Schizophrenia Part II

 

Medication

Risperidone (trade name Risperdal) is a common atypical antipsychotic medication.

The first-line treatment for schizophrenia is an antipsychotic. The first-generation antipsychotics, now called typical antipsychotics, are dopamine antagonists that block D2 receptors, and affect the neurotransmission of dopamine. Those brought out later, the second-generation antipsychotics known as atypical antipsychotics, can also have effect on another neurotransmitter, serotonin. Antipsychotics can reduce the symptoms of anxiety within hours of their use but for other symptoms they may take several days or weeks to reach their full effect. They have little effect on negative and cognitive symptoms, which may be helped by additional psychotherapies and medications. There is no single antipsychotic suitable for first-line treatment for everyone, as responses and tolerances vary between people. Stopping medication may be considered after a single psychotic episode where there has been a full recovery with no symptoms for twelve months. Repeated relapses worsen the long-term outlook and the risk of relapse following a second episode is high, and long-term treatment is usually recommended.

Tobacco smoking increases the metabolism of some antipsychotics, by strongly activitating CYP1A2, the enzyme that breaks them down, and a significant difference is found in these levels between smokers and non-smokers. It is recommended that the dosage for those smokers on clozapine be increased by 50%, and for those on olanzapine by 30%. The result of stopping smoking can lead to an increased concentration of the antipsychotic that may result in toxicity, so that monitoring of effects would need to take place with a view to decreasing the dosage; many symptoms may be noticeably worsened, and extreme fatigue, and seizures are also possible with a risk of relapse. Likewise those who resume smoking may need their dosages adjusted accordingly. The altering effects are due to compounds in tobacco smoke and not to nicotine; the use of nicotine replacement therapy therefore has the equivalent effect of stopping smoking and monitoring would still be needed.

About 30 to 50 percent of people with schizophrenia fail to accept that they have an illness or comply with their recommended treatment. For those who are unwilling or unable to take medication regularly, long-acting injections of antipsychotics may be used, which reduce the risk of relapse to a greater degree than oral medications. When used in combination with psychosocial interventions, they may improve long-term adherence to treatment.

Research findings suggested that other neurotransmission systems, including serotonin, glutamate, GABA, and acetylcholine, were implicated in the development of schizophrenia, and that a more inclusive medication was needed. A new first-in-class antipsychotic that targets multiple neurotransmitter systems called lumateperone (ITI-007), was trialed and approved by the FDA in December 2019 for the treatment of schizophrenia in adults. Lumateperone is a small molecule agent that shows improved safety, and tolerance. It interacts with dopamine, serotonin, and glutamate in a complex, uniquely selective manner, and is seen to improve negative and positive symptoms, and social functioning. Lumateperone was also found to reduce potential metabolic dysfunction, have lower rates of movement disorders, and have lower cardiovascular side effects such as a fast heart rate.

Side effects

Typical antipsychotics are associated with a higher rate of movement disorders including akathisia. Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome. Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical). A rare but potentially lethal condition of neuroleptic malignant syndrome (NMS) has been associated with the use of antipsychotics. Through its early recognition, and timely intervention rates have declined. However, an awareness of the syndrome is advised to enable intervention. Another less rare condition of tardive dyskinesia can occur due to long-term use of antipsychotics, developing after many months or years of use. It is more often reported with use of typical antipsychotics.

Clozapine is associated with side effects that include weight gain, tiredness, and hypersalivation. More serious adverse effects include seizures, NMS, neutropenia, and agranulocytosis (lowered white blood cell count) and its use needs careful monitoring. Studies have found that antipsychotic treatment following NMS and neutropenia may sometimes be successfully rechallenged (restarted) with clozapine.

Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy. A systematic review of clozapine-associated pulmonary embolism indicates that this adverse effect can often be fatal, and that it has an early onset, and is dose-dependent. The findings advised the consideration of using a prevention therapy for venous thromboembolism after starting treatment with clozapine, and continuing this for six months. Constipation is three times more likely to occur with the use of clozapine, and severe cases can lead to ileus and bowel ischemia resulting in many fatalities.

However, the risk of serious adverse effects from clozapine is low, and there are the beneficial effects to be gained of a reduced risk of suicide, and aggression. Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction. Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies. Unwanted side effects cause people to stop treatment, resulting in relapses.

Treatment resistant schizophrenia

About half of those with schizophrenia will respond favorably to antipsychotics, and have a good return of functioning. However, positive symptoms persist in up to a third of people. Following two trials of different antipsychotics over six weeks, that also prove ineffective, they will be classed as having treatment resistant schizophrenia (TRS), and clozapine will be offered. Clozapine is of benefit to around half of this group although it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people. Between 12 and 20 per cent will not respond to clozapine and this group is said to have ultra treatment resistant schizophrenia. ECT may be offered to treat TRS as an add-on therapy, and is shown to sometimes be of benefit. A review concluded that this use only has an effect on medium-term TRS and that there is not enough evidence to support its use other than for this group.

TRS is often accompanied by a low quality of life, and greater social dysfunction. TRS may be the result of inadequate rather than inefficient treatment; it also may be a false label due to medication not being taken regularly, or at all. About 16 per cent of people who had initially been responsive to treatment later develop resistance. This could relate to the length of time on APs, with treatment becoming less responsive. This finding also supports the involvement of dopamine in the development of schizophrenia. Studies suggest that TRS may be a more heritable form.

TRS may be evident from first episode psychosis, or from a relapse. It can vary in its intensity and response to other therapies. This variation is seen to possibly indicate an underlying neurobiology such as dopamine supersensitivity (DSS), glutamate or serotonin dysfunction, inflammation and oxidative stress. Studies have found that dopamine supersensitivity is found in up to 70% of those with TRS. The variation has led to the suggestion that treatment responsive and treatment resistant schizophrenia be considered as two different subtypes. It is further suggested that if the subtypes could be distinguished at an early stage significant implications could follow for treatment considerations, and for research. Neuroimaging studies have found a significant decrease in the volume of grey matter in those with TRS with no such change seen in those who are treatment responsive. In those with ultra treatment resistance the decrease in grey matter volume was larger.

A link has been made between the gut microbiota and the development of TRS. The most prevalent cause put forward for TRS is that of mutation in the genes responsible for drug effectiveness. These include liver enzyme genes that control the availability of a drug to brain targets, and genes responsible for the structure and function of these targets. In the colon the bacteria encode a hundred times more genes than exist in the human genome. Only a fraction of ingested drugs reach the colon, having been already exposed to small intestinal bacteria, and absorbed in the portal circulation. This small fraction is then subject to the metabolic action of many communities of bacteria. Activation of the drug depends on the composition and enzymes of the bacteria and of the specifics of the drug, and therefore a great deal of individual variation can affect both the usefulness of the drug and its tolerability. It is suggested that parenteral administration of antipsychotics would bypass the gut and be more successful in overcoming TRS. The composition of gut microbiota is variable between individuals, but they are seen to remain stable. However, phyla can change in response to many factors including aging, diet, substance use, and medications – especially antibiotics, laxatives, and antipsychotics. In FEP, schizophrenia has been linked to significant changes in the gut microbiota that can predict response to treatment.

Psychosocial interventions

A number of psychosocial interventions that include several types of psychotherapy may be useful in the treatment of schizophrenia such as: family therapy, group therapy, cognitive remediation therapy (CRT), cognitive behavioral therapy (CBT), and metacognitive training. Skills training, and help with substance use, and weight management – often needed as a side effect of an antipsychotic – are also offered. In the US, interventions for first episode psychosis have been brought together in an overall approach known as coordinated speciality care (CSC) and also includes support for education. In the UK care across all phases is a similar approach that covers many of the treatment guidelines recommended. The aim is to reduce the number of relapses and stays in hospital.

Other support services for education, employment, and housing are usually offered. For people with severe schizophrenia, and discharged from a stay in hospital, these services are often brought together in an integrated approach to offer support in the community away from the hospital setting. In addition to medicine management, housing, and finances, assistance is given for more routine matters such as help with shopping and using public transport. This approach is known as assertive community treatment (ACT) and has been shown to achieve positive results in symptoms, social functioning and quality of life. Another more intense approach is known as intensive care management (ICM). ICM is a stage further than ACT and emphasizes support of high intensity in smaller caseloads, (less than twenty). This approach is to provide long-term care in the community. Studies show that ICM improves many of the relevant outcomes including social functioning.

Some studies have shown little evidence for the effectiveness of CBT in either reducing symptoms or preventing relapse. However, other studies have found that CBT does improve overall psychotic symptoms (when in use with medication) and it has been recommended in Canada, but has been seen to have no effect on social function, relapse, or quality of life. In the UK it is recommended as an add-on therapy in the treatment of schizophrenia; one study questions its use in treatment resistant schizophrenia. Arts therapies are seen to improve negative symptoms in some people, and are recommended by NICE in the UK. This approach is criticized as having not been well-researched, and arts therapies are not recommended in Australian guidelines for example. Peer support, in which people with personal experience of schizophrenia, provide help to each other, is of unclear benefit.

Other

Exercise including aerobic exercise has been shown to improve positive and negative symptoms, cognition, working memory, and improve quality of life. Exercise has also been shown to increase the volume of the hippocampus in those with schizophrenia. A decrease in hippocampal volume is one of the factors linked to the development of the disease. However, there still remains the problem of increasing motivation for, and maintaining participation in physical activity. Supervised sessions are recommended. In the UK healthy eating advice is offered alongside exercise programs.

An inadequate diet is often found in schizophrenia, and associated vitamin deficiencies including those of folate, and vitamin D are linked to the risk factors for the development of schizophrenia and for early death including heart disease. Those with schizophrenia possibly have the worst diet of all the mental disorders. Lower levels of folate and vitamin D have been noted as significantly lower in first episode psychosis. The use of supplemental folate is recommended. A zinc deficiency has also been noted. Vitamin B12 is also often deficient and this is linked to worse symptoms. Supplementation with B vitamins has been shown to significantly improve symptoms, and to put in reverse some of the cognitive deficits. It is also suggested that the noted dysfunction in gut microbiota might benefit from the use of probiotics.

Violence

Most people with schizophrenia are not aggressive, and are more likely to be victims of violence rather than perpetrators. Schizophrenic people are commonly exploited and victimized by violent crime as part of a broader dynamic of social exclusion. People diagnosed with schizophrenia are also subject to forced drug injections, seclusion, and restraint at high rates.

The risk of violence by schizophrenic people is small. There are minor subgroups where the risk is high. This risk is usually associated with a comorbid disorder such as a substance use disorder – in particular alcohol, or with antisocial personality disorder. Substance use disorder is strongly linked, and other risk factors are linked to deficits in cognition and social cognition including facial perception and insight that are in part included in theory of mind impairments. Poor cognitive functioning, decision-making, and facial perception may contribute to making a wrong judgment of a situation that could result in an inappropriate response such as violence. These associated risk factors are also present in antisocial personality disorder which when present as a comorbid disorder greatly increases the risk of violence.

A review in 2012 showed that 6 percent of people convicted of homicide in Western countries had been diagnosed as schizophrenic. Another wider review put the figure at between 5 and 20 percent. People convicted of homicide were found more likely to have committed it during first episode psychosis, and this accounted for 38.5 percent (of the 5 to 20 percent of perpetrators who were diagnosed schizophrenic, so 2 to 7.7 percent of perpetrators total). The association between schizophrenia and violence is complex. Homicide is linked with young age, male sex, a history of violence, and a stressful event in the preceding year. Clinical risk factors are severe untreated psychotic symptoms – untreated due to either not taking medication or to the condition being treatment resistant. A comorbid substance use disorder or an antisocial personality disorder increases the risk for homicidal behaviour by 8-fold, in contrast to the 2-fold risk in those without the comorbid disorders. Rates of homicide linked to psychosis are similar to those linked to substance misuse, and parallel the overall rate in a region. What role schizophrenia has on violence independent of substance misuse is controversial, but certain aspects of individual histories or mental states may be factors.

Hostility is anger felt and directed at a person or group and has related dimensions of impulsiveness and aggression. When this impulsive aggression is evident in schizophrenia neuroimaging has suggested the malfunctioning of a neural circuit that modulates hostile thoughts and behaviors that are linked with negative emotions in social interactions. This circuit includes the amygdala, striatum, prefrontal cortex, anterior cingulate cortex, insula, and hippocampus. Hostility has been reported during acute psychosis, and following hospital discharge. There is a known association between low cholesterol levels, and impulsivity, and violence. A review finds that people with schizophrenia, and lower cholesterol levels are four times more likely to instigate violent acts. This association is also linked to the increased number of suicides in schizophrenia. It is suggested that cholesterol levels could serve as a biomarker for violent and suicidal tendencies.

A review found that just under 10 percent of those with schizophrenia showed violent behaviour compared to 1.6 percent of the general population. An excessive risk of violence is associated with drugs or alcohol and increases the risk by as much as 4-fold. Violence often leads to imprisonment. Clozapine is an effective medication that can be used in penal settings such as prisons. However, a condition of benign ethnic neutropenia in many African-Americans excludes them from the use of clozapine, the most effective medication. Cognitive deficits are recognized as playing an important part in the origin and maintenance of aggression, and cognitive remediation therapy may therefore help to prevent the risk of violence in schizophrenia.

Prognosis

Schizophrenia has great human and economic costs. It results in a decreased life expectancy of 20 years. This is primarily because of its association with obesity, poor diet, a sedentary lifestyle, and smoking, with an increased rate of suicide playing a lesser role. Side effects of antipsychotics may also increase the risk. These differences in life expectancy increased between the 1970s and 1990s. An Australian study puts the rate of early death at 25 years, and views the main cause to be related to heart disease.

Almost 40% of those with schizophrenia die from complications of cardiovascular disease which is seen to be increasingly associated. An underlying factor of sudden cardiac death may be Brugada syndrome (BrS) – BrS mutations that overlap with those linked with schizophrenia are the calcium channel mutations. BrS may also be drug-induced from certain antipsychotics and antidepressants. Primary polydipsia, or excessive fluid intake, is relatively common in people with chronic schizophrenia. This may lead to hyponatremia which can be life-threatening. Antipsychotics can lead to a dry mouth, but there are several other factors that may contribute to the disorder; it may reduce life expectancy by 13 per cent. Barriers to improving the mortality rate in schizophrenia are poverty, overlooking the symptoms of other illnesses, stress, stigma, and medication side effects.

Schizophrenia is a major cause of disability. In 2016, it was classed as the 12th most disabling condition. Approximately 75% of people with schizophrenia have ongoing disability with relapses and 16.7 million people globally are deemed to have moderate or severe disability from the condition. Some people do recover completely and others function well in society. Most people with schizophrenia live independently with community support. About 85% are unemployed. In people with a first episode of psychosis in schizophrenia a good long-term outcome occurs in 31%, an intermediate outcome in 42% and a poor outcome in 31%. Males are affected more often than females, and have a worse outcome; some reports find there is no difference in prevalence. Outcomes for schizophrenia appear better in the developing than the developed world. These conclusions have been questioned. Social problems, such as long-term unemployment, poverty, homelessness, exploitation, stigmatization and victimization are common consequences, and lead to social exclusion.

There is a higher than average suicide rate associated with schizophrenia estimated at around 5% to 6%, most often occurring in the period following onset or first hospital admission. Several times more (20 to 40%) attempt suicide at least once. There are a variety of risk factors, including male gender, depression, a high IQ, heavy smoking, and substance use. Repeated relapse is linked to an increased risk of suicidal behavior. The use of clozapine can reduce the risk of suicide and aggression.

A strong association between schizophrenia and tobacco smoking has been shown in worldwide studies. Smoking is especially high in those diagnosed with schizophrenia, with estimates ranging from 80 to 90% being regular smokers, as compared to 20% of the general population. Those who smoke tend to smoke heavily, and additionally smoke cigarettes with high nicotine content. Some propose that this is in an effort to improve symptoms. Among people with schizophrenia use of cannabis is also common.

Schizophrenia leads to an increased risk of dementia.

Women with schizophrenia are half as likely to attend breast cancer screening compared to the general population. This is seen as one of the factors leading to shorter life expectancy.

Epidemiology

In 2017, the Global Burden of Disease Study estimated there were 1.1 million new cases, and in 2019 the World Health Organization (WHO) reported a total of 20 million cases globally. Schizophrenia affects around 0.3–0.7% of people at some point in their life. It occurs 1.4 times more frequently in males than females and typically appears earlier in men – the peak ages of onset are 25 years for males and 27 years for females. Onset in childhood, before the age of 13 can sometimes occur. Other reviews find no difference in the prevalence of schizophrenia between the sexes. A later onset can occur between the ages of 40 and 60, known as late onset, and also after 60 known as very late onset.

Worldwide, schizophrenia is the most common psychotic disorder. The frequency of schizophrenia varies across the world, within countries, and at the local and neighborhood level. This variation has been estimated to be fivefold. It causes approximately one percent of worldwide disability adjusted life years and resulted in 17,000 deaths in 2015.

In 2000, WHO found the percentage of people affected and the number of new cases that develop each year is roughly similar around the world, with age-standardized prevalence per 100,000 ranging from 343 in Africa to 544 in Japan and Oceania for men, and from 378 in Africa to 527 in Southeastern Europe for women. About 1.1% of adults have schizophrenia in the United States. However, in areas of conflict this figure can rise to between 4.0 and 6.5%.

History

Accounts of a schizophrenia-like syndrome are rare in records before the 19th century. The earliest cases detailed were reported in 1797, and 1809. Dementia praecox, meaning premature dementia was used by German psychiatrist Heinrich Schüle in 1886, and then in 1891 by Arnold Pick in a case report of hebephrenia. In 1893 Emil Kraepelin used the term in making a distinction, known as the Kraepelinian dichotomy, between the two psychoses – dementia praecox, and manic depression (now called bipolar disorder). Kraepelin believed that dementia praecox was probably caused by a systemic disease that affected many organs and nerves, affecting the brain after puberty in a final decisive cascade. It was thought to be an early form of dementia, a degenerative disease. When it became evident that the disorder was not degenerative it was renamed schizophrenia by Eugen Bleuler in 1908.

The word schizophrenia translates as "splitting of the mind" and is Modern Latin from the Greek words schizein (σχίζειν, "to split") and phrēn, (φρήν, "mind") Its use was intended to describe the separation of function between personality, thinking, memory, and perception.

The term schizophrenia used to be associated with split personality by the general population but that usage went into decline when split personality became known as a separate disorder, first as multiple personality disorder, and later as dissociative identity disorder. In 2002 in Japan the name was changed to integration disorder, and in 2012 in South Korea, the name was changed to attunement disorder.

In the early 20th century, the psychiatrist Kurt Schneider listed the psychotic symptoms of schizophrenia into two groups of hallucinations, and delusions. The hallucinations were listed as specific to auditory, and the delusional included thought disorders. These were seen as the symptoms of first-rank importance and were termed first-rank symptoms. Whilst these were also sometimes seen to be relevant to the psychosis in manic-depression, they were highly suggestive of schizophrenia and typically referred to as first-rank symptoms of schizophrenia. The most common first-rank symptom was found to belong to thought disorders. In 2013 the first-rank symptoms were excluded from the DSM-5 criteria. First-rank symptoms are seen to be of limited use in detecting schizophrenia but may be of help in differential diagnosis.

Before the 1960s, doctors in America primarily diagnosed nonviolent petty criminals and women with schizophrenia, categorizing the latter as ill for not performing their duties within patriarchy as wives and mothers. Official descriptions emphasized the "calm" nature of such persons. In the mid-to-late 1960s, psychiatrists began diagnosing black men as schizophrenic at much higher rates, often citing their civil rights and Black Power activism as delusions, and categorizing them as "hostile and aggressive."

From the 1960s until 1989, psychiatrists in the USSR and Eastern Bloc diagnosed thousands of people with sluggish schizophrenia, based on "the assumption that symptoms would later appear," because the removal of legal rights from disabled people made it a convenient way to confine political dissidents. The sluggish schizophrenia diagnosis has been discredited and internationally condemned.

Psychiatrists committed psychosurgery on many of the first people they diagnosed as schizophrenic. These were notably frontal lobotomies carried out from the 1930s until the 1970s in the United States, and until the 1980s in France, involving either the removal of brain tissue from different regions or the severing of pathways, now widely recognized as a grave human rights abuse. In the 1930s a number of shock treatments were introduced which induced seizures (convulsions) or comas. Insulin shock therapy involved the injecting of large doses of insulin in order to induce comas, which in turn produced hypoglycemia and convulsions. The use of electricity to induce seizures was developed, and in use as electroconvulsive therapy (ECT) by 1938. Stereotactic surgeries were developed in the 1940s. In the mid-1950s scientists developed and introduced the first typical antipsychotic, chlorpromazine. In the 1970s the first atypical antipsychotic, clozapine, was introduced followed by the introduction of others.

In the early 1970s in the US, the diagnostic model used for schizophrenia was broad and clinically based using DSM II. It had been noted that schizophrenia was diagnosed far more in the US than in Europe which had been using the ICD-9 criteria. The US model was criticized for failing to demarcate clearly those people with a mental illness, and those without. In 1980 DSM III was published and showed a shift in focus from the clinically based biopsychosocial model to a reason-based medical model. DSM IV showed an increased focus to an evidence-based medical model.

Subtypes of schizophrenia classified as paranoid, disorganized, catatonic, undifferentiated, and residual type were difficult to distinguish between and are no longer recognized as separate conditions by DSM-5 (2013) or ICD-11.

Society and culture

John Nash, an American mathematician and joint recipient of the 1994 Nobel Memorial Prize in Economic Sciences, who had schizophrenia. His life was the subject of the 1998 book, A Beautiful Mind by Sylvia Nasar.

In 2002, the term for schizophrenia in Japan was changed from seishin-bunretsu-byō (精神分裂病, lit. "mind-split disease") to tōgō-shitchō-shō (統合失調症, lit. "integration-dysregulation syndrome") to reduce stigma. The new name also interpreted as "integration disorder" was inspired by the biopsychosocial model; it increased the percentage of people who were informed of the diagnosis from 37 to 70% over three years. A similar change was made in South Korea in 2012 to attunement disorder. A professor of psychiatry, Jim van Os, has proposed changing the English term to psychosis spectrum syndrome. In 2013 with the reviewed DSM-5, the DSM-5 committee was in favor of giving a new name to schizophrenia but they referred this to WHO.

In the United States, the cost of schizophrenia – including direct costs (outpatient, inpatient, drugs, and long-term care) and non-healthcare costs (law enforcement, reduced workplace productivity, and unemployment) – was estimated to be $62.7 billion in 2002. In the UK the cost in 2016 was put at £11.8 billion per year with a third of that figure directly attributable to the cost of hospital and social care, and treatment.

The book A Beautiful Mind chronicled the life of John Forbes Nash who had been diagnosed with schizophrenia and went on to win the Nobel Memorial Prize in Economic Sciences. This was later made into the film with the same name. An earlier documentary was made with the title A Brilliant Madness.

In 1964 a lengthy case study of three males diagnosed with schizophrenia who each had the delusional belief that they were Jesus Christ was published as a book. This has the title of The Three Christs of Ypsilanti, and a film with the title Three Christs was released in 2020. Such religious delusions are a fairly common feature in psychoses including schizophrenia.

Media coverage relating to violent acts by people with schizophrenia reinforces public perception of an association between schizophrenia and violence. Such sensationalist reporting stigmatizes schizophrenia more than any other mental illness. In the UK guidelines are given for the reporting of different conditions. Its campaigns have shown a reduction in negative reporting.

In contemporary films, schizophrenics are highly likely to be portrayed as a danger to others as opposed to a danger to themselves, though the opposite is true.

Research directions

Research into schizophrenia has used animal models, in particular rats, to evaluate different aspects of its development and pathology.

A 2015 Cochrane review found unclear evidence of benefit from brain stimulation techniques to treat the positive symptoms of schizophrenia, in particular auditory verbal hallucinations (AVHs). Most studies focus on transcranial direct-current stimulation (tDCM), and repetitive transcranial magnetic stimulation (rTMS). Techniques based on focused ultrasound for deep brain stimulation could provide insight for the treatment of AVHs.

An active area of research as of 2020 is the study of potential biomarkers that would help in diagnosis and treatment of schizophrenia. Possible biomarkers include markers of inflammation, neuroimaging, brain-derived neurotrophic factor (BDNF), and speech analysis. Some inflammatory markers such as C-reactive protein are useful in detecting levels of inflammation implicated in some psychiatric disorders but they are not disorder-specific. Other inflammatory cytokines are found to be elevated in first episode psychosis and acute relapse that are normalized after treatment with antipsychotics, and these may be considered as state markers. Deficits in sleep spindles in schizophrenia may serve as a marker of an impaired thalamocortical circuit, and a mechanism for memory impairment. MicroRNAs are highly influential in early neuronal development, and their disruption is implicated in several CNS disorders; circulating microRNAs (cimiRNAs) are found in body fluids such as blood and cerebrospinal fluid, and changes in their levels are seen to relate to changes in microRNA levels in specific regions of brain tissue. These studies suggest that cimiRNAs have the potential to be early and accurate biomarkers in a number of disorders including schizophrenia.