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]

Changes made

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.^[10] 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.^[10] 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.^[10]

Another major change was to remove the importance previously given to Schneider's first-rank symptoms.^[11] DSM-5 still uses the listing of schizophreniform disorder but ICD-11 no longer includes it.^[10] 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.^[11]

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.^[10] 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.^[10][12]

Two of the negative symptoms – avolition and diminished emotional expression – have been given more prominence in both manuals.^[10]

First rank symptoms

First-rank symptoms are psychotic symptoms that are particularly characteristic of schizophrenia, which were put forward by Kurt Schneider in 1959.^[13] Their reliability for the diagnosis of schizophrenia has been questioned since then.^[14] A 2015 systematic review investigated the diagnostic accuracy of first rank symptoms:

First rank symptoms for schizophrenia^[15]

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.[15]
Summary accuracy % (95% CI) Prevalence median (range) Implications Quality and comments Diagnosis of schizophrenia from all other diagnoses Sensitivity 57.0 (50.4, 63.3) Specificity 81.4 (74.0, 87.1) 48% (15% to 84%) Prevalence of 48%: 48 out of every 100 people with all other mental health diagnoses will have schizophrenia. The result means that, of these, 21 will not be identified as having schizophrenia by use of FRS (43% of 48). Then, of the 52 people really without schizophrenia, 10 may be incorrectly diagnosed with schizophrenia by the FRS. Diagnosis of schizophrenia from other types of psychosis Sensitivity 58.0 (50.3, 65.3) Specificity 74.7 (85.2, 82.3) 57% (24% to 84%) Prevalence of 57%: 57 out of every 100 people with other types of psychosis will have schizophrenia. The result means that, of these, 24 will not be identified as having schizophrenia by use of FRS (42% of 57). Then, of the 43 people really without schizophrenia, 13 may be incorrectly diagnosed with schizophrenia by the FRS. For all three estimates there are important issues regarding patient selection, use of index test and reference standard. This raises doubts about the accuracy of these findings. Also most studies were not conducted in an everyday clinical setting. Diagnosis of schizophrenia from non-psychotic disorders Sensitivity 61.8 (51.7, 71.0) Specificity 94.1 (88.0, 97.2) 55% (19% to 89%) With a prevalence of 55%, 55 out of every 100 people with non-psychotic disorders will have schizophrenia. Of these, 21 will not be identified as having schizophrenia by use of FRS (38% of 55). Then, of the 45 people really without schizophrenia, 3 may be incorrectly diagnosed with schizophrenia by the FRS.

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.^[16] 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.^[17]

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).^[18]

Comorbidities

People with schizophrenia often have additional mental health problems such as anxiety, depressive, or substance-use disorders.^[19] Schizophrenia occurs along with obsessive-compulsive disorder (OCD) considerably more often than could be explained by chance.^[20] 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 with a psychotic illness.^[21][22][23] All of these factors result in an increased range of clinical presentations and suggest a significant etiological heterogeneity.^[19]

Sex differences

See also: Sex differences in schizophrenia

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.^[24] 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.^[25]

Prelingually deaf persons

Usually, psychiatric diagnostics is carried out orally. Thus, the question about schizophrenia in prelingually deaf persons rises. Only few reports exist. A review points out that acoustic hallucinations of normal hearing schizophrenic people correspond to visual and tactile hallucinations of prelingually deaf persons. Also, the structure of the (sign-) language is altered in ill persons. As a follow, “schizophrenia does not depend on the acoustic part of language or the acquisition of spoken language”.^[26]

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.^[27][28] It is estimated that 15% of the population with schizophrenia are late-onset and 5% very-late onset.^[27][28] 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.^[27][28]

Etiology

See also: Mechanisms of schizophrenia

The pathophysiology of schizophrenia is poorly understood. Multiple hypotheses have been put forward, with evidence both supporting and contradicting them. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis.^[29] Multiple genetic and environment factors have been associated with increased risk for developing schizophrenia.^[30] Furthermore, response to treatment with anti-psychotic medication is variable, with some patients being resistant to some therapies.^[31] Together, the differences in causes, response to treatment and pathophysiology suggest schizophrenia is heterogeneous from an etiological standpoint.^[32] The differences resulting from this in terms of in clinical manifestations make the disorder harder to diagnose.^[32]

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.^[33] 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.^[34] These factors complicate the use of genetic tests in diagnosis or prediction of the onset of schizophrenia.^[35]

Differential diagnosis

See also: Comparison of bipolar disorder and schizophrenia

If signs of disturbance are present for more than a month but less than six months, the diagnosis of schizophreniform disorder is applied.^[36] 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,^[37] and borderline personality disorder.^[38] 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.^[39] In children hallucinations must be separated from typical childhood fantasies.^[40]

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.^[41] A general medical and neurological examination may also be needed to rule out medical illnesses which may rarely produce psychotic schizophrenia-like symptoms,^[36] 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.^[42] 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".^[43] Biomarkers of psychosis for use in clinical tests can be diagnostic, prognostic, predictive of conversion, or monitoring of progression.^[44] 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.^[45] Currently, no biomarkers that can be widely used in clinical practice for the diagnosis of schizophrenia have been identified.^[44]

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.^[46] Structural alterations have, however, been identified in schizophrenia, most commonly enlarged ventricles, and decreased grey matter volume in the cortex and hippocampus.^[47] Studies using functional MRI have also shown that altered connectivity and activity in present in schizophrenia.^[48]

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.^[49]

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.^[50] These effects are generally small, however, and often present only in a subset of patients, which results from the heterogeneity of the disease.^[50] Furthermore, these results are often complicated by the metabolic side effects of anti-psychotic medication.^[50] 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.^[50] Peripheral biomarkers of immune function have also been a major target of research, with over 75 candidates having been identified.^[51] Cytokines and growth factors are consistently identified as candidates by different studies, but variation in identity and direction of the correlation is common.^[50] 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.^[52] 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.^[53]

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.^[54] 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.^[55] 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.^[35] An example of a well-studied^[44] 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.^[56]

Criticisms of classification systems

Spectrum of conditions

There is an argument that the underlying issues would be better addressed as a spectrum of conditions^[57] or as individual dimensions along which everyone varies rather than by a diagnostic category based on an arbitrary cut-off between normal and ill.^[58] 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.^[59][60][61] 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.^[62][63][64]

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.^[65][66] This view is supported by other psychiatrists.^[67] 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.^[57] 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.^[68][69]

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.^[67] Citing poor interrater reliability, some psychiatrists have totally contested the concept of schizoaffective disorder as a separate entity.^[70][71] The categorical distinction between mood disorders and schizophrenia, known as the Kraepelinian dichotomy, has also been challenged by data from genetic epidemiology.^[72]

Biological validity

As clinicians and researchers become increasingly aware of the limitations of the current diagnostic systems, calls for new nosology are being made.^[73] 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.^[74] The European Roadmap for Mental Health Research (ROAMER) funding initiative shares many goals with RDoC.^[75] 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.^[76] The goal is to develop biologically valid diagnosis by defining nosology based on biological measures instead of symptom profiles, as is done currently.^[77] Initial efforts in this area have been able to stratify patients along the psychosis continuum into genetically distinct sub types based on their symptoms,^[76] brain measures such as EEG,^[78][79] and serum biomarker profiles.^[80]

References

1. van Os J, Kapur S (August 2009). "Schizophrenia". Lancet. 374 (9690): 635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006. S2CID 208792724.
2. American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (Fifth ed.). Arlington, VA: American Psychiatric Publishing. pp. 5–25. ISBN 978-0-89042-555-8.
3. Ellerby M (August 2014). "Personal experience: Diagnosis and dilemmas – what happens when we diagnose patients with the label 'schizophrenia'". Psychiatric Bulletin. 38 (4): 182–4. doi:10.1192/pb.bp.113.046631. PMC 4115427. PMID 25237543.
4. Picchioni MM, Murray RM (July 2007). "Schizophrenia". BMJ. 335 (7610): 91–5. doi:10.1136/bmj.39227.616447.BE. PMC 1914490. PMID 17626963.
5. American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington: American Psychiatric Publishing. ISBN 978-0-89042-555-8.
6. Jakobsen KD, Frederiksen JN, Hansen T, Jansson LB, Parnas J, Werge T (2005). "Reliability of clinical ICD-10 schizophrenia diagnoses". Nordic Journal of Psychiatry. 59 (3): 209–12. doi:10.1080/08039480510027698. PMID 16195122. S2CID 24590483.
7. Tandon R, Gaebel W, Barch DM, Bustillo J, Gur RE, Heckers S, et al. (October 2013). "Definition and description of schizophrenia in the DSM-5". Schizophrenia Research. 150 (1): 3–10. doi:10.1016/j.schres.2013.05.028. PMID 23800613. S2CID 17314600.
8. "The ICD-10 Classification of Mental and Behavioural Disorders" (PDF). World Health Organization. p. 26. Archived (PDF) from the original on 2016-06-18. Retrieved 2022-04-09.
9. Heinz A, Voss M, Lawrie SM, Mishara A, Bauer M, Gallinat J, et al. (September 2016). "Shall we really say goodbye to first rank symptoms?". European Psychiatry. 37: 8–13. doi:10.1016/j.eurpsy.2016.04.010. PMID 27429167. S2CID 13761854.
10. Biedermann F, Fleischhacker WW (August 2016). "Psychotic disorders in DSM-5 and ICD-11". CNS Spectrums. 21 (4): 349–54. doi:10.1017/S1092852916000316. PMID 27418328. S2CID 24728447.
11. Tandon R, Gaebel W, Barch DM, et al. (October 2013). "Definition and description of schizophrenia in the DSM-5". Schizophrenia Research. 150 (1): 3–10. doi:10.1016/j.schres.2013.05.028. PMID 23800613. S2CID 17314600.
12. Barch DM, Bustillo J, Gaebel W, et al. (October 2013). "Logic and justification for dimensional assessment of symptoms and related clinical phenomena in psychosis: relevance to DSM-5". Schizophrenia Research. 150 (1): 15–20. doi:10.1016/j.schres.2013.04.027. PMID 23706415. S2CID 10052003.
13. Schneider, K. Clinical Psychopathology. New York: Grune and Stratton. 1959.
14. Bertelsen A (2002). "Schizophrenia and related disorders: experience with current diagnostic systems". Psychopathology. 35 (2–3): 89–93. doi:10.1159/000065125. PMID 12145490. S2CID 41076230.
15. Soares-Weiser K, Maayan N, Bergman H, Davenport C, Kirkham AJ, Grabowski S, Adams CE (January 2015). "First rank symptoms for schizophrenia". The Cochrane Database of Systematic Reviews. 1 (1): CD010653. doi:10.1002/14651858.CD010653.pub2. PMC 7079421. PMID 25879096. Archived from the original on 2021-03-03. Retrieved 2022-04-09.
16. "NIMH » Schizophrenia". www.nimh.nih.gov. Archived from the original on 2019-09-06. Retrieved 2017-11-09.
17. CMS (February 23, 2010). "2010 ICD-10-CM" (web). Centers for Medicare and Medicaid Services. Archived from the original on November 26, 2011. Retrieved April 9, 2010.
18. "МКБ-10: Классификация психических и поведенческих расстройств. F2 Шизофрения, шизотипические и бредовые расстройства" [The ICD-10 Classification of Mental and Behavioural Disorders. F2 Schizophrenia, schizotypal and delusional disorders]. Archived from the original on 2020-08-04. Retrieved 2022-04-09. Russian adapted version of the ICD-10
19. Buckley PF, Miller BJ, Lehrer DS, Castle DJ (March 2009). "Psychiatric comorbidities and schizophrenia". Schizophrenia Bulletin. 35 (2): 383–402. doi:10.1093/schbul/sbn135. PMC 2659306. PMID 19011234.
20. Bottas A (15 April 2009). "Comorbidity: Schizophrenia With Obsessive-Compulsive Disorder". Psychiatric Times. 26 (4). Archived from the original on 3 April 2013.
21. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al. (January 1994). "Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey" (PDF). Archives of General Psychiatry. 51 (1): 8–19. doi:10.1001/archpsyc.1994.03950010008002. PMID 8279933. S2CID 22462381. Archived (PDF) from the original on 2021-02-26. Retrieved 2022-04-09.
22. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, Goodwin FK (November 1990). "Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study". JAMA. 264 (19): 2511–8. doi:10.1001/jama.264.19.2511. PMID 2232018.
23. Cantwell R (April 2003). "Substance use and schizophrenia: effects on symptoms, social functioning and service use". The British Journal of Psychiatry. 182 (4): 324–9. doi:10.1192/bjp.182.4.324. PMID 12668408.
24. Castle D, Wessely S, Der G, Murray RM (December 1991). "The incidence of operationally defined schizophrenia in Camberwell, 1965–84". The British Journal of Psychiatry. 159 (6): 790–4. doi:10.1192/bjp.159.6.790. PMID 1790446. S2CID 41661565.
25. Häfner H (April 2003). "Gender differences in schizophrenia". Psychoneuroendocrinology. 28 (Suppl 2): 17–54. doi:10.1016/s0306-4530(02)00125-7. PMID 12650680. S2CID 9307284.
26. Engmann, Birk (2011). "Peculiarities of schizophrenic diseases in prelingually deaf persons". MMW-Fortschritte der Medizin. Originalien. 1: 10–13. doi:10.1007/s15006-020-0358-2. PMID 21591325.
27. Howard R, Rabins PV, Seeman MV, Jeste DV (February 2000). "Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group". The American Journal of Psychiatry. 157 (2): 172–8. doi:10.1176/appi.ajp.157.2.172. PMID 10671383.
28. Wetherell JL, Jeste DV (2004). "Older adults with schizophrenia: Patients are living longer and gaining researchers' attention" (PDF). ElderCare. 3 (2): 8–11. Archived (PDF) from the original on 2014-06-11. Retrieved 2022-04-09.
29. Elert E (April 2014). "Aetiology: Searching for schizophrenia's roots". Nature. 508 (7494): S2-3. Bibcode:2014Natur.508S...2E. doi:10.1038/508S2a. PMID 24695332.
30. Insel TR (November 2010). "Rethinking schizophrenia". Nature. 468 (7321): 187–93. Bibcode:2010Natur.468..187I. doi:10.1038/nature09552. PMID 21068826. S2CID 4416517. Archived from the original on 2021-03-10. Retrieved 2022-04-09.
31. Semple.David"Oxford Handbook Of Psychiatry". Oxford Press. 2005. p 207.
32. Tsuang MT, Faraone SV (October 1995). "The case for heterogeneity in the etiology of schizophrenia". Schizophrenia Research. 17 (2): 161–75. doi:10.1016/0920-9964(95)00057-s. PMID 8562491. S2CID 2766394.
33. Arnedo J, Svrakic DM, Del Val C, Romero-Zaliz R, Hernández-Cuervo H, Fanous AH, et al. (February 2015). "Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies". The American Journal of Psychiatry. 172 (2): 139–53. doi:10.1176/appi.ajp.2014.14040435. PMID 25219520. S2CID 28470525.
34. Cross-Disorder Group of the Psychiatric Genomics Consortium (April 2013). "Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis". Lancet. 381 (9875): 1371–1379. doi:10.1016/S0140-6736(12)62129-1. PMC 3714010. PMID 23453885.
35. Kendler KS (March 2016). "The Schizophrenia Polygenic Risk Score: To What Does It Predispose in Adolescence?". JAMA Psychiatry. 73 (3): 193–4. doi:10.1001/jamapsychiatry.2015.2964. PMID 26817666.
36. American Psychiatric Association (2000). "Schizophrenia". Diagnostic and statistical manual of mental disorders: DSM-IV. Washington, DC: American Psychiatric Publishing, Inc. ISBN 0-89042-024-6. Retrieved 2008-07-04.^{[dead link‍]}
37. Pope HG (April 1983). "Distinguishing bipolar disorder from schizophrenia in clinical practice: guidelines and case reports" (PDF). Hospital & Community Psychiatry. 34 (4): 322–8. doi:10.1176/ps.34.4.322. PMID 6840720. Archived from the original (PDF) on 2008-02-27. Retrieved 2008-02-24.
38. McGlashan TH (February 1987). "Testing DSM-III symptom criteria for schizotypal and borderline personality disorders". Archives of General Psychiatry. 44 (2): 143–8. doi:10.1001/archpsyc.1987.01800140045007. PMID 3813809.
39. Bottas A (April 15, 2009). "Comorbidity: Schizophrenia With Obsessive-Compulsive Disorder". Psychiatric Times. 26 (4). Archived from the original on April 3, 2013. Retrieved January 15, 2011.
40. American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington: American Psychiatric Publishing. pp. 101–05. ISBN 978-0-89042-555-8.
41. Gabbard GO (15 May 2007). Gabbard's Treatments of Psychiatric Disorders, Fourth Edition (Treatments of Psychiatric Disorders). American Psychiatric Publishing. pp. 209–11. ISBN 978-1-58562-216-0. Archived from the original on 9 April 2022. Retrieved 9 April 2022.
42. Murray ED, Buttner N, Price BH (2012). "Depression and Psychosis in Neurological Practice". In Bradley WG, Daroff RB, Fenichel GM, Jankovic J (eds.). Bradley's neurology in clinical practice. Vol. 1 (6th ed.). Philadelphia, PA: Elsevier/Saunders. pp. 92–111. ISBN 978-1-4377-0434-1.
43. Biomarkers Definitions Working Group (March 2001). "Biomarkers and surrogate endpoints: preferred definitions and conceptual framework". Clinical Pharmacology and Therapeutics. 69 (3): 89–95. doi:10.1067/mcp.2001.113989. PMID 11240971. S2CID 288484.
44. Prata D, Mechelli A, Kapur S (September 2014). "Clinically meaningful biomarkers for psychosis: a systematic and quantitative review". Neuroscience and Biobehavioral Reviews. 45: 134–41. doi:10.1016/j.neubiorev.2014.05.010. PMID 24877683. S2CID 35897766.
45. Nelson B, Yung AR, Bechdolf A, McGorry PD (March 2008). "The phenomenological critique and self-disturbance: implications for ultra-high risk ("prodrome") research". Schizophrenia Bulletin. 34 (2): 381–92. doi:10.1093/schbul/sbm094. PMC 2632406. PMID 17702990.
46. Goulet K, Deschamps B, Evoy F, Trudel JF (July 2009). "Use of brain imaging (computed tomography and magnetic resonance imaging) in first-episode psychosis: review and retrospective study". Canadian Journal of Psychiatry. 54 (7): 493–501. doi:10.1177/070674370905400711. PMID 19660172.
47. Harrison PJ (April 1999). "The neuropathology of schizophrenia. A critical review of the data and their interpretation". Brain. 122 ( Pt 4) (4): 593–624. doi:10.1093/brain/122.4.593. PMID 10219775.
48. van den Heuvel MP, Hulshoff Pol HE (August 2010). "Exploring the brain network: a review on resting-state fMRI functional connectivity". European Neuropsychopharmacology. 20 (8): 519–34. doi:10.1016/j.euroneuro.2010.03.008. PMID 20471808. S2CID 12824218.
49. Arbabshirani MR, Plis S, Sui J, Calhoun VD (January 2017). "Single subject prediction of brain disorders in neuroimaging: Promises and pitfalls". NeuroImage. 145 (Pt B): 137–165. doi:10.1016/j.neuroimage.2016.02.079. PMC 5031516. PMID 27012503.
50. Chan MK, Gottschalk MG, Haenisch F, Tomasik J, Ruland T, Rahmoune H, et al. (November 2014). "Applications of blood-based protein biomarker strategies in the study of psychiatric disorders". Progress in Neurobiology. 122: 45–72. doi:10.1016/j.pneurobio.2014.08.002. PMID 25173695. S2CID 13553670.
51. Tomasik J, Rahmoune H, Guest PC, Bahn S (September 2016). "Neuroimmune biomarkers in schizophrenia". Schizophrenia Research. 176 (1): 3–13. doi:10.1016/j.schres.2014.07.025. PMID 25124519. S2CID 19832674.
52. Lai CY, Scarr E, Udawela M, Everall I, Chen WJ, Dean B (March 2016). "Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics". World Journal of Psychiatry. 6 (1): 102–17. doi:10.5498/wjp.v6.i1.102. PMC 4804259. PMID 27014601.
53. Schwarz E, van Beveren NJ, Ramsey J, Leweke FM, Rothermundt M, Bogerts B, et al. (July 2014). "Identification of subgroups of schizophrenia patients with changes in either immune or growth factor and hormonal pathways". Schizophrenia Bulletin. 40 (4): 787–95. doi:10.1093/schbul/sbt105. PMC 4059436. PMID 23934781.
54. Combs DR, Mueser KT, Gutierrez MM (2011). "Chapter 8: Schizophrenia: Etiological considerations". In Hersen M, Beidel DC (eds.). Adult psychopathology and diagnosis (6th ed.). John Wiley & Sons. ISBN 978-1-118-13884-7. Archived from the original on 2016-11-24. Retrieved 2022-04-09.
55. Mistry S, Harrison JR, Smith DJ, Escott-Price V, Zammit S (July 2018). "The use of polygenic risk scores to identify phenotypes associated with genetic risk of schizophrenia: Systematic review" (PDF). Schizophrenia Research. 197: 2–8. doi:10.1016/j.schres.2017.10.037. PMID 29129507. S2CID 2549646. Archived (PDF) from the original on 2022-03-12. Retrieved 2022-04-09.
56. Athanasiou MC, Dettling M, Cascorbi I, Mosyagin I, Salisbury BA, Pierz KA, et al. (April 2011). "Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis". The Journal of Clinical Psychiatry. 72 (4): 458–63. doi:10.4088/jcp.09m05527yel. PMID 20868635.
57. Tsuang MT, Stone WS, Faraone SV (July 2000). "Toward reformulating the diagnosis of schizophrenia". The American Journal of Psychiatry. 157 (7): 1041–50. doi:10.1176/appi.ajp.157.7.1041. PMID 10873908.
58. Peralta V, Cuesta MJ (June 2007). "A dimensional and categorical architecture for the classification of psychotic disorders". World Psychiatry. 6 (2): 100–1. PMC 2219908. PMID 18235866.
59. Verdoux H, van Os J (March 2002). "Psychotic symptoms in non-clinical populations and the continuum of psychosis". Schizophrenia Research. 54 (1–2): 59–65. doi:10.1016/S0920-9964(01)00352-8. PMID 11853979. S2CID 33168322.
60. Johns LC, van Os J (November 2001). "The continuity of psychotic experiences in the general population". Clinical Psychology Review. 21 (8): 1125–41. CiteSeerX 10.1.1.475.2509. doi:10.1016/S0272-7358(01)00103-9. PMID 11702510.
61. Peters E, Joseph S, Day S, Garety P (2005). "Measuring delusional ideation: the 21-item Peters et al. Delusions Inventory (PDI)". Schizophrenia Bulletin. 30 (4): 1005–22. doi:10.1093/oxfordjournals.schbul.a007116. PMID 15954204.
62. Jones E (1999). "The Phenomenology of Abnormal Belief: A Philosophical and Psychiatric Inquiry". Philosophy, Psychiatry, & Psychology. 6 (1): 1–16.
63. David AS (1999). "On the impossibility of defining delusions". Philosophy, Psychiatry, & Psychology. 6 (1): 17–20. Retrieved 2008-02-24.
64. Ghaemi SN (1999). "An Empirical Approach to Understanding Delusions". Philosophy, Psychiatry, & Psychology. 6 (1): 21–24. Retrieved 2008-02-24.
65. Andreasen NC (March 2000). "Schizophrenia: the fundamental questions". Brain Research. Brain Research Reviews. 31 (2–3): 106–12. doi:10.1016/S0165-0173(99)00027-2. PMID 10719138. S2CID 8545249.
66. Andreasen NC (September 1999). "A unitary model of schizophrenia: Bleuler's "fragmented phrene" as schizencephaly". Archives of General Psychiatry. 56 (9): 781–7. doi:10.1001/archpsyc.56.9.781. PMID 12884883.
67. Jansson LB, Parnas J (September 2007). "Competing definitions of schizophrenia: what can be learned from polydiagnostic studies?". Schizophrenia Bulletin. 33 (5): 1178–200. doi:10.1093/schbul/sbl065. PMC 3304082. PMID 17158508.
68. Green MF, Nuechterlein KH (1999). "Should schizophrenia be treated as a neurocognitive disorder?". Schizophrenia Bulletin. 25 (2): 309–19. doi:10.1093/oxfordjournals.schbul.a033380. PMID 10416733.
69. Green M (2001). Schizophrenia revealed: from neurons to social interactions. New York: W.W. Norton. ISBN 0-393-70334-7.
70. Lake CR, Hurwitz N (July 2007). "Schizoaffective disorder merges schizophrenia and bipolar disorders as one disease—there is no schizoaffective disorder". Current Opinion in Psychiatry. 20 (4): 365–79. doi:10.1097/YCO.0b013e3281a305ab. PMID 17551352. S2CID 37664803.
71. Malhi GS, Green M, Fagiolini A, Peselow ED, Kumari V (February 2008). "Schizoaffective disorder: diagnostic issues and future recommendations". Bipolar Disorders. 10 (1 Pt 2): 215–30. doi:10.1111/j.1399-5618.2007.00564.x. PMID 18199238.
72. Craddock N, Owen MJ (May 2005). "The beginning of the end for the Kraepelinian dichotomy". The British Journal of Psychiatry. 186 (5): 364–6. doi:10.1192/bjp.186.5.364. PMID 15863738.
73. Williams LM (June 2017). "Getting Personalized: Brain Scan Biomarkers for Guiding Depression Interventions". The American Journal of Psychiatry. 174 (6): 503–505. doi:10.1176/appi.ajp.2017.17030314. PMID 28565957.
74. Insel TR (April 2014). "The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry". The American Journal of Psychiatry. 171 (4): 395–7. doi:10.1176/appi.ajp.2014.14020138. PMID 24687194. S2CID 26857128.
75. Schumann G, Binder EB, Holte A, de Kloet ER, Oedegaard KJ, Robbins TW, et al. (January 2014). "Stratified medicine for mental disorders" (PDF). European Neuropsychopharmacology. 24 (1): 5–50. doi:10.1016/j.euroneuro.2013.09.010. PMID 24176673. S2CID 5733076. Archived (PDF) from the original on 2022-04-09. Retrieved 2022-04-09.
76. Marquand AF, Wolfers T, Mennes M, Buitelaar J, Beckmann CF (September 2016). "Beyond Lumping and Splitting: A Review of Computational Approaches for Stratifying Psychiatric Disorders". Biological Psychiatry. Cognitive Neuroscience and Neuroimaging. 1 (5): 433–447. doi:10.1016/j.bpsc.2016.04.002. PMC 5013873. PMID 27642641.
77. Keshavan MS, Clementz BA, Pearlson GD, Sweeney JA, Tamminga CA (May 2013). "Reimagining psychoses: an agnostic approach to diagnosis". Schizophrenia Research. 146 (1–3): 10–6. doi:10.1016/j.schres.2013.02.022. PMID 23498153. S2CID 5872571.
78. Clementz BA, Sweeney JA, Hamm JP, Ivleva EI, Ethridge LE, Pearlson GD, et al. (April 2016). "Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers". The American Journal of Psychiatry. 173 (4): 373–84. doi:10.1176/appi.ajp.2015.14091200. PMC 5314432. PMID 26651391.
79. Kranz TM, Berns A, Shields J, Rothman K, Walsh-Messinger J, Goetz RR, et al. (April 2016). "Phenotypically distinct subtypes of psychosis accompany novel or rare variants in four different signaling genes". eBioMedicine. 6: 206–214. doi:10.1016/j.ebiom.2016.03.008. PMC 4856793. PMID 27211562.
80. Schwarz E, van Beveren NJ, Ramsey J, Leweke FM, Rothermundt M, Bogerts B, et al. (July 2014). "Identification of subgroups of schizophrenia patients with changes in either immune or growth factor and hormonal pathways". Schizophrenia Bulletin. 40 (4): 787–95. doi:10.1093/schbul/sbt105. PMC 4059436. PMID 23934781.

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