1. Spring, Summer, Fall, Winter....and Spring: influence of season of birth on affective temperaments, affective illness and suicide Xenia Gonda Department of Clinical and Theoretical Mental Health, Semmelweis University Budapest Department of Pharmacodynamics, Semmelweis University Budapest MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Budapest

2. Seasonality Natural patterns in the environment in moderate climates follow seasons Adaptation to changing environment to increase fitness – Physiological – Psychological: neurotransmitter changes in parallel to season SAD Cyclothymic temperament Seasonal patterns in manifestation of mental conditions – Onset – Hospital admissions – Decompensations – Psychiatry: several manifestation show seasonality Season of birth – Associations lasting into adulthood – effects season-related environmental patterns during gestation-early development

3. Seasonality of manifestation of affective disorders and suicidal behaviour

4. Seasonality of hospital admissions for depression in Bipolar I and Bipolar II female patients 28 19 21 32 30 27 25 18 0 5 10 15 20 25 30 35 SpringSummerAutumnWinter Rihmer 1980;Psych Res 3: 247–251 Bipolar I (181 adm) Bipolar II (204 adm) % p=0.02

5. Hospital admissions for mania and depression in Bipolar I female patients Rihmer 1980; Psych Res 3: 247–251 0 5 10 15 20 25 30 35 SpringSummerAutumnWinter Depression Mania % 32 21 19 28 19 28 24 29 p=0.02

6. Seasonality of suicides with and without mood disorders Spring/early summer peak, winter low One peak for males, two peaks for females Seasonality of suicide is more pronounced: – among males – among those who used violent method – farther from the Equator – in rural areas, – among those with depression-related suicide Eastwood and Peacocke, Brit J Psychiat, 1976; 129: 472-475. Maes et al, Amer J Psychiat, 1993; 150: 1380-1385. Flischer et al, Psychiat Res, 1997; 66: 13-22. Postolache et al, J Affect Disord, 2010; 121: 88-93.

7. Biological parameters related to seasonal manifestation of affective episodes / suicides Seasonality of violent suicides is significantly related to seasonal variation of brain L-tryptophan availability and 5-HT levels (Maes et al, 1995) Peak suicide mortality is significantly related to the rapid increase of environmental light in spring (Rocchi et al, 2007) Brain serotonin transporter binding capacity shows a seasonal variation and correlates negatively with a daily sunshine - highest binding in winter season (Praschak-Rieder et al, 2008) 5-HIAA levels low during winer season (Lambert et al., 2002) 5HTT availability fluctuates around the year, most pronounced effect in s allele carriers - responsible for mediating responses to environmental changes based on an assessment of the expected “safety” of the environment (Kalblitzer et al., 2013) In summary: changes in cerebral 5HTergic transmission in response to environmental and seasonal change

8. Effects of season of birth

9. Season of birth Varied effects on different aspects of human health – Somatic disease risk – Neuropsychiatric illness risk Schizophrenia, affective disorder, eating disorder, epilepsy, substance- use disorder, brain tumours, suicide – Normal physiological and psychological features Handedness, adult height, total and reproductive life span, academic performance, intelligence, personality traits, sleep patterns Illness-relevant features: Neuroticism, impulsivity, venturesomeness, Novelty seeking, reward dependence If season of birth is related to physiological changes in the brain, physiological conditions related to season during designated periods of CNS development will have a long-lasting effect Gonda et al 2011, 2012, Chotai et al., 1999, 2005; Dome et al., 2010, Tochigi et al., 2004, Bibby et al., 1996, Torrey et al., 2000; Bibby et al., 1996, Davies et al., 2003; Brenner et al., 2004

10. Effect of season of birth on risk of suicide Dome et al., 2010 Significant association between birth month and risk of suicide In total population and in stratified populations (M/F, violent/nonviolent) July borns highest, December borns lowest risk: elevated risk during spring- summer borns Excess risk in summer: 13.8% (in line with previous data: 14% in England and Wales, 18% in Scotland) More pronounced association – in males – In violent methods

11. Seasonality of births in Bipolar I and Bipolar II female patients 0 5 10 15 20 25 30 35 SpringSummerAutumnWinter Bipolar I (n=50) Bipolar II (n=42) % 20 32 30 18 21 29 10 40 Rihmer 1980; 3: 247–251 p=0.02

12. Seasonality of births and hospital admissions for depression and mania in Bipolar I female patients 0 5 10 15 20 25 30 35 SpringSummerAutumnWinter % Rihmer 1980; 3: 247–251 32 21 19 28 20 32 18 30 Bipolar I adm for D Bipolar I births Bipolar I adm for M p=0.001

13. Seasonality of births and hospital admissions for depression in Bipolar II female patients Rihmer 1980; 3: 247–251 0 5 10 15 20 25 30 35 SpringSummerAutumnWinter % 40 10 21 29 30 27 25 18 Bipolar II births Bipolar II admissions p=0.02

14. Association of affective temperaments with season of birth VariableAnxiousCyclothymicDepressiveHyperthymicIrritable C0,06500,00000,00070,00000,0001 Spring0,33780,73860,40540,0068**0,0112* Summer0,46320,0345*0,75740,42090,0001*** Autumn0,38130,75710,0138* 0,0003*** Adj R²0,06020,0381*0,0499*0,0373*0,0496* 366 university students (258 males, 108 females; 20.59 yrs, SD:1.96), OLS regression, *p<0.05 ** p<0.01 ***p<0.001

15. Association of affective temperaments with month and season of birth 0,1 0,2 0,3 0,4 0,5 0,6 0,7 January February MarchAprilMayJune July August September October November December SummerAutumn Winter Spring 0,1 0,2 0,3 0,4 0,5 0,6 0,7 Hyperthymic Cyclothymic Irritable Depressed Anxious

16. Association of affective temperaments with month and season of birth SummerAutumn Winter Spring 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,1 0,2 0,3 0,4 0,5 0,6 0,7 January February MarchAprilMayJune July August September October November December H YPERTHYMIC Cyclothymic Irritable D EPRESSED Anxious

17. Season of birth and affective temperaments

18. Rihmer, Psych Res, 1980 Rihmer, Curr Opin Psychiatry 2010 Season of birth and bipolar disorder

19. Season of incidence of affective episodes Rihmer 1980

20. Season of birth Complex and unspecific indicator Conditions during conception, gestation, prenatal, perinatal and early postnatal life Temperature, PHOTOPERIOD, weather, nutrients, vitamins, infectious agents, allergens, toxins, maternal hormones, physical activity, complications Behavioural rhythms, stress and lifestyle Effect on – Neurochemical factors – Through genetic factors, by influencing selection of genotypes associated with illnesses or other endophenotypes Gortmaker et al., 1997, Kamata et al., 2009, Natale and Adan, 1999, Natale, 2007

21. Explanation of association of psychological phenomena with season of birth Seasonal factors during gestation may influence monoamine gene expression Serotonergic variations by season of birth – 5-HIAA variations vary with season of birth in adults and infants Winter-spring (December-April) births: lower 5-HIAA levels – predicts suicide – Seasonal changes in serotonergic elements CNS 5HT transporter density Platelet 5HT2A receptor binding – Other system functions also vary by season of birth HVA and MHPG lower in summer borns Spring borns: lower 5-HIAA, Novelty seeking ↑ (DA↓) – in winter borns low NS, high MHPG Chotai and Asberg, 1999; Chotai and Adolfsson, 2002; Chotai et al., 2006

22. Association of birth season with s allele frequency 0,0 0,2 0,4 0,6 0,8 1,0 Relative Frequency of s Allele Carriers January February MarchAprilMayJune July August September October November December Gonda et al., 2012 p=0.05 p=0.04 p=0.03

23. Association of birth season with s allele frequency S allele frequency significantly higher in July compared to rest of the year – Higher risk of completed suicide in July borns July peak and autumn low – Higher scores of July borns and lower scores of autumn borns on irritable, cyclothymic, depressive and anxious temperaments Gonda et al., 2012

24. Behavioural-genetic reasons of birth seasonality possible impact of environmental factors in effect during conception, gestation, perinatally or in the early postnatal period influencing genotype selection or frequency in a given population SAD shows birth excess in spring-summer S allele – risk of affective disorder and SAD Those with SAD or seasonal worsening of depression are less likely to procreate during late autumn and winter Those born during late summer and autumn are less likely to carry the s allele Pjrek et al., 2004; Gonda et al., 2012

25. Conclusion Seasonal variation of affective illness manifestations are underlined and complemented by effects of birth season: risk of development, manifestation, genetic vulnerability, endophenotypes, related neurochemical markers Birth season is a proxy for environmental effects in effect during key periods of neurodevelopment Effect of birth season on monoaminergic dynamics lasting into adulthood may be a key factor Behavioural-genetic mechanisms also play a role Adapting to varying environmental conditions increases fitness ► personality traits and temperaments appeared in evolution to provide for this ► illnesses may be the effects of the dysregulation of this adaptive mechanisms So taking into account of the effect of birth season may shape our view of affective illness and its related endophenotypes

26. With memories of Franco Benazzi

27. Thank you for your attention gonda.xenia@med.semmelweis-univ.hu