Editorial comment

The thrifty psychiatric phenotype

Van Ockenburg and colleagues (1) assessed thecorrelation between adverse life events and physio-logical status in a large population-based cohort,as psychosocial stress might correlate with adversehealth outcomes. Although diverse methodologicalaspects were clinically considered (for instance,psychiatric conditions such as depressive symp-toms, or diverse pharmacological treatments), theirconclusions reected no association with thestress-responsiveness conditions studied.Nevertheless, it raised the issue of early pro-

gramming in modern physiology and its transla-tional relevance to psychiatry.Current literature in developmental biology sug-

gests that environmental factors acting early in lifehave consequences which become manifest as analtered disease risk in adulthood. This early pro-gramming research has mainly focused in the path-ways that predict medical illnesses later in life suchas adult cardiovascular diseases (CVD) and type 2diabetes mellitus (T2DM). However, adversedevelopmental events can also aect the brain mat-uration, leading to impaired cognitive functionand poor mental health (2).Patients suering from serious mental illnesses

(SMI) exhibit a reduced average life span. Anincreased suicide rate, poor health habits, and lim-ited access to medical care all contribute to theexcess risk. However, the leading cause are medi-cal-related diseases (3) such as the metabolic syn-drome and other chronic pathologies, speciallyT2DM, atherosclerosis, and CVD.The current state of evidence suggests that previ-

ous medical diseases are related not only to geneticand adult lifestyle factors but also to environmen-tal factors acting early in life. This fetal origin ofdisease concept was initially described by Barkerand Hales (4) and is referred to as the thrifty phe-notype hypothesis. The concept relies on the factthat adverse gestational events (infections, pla-centa dysfunction, maternal stress, or malnourish-ment) interact with genetic factors and programthe fetus to thrive in an environment in adult lifethat is characterized by poor nutrition. This devel-opmental trade-o promotes early survival,through permanent changes (for instance, inglucose-insulin metabolism), but in an auent

society, those changes will lead to the developmentof T2DM and CVD. Later, epidemiological studieshave shown that not only prenatal, but also post-natal factors can modify the early programming,setting up the present concept of developmentalorigins of health and disease (DOHaD) (2).Extensive research has focused on its pathophys-

iology; studies of the Dutch Hunger Winter andthe 19591961 Chinese famine found that individu-als exposed in utero during the famine had lowbirth weight and developed impaired glucose toler-ance, suggesting glucoseinsulin abnormalities (5)with dierent patterns depending on the stage ofgestation when the fetus was aected by famine.Individuals exposed to these famines not only suf-fered from higher ratio of medical conditions butalso had an increased risk of developing schizo-phrenia (6) and major aective disorders (7). Inter-estingly, besides the genetic risk of familiarinheritance, the most important known factor forSMI, obstetric complications account for animportant risk of developing SMI over time.With the previous rationale, we aim to defend

the hypothesis that part of the increased prevalenceof medical diseases in SMI, and consequent mor-bidity and mortality, is directly explained by theDOHaD model. Abnormal intrauterine and earlypostnatal growth, due to environmental distur-bances, increase the risk of both metabolic abnor-malities and SMI. We will focus on three SMIdiagnoses, schizophrenia, major depressive disor-der, and bipolar disorder, being the most prevalentand studied.Patients with schizophrenia exhibit an increased

risk of obstetric complications, with maternal dia-betes and low birth weight conferring a large andmedium eect size respectively (8). Diverse envi-ronmental factors, both prenatal (infections,hypertension during pregnancy, and placentalabnormalities) (9) and postnatal (10) increase therisk of psychosis. Patients diagnosed with schizo-phrenia exhibit a reduced life expectancy, mainlydue to an increased prevalence of diseases andmedical conditions (11). In between those, T2DMhas been historically related to schizophrenia; SirHenry Maudsley stated in his book The Pathologyof Mind (1879) that diabetes is a disease that

18

Acta Psychiatr Scand 2015: 131: 1820 2014 John Wiley & Sons A/S. Published by John Wiley & Sons LtdAll rights reservedDOI: 10.1111/acps.12309

ACTA PSYCHIATRICA SCANDINAVICA

often shows itself in families where insanity pre-vails. Since Maudsley, several other contemporaryauthors (12) delved deeper into the association withdiverse methodological diculties till the appear-ance of the studies in nave rst episode psychosis,which avoided the confounding factor of pharma-cological treatment. Those studies described abnor-mal glucose metabolism (higher fasting glucosevalues and an insulin resistant state) (13); however,higher cortisol values might have biased the results.Nevertheless, the physiological challenge of an oralglucose tolerance test did conrm the underlyingglucose disturbances (14), suggesting an abnormalglucose homeostasis in individuals quite young tobe aected by regular risk factors associated withmental health (unhealthy habits, obesity, and sed-entary lifestyle) (15).Patients with major aective disorders have

repeatedly been associated with obstetric dicul-ties, specially stressful events during the secondand third trimester (7). Some data even suggestthat an earlier onset of aective disorder is directlyassociated with obstetric abnormalities (16). Areview of obstetric complications in bipolar disor-der did not nd any robust conclusion (17); how-ever, methodological inadequacies might havebiased the conclusions; irrespective a critical reviewof those studies does suggest an unexpected rela-tionship with bipolar disorder.Depression will be the second contributor to the

global burden of disease by 2020 according to theWorld Health Organization, due not only to psy-chiatric disability but also to the associated comor-bidity with physical diseases (18). As early as the17th century, Thomas Willis, the physician whodescribed glycosuria as a sign of diabetes, statedthat it was caused by sadness or long sorrow andother depressions (19). Later, epidemiologicalstudies conrmed the relationship between T2DMand major depression disorder, even suggesting adirectionality from depression toward the onset ofT2DM (20) in young patients. Studies in navepopulation aected from major depression disor-der have shown several metabolic disturbances,including an abnormal glucose metabolism state(21).The interest of research with respect to CVD,

T2DM, and metabolic disturbances in manic-depressive illness began with a seminal study byDerby in 1933 (22). Increased morbidity andmortality in bipolar disorder has been justiedmainly due to an increase ratio of medical-relatedpathologies (18). In between those, glycemicabnormalities are a consistent nding, recallingpre-antipsychotic studies that highlighted an unex-pected relationship between manic-depressive

illness and glucose metabolism (12). Although todate, we have conducted the only one study indrug-nave bipolar subjects, describing glucoseabnormalities through an increased 2-h glucoseload (23). Indeed, altered glucose homeostasis(insulin dysfunction) has been theorized as the rea-son of the increased amount of medical comorbidi-ties found in bipolar disorder (24).The available research data in SMI suggest that

part of the relationship between these neuropsychi-atric disorders and metabolic abnormalities mightbe explained by the DOHaD model. We havefocused in the glucose-insulin metabolism as it wasthe initial pathway studied. Glycemic abnormali-ties have been described to have a familial back-ground besides being associated with factors suchas obesity and sedentary lifestyle. However, studiesin young nave psychiatric patients, well matchedwith regard to body mass index and other poten-tially confounding factors (14, 21, 23), may suggestthat their impaired glucose tolerance is related tothe same early environmental factors that led totheir psychiatric disorder.Although the thrifty phenotype hypothesis is

one of the several models proposed to explain themechanism of the early programming of diversemedical conditions, we have adopted its name, rstas a tribute to the seminal work of Barker andHales (4) and second as a comprehensive explana-tion of the idea. The thrifty psychiatric phenotypeconcept does not aim to explain all the relationshipbetween these neuropsychiatric disorders and theirmedical comorbidity and mortality. However, itdoes lend itself to specic hypothesis testing. Forinstance, other major psychiatric disorders, such asobsessivecompulsive disorder or autism spectrumdisorders have been described to present anincreased prevalence of medical conditions. Arethese also related to adverse early events?SMI, from a metabolic point of view, might rep-

resent a selection bias of patients who, after knownor unknown early life stressors, develop cardiovas-cular and metabolic related pathologies (3) with alater augmented risk due to pharmacological treat-ments (antipsychotics, mood stabilizers, and an-tidepressants). The psychiatric diagnose would bethe factor that makes us, clinicians, conduct a com-plete metabolic assessment (biochemical andanthropometric) and alerts us of the increased riskof cardiovascular events.

Declaration of interest

Drs. Garcia-Rizo and Fernandez-Egea have nothing todisclose. Dr. Bernardo received consultant fees from Bristol-Meyer-Squibb and Wyeth, and honoraria from Janssen-Cilag,

19

Editorial comment

Eli Lilly, Pzer, Synthelab, Glaxo Smith Kline and Astra-Zeneca. Dr. Kirkpatrick received consulting fees from Roche,Genentech, and he has nancial relationship with Prophase,Inc.

C. Garcia-Rizo1,2,E. Fernandez-Egea2,3,4, M. Bernardo1,2,5

and B. Kirkpatrick61Barcelona Clinic Schizophrenia Unit, Neuroscience

Institute, University of Barcelona, Barcelona,2CIBERSAM, Madrid, Spain, 3Department of

Psychiatry, Addenbrooke0s Hospital, University ofCambridge, Cambridge, UK,

4Cambridgeshire and Peterborough NHS Founda-tion Trust, Huntingdon, UK, 5Institute of Biomedi-

cal Research Agusti Pi i Sunyer (IDIBAPS),Barcelona, Spain and 6Department of Psychiatryand Behavioral Sciences, University of Nevada

School of Medicine, Reno, NV, USAE-mail: cgarcia3@clinic.ub.es

References

1. Van Ockenburg SL, Tak LM, Bakker SJ, Gans RO, de Jon-ge P, Rosmalen JG. Eects of adverse life events on heartrate variability, cortisol, and C-reactive protein. Acta Psy-chiatr Scand 2015;131:4050.

2. Gluckman PD, Hanson MA. Developmental origins ofhealth and disease. New York: Cambridge UniversityPress, 2006.

3. NordentoftM,Wahlbeck K, Hallgren J, et al. Excess mor-tality, causes of death and life expectancy in 270,770patients with recent onset of mental disorders in Denmark,Finland and Sweden. PLoS One 2013;8:e55176.

4. Hales CN, Barker DJ. The thrifty phenotype hypothesis.Br Med Bull 2001;60:520.

5. Ravelli AC, van der Meulen JH, Michels RP, et al. Glu-cose tolerance in adults after prenatal exposure to famine.Lancet 1998;351:173177.

6. Susser E, St Clair D. Prenatal famine and adult mental ill-ness: interpreting concordant and discordant results fromthe Dutch and Chinese Famines. Soc Sci Med 2013;97:325330.

7. Brown AS, van Os J, Driessens C, Hoek HW, Susser ES.Further evidence of relation between prenatal famine andmajor aective disorder. Am J Psychiatry 2000;157:190195.

8. Matheson SL, Shepherd AM, Laurens KR, Carr VJ. A sys-tematic meta-review grading the evidence for non-geneticrisk factors and putative antecedents of schizophrenia.Schizophr Res 2011;133:133142.

9. Suvisaari JM, Taxell-Lassas V, Pankakoski M, Haukka JK,Lonnqvist JK, Hakkinen LT. Obstetric complications asrisk factors for schizophrenia spectrum psychoses in o-spring of mothers with psychotic disorder. Schizophr Bull2013;39:10561066.

10. Varese F, Smeets F, Drukker M, et al. Childhood adversi-ties increase the risk of psychosis: a meta-analysis ofpatient-control, prospective- and cross-sectional cohortstudies. Schizophr Bull 2012;38:661671.

11. Saha S, Chant D, McGrath J. A systematic review of mor-tality in schizophrenia: is the dierential mortality gapworsening over time? Arch Gen Psychiatry 2007;64:11231131.

12. McIntyre RS, Mancini DA, Pearce MM, et al. Mood andpsychotic disorders and type 2 diabetes: a metabolic triad.Can J Diabetes 2005;29:122132.

13. RyanMC, Collins P, Thakore JH. Impaired fasting glucosetolerance in rst-episode, drug-naive patients with schizo-phrenia. Am J Psychiatry 2003;160:284289.

14. Fernandez-Egea E, Bernardo M, Donner T, et al. Meta-bolic prole of antipsychotic-naive individuals with non-aective psychosis. Br J Psychiatry 2009;194:434438.

15. Kirkpatrick B, Miller BJ, Garcia-Rizo C, Fernandez-EgeaE, Bernardo M. Is abnormal glucose tolerance in antipsy-chotic-naive patients with nonaective psychosis con-founded by poor health habits? Schizophr Bull2012;38:280284.

16. Guth C, Jones P, Murray R. Familial psychiatric illnessand obstetric complications in early-onset aective disor-der. A casecontrol study. Br J Psychiatry 1993;163:492498.

17. Scott J, McNeill Y, Cavanagh J, Cannon M, Murray R.Exposure to obstetric complications and subsequent devel-opment of bipolar disorder: systematic review. Br J Psy-chiatry 2006;189:311.

18. Osby U, Brandt L, Correia N, Ekbom A, Sparen P. Excessmortality in bipolar and unipolar disorder in Sweden.Arch Gen Psychiatry 2001;58:844850.

19. Willis T. A medical odyssey. New York: Tuckahoe, 1971.20. Brown LC, Majumdar SR, Newman SC, Johnson JA.

History of depression increases risk of type 2 diabetesin younger adults. Diabetes Care 2005;28:10631067.

21. Garcia-Rizo C, Fernandez-Egea E, Miller BJ, et al. Abnor-mal glucose tolerance, white blood cell count, and telomerelength in newly diagnosed, antidepressant-naive patientswith depression. Brain Behav Immun 2013;28:4953.

22. Derby IM. Manic-depressive Exhaustion deaths. Psychi-atr Q 1933;7:439449.

23. Garcia-Rizo C, Kirkpatrick B, Fernandez-Egea E, et al. Isbipolar disorder an endocrine condition? Glucose abnor-malities in bipolar disorder. Acta Psychiatr Scand2014;129:7374.

24. Brietzke E, Kapczinski F, Grassi-Oliveira R, Grande I,Vieta E, McIntyre RS. Insulin dysfunction and allostaticload in bipolar disorder. Expert Rev Neurother2011;11:10171028.

20

Editorial comment