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A typological model of schizophrenia based on age at onset, sex and familial morbidity
Abstract
We investigated the age at onset distributions of schizophrenia in men and women and the relationship of age at onset and sex to the familial rates of schizophrenia and manic‐depression in data from a Swedish family study of 270 schizophrenic probands. On the logarithmic scale, the age at onset distribution of schizophrenia in both male and female relatives was bimodal, suggesting that broadly defined schizophrenia may be a mixture of 2 (probably related) disorders. The risk of schizophrenia in relatives decreased as a function of the age at onset of the proband, irrespective of the sex of the proband or relative. In contrast, the risk of manic‐depression was significantly higher in relatives of female probands with an age at onset in the twenties than in relatives of female probands with earlier or later onset, or in relatives of male probands. This suggests a third disorder related to affective psychosis, with an intermediate age at onset and female preponderance.
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“Second, the theory must account for why the symptoms of schizophrenia so commonly first present in late adolescence and early adulthood, with the majority of cases occurring between the ages of 16 and 30 years.5”
From Schizophrenia, myelination, and delayed corollary discharges: a hypothesis (2012) · cites this paper as [5]
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“[27] studied 270 schizophrenic probands in an older Swedish study and found that for both males and females there was a rapid increase in the onset of schizophrenia in late teens and early twenties followed by a lower risk of onset in the late twenties.”
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“The onset of schizophrenia typically occurs around late adolescent to early adulthood [4], with males having an earlier age of onset, while females exhibit a second postmenopausal peak [5].”
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The case for heterogeneity in the etiology of schizophrenia
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Early‐onset obsessive‐compulsive disorder: a subgroup with a specific clinical and familial pattern?
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Gender Differences in Schizophrenia: Hormonal Effect or Subtypes?
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“Sham et al. (1994) , in a Scandinavian data set, found that relatives of females with schizophrenia had a higher rate of manic depression than did relatives of males with schizophrenia.”
Parellada, M., Boada, L., Fraguas, D., Reig, S., Castro‐Fornieles, J., Moreno, D. M., González-Pinto, A. M., Otero, S., Rapado‐Castro, M., Graell, M., et al. (2010) · Schizophrenia Bulletin · doi:10.1093/schbul/sbq109 · Cited by 111
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Cerebral white matter in early puberty is associated with luteinizing hormone concentrations
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Self-citationDe novo variants in sporadic cases of childhood onset schizophrenia
Ambalavanan, A., Girard, S., Ahn, K., Zhou, S., Dionne‐Laporte, A., Spiegelman, D., Bourassa, C. V., Gauthier, J., Hamdan, F. F., Xiong, L., et al. (2015) · European Journal of Human Genetics · doi:10.1038/ejhg.2015.218 · Cited by 98
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Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders
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“Findings on the role of sex differences in the transmission of schizophrenia have been inconclusive, due to differences in sampling, phenotypic definitions and study designs.(3,77,78) However, Goldstein and colleagues(3) propose that there may be sex differences in liability thresholds to schizophrenia due to greater…”
ResultKempf, L., Hussain, N., & Potash, J. B. (2005) · International Review of Psychiatry · doi:10.1080/09540260500064959 · Cited by 84
“Indeed, four studies have suggested that elevated familial rates of mood disorder may occur in a subset of SZ subjects (DeLisi et al., 1987; Kendler et al., 1997; Sham et al., 1994; 1996).”
BackgroundSocial Identity and Psychosis: Associations and Psychological Mechanisms
McIntyre, J. C., Wickham, S. L., Barr, B., & Bentall, R. P. (2017) · Schizophrenia Bulletin · doi:10.1093/schbul/sbx110 · Cited by 83
Kishi, T., Ikuta, T., Matsui, Y., Inada, K., Matsuda, Y., Mishima, K., & Iwata, N. (2018) · Psychological Medicine · doi:10.1017/s0033291718001393 · Cited by 77
“Its onset is normally first observed during early adulthood (Sham et al., 1994), and patients with schizophrenia tend to show repeated relapses (Emsley et al.”
BackgroundVanderplow, A. M., Eagle, A. L., Kermath, B. A., Bjornson, K. J., Robison, A. J., & Cahill, M. E. (2021) · Neuron · doi:10.1016/j.neuron.2021.03.008 · Cited by 74
Shankman, S. A., & Gorka, S. M. (2015) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2015.01.001 · Cited by 79
“…if the unaffected sibling of someone with schizophrenia is in his or her 50's and has yet to develop schizophrenia, it may be difficult to argue that the biomarker represents a risk factor for that sibling, as the first onset of schizophrenia is almost always prior to age 40 (Sham et al., 1994).”
BackgroundWilson, M. P., Nordstrom, K., Anderson, E., Ng, A., Zun, L. S., Peltzer-Jones, J. M., & Allen, M. H. (2017) · Western Journal of Emergency Medicine · doi:10.5811/westjem.2017.3.32259 · Cited by 71
Matheson, S. L., Vijayan, H., Dickson, H., Shepherd, A. M., Carr, V. J., & Laurens, K. R. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.03.013 · Cited by 69
“, 16e25 years; (Sham et al., 1994)]; therefore, some participants who reported increased childhood social withdrawal may have developed schizophrenia/non-affective psychosis beyond the term of study follow-up.”
BackgroundLife satisfaction and happiness among young adults with schizophrenia
Fervaha, G., Agid, O., Takeuchi, H., Foussias, G., & Remington, G. (2016) · Psychiatry Research · doi:10.1016/j.psychres.2016.05.046 · Cited by 61
Age of onset in familial and sporadic schizoph4.4.renia
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The iPSC perspective on schizophrenia
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“First, the typical age at onset for schizophrenia is from the early 20s to 30s following the peak period of synaptic pruning [6,7].”
Family structure and risk factors for schizophrenia: case-sibling study
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“However, although some studies have found that obstetric complications are more common among adolescent mothers [29], this is not the case in Finland [ 24 ,30].”
BackgroundResultInfluentialPruning hypothesis comes of age
Johnson, M. B., & Stevens, B. (2018) · Nature · doi:10.1038/d41586-018-02053-7 · Cited by 48
Changes in male brain responses to emotional faces from adolescence to middle age
Deeley, Q., Daly, E., Azuma, R., Surguladze, S., Giampietro, V., Brammer, M. J., Hallahan, B. P., Dunbar, R., Phillips, M. L., & Murphy, D. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2007.11.023 · Cited by 47
“This is an important period for investigations of the effects of aging on social cognition because it encompasses the transition from adolescence to adulthood, a critical period of social development associated with the peak incidence of adult-onset psychiatric disorders such as schizophrenia (Sham et al., 1994).”
BackgroundInfluentialBridges, J. F. P., Beusterien, K. M., Heres, S., Such, P., Sánchez-Covisa, J., Nylander, A.-G., Chan, E., & de Jong-Laird, A. (2018) · Patient Preference and Adherence · doi:10.2147/ppa.s152870 · Cited by 45
“Following the diagnosis of the first acute psychotic episode – at the average age of 18 and 25 years in men and women, 8 respectively, – treatment is recommended primarily with second-generation antipsychotics at the lower end of the standard dose range.”
InfluentialModeling neurodevelopmental disorders using human neurons
Chailangkarn, T., Acab, A., & Muotri, A. R. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.04.004 · Cited by 44
Kishi, T., Oya, K., & Iwata, N. (2016) · Psychiatry Research · doi:10.1016/j.psychres.2016.10.053 · Cited by 43
Endophenotypes in Schizophrenia: Digging Deeper to Identify Genetic Mechanisms
Greenwood, T. A., Shutes‐David, A., & Tsuang, D. W. (2019) · Journal of Psychiatry and Brain Science · doi:10.20900/jpbs.20190005 · Cited by 46
“The onset of SZ most commonly occurs in late adolescence or early adulthood [3] and is generally chronic and unremitting, often requiring multiple hospitalizations over the course of a lifetime [4].”
BackgroundDevelopmental insanity or dementia praecox: was the wrong concept adopted?
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Perinatal complications and schizophrenia: involvement of the immune system
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“Most patients experience their first symptoms of schizophrenia between the ages of 15 and 25 [106].”
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“, any active illness that may affect the brain such as blood dyscrasias, lymphomas, endocrinopathies, renal failure, chronic obstructive lung disease, systemic autoimmune disorders or malignancy); 2) current alcohol or substance use disorder (past diagnosis allowed if in remission for ≥ 6 months); 3) other current or…”
Delusional disorder and schizophrenia: a comparative study across multiple domains
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“1977), which served to calculate the familial loading score that takes into account family size and age structure (Sham et al. 1994).”
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“In an attempt to further investigate the effect of age at onset we grouped this variable into finer categories: <20, 21–30, 31–40 and440 years, following the categorization of age at onset in another Swedish cohort [7].”
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Steinberg, L. J., Rubin‐Falcone, H., Galfalvy, H., Kaufman, J., Miller, J. M., Sublette, M. E., Cooper, T. B., Min, E., Keilp, J. G., Stanley, B., et al. (2019) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyz009 · Cited by 34
“Exclusion criteria included presence of significant medical conditions, alcohol or other substance use disorder unless in complete remission for >6 months, dementia, neurological disease, head injury with loss of consciousness, pregnancy, first-degree family history of schizophrenia if subject was <33 years old (Sham…”
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LE, L., R, K., B, M., & MJ, G. (2020) · Psychiatry Research · doi:10.1016/j.psychres.2020.112852 · Cited by 32
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“Despite the increasing prevalence of recreational cannabis use among the young population [40] and medical students [41], mainly for its rewarding effects [42,43], the use of cannabinoids among students might also be explained by their anxiolytic, antidepressant, and sleep-promoting effects [44] as a means to mitigate…”
BackgroundGupta, A. K., Pokhriyal, R., Khan, M. I., Kumar, D. R., Gupta, R., Chadda, R. K., Ramachandran, R., Goyal, V., Tripathi, M., & Hariprasad, G. (2019) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s214217 · Cited by 20
“incidence of Parkinson’s disease increases above the age of 60 years, with only 4% who are under the age of 50 years,(28) whereas the incidence of schizophrenia is 16–25 years.(29) Biological Process And Molecular Function Of Identified Proteins There are minimal variations in the number of identified proteins represe…”
BackgroundTwo-Year Clinical and Functional Outcomes of an Asian Cohort at Ultra-High Risk of Psychosis
Chan, C. T., Abdin, E., Subramaniam, M., Tay, S. A., Lim, L. K., & Verma, S. K. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00758 · Cited by 19
“before the age of 25 in men and between 25 and 35 for women (30).”
BackgroundPain Processing in Psychiatric Conditions: A Systematic Review
Vaughan, S., Failla, M. D., Poole, H. M., Forshaw, M. J., McGlone, F., Cascio, C. J., & Moore, D. (2019) · Review of General Psychology · doi:10.1177/1089268019842771 · Cited by 18
Perrottelli, A., Marzocchi, F. F., Caporusso, E., Giordano, G. M., Giuliani, L., Melillo, A., Pezzella, P., Bucci, P., Mucci, A., & Galderisi, S. (2024) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.230112 · Cited by 17
“The most common age of illness onset for schizo phrenia is in the early 20s to 30s, 190,191 which coincides with the physiologic peak period of synaptic pruning.”
BackgroundRoomruangwong, C., Noto, C. D. S., Kanchanatawan, B., Anderson, G., Kubera, M., Carvalho, A. F., & Maes, M. H. J. (2018) · Preprints.org · doi:10.20944/preprints201809.0289.v1 · Cited by 15
The many roads to psychosis: recent advances in understanding risk and mechanisms
Bearden, C. E., & Forsyth, J. K. (2018) · F1000Research · doi:10.12688/f1000research.16574.1 · Cited by 16
A Cost-effectiveness Analysis of Antipsychotics for Treatment of Schizophrenia in Uganda
Lubinga, S. J., Mutamba, B. B., Nganizi, A., & Babigumira, J. B. (2015) · Applied Health Economics and Health Policy · doi:10.1007/s40258-015-0176-3 · Cited by 15
Familial liability and schizophrenia phenotypes: A polydiagnostic approach
Peralta, V., & Cuesta, M. J. (2007) · Schizophrenia Research · doi:10.1016/j.schres.2007.07.028 · Cited by 14
“Familial liability was particularly related to early age at onset, which concurs with previous studies reporting an inverse relationship between age at onset in the proband and risk of schizophrenia in relatives (Sham et al., 1994) and supports the consideration of early onset as the most important clinical trait to t…”
ResultPatterns of Care for Adolescent With Schizophrenia: A Delphi-Based Consensus Study
Vita, A., Barlati, S., Bellomo, A., Fusar‐Poli, P., Masi, G., Nobili, L., Serafini, G., Zuddas, A., & Vicari, S. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.844098 · Cited by 13
“Hence if schizophrenia peak onset is generally between 15 and 25 years of age (8), incidence rates increase around 14 years of age (9), with ∼39% of male and 23% of female patients developing schizophrenia before 19 years of age (10).”
BackgroundΣκώκου, Μ., Katrivanou, A., Andriopoulos, I., & Gourzis, P. (2012) · Revista de Psiquiatría y Salud Mental · doi:10.1016/j.rpsm.2012.03.002 · Cited by 13
An empirical study of five sets of diagnostic criteria for delusional disorder
Peralta, V., & Cuesta, M. J. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.04.027 · Cited by 13
Zhou, J., Xia, Y., Li, M., Chen, Y., Dai, R., Liu, C., & Chen, C. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02243-4 · Cited by 15
“Evidence from family studies [11, 12] and the study of mutations [10] supports the hypothesis that female SCZ patients carry greater genetic liability than males.”
Husted, J., Greenwood, C. M. T., & Bassett, A. S. (2005) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-005-0629-z · Cited by 13
“Some studies have reported an association between early onset schizophrenia and an increased risk of schizophrenia in relatives [1, 2, 20, 26, 32, 33, 35], suggesting that the early form of illness may have a higher familial liability to schizophrenia than later onset forms.”
BackgroundGupta, A. K., Kumar, G. K., Rani, K., Pokhriyal, R., Khan, M. I., Kumar, D. R., Goyal, V., Tripathi, M., Gupta, R., Chadda, R. K., et al. (2019) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s198559 · Cited by 11
“was 16–25 years.(46) The age was considered a factor that could affect protein expression and has been addressed by a statistical analysis that is discussed in subsequent paragraphs.”
BackgroundFialkowski, A., & Tiwari, H. K. (2019) · The R Journal · doi:10.32614/rj-2019-022 · Cited by 10
“In schizophrenia research, Gaussian mixture distributions have frequently described the earlier age of onset in men than in women and the vast phenotypic heterogeneity in the disorder spectrum (Everitt, 1996; Lewine, 1981; Sham et al., 1994; Welham et al., 2000).”
BackgroundSchizophrene Erkrankungen im Jugendalter
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Metadata
- Authors
- Sham, P. C., MacLean, C. J., & Kendler, K. S.
- Affiliations
- Virginia Commonwealth University (US)
- Corresponding author
- Sham, P.C.
- Venue
- Acta Psychiatrica Scandinavica
- Publisher
- Wiley
- Published
- 1994-02
- Volume
- 89
- Issue
- 2
- Pages
- 135-141
- ISSN
- 0001-690X (ISSN-L)
- 1600-0447
- OpenAlex
- W2139391643
- Cited by
- 122
- References
- 37
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 12 · 2018: 8 · 2017: 15 · 2016: 6 · 2015: 6 · 2014: 1 · 2013: 10 · 2012: 5
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Psychiatrica Scandinavica (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- John D. and Catherine T. MacArthur Foundation
- Wellcome Trust
- National Institute of Mental Health (R01MH041953, NIMH MH41953)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
- Keywords
- schizophrenia, age of onset, sex differences, familial risk, bipolar disorder, affective psychosis, bimodal age distribution, probands, family studies, schizophrenia subtypes
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Bipolar Disorder, Child, Female, Humans, Male, Middle Aged, Models, Genetic, Phenotype, Risk Factors, Schizophrenia, Schizophrenic Psychology, Sex Factors, Sweden
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