Schizophrenia

Positive symptoms are those symptoms that are not normally experienced, but are present in people during a psychotic episode in schizophrenia. They include delusions, hallucinations, and disorganized thoughts and speech, typically regarded as manifestations of psychosis.[30] Hallucinations most commonly involve the sense of hearing as hearing voices but can sometimes involve any of the other senses of taste, sight, smell, and touch.[32] They are also typically related to the content of the delusional theme.[33] Delusions are bizarre or persecutory in nature. Distortions of self-experience such as feeling as if one's thoughts or feelings are not really one's own, to believing that thoughts are being inserted into one's mind, sometimes termed passivity phenomena, are also common.[34] Thought disorders can include thought blocking, and disorganized speech – speech that is not understandable is known as word salad.[3][35] Positive symptoms generally respond well to medication,[5] and become reduced over the course of the illness, perhaps related to the age-related decline in dopamine activity.[7]

Negative symptoms are deficits of normal emotional responses, or of other thought processes. The five recognised domains of negative symptoms are: blunted affect – showing flat expressions or little emotion; alogia – a poverty of speech; anhedonia – an inability to feel pleasure; asociality – the lack of desire to form relationships, and avolition – a lack of motivation and apathy.[36][37] Avolition and anhedonia are seen as motivational deficits resulting from impaired reward processing.[38][39] Reward is the main driver of motivation and this is mostly mediated by dopamine.[39] It has been suggested that negative symptoms are multidimensional and they have been categorised into two subdomains of apathy or lack of motivation, and diminished expression.[36][40] Apathy includes avolition, anhedonia, and social withdrawal; diminished expression includes blunt effect, and alogia.[41] Sometimes diminished expression is treated as both verbal and non-verbal.[42] Apathy accounts for around 50 per cent of the most often found negative symptoms and affects functional outcome and subsequent quality of life. Apathy is related to disrupted cognitive processing affecting memory and planning including goal-directed behaviour.[43] The two subdomains has suggested a need for separate treatment approaches.[44] A lack of distress – relating to a reduced experience of depression and anxiety is another noted negative symptom.[45] A distinction is often made between those negative symptoms that are inherent to schizophrenia, termed primary; and those that result from positive symptoms, from the side effects of antipsychotics, substance abuse, and social deprivation - termed secondary negative symptoms.[46] Negative symptoms are less responsive to medication and the most difficult to treat.[44] However if properly assessed, secondary negative symptoms are amenable to treatment.[40]

Scales for specifically assessing the presence of negative symptoms, and for measuring their severity, and their changes have been introduced since the earlier scales such as the PANNS that deals with all types of symptoms.[44] These scales are the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptom Scale (BNSS) also known as second-generation scales.[44][45][47] In 2020, ten years after its introduction a cross-cultural study of the use of BNSS found valid and reliable psychometric evidence for the five-domain structure cross-culturally.[45] The BNSS is designed to assess both the presence and severity and change of negative symptoms of the five recognised domains, and the additional item of reduced normal distress.[45] BNSS can register changes in negative symptoms in relation to psychosocial and pharmacological intervention trials. BNSS has also been used to study a proposed non-D2 treatment called SEP-363856. Findings supported the favouring of five domains over the two-dimensional proposition.[45]

Cognitive deficits are the earliest and most constantly found symptoms in schizophrenia. They are often evident long before the onset of illness in the prodromal stage, and may be present in early adolescence, or childhood.[48][49] They are a core feature but not considered to be core symptoms, as are positive and negative symptoms.[50][51] However, their presence and degree of dysfunction is taken as a better indicator of functionality than the presentation of core symptoms.[48] Cognitive deficits become worse at first episode psychosis but then return to baseline, and remain fairly stable over the course of the illness.[52][53]

The deficits in cognition are seen to drive the negative psychosocial outcome in schizophrenia, and are claimed to equate to a possible reduction in IQ from the norm of 100 to 70–85.[54][55] Cognitive deficits may be of neurocognition (nonsocial) or of social cognition.[56] Neurocognition is the ability to receive and remember information, and includes verbal fluency, memory, reasoning, problem solving, speed of processing, and auditory and visual perception.[53] Verbal memory and attention are seen to be the most affected.[55][57] Verbal memory impairment is associated with a decreased level of semantic processing (relating meaning to words).[58] Another memory impairment is that of episodic memory.[59] An impairment in visual perception that is consistently found in schizophrenia is that of visual backward masking.[53] Visual processing impairments include an inability to perceive complex visual illusions.[60] Social cognition is concerned with the mental operations needed to interpret, and understand the self and others in the social world.[53][56] This is also an associated impairment, and facial emotion perception is often found to be difficult.[61][62] Facial perception is critical for ordinary social interaction.[63] Cognitive impairments do not usually respond to antipsychotics, and there are a number of interventions that are used to try to improve them; cognitive remediation therapy has been found to be of particular help.[51]

Onset typically occurs between the late teens and early 30s, with the peak incidence occurring in males in the early to mid twenties, and in females in the late twenties.[3][7][11] Onset before the age of 17 is known as early-onset,[64] and before the age of 13, as can sometimes occur, is known as childhood schizophrenia or very early-onset.[7][65] A later stage of onset can occur between the ages of 40 and 60, known as late-onset schizophrenia.[56] A later onset over the age of 60, which may be difficult to differentiate as schizophrenia, is known as very-late-onset schizophrenia-like psychosis.[56] Late onset has shown that a higher rate of females are affected; they have less severe symptoms and need lower doses of antipsychotics.[56] The tendency for earlier onset in males is later seen to be balanced by a post-menopausal increase in the development in females. Estrogen produced pre-menopause has a dampening effect on dopamine receptors but its protection can be overridden by a genetic overload.[66] There has been a dramatic increase in the numbers of older adults with schizophrenia.[67] An estimated 70% of those with schizophrenia have cognitive deficits, and these are most pronounced in early onset and late-onset illness.[56][68]

Onset may happen suddenly or may occur after the slow and gradual development of a number of signs and symptoms, a period known as the prodromal stage.[7] Up to 75% of those with schizophrenia go through a prodromal stage.[69] The negative and cognitive symptoms in the prodrome stage can precede FEP by many months and up to five years.[52][70] The period from FEP and treatment is known as the duration of untreated psychosis (DUP) which is seen to be a factor in functional outcome. The prodromal stage is the high-risk stage for the development of psychosis.[53] Since the progression to first episode psychosis is not inevitable, an alternative term is often preferred of at risk mental state[53] Cognitive dysfunction at an early age impact a young person's usual cognitive development.[71] Recognition and early intervention at the prodromal stage would minimize the associated disruption to educational and social development and has been the focus of many studies.[52][70] It is suggested that the use of anti-inflammatory compounds such as D-serine may prevent the transition to schizophrenia.[52] Cognitive symptoms are not secondary to positive symptoms or to the side effects of antipsychotics.[53]

Cognitive impairments in the prodromal stage become worse after first episode psychosis (after which they return to baseline and then remain fairly stable), making early intervention to prevent such transition of prime importance.[52] Early treatment with cognitive behavioral therapies are the gold standard.[70] Neurological soft signs of clumsiness and loss of fine motor movement are often found in schizophrenia, which may resolve with effective treatment of FEP.[11][72]

Estimates of the heritability of schizophrenia are between 70% and 80%, which implies that 70% to 80% of the individual differences in risk to schizophrenia is associated with genetics.[16][77] These estimates vary because of the difficulty in separating genetic and environmental influences, and their accuracy has been queried.[78][79] The greatest risk factor for developing schizophrenia is having a first-degree relative with the disease (risk is 6.5%); more than 40% of identical twins of those with schizophrenia are also affected.[80] If one parent is affected the risk is about 13% and if both are affected the risk is nearly 50%.[77] However, DSM-5 points out that most people with schizophrenia have no family history of psychosis.[7] Results of candidate gene studies of schizophrenia have generally failed to find consistent associations,[81] and the genetic loci identified by genome-wide association studies explain only a small fraction of the variation in the disease.[82]

Many genes are known to be involved in schizophrenia, each with small effect and unknown transmission and expression.[16][83] The summation of these effect sizes into a polygenic risk score can explain at least 7% of the variability in liability for schizophrenia.[84] Around 5% of cases of schizophrenia are understood to be at least partially attributable to rare copy-number variations (CNVs); these structural variations are associated with known genomic disorders involving deletions at 22q11.2 (DiGeorge syndrome) and 17q12 (17q12 microdeletion syndrome), duplications at 16p11.2 16p11.2 duplication (most frequently found) and deletions at 15q11.2 (Burnside-Butler syndrome).[85] Some of these CNVs increase the risk of developing schizophrenia by as much as 20-fold, and are frequently comorbid with autism and intellectual disabilities.[85]

The genes CRHR1 and CRHBP have been shown to be associated with a severity of suicidal behavior. These genes code for stress response proteins needed in the control of the HPA axis, and their interaction can affect this axis. Response to stress can cause lasting changes in the function of the HPA axis possibly disrupting the negative feedback mechanism, homeostasis, and the regulation of emotion leading to altered behaviors.[75]

The question of how schizophrenia could be primarily genetically influenced, given that people with schizophrenia have lower fertility rates, is a paradox. It is expected that genetic variants that increase the risk of schizophrenia would be selected against due to their negative effects on reproductive fitness. A number of potential explanations have been proposed, including that alleles associated with schizophrenia risk confers a fitness advantage in unaffected individuals.[86][87] While some evidence has not supported this idea,[79] others propose that a large number of alleles each contributing a small amount can persist.[88]

Environmental factors, each associated with a slight risk of developing schizophrenia in later life include oxygen deprivation, infection, prenatal maternal stress, and malnutrition in the mother during prenatal development.[89] A risk is also associated with maternal obesity, in increasing oxidative stress, and dysregulating the dopamine and serotonin pathways.[90] Both maternal stress and infection have been demonstrated to alter fetal neurodevelopment through an increase of pro-inflammatory cytokines.[91] There is a slighter risk associated with being born in the winter or spring possibly due to vitamin D deficiency[92] or a prenatal viral infection.[80] Other infections during pregnancy or around the time of birth that have been linked to an increased risk include infections by Toxoplasma gondii and Chlamydia.[93] The increased risk is about five to eight percent.[94] Viral infections of the brain during childhood are also linked to a risk of schizophrenia during adulthood.[95]

Adverse childhood experiences (ACEs), severe forms of which are classed as childhood trauma, range from being bullied or abused, to the death of a parent.[96] Many adverse childhood experiences can cause toxic stress and increase the risk of psychosis.[96][97][98] Chronic trauma can promote lasting inflammatory dysregulation throughout the nervous system.[99] It is suggested that early stress may contribute to the developmenmt of schizophrenia through these alterations in the immune system.[99] Schizophrenia was the last diagnosis to benefit from the link made between ACEs and adult mental health outcomes.[100]

Living in an urban environment during childhood or as an adult has consistently been found to increase the risk of schizophrenia by a factor of two,[22][101] even after taking into account drug use, ethnic group, and size of social group.[102] A possible link between the urban environment and pollution has been suggested to be the cause of the elevated risk of schizophrenia.[103]

Other risk factors of importance include social isolation, immigration related to social adversity and racial discrimination, family dysfunction, unemployment, and poor housing conditions.[80][104] Having a father older than 40 years, or parents younger than 20 years are also associated with schizophrenia.[5][105] It has been suggested that apart from gene-environment interactions, environment-environment interactions also be taken into account as each environmental risk factor on its own is not enough.[89]

About half of those with schizophrenia use recreational drugs, including cannabis, tobacco, and alcohol excessively.[106][107] Use of stimulants such as amphetamine and cocaine can lead to a temporary stimulant psychosis, which presents very similarly to schizophrenia. Rarely, alcohol use can also result in a similar alcohol-related psychosis.[80][108] Drugs may also be used as coping mechanisms by people who have schizophrenia, to deal with depression, anxiety, boredom, and loneliness.[106][109] The use of cannabis and tobacco are not associated with the development of cognitive deficits, and sometimes a reverse relationship is found where their use improves these symptoms.[51] However, substance abuse is associated with an increased risk of suicide, and a poor response to treatment.[110]

Cannabis-use may be a contributory factor in the development of schizophrenia, potentially increasing the risk of the disease in those who are already at risk.[17] The increased risk may require the presence of certain genes within an individual.[17] Its use is associated with doubling the rate.[111] The use of more potent strains of cannabis having a high level of its active ingredient tetrahydrocannabinol (THC), increases the risk further. One of these strains is well known as skunk.[112][113]

Schizophrenia is diagnosed based on criteria in either the Diagnostic and Statistical Manual of Mental Disorders (DSM) published by the American Psychiatric Association or the International Statistical Classification of Diseases and Related Health Problems (ICD) published by the World Health Organization. These criteria use the self-reported experiences of the person and reported abnormalities in behavior, followed by a psychiatric assessment. The mental status examination is an important part of the assessment.[151] An established tool for assessing the severity of positive and negative symptoms is the Positive and Negative Syndrome Scale (PANSS).[152] This has been seen to have shortcomings relating to negative symptoms, and other scales – the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptoms Scale (BNSS) have been introduced.[44] The DSM-5, published in 2013, gives a Scale to Assess the Severity of Symptom Dimensions outlining eight dimensions of symptoms.[50]

DSM-5 states that to be diagnosed with schizophrenia, two diagnostic criteria have to be met over the period of one month, with a significant impact on social or occupational functioning for at least six months. One of the symptoms needs to be either delusions, hallucinations, or disorganized speech. A second symptom could be one of the negative symptoms, or severely disorganized or catatonic behaviour.[7] A different diagnosis of schizophreniform disorder can be made before the six months needed for the diagnosis of schizophrenia.[7]

In Australia the guideline for diagnosis is for six months or more with symptoms severe enough to affect ordinary functioning.[153] In the UK diagnosis is based on having the symptoms for most of the time for one month, with symptoms that significantly affect the ability to work, study, or to carry on ordinary daily living, and with other similar conditions ruled out.[154]

The ICD criteria are typically used in European countries; the DSM criteria are used predominantly in the United States and Canada, and are prevailing in research studies. In practice, agreement between the two systems is high.[155] The current proposal for the ICD-11 criteria for schizophrenia recommends adding self-disorder as a symptom.[34]

A major unresolved difference between the two diagnostic systems is that of the requirement in DSM of an impaired functional outcome. WHO for ICD argues that not all people with schizophrenia have functional deficits and so these are not specific for the diagnosis.[50]

Both manuals have adopted the chapter heading of Schizophrenia spectrum and other psychotic disorders; ICD modifying this as Schizophrenia spectrum and other primary psychotic disorders.[50] The definition of schizophrenia remains essentially the same as that specified by the 2000 text revised DSM-IV (DSM-IV-TR). However, with the publication of DSM-5, the APA removed all sub-classifications of schizophrenia.[50] ICD-11 has also removed subtypes. The removed subtype from both, of catatonic has been relisted in ICD-11 as a psychomotor disturbance that may be present in schizophrenia.[50]

Another major change was to remove the importance previously given to Schneider's first-rank symptoms.[156] DSM-5 still uses the listing of schizophreniform disorder but ICD-11 no longer includes it.[50] DSM-5 also recommends that a better distinction be made between a current condition of schizophrenia and its historical progress, to achieve a clearer overall characterization.[156]

A dimensional assessment has been included in DSM-5 covering eight dimensions of symptoms to be rated (using the Scale to Assess the Severity of Symptom Dimensions) – these include the five diagnostic criteria plus cognitive impairments, mania, and depression.[50] This can add relevant information for the individual in regard to treatment, prognosis, and functional outcome; it also enables the response to treatment to be more accurately described.[50][157]

Two of the negative symptoms – avolition and diminished emotional expression, have been given more prominence in both manuals.[50]

Many people with schizophrenia may have one or more other mental disorders, such as panic disorder, obsessive-compulsive disorder, or substance use disorder. These are separate disorders that require treatment.[7] When comorbid with schizophrenia, substance use disorder and antisocial personality disorder both increase the risk for violence.[158] Comorbid substance abuse also increases risk for suicide.[110]

Sleep disorders often co-occur with schizophrenia, and may be an early sign of relapse.[159] Sleep disorders are linked with positive symptoms such as disorganized thinking and can adversely affect cortical plasticity and cognition.[159] The consolidation of memories is disrupted in sleep disorders.[160] They are associated with severity of illness, a poor prognosis, and poor quality of life.[161][162] Sleep onset and maintenance insomnia is a common symptom, regardless of whether treatment has been received or not.[161] Genetic variations have been found associated with these conditions involving the circadian rhythm, dopamine and histamine metabolism, and signal transduction.[163] Limited positive evidence has been found for the use of acupuncture as an add-on.[164]

To make a diagnosis of schizophrenia other possible causes of psychosis need to be excluded.[165] Psychotic symptoms lasting less than a month may be diagnosed as brief psychotic disorder, or as schizophreniform disorder. Psychosis is noted in Other specified schizophrenia spectrum and other psychotic disorders as a DSM-5 category. Schizoaffective disorder is diagnosed if symptoms of mood disorder are substantially present alongside psychotic symptoms. Psychosis that results from a general medical condition or substance is termed secondary psychosis.[7] Psychotic symptoms may be present in several other conditions, including bipolar disorder,[8] borderline personality disorder,[9] substance intoxication, substance-induced psychosis, and a number of drug withdrawal syndromes. Non-bizarre delusions are also present in delusional disorder, and social withdrawal in social anxiety disorder, avoidant personality disorder and schizotypal personality disorder. Schizotypal personality disorder has symptoms that are similar but less severe than those of schizophrenia.[7] Schizophrenia occurs along with obsessive-compulsive disorder (OCD) considerably more often than could be explained by chance, although it can be difficult to distinguish obsessions that occur in OCD from the delusions of schizophrenia.[166] There can be considerable overlap with the symptoms of post-traumatic stress disorder.[167]

A more general medical and neurological examination may be needed to rule out medical illnesses which may rarely produce psychotic schizophrenia-like symptoms, such as metabolic disturbance, systemic infection, syphilis, HIV-associated neurocognitive disorder, epilepsy, limbic encephalitis, and brain lesions. Stroke, multiple sclerosis, hyperthyroidism, hypothyroidism, and dementias such as Alzheimer's disease, Huntington's disease, frontotemporal dementia, and the Lewy body dementias may also be associated with schizophrenia-like psychotic symptoms.[168] It may be necessary to rule out a delirium, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, and indicates an underlying medical illness. Investigations are not generally repeated for relapse unless there is a specific medical indication or possible adverse effects from antipsychotic medication. In children hallucinations must be separated from typical childhood fantasies.[7] It is difficult to distinguish childhood schizophrenia from autism.[65]

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.[30][177] They have little effect on negative and cognitive symptoms, which may be helped by additional psychotherapies and medications.[178] There is no single antipsychotic suitable for first-line treatment for everyone, as responses and tolerances vary between people.[179] 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.[180][181]

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.[182][183][184] It is recommended that the dosage for those smokers on clozapine be increased by 50%, and for those on olanzapine by 30%.[183] 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.[182][185] 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.[182]

About 30 to 50 percent of people with schizophrenia fail to accept that they have an illness or comply with their recommended treatment.[186] For those who are unwilling or unable to take medication regularly, long-acting injections of antipsychotics may be used,[187] which reduce the risk of relapse to a greater degree than oral medications.[188] When used in combination with psychosocial interventions, they may improve long-term adherence to treatment.[189]

Research findings suggested that other neurotransmission systems, including serotonin, glutamate, GABA, and acetycholine, were implicated in the development of schizophrenia, and that a more inclusive medication was needed.[184] 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.[184][190][191] 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.[192] 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.[184]

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.[193] Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical).[193] 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.[194] 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.[195]

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.[196][197] Studies have found that antipsychotic treatment following NMS and neutropenia may sometimes be successfully rechallenged (restarted) with clozapine.[198][199]

Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy.[200][201] 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.[201] 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.[196]

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.[202][203] Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction.[80] Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies.[204] Unwanted side effects cause people to stop treatment, resulting in relapses.[205]

About half of those with schizophrenia will respond favourably to antipsychotics, and have a good return of functioning.[206] 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.[207][24] 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.[22][80][208] Between 12 and 20 per cent will not respond to clozapine and this group is said to have ultra treatment resistant schizophrenia.[207][209] ECT may be offered to treat TRS as an add-on therapy, and is shown to sometimes be of benefit.[209] 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.[210]

TRS is often accompanied by a low quality of life, and greater social dysfunction.[211] 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.[203] 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.[212] This finding also supports the involvement of dopamine in the development of schizophrenia.[203] Studies suggest that TRS may be a more heritable form.[213]

TRS may be evident from first episode psychosis, or from a relapse. It can vary in its intensity and response to other therapies.[211] This variation is seen to possibly indicate an underlying neurobiology such as dopamine supersensitivity (DSS), glutamate or serotonin dysfunction, inflammation and oxidative stress.[207] Studies have found that dopamine supersensitivity is found in up to 70% of those with TRS.[214] The variation has led to the suggestion that treatment responsive and treatment resistant schizophrenia be considered as two different subtypes.[207][213] 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.[209] 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.[209] In those with ultra treatment resistance the decrease in grey matter volume was larger.[207][209]

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 ageing, 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.[215]

A number of psychosocial interventions that include several types of psychotherapy may be useful in the treatment of schizophrenia such as: family therapy,[216] group therapy, cognitive remediation therapy,[217] cognitive behavioral therapy, and metacognitive training.[218] Skills training, and help with substance use, and weight management– often needed as a side effect of an antipsychotic, are also offered.[219] 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.[30] In the UK care across all phases is a similar approach that covers many of the treatment guidelines recommended.[28] The aim is to reduce the number of relapses and stays in hospital.[216]

Other support services for education, employment, and housing are usually offered. For people suffering from 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.[220][221] Another more intense approach is known as intensive care management (ICM). ICM is a stage further than ACT and emphasises 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.[222]

Some studies have shown little evidence for the effectiveness of cognitive behavioral therapy (CBT) in either reducing symptoms or preventing relapse.[223][224] However, other studies have found that CBT does improve overall psychotic symptoms (when in use with medication) and has been recommended in Canada, but it has been seen here to have no effect on social function, relapse, or quality of life.[225] In the UK it is recommended as an add-on therapy in the treatment of schizophrenia, but is not supported for use in treatment resistant schizophrenia.[224][226] Arts therapies are seen to improve negative symptoms in some people, and are recommended by NICE in the UK.[177][227] This approach however, is criticised as having not been well-researched, and arts therapies are not recommended in Australian guidelines for example.[227][228][229] Peer support, in which people with personal experience of schizophrenia, provide help to each other, is of unclear benefit.[230]

Exercise including aerobic exercise has been shown to improve positive and negative symptoms, cognition, working memory, and improve quality of life.[231][232] 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.[231] However, there still remains the problem of increasing motivation for, and maintaining participation in physical activity.[233] Supervised sessions are recommended.[232] In the UK healthy eating advice is offered alongside exercise programs.[234]

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.[235][236] 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.[235] The use of supplemental folate is recommended.[237] A zinc deficiency has also been noted.[238] 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.[235] It is also suggested that the noted dysfunction in gut microbiota might benefit from the use of probiotics.[238]