Diagnosis of schizophrenia

The diagnosis of schizophrenia, a psychotic disorder, is based on criteria in either the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, or the World Health Organization's International Classification of Diseases (ICD).[1] Clinical assessment of schizophrenia is carried out by a mental health professional based on observed behavior, reported experiences, and reports of others familiar with the person.[2] Diagnosis is usually made by a psychiatrist.[3] Associated symptoms occur along a continuum in the population and must reach a certain severity and level of impairment before a diagnosis is made.[4] Schizophrenia has a prevalence rate of 0.3-0.7% in the United States [5]

Criteria

In 2013, the American Psychiatric Association released the fifth edition of the DSM (DSM-5). According to the manual, to be diagnosed with schizophrenia, two diagnostic criteria have to be met over much of the time of a period of at least one month, with a significant impact on social or occupational functioning for at least six months. The DSM diagnostic criteria outlines that the person has to be experiencing either delusions, hallucinations, or disorganized speech. In other words, an individual does not have to be experiencing delusions or hallucinations to receive a diagnosis of schizophrenia. A second symptom could be negative symptoms, or severely disorganized or catatonic behavior.[5] Only two symptoms are required for a diagnosis of schizophrenia, resulting in different presentations for the same disorder.[5]

In practice, agreement between the two systems is high.[6] The DSM-5 criteria puts more emphasis on social or occupational dysfunction than the ICD-10.[7] The ICD-10, on the other hand, puts more emphasis on first-rank symptoms.[2][8] The current proposal for the ICD-11 criteria for schizophrenia recommends adding self-disorder as a symptom.[9]

First rank symptoms

First-rank symptoms are psychotic symptoms that are particularly characteristic of schizophrenia, which were put forward by Kurt Schneider in 1959.[10] Their reliability for the diagnosis of schizophrenia has been questioned since then.[11] A 2015 systematic review investigated the diagnostic accuracy of first rank symptoms:

First rank symptoms for schizophrenia[12]
Summary
These studies were of limited quality. Results show correct identification of people with schizophrenia in about 75-95% of the cases although it is recommended to consult an additional specialist. The sensitivity of FRS was about 60%, so it can help diagnosis and, when applied with care, mistakes can be avoided. In lower resource settings, when more sophisticated methods are not available, first rank symptoms can be very valuable.[12]

DSM-5

The definition of schizophrenia remained essentially the same as that specified by the 2000 version of DSM (DSM-IV-TR), but DSM-5 makes a number of changes:[5]

  • Subtype classifications were removed.[7]
  • Catatonia is no longer so strongly associated with schizophrenia.[13]
  • In describing a person's schizophrenia, it is recommended that a better distinction be made between the current state of the condition and its historical progress, to achieve a clearer overall characterization.[7]
  • Special treatment of Schneider's first-rank symptoms is no longer recommended.[7]
  • Schizoaffective disorder is better defined to demarcate it more cleanly from schizophrenia.[7]
  • An assessment covering eight domains of psychopathology – including reality distortion, negative symptoms, thought and action disorganization, cognition impairment, catatonia, and symptoms similar to those found in certain mood disorders, such as whether hallucination or mania is experienced – is recommended to help clinical decision-making.[14]

Heterogeneity

Sub-classifications

The DSM-IV-TR contained five sub-classifications of schizophrenia. The sub-classifications were removed in the DSM-5 due to the conditions' heterogeneous nature and their historical insignificance in clinical practice.[15] These were retained in previous revisions largely for reasons of tradition, but had subsequently proved to be of little worth.[7]

The ICD-10 defines seven sub-classifications of schizophrenia.[8] These sub-classifications are:

Sub-classifications of Schizophrenia
ICD-10 Description DSM-IV-TR Equivalent
Paranoid (F20.0 Delusions and hallucinations are present but thought disorder, disorganized behavior, and affective flattening are not prominent. Paranoid type (295.3)
Hebephrenic (F20.1) Thought disorder and flat affect are present together. Disorganized type (295.1)
Catatonic (F20.2) Psychomotor disturbances are dominant features. Symptoms can include catatonic stupor and waxy flexibility. Catatonic type (295.2)
Undifferentiated (F20.3) Psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met. Undifferentiated type (295.9)
Post-schizophrenic depression (F20.4) A depressive episode arising in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms may still be present. Not present
Residual (F20.5) Positive symptoms are present at a low intensity and negative symptoms are prominent. Residual type (295.6)
Simple (F20.6) Delusions and hallucinations are not evident and negative symptoms progress slowly. Not present
Other (F20.8) Includes cenesthopathic schizophrenia and schizophreniform disorder NOS Not present

Country-specific versions

The ICD-10 Clinical Modification, used for medical coding and reporting in the United States excludes the Post-schizophrenic depression (F20.4) and the Simple (F20.6) sub-classifications.[16]

The Russian version of the ICD-10 includes additional four sub-classifications of schizophrenia: hypochondriacal (F20.801), cenesthopathic (F20.802), childhood type (F20.803), and atypical (F20.804).[17]

Comorbidities

People with schizophrenia often have additional mental health problems such as anxiety, depressive, or substance-use disorders.[18] Schizophrenia occurs along with obsessive-compulsive disorder (OCD) considerably more often than could be explained by chance.[19] An estimated 21% to 47% of patients with schizophrenia have a substance misuse disorder at some time in their life, and the chances of developing a substance misuse disorder is significantly higher among patients suffering from a psychotic illness.[20][21][22] All of these factors result in an increased range of clinical presentations and suggest a significant etiological heterogeneity.[18]

Sex differences

Schizophrenia is diagnosed 1.4 times more frequently in males than females, with onset peaking at ages 20–28 years for males and 4–10 years later in females [23] Females show more psychotic and affective symptoms than males, and have less social impairment. Men present more often with negative symptoms and disorganization.[2] These differences are likely due to the protective effects of estrogen and are correlated with estrogen expression.[24]

Onset

Early-onset schizophrenia occurs from ages 20–30, late-onset occurs after the age of 40, and very-late-onset after the age of 60.[25][26] It is estimated that 15% of the population with schizophrenia are late-onset and 5% very-late onset.[25][26] Many of the symptoms of late-onset schizophrenia are similar to the early-onset. However, individuals with late-onsets are more likely to report hallucinations in all sensory modalities, as well as persecutory and partition delusions. On the other hand, late-onset cases are less likely to present with formal thought disorder, affective symptoms. Negative symptoms and cognitive impairment are also rarer in very-late onset cases.[25][26]

Etiology

The pathophysiology of schizophrenia is poorly understood. Multiple hypothesis have been put forward, with evidence both supporting and contradicting them. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis.[27] Multiple genetic and environment factors have been associated with increased risk for developing schizophrenia.[28] Furthermore, response to treatment with anti-psychotic medication is variable, with some patients being resistant to some therapies.[29] Together, the differences in causes, response to treatment and pathophysiology suggest schizophrenia is heterogeneous from an etiological standpoint.[30] The differences resulting from this in terms of in clinical manifestations make the disorder harder to diagnose.[30]

Genetic

Multiple genetic and environmental factors contribute to the development of the schizophrenic phenotype. Distinct symptomatic sub types of schizophrenia groups show distinct patterns of SNP variations, reflecting the heterogeneous nature of the disease.[31] Studies also suggest there is a genetic overlap between schizophrenia and other psychiatric disorders, such as autism spectrum disorders, attention deficit-hyperactivity disorder, bipolar disorder, and major depressive disorder.[32] These factors complicate the use of genetic tests in diagnosis or prediction of the onset of schizophrenia.[33]

Pregnancy

The likelihood that someone will be diagnosed with Schizophrenia may be indicative of their mothers experiences and exposures. Etiological factors of Schizophrenia is at the forefront of current research efforts. For example, many studies have evaluated pregnant mothers and their experiences during pregnancy. Certain complications during pregnancy may increase the likelihood for mothers to give birth to children with mental health disorders.[34] Pregnant mothers who are exposed to teratogens during their pregnancy may be more likely to give birth to children that will receive a Schizophrenia diagnosis. These include Rubella, Influenza, Toxoplasma Gondii, and Herpes Simplex Virus Type 2. For example, children who are exposed to the Rubella virus in utero are 20% more likely to be diagnosed with Schizophrenia or another psychotic disorder.[35]

Children who are exposed to the parasite Toxoplasma Gondii are two times more likely to be diagnosed with schizophrenia and the diagnosis can be predicted as early as one week of life among newborns.[36][37] Although mothers may not have experienced symptoms of Rubella or Toxoplasma Gondii, higher levels of antibodies associated with these infections during pregnancy is associated to a higher probability that their child will have schizophrenia.[38] Elevated antibodies of cytomegalovirus and HPV were also found to be predictors.[38]

One hypothesis for these connections is that Rubella and Toxoplasma Gondii stimulate the development of cytokines, which lead to the inflammation of microglia and astroglia in the brain.[39] Microglia are small cells composed of glia. These cells act as a clean-up system and remove dead cells. Astroglia are star-shaped cells composed of glia that have extensions in all directions. They receive and monitor the activity of nearby neurons and help relay information.[40] When these cells become inflamed, they produce nitric oxide and amino acids, contributing to neuronal death. This results in differential brain development starting in utero, and can influence the way the brain forms and therefore further develops and functions. The hypothesis states that these alterations in functioning may contribute to the onset of Schizophrenia later in adulthood.[39]

The influence of other illnesses, such as Influenza and Herpes Simplex Virus Type 2, is still under debate. The timing of the exposure is still under research, as some studies suggest that mothers who are exposed to Influenza in the first trimester are seven times more likely to have children with schizophrenia, but also suggest that there is no increased risk during the second and third trimesters.[41] However, other studies suggest that exposure to the influenza virus in the second trimester is attributed to a high risk of schizophrenia among offspring. Similarly, research surveying maternal exposure to Herpes Type 2 demonstrates contrasting outcomes. According to antibody levels collected via blood sample among expecting mothers, exposure to HSV-2 is not significantly associated with offspring who have a Schizophrenia diagnosis.[42] A longitudinal study following a birth cohort in from 1959-1997 found similar results that refuted the association between the virus and subsequent diagnosis.[43] A body of literature has also suggested that mothers who are exposed to Herpes Simplex Virus Type 2 are associated with having babies that have psychotic disorders, including schizophrenia; however this risk may be partially influenced by paternal psychiatric history.[38][44] The inconsistent findings among the literature may be accounted for by the timing of maternal exposure to HSV-2. Animal models of HSV-2 among expecting mothers have demonstrated that rats exposed to HSV-2 earlier in development display greater maladaptation's in functioning.[45] These findings suggest that similar to Influenza, the timing of maternal exposure to the virus may play a greater role as compared to overall exposure.

Environment

Several studies have evaluated the environmental risks associated with schizophrenia diagnosis. Those who live in urban areas are at a greater risk of diagnosis [46] Although  environmental factors may increase the risk, encouraging and supportive communities may decrease the likelihood of schizophrenia. This belongingness allows for individuals to have a support system which decreases the likelihood that they will be isolated, which may be a contributing factor to the urban areas that have greater prevalence rates of schizophrenia.[47] Resiliency factors are present among many different mental health disorders. Having a community and a sense of belonging may help protect against a Schizophrenia diagnosis.[47] However, epigenetics plays a role in the diagnosis of Schizophrenia as well. In other words, environmental factors are only one piece of the puzzle.[40]

Differential diagnosis

If signs of disturbance are present for more than a month but less than six months, the diagnosis of schizophreniform disorder is applied.[48] Psychotic symptoms lasting less than a month may be diagnosed as brief psychotic disorder, and various conditions may be classed as psychotic disorder not otherwise specified. Schizoaffective disorder is diagnosed if symptoms of mood disorder are substantially present alongside psychotic symptoms.

Psychotic symptoms may be present in several other mental disorders, including bipolar disorder,[49] and borderline personality disorder.[50] Delusions ("non-bizarre") are also present in delusional disorder, and social withdrawal in social anxiety disorder, avoidant personality disorder and schizotypal personality disorder. Schizophrenia cannot be diagnosed if symptoms of mood disorder are substantially present, or if symptoms of pervasive developmental disorder are present unless prominent delusions or hallucinations are also present. Schizophrenia is further complicated with obsessive-compulsive disorder (OCD), and it can be difficult to distinguish obsessions that occur in OCD from the delusions of schizophrenia.[51] In children hallucinations must be separated from typical childhood fantasies.[52]

A urine drug screen must be performed to determine if the cause for symptoms could be drug intoxication or drug-induced psychosis. For example, a few people withdrawing from benzodiazepines experience a severe withdrawal syndrome which may last a long time and can resemble schizophrenia.[53] A general medical and neurological examination may also be needed to rule out medical illnesses which may rarely produce psychotic schizophrenia-like symptoms,[48] such as metabolic disturbance, systemic infection, syphilis, HIV infection, epilepsy, 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.[54] 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.

Biomarkers

A biomarker, as defined by the National Institutes of Health Biomarkers Definitions Working Group, is "a biologic characteristic objectively measured and evaluated as an indicator of normal or pathogenic processes; or of response to a treatment or challenge".[55] Biomarkers of psychosis for use in clinical tests can be diagnostic, prognostic, predictive of conversion, or monitoring of progression.[56] Clinical tests have many benefits: they can provide confidence in a diagnosis, allow clinicians to make better informed choices in regard to treatment, or even make it possible to identify subjects which can benefit from therapy to prevent transition into schizophrenia.[57] Currently, no biomarkers that can be widely used in clinical practice for the diagnosis of schizophrenia have been identified.[56]

Imaging

Brain imaging, such as CT and MRI scans, are currently only used to rule out brain abnormalities, and their benefit is very limited at that.[58] Structural alterations have, however, been identified in schizophrenia, most commonly enlarged ventricles, and decreased grey matter volume in the cortex and hippocampus.[59] Studies using functional MRI have also shown that altered connectivity and activity in present in schizophrenia.[60]

In the last decade interest has grown in the use of machine learning to automatically perform the diagnosis task using brain imaging data. While these algorithms are very robust at distinguishing schizophrenia patients from healthy subjects, they still cannot perform the tasks clinicians struggle the most with - differential diagnosis and treatment selection.[61]

Blood-based

Blood-based biomarkers those are obtained from plasma or serum samples. Since the prevalence of metabolic syndromes is increased in schizophrenia patients, makers of those syndromes have been common targets of research. Differences between patients and controls have been found in insulin levels, insulin resistance, and glucose tolerance.[62] These effects are generally small, however, and often present only in a subset of patients, which results from the heterogeneity of the disease.[62] Furthermore, these results are often complicated by the metabolic side effects of anti-psychotic medication.[62] Serum levels of hormones typically active in the hypothalamic pituitary adrenal (HPA) axis, such as cortisol and acetylcholine, have also been correlated with symptoms and progression of schizophrenia.[62] Peripheral biomarkers of immune function have also been a major target of research, with over 75 candidates having been identified.[63] Cytokines and growth factors are consistently identified as candidates by different studies, but variation in identity and direction of the correlation is common.[62] In recent years, markers of oxidative stress, epigentic methylation, mRNA transcription, and proteomic expression have also been targets of research, with their potential still to be determined.[64] It is likely that no single biomarker will be clinically useful, but rather a biomarker assay would have to be performed, like the well-performing 51 marker assay developed by E. Schwarz and colleagues.[65]

Genetic

Estimates of the heritability of schizophrenia is around 80%, which implies that 80% of the individual differences in risk to schizophrenia is explained by individual differences in genetics.[66] Although many genetic variants associated with schizophrenia have been identified, their effects are usually very small, so they are combined onto a polygenic risk score.[67] These scores, despite accounting for hundreds of variants, only explain up to 6% in symptom variation and 7% of the risk for developing the disease.[33] An example of a well-studied[56] genetic biomarker in schizophrenia is the single nucleotide polymorphism in the HLA-DQB1 gene, which is part of the human leukocyte antigen (HLA) complex. A G to C replacement on position 6672 predicts risk of agranulocytosis, a side effect of clozapine that can be fatal.[68]

Criticisms of classification systems

Spectrum of conditions

There is an argument that the underlying issues would be better addressed as a spectrum of conditions[69] or as individual dimensions along which everyone varies rather than by a diagnostic category based on an arbitrary cut-off between normal and ill.[70] This approach appears consistent with research on schizotypy, and with a relatively high prevalence of psychotic experiences, mostly non-distressing delusional beliefs, among the general public.[71][72][73] In concordance with this observation, psychologist Edgar Jones, and psychiatrists Tony David and Nassir Ghaemi, surveying the existing literature on delusions, pointed out that the consistency and completeness of the definition of delusion have been found wanting by many; delusions are neither necessarily fixed nor false, and need not involve the presence of incontrovertible evidence.[74][75][76]

Diagnostic criteria

Nancy Andreasen has criticized the current DSM-IV and ICD-10 criteria for sacrificing diagnostic validity for the sake of artificially improving reliability. She argues that overemphasis on psychosis in the diagnostic criteria, while improving diagnostic reliability, ignores more fundamental cognitive impairments that are harder to assess due to large variations in presentation.[77][78] This view is supported by other psychiatrists.[79] In the same vein, Ming Tsuang and colleagues argue that psychotic symptoms may be a common end-state in a variety of disorders, including schizophrenia, rather than a reflection of the specific etiology of schizophrenia, and warn that there is little basis for regarding DSM's operational definition as the "true" construct of schizophrenia.[69] Neuropsychologist Michael Foster Green went further in suggesting the presence of specific neurocognitive deficits may be used to construct phenotypes that are alternatives to those that are purely symptom-based. These deficits take the form of a reduction or impairment in basic psychological functions such as memory, attention, executive function and problem solving.[80][81]

The exclusion of affective components from the criteria for schizophrenia, despite their ubiquity in clinical settings, has also caused contention. This exclusion in the DSM has resulted in a "rather convoluted" separate disorder—schizoaffective disorder.[79] Citing poor interrater reliability, some psychiatrists have totally contested the concept of schizoaffective disorder as a separate entity.[82][83] The categorical distinction between mood disorders and schizophrenia, known as the Kraepelinian dichotomy, has also been challenged by data from genetic epidemiology.[84]

Biological validity

As clinicians and researchers become increasingly aware of the limitations of the current diagnostic systems, calls for new nosology are being made.[85] The National Institute of Health's Research of Domain Criteria (RDoC) research program, launched in 2009, is perhaps the largest combined effort to address the need for a new approach in classifying mental disorders.[86] The European Roadmap for Mental Health Research (ROAMER) funding initiative shares many goals with RDoC.[87] These initiatives encourage researchers to consider diagnosis as dimensional, instead of a clear-cut between patients and healthy subjects, and to cut across diagnostic boundaries.[88] The goal is to develop biologically valid diagnosis by defining nosology based on biological measures instead of symptom profiles, as is done currently.[89] Initial efforts in this area have been able to stratify patients along the psychosis continuum into genetically distinct sub types based on their symptoms,[88] brain measures such as EEG,[90][91] and serum biomarker profiles.[92]

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