disorder. People living with diabetes experience significant stress from the biological impact of the disease, which places them at risk for developing anxiety and depression. Diabetic patients also have to deal with emotional stress trying to manage the disease. Conditions like heart disease, stroke, respiratory conditions, cancer, and arthritis increase the risk of developing a mental disorder when compared to the general population.

Personality traits

Risk factors for mental illness include a propensity for high neuroticism or "emotional instability". In anxiety, risk factors may include temperament and attitudes (e.g. pessimism). Key personality traits, including Neuroticism, Extraversion, Agreeableness, Conscientiousness, and Openness, significantly influence various dimensions of mental health, as measured by the General Health Questionnaire(GHQ-12). The GHQ-12 assesses mental health across three dimensions: GHQ-12A (social dysfunction & anhedonia), GHQ-12B (depression & anxiety), and GHQ-12C (loss of confidence). Neuroticism was found to be strongly linked to all three dimensions, indicating greater vulnerability to mental health issues, while Extraversion was negatively associated with social dysfunction and depression, suggesting better mental health outcomes.Agreeableness and Conscientiousness were both negatively related to social dysfunction and loss of confidence, highlighting their protective roles. Openness showed a negative relationship with depression and anxiety.

These findings support several models of personality's impact on mental health, including the predisposition/vulnerability, complication/scar, and pathoplasty/exacerbation models. This underscores the importance of considering personality traits in mental health assessments and interventions, as they help identify individuals at higher risk for mental health challenges and guide targeted psychological care.

Causal models

Mental disorders can arise from multiple sources, and in many cases there is no single accepted or consistent cause currently established. An eclectic or pluralistic mix of models may be used to explain particular disorders. The primary paradigm of contemporary mainstream Western psychiatry is said to be the biopsychosocial model which incorporates biological, psychological and social factors, although this may not always be applied in practice.

Biological psychiatry follows a biomedical model where many mental disorders are conceptualized as disorders of brain circuits likely caused by developmental processes shaped by a complex interplay of genetics and experience. A common assumption is that disorders may have resulted from genetic and developmental vulnerabilities, exposed by stress in life (for example in a diathesis–stress model), although there are various views on what causes differences between individuals. Some types of mental disorders may be viewed as primarily neurodevelopmental disorders.

Evolutionary psychology may be used as an overall explanatory theory, while attachment theory is another kind of evolutionary-psychological approach sometimes applied in the context of mental disorders. Psychoanalytic theories have continued to evolve alongside and cognitive-behavioral and systemic-family approaches. A distinction is sometimes made between a "medical model" or a "social model" of psychiatric disability.

Diagnosis

Psychiatrists seek to provide a medical diagnosis of individuals by an assessment of symptoms, signs and impairment associated with particular types of mental disorder. Other mental health professionals, such as clinical psychologists, may or may not apply the same diagnostic categories to their clinical formulation of a client's difficulties and circumstances.^[110] The majority of mental health problems are, at least initially, assessed and treated by family physicians (in the UK general practitioners) during consultations, who may refer a patient on for more specialist diagnosis in acute or chronic cases.

Routine diagnostic practice in mental health services typically involves an interview known as a mental status examination, where evaluations are made of appearance and behavior, self-reported symptoms, mental health history, and current life circumstances. The views of other professionals, relatives, or other third parties may be taken into account. A physical examination to check for ill health or the effects of medications or other drugs may be conducted. Psychological testing is sometimes used via paper-and-pen or computerized questionnaires, which may include algorithms based on ticking off standardized diagnostic criteria, and in rare specialist cases neuroimaging tests may be requested, but such methods are more commonly found in research studies than routine clinical practice.

Time and budgetary constraints often limit practicing psychiatrists from conducting more thorough diagnostic evaluations. It has been found that most clinicians evaluate patients using an unstructured, open-ended approach, with limited training in evidence-based assessment methods, and that inaccurate diagnosis may be common in routine practice. In addition, comorbidity is very common in psychiatric diagnosis, where the same person meets the criteria for more than one disorder. On the other hand, a person may have several different difficulties only some of which meet the criteria for being diagnosed. There may be specific problems with accurate diagnosis in developing countries.

More structured approaches are being increasingly used to measure levels of mental illness.

• HoNOS is the most widely used measure in English mental health services, being used by at least 61 trusts. In HoNOS a score of 0–4 is given for each of 12 factors, based on functional living capacity. Research has been supportive of HoNOS, although some questions have been asked about whether it provides adequate coverage of the range and complexity of mental illness problems, and whether the fact that often only 3 of the 12 scales vary over time gives enough subtlety to accurately measure outcomes of treatment.

Criticism

Since the 1980s, Paula Caplan has been concerned about the subjectivity of psychiatric diagnosis, and people being arbitrarily "slapped with a psychiatric label." Caplan says because psychiatric diagnosis is unregulated, doctors are not required to spend much time interviewing patients or to seek a second opinion. The Diagnostic and Statistical Manual of Mental Disorders can lead a psychiatrist to focus on narrow checklists of symptoms, with little consideration of what is actually causing the person's problems. So, according to Caplan, getting a psychiatric diagnosis and label often stands in the way of recovery.

In 2013, psychiatrist Allen Frances wrote a paper entitled "The New Crisis of Confidence in Psychiatric Diagnosis", which said that "psychiatric diagnosis... still relies exclusively on fallible subjective judgments rather than objective biological tests." Frances was also concerned about "unpredictable overdiagnosis". For many years, marginalized psychiatrists (such as Peter Breggin, Thomas Szasz) and outside critics (such as Stuart A. Kirk) have "been accusing psychiatry of engaging in the systematic medicalization of normality." More recently these concerns have come from insiders who have worked for and promoted the American Psychiatric Association (e.g., Robert Spitzer, Allen Frances). A 2002 editorial in the British Medical Journal warned of inappropriate medicalization leading to disease mongering, where the boundaries of the definition of illnesses are expanded to include personal problems as medical problems or risks of diseases are emphasized to broaden the market for medications.

Gary Greenberg, a psychoanalyst, in his book "the Book of Woe", argues that mental illness is really about suffering and how the DSM creates diagnostic labels to categorize people's suffering.^[123] Indeed, the psychiatrist Thomas Szasz, in his book "the Medicalization of Everyday Life", also argues that what is psychiatric illness, is not always biological in nature (i.e. social problems, poverty, etc.), and may even be a part of the human condition.

Potential routine use of MRI/fMRI in diagnosis

in 2018 the American Psychological Association commissioned a review to reach a consensus on whether modern clinical MRI/fMRI will be able to be used in the diagnosis of mental health disorders. The criteria presented by the APA stated that the biomarkers used in diagnosis should:

1. "have a sensitivity of at least 80% for detecting a particular psychiatric disorder"
2. should "have a specificity of at least 80% for distinguishing this disorder from other psychiatric or medical disorders"
3. "should be reliable, reproducible, and ideally be noninvasive, simple to perform, and inexpensive"
4. proposed biomarkers should be verified by 2 independent studies each by a different investigator and different population samples and published in a peer-reviewed journal.

The review concluded that although neuroimaging diagnosis may technically be feasible, very large studies are needed to evaluate specific biomarkers which were not available.

Prevention

Main article: Prevention of mental disorders

The 2004 WHO report "Prevention of Mental Disorders" stated that "Prevention of these disorders is obviously one of the most effective ways to reduce the [disease] burden." The 2011 European Psychiatric Association (EPA) guidance on prevention of mental disorders states "There is considerable evidence that various psychiatric conditions can be prevented through the implementation of effective evidence-based interventions." A 2011 UK Department of Health report on the economic case for mental health promotion and mental illness prevention found that "many interventions are outstandingly good value for money, low in cost and often become self-financing over time, saving public expenditure". In 2016, the National Institute of Mental Health re-affirmed prevention as a research priority area.

Parenting may affect the child's mental health, and evidence suggests that helping parents to be more effective with their children can address mental health needs.

Universal prevention (aimed at a population that has no increased risk for developing a mental disorder, such as school programs or mass media campaigns) need very high numbers of people to show effect (sometimes known as the "power" problem). Approaches to overcome this are (1) focus on high-incidence groups (e.g. by targeting groups with high risk factors), (2) use multiple interventions to achieve greater, and thus more statistically valid, effects, (3) use cumulative meta-analyses of many trials, and (4) run very large trials.

Management

Main articles: Treatment of mental disorders, Services for mental disorders, and Mental health professional

The "Haus Tornow am See" (former manor house) in Germany from 1912 is today separated into a special education school and a hotel with integrated work/job- and rehabilitation-training for people with mental disorders.

Treatment and support for mental disorders are provided in psychiatric hospitals, clinics or a range of community mental health services. In some countries services are increasingly based on a recovery approach, intended to support individual's personal journey to gain the kind of life they want.

There is a range of different types of treatment and what is most suitable depends on the disorder and the individual. Many things have been found to help at least some people, and a placebo effect may play a role in any intervention or medication. In a minority of cases, individuals may be treated against their will, which can cause particular difficulties depending on how it is carried out and perceived. Compulsory treatment while in the community versus non-compulsory treatment does not appear to make much of a difference except by maybe decreasing victimization.

Lifestyle

Lifestyle strategies, including dietary changes, exercise and quitting smoking may be of benefit.

Dietary patterns can influence the risk and management of mental disorders. Observational studies have shown that nutrient-dense, whole-food diets - such as the Mediterranean diet, which is rich in fruits, vegetables, whole grains, legumes, nuts, fish, and healthy fats like olive oil - are associated with a lower risk of depression and anxiety. In contrast, Western diets high in ultra-processed foods, refined sugars, and saturated fats are linked to a greater incidence of mental health disorders, potentially due to their impact on neuroinflammation, oxidative stress, gut microbiota, and neuroplasticity.

Therapy

There is also a wide range of psychotherapists (including family therapy), counselors, and public health professionals. In addition, there are peer support roles where personal experience of similar issues is the primary source of expertise.

A major option for many mental disorders is psychotherapy. There are several main types. Cognitive behavioral therapy (CBT) is widely used and is based on modifying the patterns of thought and behavior associated with a particular disorder. Other psychotherapies include dialectic behavioral therapy (DBT) and interpersonal psychotherapy (IPT). Psychoanalysis, addressing underlying psychic conflicts and defenses, has been a dominant school of psychotherapy and is still in use. Systemic therapy or family therapy is sometimes used, addressing a network of significant others as well as an individual.

Some psychotherapies are based on a humanistic approach. There are many specific therapies used for particular disorders, which may be offshoots or hybrids of the above types. Mental health professionals often employ an eclectic or integrative approach. Much may depend on the therapeutic relationship, and there may be problems with trust, confidentiality and engagement.

Medication

A major option for many mental disorders is psychiatric medication and there are several main groups. Antidepressants are used for the treatment of clinical depression, as well as often for anxiety and a range of other disorders. Anxiolytics (including sedatives) are used for anxiety disorders and related problems such as insomnia. Mood stabilizers are used primarily in bipolar disorder. Antipsychotics are used for psychotic disorders, notably for positive symptoms in schizophrenia, and also increasingly for a range of other disorders. Stimulants are commonly used, notably for ADHD.

Other

Electroconvulsive therapy (ECT) is sometimes used in severe cases when other interventions for severe intractable depression have failed. ECT is usually indicated for treatment resistant depression, severe vegetative symptoms, psychotic depression, intense suicidal ideation, depression during pregnancy, and catatonia. Psychosurgery is considered experimental but is advocated by some neurologists in certain rare cases.

Counseling (professional) and co-counseling (between peers) may be used. Psychoeducation programs may provide people with the information to understand and manage their problems. Creative therapies are sometimes used, including music therapy, art therapy or drama therapy. Lifestyle adjustments and supportive measures are often used, including peer support, self-help groups for mental health and supported housing or supported employment (including social firms). Some advocate dietary supplements.

Reasonable accommodations (adjustments and supports) might be put in place to help an individual cope and succeed in environments despite potential disability related to mental health problems. This could include an emotional support animal or specifically trained psychiatric service dog. As of 2019 cannabis is specifically not recommended as a treatment.

Epidemiology

Main article: Prevalence of mental disorders

Deaths from mental and behavioral disorders per million persons in 2012

  0–6

  7–9

  10–15

  16–24

  25–31

  32–39

  40–53

  54–70

  71–99

  100–356

Disability-adjusted life year for neuropsychiatric conditions per 100,000 inhabitants in 2004

  <2,200

  2,200–2,400

  2,400–2,600

  2,600–2,800

  2,800–3,000

  3,000–3,200

  3,200–3,400

  3,400–3,600

  3,600–3,800

  3,800–4,000

  4,000–4,200

  >4,200

Mental disorders are common. Worldwide, more than one in three people in most countries report sufficient criteria for at least one at some point in their life. In the United States, 46% qualify for a mental illness at some point. An ongoing survey indicates that anxiety disorders are the most common in all but one country, followed by mood disorders in all but two countries, while substance disorders and impulse-control disorders were consistently less prevalent. Rates varied by region.

A review of anxiety disorder surveys in different countries found average lifetime prevalence estimates of 16.6%, with women having higher rates on average. A review of mood disorder surveys in different countries found lifetime rates of 6.7% for major depressive disorder (higher in some studies, and in women) and 0.8% for Bipolar I disorder.

In the United States the frequency of disorder is: anxiety disorder (28.8%), mood disorder (20.8%), impulse-control disorder (24.8%) or substance use disorder (14.6%).

A 2004 cross-Europe study found that approximately one in four people reported meeting criteria at some point in their life for at least one of the DSM-IV disorders assessed, which included mood disorders (13.9%), anxiety disorders (13.6%), or alcohol disorder (5.2%). Approximately one in ten met the criteria within a 12-month period. Women and younger people of either gender showed more cases of the disorder. A 2005 review of surveys in 16 European countries found that 27% of adult Europeans are affected by at least one mental disorder in a 12-month period.

An international review of studies on the prevalence of schizophrenia found an average (median) figure of 0.4% for lifetime prevalence; it was consistently lower in poorer countries.

Studies of the prevalence of personality disorders (PDs) have been fewer and smaller-scale, but one broad Norwegian survey found a five-year prevalence of almost 1 in 7 (13.4%). Rates for specific disorders ranged from 0.8% to 2.8%, differing across countries, and by gender, educational level and other factors. A US survey that incidentally screened for personality disorder found a rate of 14.79%.

Approximately 7% of a preschool pediatric sample were given a psychiatric diagnosis in one clinical study, and approximately 10% of 1- and 2-year-olds receiving developmental screening have been assessed as having significant emotional/behavioral problems based on parent and pediatrician reports.

While rates of psychological disorders are often the same for men and women, women tend to have a higher rate of depression. Each year 73 million women are affected by major depression, and suicide is ranked 7th as the cause of death for women between the ages of 20–59. Depressive disorders account for close to 41.9% of the psychiatric disabilities among women compared to 29.3% among men.

History

Main article: History of mental disorders

Ancient civilizations

Ancient civilizations described and treated a number of mental disorders. Mental illnesses were well known in ancient Mesopotamia, where diseases and mental disorders were believed to be caused by specific deities. Because hands symbolized control over a person, mental illnesses were known as "hands" of certain deities. One psychological illness was known as Qāt Ištar, meaning "Hand of Ishtar". Others were known as "Hand of Shamash", "Hand of the Ghost", and "Hand of the God". Descriptions of these illnesses, however, are so vague that it is usually impossible to determine which illnesses they correspond to in modern terminology. Mesopotamian doctors kept detailed record of their patients' hallucinations and assigned spiritual meanings to them. The royal family of Elam was notorious for its members often being insane. The Greeks coined terms for melancholy, hysteria and phobia and developed the humorism theory. Mental disorders were described, and treatments developed, in Persia, Arabia and in the medieval Islamic world.

Europe

Middle Ages

Conceptions of madness in the Middle Ages in Christian Europe were a mixture of the divine, diabolical, magical and humoral, and transcendental. In the early modern period, some people with mental disorders may have been victims of the witch-hunts. While not every witch and sorcerer accused were mentally ill, all mentally ill were considered to be witches or sorcerers. Many terms for mental disorders that found their way into everyday use first became popular in the 16th and 17th centuries.

Eighteenth century

Eight patients representing mental diagnoses as of the 19th century at the Salpêtrière, Paris

By the end of the 17th century and into the Enlightenment, madness was increasingly seen as an organic physical phenomenon with no connection to the soul or moral responsibility. Asylum care was often harsh and treated people like wild animals, but towards the end of the 18th century a moral treatment movement gradually developed. Clear descriptions of some syndromes may be rare before the 19th century.

Nineteenth century

Industrialization and population growth led to a massive expansion of the number and size of insane asylums in every Western country in the 19th century. Numerous different classification schemes and diagnostic terms were developed by different authorities, and the term psychiatry was coined (1808), though medical superintendents were still known as alienists.

Twentieth century

A patient in a strait-jacket and barrel contraption, 1908

The turn of the 20th century saw the development of psychoanalysis, which would later come to the fore, along with Kraepelin's classification scheme. Asylum "inmates" were increasingly referred to as "patients", and asylums were renamed as hospitals.

Europe and the United States

Insulin shock procedure, 1950s

Early in the 20th century in the United States, a mental hygiene movement developed, aiming to prevent mental disorders. Clinical psychology and social work developed as professions. World War I saw a massive increase of conditions that came to be termed "shell shock".

World War II saw the development in the U.S. of a new psychiatric manual for categorizing mental disorders, which along with existing systems for collecting census and hospital statistics led to the first Diagnostic and Statistical Manual of Mental Disorders. The International Classification of Diseases (ICD) also developed a section on mental disorders. The term stress, having emerged from endocrinology work in the 1930s, was increasingly applied to mental disorders.

Electroconvulsive therapy, insulin shock therapy, lobotomies and the neuroleptic chlorpromazine came to be used by mid-century. In the 1960s there were many challenges to the concept of mental illness itself. These challenges came from psychiatrists like Thomas Szasz who argued that mental illness was a myth used to disguise moral conflicts; from sociologists such as Erving Goffman who said that mental illness was merely another example of how society labels and controls non-conformists; from behavioral psychologists who challenged psychiatry's fundamental reliance on unobservable phenomena; and from gay rights activists who criticised the APA's listing of homosexuality as a mental disorder. A study published in Science by Rosenhan received much publicity and was viewed as an attack on the efficacy of psychiatric diagnosis.

Deinstitutionalization gradually occurred in the West, with isolated psychiatric hospitals being closed down in favor of community mental health services. A consumer/survivor movement gained momentum. Other kinds of psychiatric medication gradually came into use, such as "psychic energizers" (later antidepressants) and lithium. Benzodiazepines gained widespread use in the 1970s for anxiety and depression, until dependency problems curtailed their popularity.

Advances in neuroscience, genetics, and psychology led to new research agendas. Cognitive behavioral therapy and other psychotherapies developed. The DSM and then ICD adopted new criteria-based classifications, and the number of "official" diagnoses saw a large expansion. Through the 1990s, new SSRI-type antidepressants became some of the most widely prescribed drugs in the world, as later did antipsychotics. Also during the 1990s, a recovery approach developed.

Africa and Nigeria

Most Africans view mental disturbances as external spiritual attack on the person. Those who have a mental illness are thought to be under a spell or bewitched. Often than usual, People view a mentally ill person as possessed of an evil spirit and is seen as more of sociological perspective than a psychological order.

The WHO estimated that fewer than 10% of mentally ill Nigerians have access to a psychiatrist or health worker, because there is a low ratio of mental-health specialists available in a country of 200 million people. WHO estimates that the number of mentally ill Nigerians ranges from 40 million to 60 million. Disorders such as depression, anxiety, schizophrenia, personality disorder, old age-related disorder, and substance-abuse disorder are common in Nigeria, as in other countries in Africa.

Nigeria is still nowhere near being equipped to solve prevailing mental health challenges. With little scientific research carried out, coupled with insufficient mental-health hospitals in the country, traditional healers provide specialized psychotherapy care to those that require their services and pharmacotherapy.

China

The history of mental illness management in China dates back to the Tang Dynasty (618-907 AD), when the Bei Tian Fang, a charity facility run by monks, provided care for homeless widows, orphans, and individuals with mental illness. This early approach laid the foundation for structured mental health care. The first Western-style psychiatric hospital was established in 1898 by American missionary John Kerr in what is now the Guangzhou Brain Hospital. However, psychiatric hospital development was slow over the next 50 years, with only a handful of facilities emerging in major cities. By mid-20th century, China had approximately 100 psychiatrists and 1,000 psychiatric beds.

Following the establishment of the People's Republic of China in 1949, psychiatric hospitals were introduced in every province, primarily aimed at maintaining social stability. The first National Mental Health Meeting in 1958 initiated community mental health programs in key regions like Beijing, Shanghai, Hunan, Sichuan, and Jiangsu. These programs focused on professional training, early intervention, and relapse prevention. However, during the Cultural Revolution (1966-1976), most community mental health initiatives ceased, although localized rehabilitation centers and community care networks persisted in places like Shanghai and Beijing.

Society and culture

Different societies or cultures, even different individuals in a subculture, can disagree as to what constitutes optimal versus pathological biological and psychological functioning. Research has demonstrated that cultures vary in the relative importance placed on, for example, happiness, autonomy, or social relationships for pleasure. Likewise, the fact that a behavior pattern is valued, accepted, encouraged, or even statistically normative in a culture does not necessarily mean that it is conducive to optimal psychological functioning.

People in all cultures find some behaviors bizarre or even incomprehensible. But just what they feel is bizarre or incomprehensible is ambiguous and subjective. These differences in determination can become highly contentious. The process by which conditions and difficulties come to be defined and treated as medical conditions and problems, and thus come under the authority of doctors and other health professionals, is known as medicalization or pathologization.

Mental illness in the Latin American community

There is a perception in Latin American communities, especially among older people, that discussing problems with mental health can create embarrassment and shame for the family. This results in fewer people seeking treatment.

Latin Americans from the US are slightly more likely to have a mental health disorder than first-generation Latin American immigrants, although differences between ethnic groups were found to disappear after adjustment for place of birth.

From 2015 to 2018, rates of serious mental illness in young adult Latin Americans increased by 60%, from 4% to 6.4%. The prevalence of major depressive episodes in young and adult Latin Americans increased from 8.4% to 11.3%. More than a third of Latin Americans reported more than one bad mental health day in the last three months. The rate of suicide among Latin Americans was about half the rate of non-Latin American white Americans in 2018, and this was the second-leading cause of death among Latin Americans ages 15 to 34. However, Latin American suicide rates rose steadily after 2020 in relation to the COVID-19 pandemic, even as the national rate declined.

Family relations are an integral part of the Latin American community. Some research has shown that Latin Americans are more likely rely on family bonds, or familismo, as a source of therapy while struggling with mental health issues. Because Latin Americans have a high rate of religiosity, and because there is less stigma associated with religion than with psychiatric services, religion may play a more important therapeutic role for the mentally ill in Latin American communities. However, research has also suggested that religion may also play a role in stigmatizing mental illness in Latin American communities, which can discourage community members from seeking professional help.

Religion

See also: Psychology of religion

Religious, spiritual, or transpersonal experiences and beliefs meet many criteria of delusional or psychotic disorders. A belief or experience can sometimes be shown to produce distress or disability—the ordinary standard for judging mental disorders. There is a link between religion and schizophrenia, a complex mental disorder characterized by a difficulty in recognizing reality, regulating emotional responses, and thinking in a clear and logical manner. Those with schizophrenia commonly report some type of religious delusion, and religion itself may be a trigger for schizophrenia.

Movements

Giorgio Antonucci

Thomas Szasz

Controversy has often surrounded psychiatry, and the term anti-psychiatry was coined by the psychiatrist David Cooper in 1967. The anti-psychiatry message is that psychiatric treatments are ultimately more damaging than helpful to patients, and psychiatry's history involves what may now be seen as dangerous treatments. Electroconvulsive therapy was one of these, which was used widely between the 1930s and 1960s. Lobotomy was another practice that was ultimately seen as too invasive and brutal. Diazepam and other sedatives were sometimes over-prescribed, which led to an epidemic of dependence. There was also concern about the large increase in prescribing psychiatric drugs for children. Some charismatic psychiatrists came to personify the movement against psychiatry. The most influential of these was R.D. Laing who wrote a series of best-selling books, including The Divided Self. Thomas Szasz wrote The Myth of Mental Illness. Some ex-patient groups have become militantly anti-psychiatric, often referring to themselves as survivors. Giorgio Antonucci has questioned the basis of psychiatry through his work on the dismantling of two psychiatric hospitals (in the city of Imola), carried out from 1973 to 1996.

The consumer/survivor movement (also known as user/survivor movement) is made up of individuals (and organizations representing them) who are clients of mental health services or who consider themselves survivors of psychiatric interventions. Activists campaign for improved mental health services and for more involvement and empowerment within mental health services, policies and wider society. Patient advocacy organizations have expanded with increasing deinstitutionalization in developed countries, working to challenge the stereotypes, stigma and exclusion associated with psychiatric conditions. There is also a carers rights movement of people who help and support people with mental health conditions, who may be relatives, and who often work in difficult and time-consuming circumstances with little acknowledgement and without pay. An anti-psychiatry movement fundamentally challenges mainstream psychiatric theory and practice, including in some cases asserting that psychiatric concepts and diagnoses of 'mental illness' are neither real nor useful.

Alternatively, a movement for global mental health has emerged, defined as 'the area of study, research and practice that places a priority on improving mental health and achieving equity in mental health for all people worldwide'.

Cultural bias

See also: Depression and culture and Cultural competence in healthcare

Diagnostic guidelines of the 2000s, namely the DSM and to some extent the ICD, have been criticized as having a fundamentally Euro-American outlook. Opponents argue that even when diagnostic criteria are used across different cultures, it does not mean that the underlying constructs have validity within those cultures, as even reliable application can prove only consistency, not legitimacy. Advocating a more culturally sensitive approach, critics such as Carl Bell and Marcello Maviglia contend that the cultural and ethnic diversity of individuals is often discounted by researchers and service providers.

Cross-cultural psychiatrist Arthur Kleinman contends that the Western bias is ironically illustrated in the introduction of cultural factors to the DSM-IV. Disorders or concepts from non-Western or non-mainstream cultures are described as "culture-bound", whereas standard psychiatric diagnoses are given no cultural qualification whatsoever, revealing to Kleinman an underlying assumption that Western cultural phenomena are universal. Kleinman's negative view towards the culture-bound syndrome is largely shared by other cross-cultural critics. Common responses included both disappointment over the large number of documented non-Western mental disorders still left out and frustration that even those included are often misinterpreted or misrepresented.

Many mainstream psychiatrists are dissatisfied with the new culture-bound diagnoses, although for partly different reasons. Robert Spitzer, a lead architect of the DSM-III, has argued that adding cultural formulations was an attempt to appease cultural critics, and has stated that they lack any scientific rationale or support. Spitzer also posits that the new culture-bound diagnoses are rarely used, maintaining that the standard diagnoses apply regardless of the culture involved. In general, mainstream psychiatric opinion remains that if a diagnostic category is valid, cross-cultural factors are either irrelevant or are significant only to specific symptom presentations.

Clinical conceptions of mental illness also overlap with personal and cultural values in the domain of morality, so much so that it is sometimes argued that separating the two is impossible without fundamentally redefining the essence of being a particular person in a society. In clinical psychiatry, persistent distress and disability indicate an internal disorder requiring treatment; but in another context, that same distress and disability can be seen as an indicator of emotional struggle and the need to address social and structural problems. This dichotomy has led some academics and clinicians to advocate a postmodernist conceptualization of mental distress and well-being.

Such approaches, along with cross-cultural and "heretical" psychologies centered on alternative cultural and ethnic and race-based identities and experiences, stand in contrast to the mainstream psychiatric community's alleged avoidance of any explicit involvement with either morality or culture. In many countries there are attempts to challenge perceived prejudice against minority groups, including alleged institutional racism within psychiatric services. There are also ongoing attempts to improve professional cross cultural sensitivity.

Laws and policies

See also: Mental health law

Three-quarters of countries around the world have mental health legislation. Compulsory admission to mental health facilities (also known as involuntary commitment) is a controversial topic. It can impinge on personal liberty and the right to choose, and carry the risk of abuse for political, social, and other reasons; yet it can potentially prevent harm to self and others, and assist some people in attaining their right to healthcare when they may be unable to decide in their own interests. Because of this it is a concern of medical ethics.

All human rights oriented mental health laws require proof of the presence of a mental disorder as defined by internationally accepted standards, but the type and severity of disorder that counts can vary in different jurisdictions. The two most often used grounds for involuntary admission are said to be serious likelihood of immediate or imminent danger to self or others, and the need for treatment. Applications for someone to be involuntarily admitted usually come from a mental health practitioner, a family member, a close relative, or a guardian. Human-rights-oriented laws usually stipulate that independent medical practitioners or other accredited mental health practitioners must examine the patient separately and that there should be regular, time-bound review by an independent review body. The individual should also have personal access to independent advocacy.

For involuntary treatment to be administered (by force if necessary), it should be shown that an individual lacks the mental capacity for informed consent (i.e. to understand treatment information and its implications, and therefore be able to make an informed choice to either accept or refuse). Legal challenges in some areas have resulted in supreme court decisions that a person does not have to agree with a psychiatrist's characterization of the issues as constituting an "illness", nor agree with a psychiatrist's conviction in medication, but only recognize the issues and the information about treatment options.

Proxy consent (also known as surrogate or substituted decision-making) may be transferred to a personal representative, a family member, or a legally appointed guardian. Moreover, patients may be able to make, when they are considered well, an advance directive stipulating how they wish to be treated should they be deemed to lack mental capacity in the future. The right to supported decision-making, where a person is helped to understand and choose treatment options before they can be declared to lack capacity, may also be included in the legislation. There should at the very least be shared decision-making as far as possible. Involuntary treatment laws are increasingly extended to those living in the community, for example outpatient commitment laws (known by different names) are used in New Zealand, Australia, the United Kingdom, and most of the United States.

The World Health Organization reports that in many instances national mental health legislation takes away the rights of persons with mental disorders rather than protecting rights, and is often outdated.^[209] In 1991, the United Nations adopted the Principles for the Protection of Persons with Mental Illness and the Improvement of Mental Health Care, which established minimum human rights standards of practice in the mental health field. In 2006, the UN formally agreed the Convention on the Rights of Persons with Disabilities to protect and enhance the rights and opportunities of disabled people, including those with psychiatric disabilities.

The term insanity, sometimes used colloquially as a synonym for mental illness, is often used technically as a legal term. The insanity defense may be used in a legal trial (known as the mental disorder defence in some countries).

Perception and discrimination

Further information: Schizophrenogenic parents, Refrigerator mother, and Mentalism (discrimination)

Stigma

The social stigma associated with mental disorders is a widespread problem. The US Surgeon General stated in 1999 that: "Powerful and pervasive, stigma prevents people from acknowledging their own mental health problems, much less disclosing them to others."^[213] Additionally, researcher Wulf Rössler in 2016, in his article, "The Stigma of Mental Disorders" stated:

For millennia, society did not treat persons suffering from depression, autism, schizophrenia and other mental illnesses much better than slaves or criminals: they were imprisoned, tortured or killed.

In the United States, racial and ethnic minorities are more likely to experience mental health disorders often due to low socioeconomic status, and discrimination. In Taiwan, people with mental disorders often face misconceptions from the general public. These misconceptions include the belief that mental health issues stem from excessive worry, having too much free time, a lack of progress or ambition, not taking life seriously, neglecting real-life responsibilities, mental weakness, unwillingness to be resilient, perfectionism, or a lack of courage.

Employment discrimination is reported to play a significant part in the high rate of unemployment among those with a diagnosis of mental illness. An Australian study found that having a psychiatric disability is a bigger barrier to employment than a physical disability. The mentally ill are stigmatized in Chinese society and can not legally marry.

Efforts are being undertaken worldwide to eliminate the stigma of mental illness, although the methods and outcomes used have sometimes been criticized.

Media and general public

Main article: Mental disorders in fiction

Media coverage of mental illness comprises predominantly negative and pejorative depictions, for example, of incompetence, violence or criminality, with far less coverage of positive issues such as accomplishments or human rights issues. Such negative depictions, including in children's cartoons, are thought to contribute to stigma and negative attitudes in the public and in those with mental health problems themselves, although more sensitive or serious cinematic portrayals have increased in prevalence.

In the United States, the Carter Center has created fellowships for journalists in South Africa, the U.S., and Romania, to enable reporters to research and write stories on mental health topics. Former US First Lady Rosalynn Carter began the fellowships not only to train reporters in how to sensitively and accurately discuss mental health and mental illness, but also to increase the number of stories on these topics in the news media. There is also a World Mental Health Day, which in the United States and Canada falls within a Mental Illness Awareness Week.

The general public have been found to hold a strong stereotype of dangerousness and desire for social distance from individuals described as mentally ill. A US national survey found that a higher percentage of people rate individuals described as displaying the characteristics of a mental disorder as "likely to do something violent to others", compared to the percentage of people who are rating individuals described as being troubled. In the article, "Discrimination Against People with a Mental Health Diagnosis: Qualitative Analysis of Reported Experiences", an individual who has a mental disorder, revealed that, "If people don't know me and don't know about the problems, they'll talk to me quite happily. Once they've seen the problems or someone's told them about me, they tend to be a bit more wary." In addition, in the article, "Stigma and its Impact on Help-Seeking for Mental Disorders: What Do We Know?" by George Schomerus and Matthias Angermeyer, it is affirmed that "Family doctors and psychiatrists have more pessimistic views about the outcomes for mental illnesses than the general public (Jorm et al., 1999), and mental health professionals hold more negative stereotypes about mentally ill patients, but, reassuringly, they are less accepting of restrictions towards them."

Recent depictions in media have included leading characters successfully living with and managing a mental illness, including in bipolar disorder in Homeland (2011) and post-traumatic stress disorder in Iron Man 3 (2013).

Violence

Despite public or media opinion, national studies have indicated that severe mental illness does not independently predict future violent behavior, on average, and is not a leading cause of violence in society. There is a statistical association with various factors that do relate to violence (in anyone), such as substance use and various personal, social, and economic factors. A 2015 review found that in the United States, about 4% of violence is attributable to people diagnosed with mental illness, and a 2014 study found that 7.5% of crimes committed by mentally ill people were directly related to the symptoms of their mental illness. The majority of people with serious mental illness are never violent.

In fact, findings consistently indicate that it is many times more likely that people diagnosed with a serious mental illness living in the community will be the victims rather than the perpetrators of violence. In a study of individuals diagnosed with "severe mental illness" living in a US inner-city area, a quarter were found to have been victims of at least one violent crime over the course of a year, a proportion eleven times higher than the inner-city average, and higher in every category of crime including violent assaults and theft. People with a diagnosis may find it more difficult to secure prosecutions, however, due in part to prejudice and being seen as less credible.

However, there are some specific diagnoses, such as childhood conduct disorder or adult antisocial personality disorder or psychopathy, which are defined by, or are inherently associated with, conduct problems and violence. There are conflicting findings about the extent to which certain specific symptoms, notably some kinds of psychosis (hallucinations or delusions) that can occur in disorders such as schizophrenia, delusional disorder or mood disorder, are linked to an increased risk of serious violence on average. The mediating factors of violent acts, however, are most consistently found to be mainly socio-demographic and socio-economic factors such as being young, male, of lower socioeconomic status and, in particular, substance use (including alcohol use) to which some people may be particularly vulnerable.

High-profile cases have led to fears that serious crimes, such as homicide, have increased due to deinstitutionalization, but the evidence does not support this conclusion. Violence that does occur in relation to mental disorder (against the mentally ill or by the mentally ill) typically occurs in the context of complex social interactions, often in a family setting rather than between strangers. It is also an issue in health care settings and the wider community.

Mental health

Main article: Mental health

The recognition and understanding of mental health conditions have changed over time and across cultures and there are still variations in definition, assessment, and classification, although standard guideline criteria are widely used. In many cases, there appears to be a continuum between mental health and mental illness, making diagnosis complex. According to the World Health Organization, over a third of people in most countries report problems at some time in their life which meet the criteria for diagnosis of one or more of the common types of mental disorder. Corey M Keyes has created a two continua model of mental illness and health which holds that both are related, but distinct dimensions: one continuum indicates the presence or absence of mental health, the other the presence or absence of mental illness. For example, people with optimal mental health can also have a mental illness, and people who have no mental illness can also have poor mental health.

Other animals

Main article: Animal psychopathology

Psychopathology in non-human primates has been studied since the mid-20th century. Over 20 behavioral patterns in captive chimpanzees have been documented as (statistically) abnormal for frequency, severity or oddness—some of which have also been observed in the wild. Captive great apes show gross behavioral abnormalities such as stereotypy of movements, self-mutilation, disturbed emotional reactions (mainly fear or aggression) towards companions, lack of species-typical communications, and generalized learned helplessness. In some cases such behaviors are hypothesized to be equivalent to symptoms associated with psychiatric disorders in humans such as depression, anxiety disorders, eating disorders and post-traumatic stress disorder. Concepts of antisocial, borderline and schizoid personality disorders have also been applied to non-human great apes.

The risk of anthropomorphism is often raised concerning such comparisons, and assessment of non-human animals cannot incorporate evidence from linguistic communication. However, available evidence may range from nonverbal behaviors—including physiological responses and homologous facial displays and acoustic utterances—to neurochemical studies. It is pointed out that human psychiatric classification is often based on statistical description and judgment of behaviors (especially when speech or language is impaired) and that the use of verbal self-report is itself problematic and unreliable.

Psychopathology has generally been traced, at least in captivity, to adverse rearing conditions such as early separation of infants from mothers; early sensory deprivation; and extended periods of social isolation. Studies have also indicated individual variation in temperament, such as sociability or impulsiveness. Particular causes of problems in captivity have included integration of strangers into existing groups and a lack of individual space, in which context some pathological behaviors have also been seen as coping mechanisms. Remedial interventions have included careful individually tailored re-socialization programs, behavior therapy, environment enrichment, and on rare occasions psychiatric drugs. Socialization has been found to work 90% of the time in disturbed chimpanzees, although restoration of functional sexuality and caregiving is often not achieved.

Laboratory researchers sometimes try to develop animal models of human mental disorders, including by inducing or treating symptoms in animals through genetic, neurological, chemical or behavioral manipulation, but this has been criticized on empirical grounds and opposed on animal rights grounds.