Diagnosis of schizophrenia
The diagnosis of schizophrenia is based on criteria in either the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, version DSM-5, or the World Health Organization's International Statistical Classification of Diseases and Related Health Problems, the ICD-10. Clinical assessment is performed by a mental health professional based on observed behavior, reported experiences, and reports of others familiar with the person. Symptoms associated with schizophrenia occur along a continuum in the population and must reach a certain severity and level of impairment before a diagnosis is made.
- 1 Criteria
- 2 Heterogeneity
- 3 Differential diagnosis
- 4 Biomarkers
- 5 Criticisms of classification systems
- 6 References
The ICD-10 criteria are typically used in most of the world, while the DSM-5 criteria are used in USA.
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 person has to be suffering from delusions, hallucinations, or disorganized speech. A second symptom could be negative symptoms, or severely disorganized or catatonic behavior.
In practice, agreement between the two systems is high. The DSM-5 criteria puts more emphasis on social or occupational dysfunction than the ICD-10. The ICD-10, on the other hand, puts more emphasis on first-rank symptoms. The current proposal for the ICD-11 criteria for schizophrenia recommends adding self-disorder as a symptom.
First rank symptoms
First-rank symptoms are psychotic symptoms that are particularly characteristic of schizophrenia, which were put forward by Kurt Schneider in 1959. Their reliability for the diagnosis of schizophrenia has been questioned since then. A 2015 systematic review investigated the diagnostic accuracy of first rank symptoms:
|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.|
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:
- Subtype classifications were removed.
- Catatonia is no longer so strongly associated with schizophrenia.
- 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.
- Special treatment of Schneider's first-rank symptoms is no longer recommended.
- Schizoaffective disorder is better defined to demarcate it more cleanly from schizophrenia.
- 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.
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. These were retained in previous revisions largely for reasons of tradition, but had subsequently proved to be of little worth.
The ICD-10 defines seven sub-classifications of schizophrenia. These sub-classifications are:
|Paranoid (F20.0||Delusions and hallucinations are present but thought disorder, disorganized behavior, and effective 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|
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).
People with schizophrenia often have additional mental health problems such as anxiety, depressive, or substance-use disorders. Schizophrenia occurs along with obsessive-compulsive disorder (OCD) considerably more often than could be explained by chance. 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. All of these factors result in an increased range of clinical presentations and suggest a significant etiological heterogeneity.
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  Females show more psychotic and affective symptoms than males, and have less social impairment. Men present more often with negative symptoms and disorganization. These differences are likely due to the protective effects of estrogen and are correlated with estrogen expression.
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. It is estimated that 15% of the population with schizophrenia are late-onset and 5% very-late onset. 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 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.
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. Multiple genetic and environment factors have been associated with increased risk for developing schizophrenia. Furthermore, response to treatment with anti-psychotic medication is variable, with some patients being resistant to some therapies. Together, the differences in causes, response to treatment and pathophysiology suggest schizophrenia is heterogeneous from an etiological standpoint. The differences resulting from this in terms of in clinical manifestations make the disorder harder to diagnose.
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. 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. These factors complicate the use of genetic tests in diagnosis or prediction of the onset of schizophrenia.
If signs of disturbance are present for more than a month but less than six months, the diagnosis of schizophreniform disorder is applied. 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, and borderline personality disorder. 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. In children hallucinations must be separated from typical childhood fantasies.
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. A general medical and neurological examination may also be needed to rule out medical illnesses which may rarely produce psychotic schizophrenia-like symptoms, 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. 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.
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". Biomarkers of psychosis for use in clinical tests can be diagnostic, prognostic, predictive of conversion, or monitoring of progression. 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. Currently, no biomarkers than can be widely used in clinical practice for the diagnosis of schizophrenia have been identified.
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. Structural alterations have, however, been identified in schizophrenia, most commonly enlarged ventricles, and decreased grey matter volume in the cortex and hippocampus. Studies using functional MRI have also shown that altered connectivity and activity in present in schizophrenia.
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.
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. These effects are generally small, however, and often present only in a subset of patients, which results from the heterogeneity of the disease. Furthermore, these results are often complicated by the metabolic side effects of anti-psychotic medication. 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. Peripheral biomarkers of immune function have also been a major target of research, with over 75 candidates having been identified. Cytokines and growth factors are consistently identified as candidates by different studies, but variation in identity and direction of the correlation is common. 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. 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.
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. 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. 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. An example of a well-studied 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.
Criticisms of classification systems
Spectrum of conditions
There is an argument that the underlying issues would be better addressed as a spectrum of conditions or as individual dimensions along which everyone varies rather than by a diagnostic category based on an arbitrary cut-off between normal and ill. 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. 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.
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. This view is supported by other psychiatrists. 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. 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.
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. Citing poor interrater reliability, some psychiatrists have totally contested the concept of schizoaffective disorder as a separate entity. The categorical distinction between mood disorders and schizophrenia, known as the Kraepelinian dichotomy, has also been challenged by data from genetic epidemiology.
As clinicians and researchers become increasingly aware of the limitations of the current diagnostic systems, calls for new nosology are being made. 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. The European Roadmap for Mental Health Research (ROAMER) funding initiative shares many goals with RDoC. 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. The goal is to develop biologically valid diagnosis by defining nosology based on biological measures instead of symptom profiles, as is done currently. Initial efforts in this area have been able to stratify patients along the psychosis continuum into genetically distinct sub types based on their symptoms, brain measures such as EEG, and serum biomarker profiles.
- van Os J, Kapur S. Schizophrenia. Lancet. 2009;374(9690):635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006.
- 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.
- Picchioni MM, Murray RM. Schizophrenia. BMJ. 2007;335(7610):91–5. doi:10.1136/bmj.39227.616447.BE. PMID 17626963.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington: American Psychiatric Publishing. ISBN 978-0-89042-555-8.
- Jakobsen KD, Frederiksen JN, Hansen T, et al.. Reliability of clinical ICD-10 schizophrenia diagnoses. Nordic Journal of Psychiatry. 2005;59(3):209–12. doi:10.1080/08039480510027698. PMID 16195122.
- Tandon R, Gaebel W, Barch DM, Bustillo J, Gur RE, Heckers S, Malaspina D, Owen MJ, Schultz S, Tsuang M, Van Os J, Carpenter W (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.
- "The ICD-10 Classification of Mental and Behavioural Disorders" (PDF). World Health Organization. p. 26.
- Heinz A, Voss M, Lawrie SM, Mishara A, Bauer M, Gallinat J, Juckel G, Lang U, Rapp M, Falkai P, Strik W, Krystal J, Abi-Dargham A, Galderisi S (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.
- Schneider, K. Clinical Psychopathology. New York: Grune and Stratton. 1959.
- Bertelsen A (2002). "Schizophrenia and related disorders: experience with current diagnostic systems". Psychopathology. 35 (2–3): 89–93. doi:10.1159/000065125. PMID 12145490.
- Soares-Weiser, K; Maayan, N; Bergman, H (2015). "First rank symptoms for schizophrenia". Cochrane Database of Systematic Reviews. 1: CD010653.pub2. doi:10.1002/14651858.CD010653.pub2. PMID 25879096.
- As referenced from PMID 23800613, Heckers S, Tandon R, Bustillo J (March 2010). "Catatonia in the DSM--shall we move or not?". Schizophrenia Bulletin (Editorial). 36 (2): 205–7. doi:10.1093/schbul/sbp136. PMC 2833126. PMID 19933711.
- Barch DM, Bustillo J, Gaebel W, Gur R, Heckers S, Malaspina D, Owen MJ, Schultz S, Tandon R, Tsuang M, Van Os J, Carpenter W (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.
- "NIMH » Schizophrenia". www.nimh.nih.gov. Retrieved 2017-11-09.
- "The ICD-10 Classification of Mental and Behavioural Disorders" (PDF). World Health Organization. p. 26.
- CMS (February 23, 2010). "2010 ICD-10-CM" (web). Centers for Medicare and Medicaid Services. Retrieved April 9, 2010.
- 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]. Russian.
- 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.
- Bottas A (15 April 2009). "Comorbidity: Schizophrenia With Obsessive-Compulsive Disorder". Psychiatric Times. 26 (4). Archived from the original on 3 April 2013.
- Kessler RC; McGonagle KA; Zhao S; Nelson CB; Hughes M; Eshleman S; Wittchen HU; Kendler KS (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.
- Regier DA; Farmer ME; Rae DS; Locke BZ; Keith SJ; Judd LL; Goodwin FK (1990). "Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study". JAMA. 264 (19): 2511–18. doi:10.1001/jama.264.19.2511. PMID 2232018.
- Cantwell, R; Scottish Comorbidity Study Group (2003). "Substance use and schizophrenia: effects on symptoms, social functioning and service use". British Journal of Psychiatry. 182 (4): 324–9. doi:10.1192/bjp.182.4.324. PMID 12668408.
- Castle D, Wessely S, Der G, Murray RM. The incidence of operationally defined schizophrenia in Camberwell, 1965–84. The British Journal of Psychiatry. 1991;159:790–4. doi:10.1192/bjp.159.6.790. PMID 1790446.
- Häfner, H (2003). "Gender differences in schizophrenia". Psychoneuroendocrinology. 28: 17–54. doi:10.1016/s0306-4530(02)00125-7. PMID 12650680.
- Howard, R., Rabins, P. V., Seeman, M. V., Jeste, D. V., International Late-Onset Schizophrenia Group (2000). Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: An international consensus. The American Journal of Psychiatry, 157(2), 172-178. Retrieved fromhttp://ajp.psychiatryonline.org/data/Journals/AJP/3709/172.pdf
- Wetherell, J. L. & Jeste, D. V. (2004). Older adults with schizophrenia: Patients are living longer and gaining researchers’ attention. ElderCare, 3(2), 8-11. Retrieved from www.stanford.edu/group/usvh/stanford/misc/Schizophrenia 2.pdf
- Elert, E (2014). "Aetiology: Searching for schizophrenia's roots". Nature. 508 (7494): S2–3. doi:10.1038/508S2a. PMID 24695332.
- Insel, Thomas R. (2010). "Rethinking schizophrenia". Nature. 468 (7321): 187–93. doi:10.1038/nature09552. PMID 21068826.
- Semple.David"Oxford Handbook Of Psychiatry". Oxford Press. 2005. p 207.
- Tsuang, M (1995). "The case for heterogeneity in the etiology of schizophrenia". Schizophrenia Research. 17 (2): 161–175. doi:10.1016/0920-9964(95)00057-s.
- Arnedo J, Svrakic DM, del Val CP, Romero-Zaliz R, Hernández-Cuervo H, Molecular Genetics of Schizophrenia Consortium, Fanous AH, Pato MT, Pato CN, de Erausquin GA, Cloninger R, Zwir I; Svrakic; Del Val; Romero-Zaliz; Hernández-Cuervo; Fanous; Pato; Pato; De Erausquin; Cloninger; Zwir (2014). "Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide- Association Studies". American Journal of Psychiatry. 172 (AJP in Advance): 139–153. doi:10.1176/appi.ajp.2014.14040435. PMID 25219520.CS1 maint: Multiple names: authors list (link)
- Cross-Disorder Group of the Psychiatric Genomics Consortium (2013). "Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis". The Lancet. 381 (9875): 1371–9. doi:10.1016/S0140-6736(12)62129-1. PMC 3714010. PMID 23453885.
- 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.
- American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV. Washington, DC: American Psychiatric Publishing, Inc.; 2000 [Retrieved 2008-07-04]. ISBN 0-89042-024-6. Schizophrenia.
- Pope HG. Distinguishing bipolar disorder from schizophrenia in clinical practice: guidelines and case reports [PDF]. Hospital and Community Psychiatry. 1983 [archived 2008-02-27; Retrieved 2008-02-24];34:322–28.
- McGlashan TH. Testing DSM-III symptom criteria for schizotypal and borderline personality disorders. Archives of General Psychiatry. 1987;44(2):143–8. doi:10.1001/archpsyc.1987.01800140045007. PMID 3813809.
- Bottas A. Comorbidity: Schizophrenia With Obsessive-Compulsive Disorder. Psychiatric Times. April 15, 2009;26(4).
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington: American Psychiatric Publishing. pp. 101–05. ISBN 978-0-89042-555-8.
- 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.
- Murray ED, Buttner N, Price BH (2012). "Depression and Psychosis in Neurological Practice". In Bradley WG, Daroff RB, Fenichel GM, Jankovic J. Bradley's neurology in clinical practice. 1 (6th ed.). Philadelphia, PA: Elsevier/Saunders. pp. 92–111. ISBN 978-1-4377-0434-1.
- Biomarkers Definitions Working Group (2001-03-01). "Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework". Clinical Pharmacology & Therapeutics. 69 (3): 89–95. doi:10.1067/mcp.2001.113989. ISSN 1532-6535. PMID 11240971.
- Prata, Diana; Mechelli, Andrea; Kapur, Shitij (2014). "Clinically meaningful biomarkers for psychosis: A systematic and quantitative review". Neuroscience & Biobehavioral Reviews. 45: 134–141. doi:10.1016/j.neubiorev.2014.05.010. PMID 24877683.
- Nelson, Barnaby; Yung, Alison R.; Bechdolf, Andreas; McGorry, Patrick D. (2008-03-01). "The Phenomenological Critique and Self-disturbance: Implications for Ultra-High Risk ("Prodrome") Research". Schizophrenia Bulletin. 34 (2): 381–392. doi:10.1093/schbul/sbm094. ISSN 0586-7614. PMID 17702990.
- Goulet, Karine; Deschamps, Benoit; Evoy, François; Trudel, Jean-François (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. ISSN 1497-0015. PMID 19660172.
- Harrison, Paul J. (1999-04-01). "The neuropathology of schizophrenia". Brain. 122 (4): 593–624. doi:10.1093/brain/122.4.593. ISSN 0006-8950.
- van den Heuvel, Martijn P.; Pol, Hilleke E. Hulshoff (2010). "Exploring the brain network: A review on resting-state fMRI functional connectivity". European Neuropsychopharmacology. 20 (8): 519–534. doi:10.1016/j.euroneuro.2010.03.008. PMID 20471808.
- Arbabshirani, Mohammad R.; Plis, Sergey; Sui, Jing; Calhoun, Vince D. (2017). "Single subject prediction of brain disorders in neuroimaging: Promises and pitfalls". NeuroImage. 145: 137–165. doi:10.1016/j.neuroimage.2016.02.079.
- Chan, Man K.; Gottschalk, Michael G.; Haenisch, Frieder; Tomasik, Jakub; Ruland, Tillmann; Rahmoune, Hassan; Guest, Paul C.; Bahn, Sabine (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.
- Tomasik, Jakub; Rahmoune, Hassan; Guest, Paul C.; Bahn, Sabine (2016). "Neuroimmune biomarkers in schizophrenia". Schizophrenia Research. 176 (1): 3–13. doi:10.1016/j.schres.2014.07.025.
- Lai, Chi-Yu; Scarr, Elizabeth; Udawela, Madhara; Everall, Ian; Chen, Wei J; Dean, Brian (2016-03-22). "Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics". World Journal of Psychiatry. 6 (1): 102. doi:10.5498/wjp.v6.i1.102.
- Shim, Seong S. (January 2002). "Action of atypical antipsychotics". The American Journal of Psychiatry. 159 (1): 154–155. doi:10.1176/appi.ajp.159.1.154. ISSN 0002-953X. PMID 11772719.
- Combs DR, Mueser KT, Gutierrez MM (2011). "Chapter 8: Schizophrenia: Etiological considerations". In Hersen M, Beidel DC. Adult psychopathology and diagnosis (6th ed.). John Wiley & Sons. ISBN 978-1-118-13884-7.
- Mistry, Sumit; Harrison, Judith R.; Smith, Daniel J.; Escott-Price, Valentina; Zammit, Stanley (2018). "The use of polygenic risk scores to identify phenotypes associated with genetic risk of schizophrenia: Systematic review". Schizophrenia Research. 197: 2–8. doi:10.1016/j.schres.2017.10.037. PMID 29129507.
- Athanasiou, Maria C.; Dettling, Michael; Cascorbi, Ingolf; Mosyagin, Igor; Salisbury, Benjamin A.; Pierz, Kerri A.; Zou, Wei; Whalen, Heidi; Malhotra, Anil K. (2010-09-21). "Candidate Gene Analysis Identifies a Polymorphism inHLA-DQB1Associated With Clozapine-Induced Agranulocytosis". The Journal of Clinical Psychiatry. 72 (4): 458–463. doi:10.4088/jcp.09m05527yel. ISSN 0160-6689. PMID 20868635.
- Tsuang MT, Stone WS, Faraone SV. Toward reformulating the diagnosis of schizophrenia. American Journal of Psychiatry. 2000;157(7):1041–50. doi:10.1176/appi.ajp.157.7.1041. PMID 10873908.
- Peralta V, Cuesta MJ. A dimensional and categorical architecture for the classification of psychotic disorders. World Psychiatry. 2007;6(2):100–1. PMID 18235866.
- Verdoux H, van Os J. Psychotic symptoms in non-clinical populations and the continuum of psychosis. Schizophrenia Research. 2002;54(1–2):59–65. doi:10.1016/S0920-9964(01)00352-8. PMID 11853979.
- Johns LC, van Os J. The continuity of psychotic experiences in the general population. Clinical Psychology Review. 2001;21(8):1125–41. doi:10.1016/S0272-7358(01)00103-9. PMID 11702510.
- Peters ER, Day S, McKenna J, Orbach G. Measuring delusional ideation: the 21-item Peters et al. Delusions Inventory (PDI). Schizophrenia Bulletin. 2005;30(4):1005–22. doi:10.1093/oxfordjournals.schbul.a007116. PMID 15954204.
- Jones E. The Phenomenology of Abnormal Belief: A Philosophical and Psychiatric Inquiry. Philosophy, Psychiatry and Psychology. 1999;6(1):1–16.
- David AS. On the impossibility of defining delusions. Philosophy, Psychiatry and Psychology. 1999 [Retrieved 2008-02-24];6(1):17–20.
- Ghaemi SN. An Empirical Approach to Understanding Delusions. Philosophy, Psychiatry and Psychology. 1999 [Retrieved 2008-02-24];6(1):21–24.
- Andreasen NC. Schizophrenia: the fundamental questions. Brain Res. Brain Res. Rev.. 2000;31(2–3):106–12. doi:10.1016/S0165-0173(99)00027-2. PMID 10719138.
- Andreasen NC. A unitary model of schizophrenia: Bleuler's "fragmented phrene" as schizencephaly. Archives of General Psychiatry. 1999;56(9):781–7. doi:10.1001/archpsyc.56.9.781. PMID 12884883.
- Jansson LB, Parnas J. Competing definitions of schizophrenia: what can be learned from polydiagnostic studies?. Schizophr Bull. 2007;33(5):1178–200. doi:10.1093/schbul/sbl065. PMID 17158508.
- Green MF, Nuechterlein KH. Should schizophrenia be treated as a neurocognitive disorder?. Schizophr Bull. 1999;25(2):309–19. PMID 10416733.
- Green, Michael. Schizophrenia revealed: from neurons to social interactions. New York: W.W. Norton; 2001. ISBN 0-393-70334-7. Lay summary: NEJM book review.
- Lake CR, Hurwitz N. Schizoaffective disorder merges schizophrenia and bipolar disorders as one disease—there is no schizoaffective disorder. Curr Opin Psychiatry. 2007;20(4):365–79. doi:10.1097/YCO.0b013e3281a305ab. PMID 17551352.
- Malhi GS, Green M, Fagiolini A, Peselow ED, Kumari V. Schizoaffective disorder: diagnostic issues and future recommendations. Bipolar Disorders. 2008;10(1 Pt 2):215–30. doi:10.1111/j.1399-5618.2007.00564.x. PMID 18199238.
- Craddock N, Owen MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry. 2005;186:364–6. doi:10.1192/bjp.186.5.364. PMID 15863738.
- Williams, Leanne M. (2017-06-01). "Getting Personalized: Brain Scan Biomarkers for Guiding Depression Interventions". American Journal of Psychiatry. 174 (6): 503–505. doi:10.1176/appi.ajp.2017.17030314. ISSN 0002-953X. PMID 28565957.
- Insel, Thomas R. (2014-04-01). "The NIMH Research Domain Criteria (RDoC) Project: Precision Medicine for Psychiatry". American Journal of Psychiatry. 171 (4): 395–397. doi:10.1176/appi.ajp.2014.14020138. ISSN 0002-953X.
- Schumann, Gunter; Binder, Elisabeth B.; Holte, Arne; Kloet, E. Ronald de; Oedegaard, Ketil J.; Robbins, Trevor W.; Walker-Tilley, Tom R.; Bitter, Istvan; Brown, Verity J. (2014). "Stratified medicine for mental disorders". European Neuropsychopharmacology. 24 (1): 5–50. doi:10.1016/j.euroneuro.2013.09.010.
- Marquand, Andre F.; Wolfers, Thomas; Mennes, Maarten; Buitelaar, Jan; Beckmann, Christian F. (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.
- Keshavan, Matcheri S.; Clementz, Brett A.; Pearlson, Godfrey D.; Sweeney, John A.; Tamminga, Carol A. (2013). "Reimagining psychoses: An agnostic approach to diagnosis". Schizophrenia Research. 146 (1–3): 10–16. doi:10.1016/j.schres.2013.02.022. PMID 23498153.
- Clementz, Brett A.; Sweeney, John A.; Hamm, Jordan P.; Ivleva, Elena I.; Ethridge, Lauren E.; Pearlson, Godfrey D.; Keshavan, Matcheri S.; Tamminga, Carol A. (2015-12-07). "Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers". American Journal of Psychiatry. 173 (4): 373–384. doi:10.1176/appi.ajp.2015.14091200. ISSN 0002-953X. PMID 26651391.
- Kranz, Thorsten M.; Berns, Adam; Shields, Jerry; Rothman, Karen; Walsh-Messinger, Julie; Goetz, Raymond R.; Chao, Moses V.; Malaspina, Dolores (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. PMID 27211562.
- Schwarz, E.; Beveren, N. J. M. van; Ramsey, J.; Leweke, F. M.; Rothermundt, M.; Bogerts, B.; Steiner, J.; Guest, P. C.; Bahn, S. (2014-07-01). "Identification of Subgroups of Schizophrenia Patients With Changes in Either Immune or Growth Factor and Hormonal Pathways". Schizophrenia Bulletin. 40 (4): 787–795. doi:10.1093/schbul/sbt105. ISSN 0586-7614. PMC 4059436. PMID 23934781.