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Coffee, caffeine, and risk of completed suicide: Results from three prospective cohorts of American adults

Authors:

Abstract

Objective: To evaluate the association between coffee and caffeine consumption and suicide risk in three large-scale cohorts of US men and women. Methods: We accessed data of 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988-2008), 73,820 women in the Nurses' Health Study (NHS, 1992-2008), and 91,005 women in the NHS II (1993-2007). Consumption of caffeine, coffee, and decaffeinated coffee, was assessed every 4 years by validated food-frequency questionnaires. Deaths from suicide were determined by physician review of death certificates. Multivariate adjusted relative risks (RRs) were estimated with Cox proportional hazard models. Cohort specific RRs were pooled using random-effect models. Results: We documented 277 deaths from suicide. Compared to those consuming ≤ 1 cup/week of caffeinated coffee (< 8 oz/237 ml), the pooled multivariate RR (95% confidence interval [CI]) of suicide was 0.55 (0.38-0.78) for those consuming 2-3 cups/day and 0.47 (0.27-0.81) for those consuming ≥ 4 cups/day (P trend < 0.001). The pooled multivariate RR (95% CI) for suicide was 0.75 (0.63-0.90) for each increment of 2 cups/day of caffeinated coffee and 0.77 (0.63-0.93) for each increment of 300 mg/day of caffeine. Conclusions: These results from three large cohorts support an association between caffeine consumption and lower risk of suicide.
ORIGINAL INVESTIGATION
Coffee, caffeine, and risk of completed suicide: Results from three
prospective cohorts of American adults
MICHEL LUCAS
1
, EILIS J. O REILLY
1,2
, AN PAN
1
, FARIBA MIRZAEI
1
,
WALTER C. WILLETT
1,2,3
, OLIVIA I. OKEREKE
2,3,4
& ALBERTO ASCHERIO
1,2,3
1
Department of Nutrition, Harvard School of Public Health, Boston, MA, USA,
2
Department of Epidemiology, Harvard School
of Public Health, Boston, MA, USA,
3
Channing Division of Network Medicine, Department of Medicine, Harvard Medical
School, Boston, MA, USA, and
4
Department of Psychiatry, Brigham and Women s Hospital and Harvard Medical School,
Boston, MA, USA
Abstract
Objective. To evaluate the association between coffee and caffeine consumption and suicide risk in three large-scale cohorts
of US men and women. Methods. We accessed data of 43,599 men enrolled in the Health Professionals Follow-up Study
(HPFS, 1988 2008), 73,820 women in the Nurses Health Study (NHS, 1992 2008), and 91,005 women in the NHS II
(1993 2007). Consumption of caffeine, coffee, and decaffeinated coffee, was assessed every 4 years by validated food-
frequency questionnaires. Deaths from suicide were determined by physician review of death certifi cates. Multivariate
adjusted relative risks (RRs) were estimated with Cox proportional hazard models. Cohort specifi c RRs were pooled using
random-effect models. Results. We documented 277 deaths from suicide. Compared to those consuming 1 cup/week of
caffeinated coffee ( 8 oz/237 ml), the pooled multivariate RR (95% confi dence interval [CI]) of suicide was 0.55 (0.38
0.78) for those consuming 2 3 cups/day and 0.47 (0.27 0.81) for those consuming 4 cups/day ( P trend 0.001). The
pooled multivariate RR (95% CI) for suicide was 0.75 (0.63 0.90) for each increment of 2 cups/day of caffeinated coffee
and 0.77 (0.63 0.93) for each increment of 300 mg/day of caffeine. Conclusions. These results from three large cohorts
support an association between caffeine consumption and lower risk of suicide.
Key words:
Coffee , caffeine , suicide , cohorts , food-frequency questionnaires
Introduction
Caffeine is a widely used psychostimulant that at low
doses reduces fatigue and improves vigilance and
locomotor performance (Fredholm et al. 1999;
Haskell et al. 2005). The effects of caffeine in the
central nervous system are mediated by adenosine
receptor antagonism, and include the accelerated
turnover of several monoamine neurotransmitters,
including serotonin and dopamine, which are
involved in depression (Fredholm et al. 1999). These
pharmacological actions suggest that caffeine could
have antidepressant effects, a hypothesis supported
by the observation, in epidemiological studies, that
risk of depression (Ruusunen et al. 2010; Lucas et al.
2011) and suicide (Klatsky et al. 1993; Kawachi
et al. 1996) is lower in a dose-dependent manner
with increasing consumption of caffeinated coffee.
An exception is the J-shaped relation between coffee
and suicide risk noted in one study where the highest
suicide rate was in individuals consuming 8 or more
cups of coffee daily (Tanskanen et al. 2000). Previous
investigations relied on a single assessment of coffee
consumption to predict suicide risk over a long fol-
low-up period, and did not ascertain decaffeinated
coffee consumption without which it is diffi cult to
isolate the role of caffeine. We therefore accessed data
from three large US cohorts in which consumption
of caffeinated and non-caffeinated beverages was
assessed every four years to investigate coffee and
caffeine consumption and suicide risk.
Correspondence: Dr Alberto Ascherio, Department of Nutrition, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA
02115, USA. Tel: 1 617 432 0093. Fax: 1 617 432 2435. E-mail: aascheri@hsph.harvard.edu
(Received 29 October 2012 ; accepted 22 March 2013 )
The World Journal of Biological Psychiatry, 2013; Early Online: 1–10
ISSN 1562-2975 print/ISSN 1814-1412 online © 2013 Informa Healthcare
DOI: 10.3109/15622975.2013.795243
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2 M. Lucas et al.
oz/237ml), 47 mg per cup of tea, 46 mg per can of
soft drink, and 7 mg per serving of chocolate. The
food-frequency questionnaires have been evaluated
in detail with regard to reproducibility and validity
(Willett et al. 1985; Salvini et al. 1989; Willett 1998).
Correlations between self-reported coffee intake
according to the food-frequency questionnaires and
consumption during the 2 or 4 weeks of diet records
in both men ( r 0.93) (Feskanich et al. 1993) and
women ( r 0.78) were high (Salvini et al. 1989).
Case ascertainment
Deaths were identifi ed by next of kin or postal
authorities, or by searching the National Death
Index. At least 98% of deaths among the study par-
ticipants were identifi ed (Rich-Edwards et al. 1994).
Physicians reviewed death certifi cates to classify
individual causes of death. The end point of our
study comprised all cases of suicide and self-infl icted
injuries (Eighth Revision International Classifi cation
of Diseases [ICD] codes E950 to E959) (US Dept
of Health 1965).
Statistical analysis
Person-years of follow-up were calculated from the
date of return of the baseline follow-up question-
naire (1988 for HPFS, 1992 for NHS, and 1993 for
NHS II) to the earliest of: date of death from suicide
or another cause; end of follow-up (1 January 2008
for HPFS, 30 June 2008 for NHS and, 30 June 2007
for NHS II); or return date of the last questionnaire
received during follow-up. Cox proportional hazards
models, stratifi ed on age in months and question-
naire cycle, were used to estimate relative risks (RRs)
and 95% confi dence intervals [CIs]. To account for
changes over time and reduce random measurement
error, we used the cumulative average of exposure
intake from all the available questionnaires. To min-
imize reverse causation (effect of mental health on
coffee consumption) we allowed a 2-year interval
between assessment of intake and the start of a
follow-up cycle (Hu et al. 1999). For example, in
NHS the cumulative average of coffee intake using
questionnaires from 1980 through 1990 was used to
predict suicide in 1992 1994 and 1994 1996 while
intakes from 1980 through 1994 were used to pre-
dict suicide in 1996 1998 and in 1998 2000, and so
on. In sensitivity analyses, a minimum of 4-year
latency of exposure was applied. Similar analyses
were conducted for categories of caffeine, non-coffee
sources of caffeine, and decaffeinated coffee con-
sumption. When a questionnaire was missing, the
cumulative average of exposure was based on the
Subjects and methods
Study population
The designs of the Health Professionals Follow-up
Study (HPFS), Nurses Health Study (NHS) and
Nurses Health Study-II (NHS II) have been
described previously (Ascherio et al. 2001; Colditz
and Hankinson 2005). The NHS is a prospective
cohort study comprising 121,700 female US regis-
tered nurses aged 30 55 years in 1976. The HPFS
is a prospective cohort study comprising 51,529
male US health professionals aged 40 75 years in
1986. The NHS II is a prospective cohort study
comprising 116,671 female US registered nurses
aged 25 42 years in 1989. Participants in all cohorts
were followed with biennial questionnaires on life-
style (including diet every 4 years), medication use,
and disease incidence.
To identify a healthy population, we excluded par-
ticipants with diagnoses of cardiovascular disease or
cancer at baseline. The main analyses in the present
report use 1992 as the baseline for NHS because a
previous report has been published on coffee and
suicide risk between 1980 and 1990 (Kawachi et al.
1996). After exclusions, data from 43,599 HPFS,
73,820 NHS and 91,005 NHS II participants were
available for analysis. The study protocol was
approved by the institutional review boards of
Brigham and Women s Hospital and Harvard School
of Public Health.
Assessment of exposure
In 1980, NHS participants reported their usual food
and beverage intake during the previous year on a
61-item food-frequency questionnaire. In 1984,
1986, 1990, 1994, 1998, and 2002, similar but
expanded 131-item questionnaire were sent to these
participants. Similar expanded questionnaires were
administered to HPFS participants in 1986, 1990,
1994, 1998, and 2002, and to NHS II participants
in 1991, 1995, 1999, and 2003. The questionnaires
included coffee ( coffee with caffeine and decaf-
feinated coffee ), tea ( nonherbal tea ), carbonated
soft drinks (with or without caffeine), and chocolate.
Hereinafter, coffee means caffeinated coffee. Each
item on the questionnaire referred to a specifi ed
amount (e.g., 1 cup for coffee, decaffeinated coffee
and tea, 1 glass or can for soft drinks, 1 bar or packet
for chocolate) and nine response categories ranging
from never to 6 or more per day. Intakes of nutrients
and caffeine were calculated, as described elsewhere
(Willett et al. 1985), primarily using concurrent US
Department of Agriculture food composition data.
In these calculations, we assumed that the caffeine
content was 137 mg per cup of coffee (1 cup 8
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Coffee, caffeine and suicide risk 3
and suicide associations. All analyses were performed
with SAS software, version 9.2 (SAS Institute Inc.,
2003). All P values reported are two-sided.
Results
Participant characteristics according to categories of
coffee are presented in Table I. Compared with those
with least frequent consumption of coffee ( 1 cup/
week), regular coffee drinkers ( 4 cups/day) were
more likely to be current smokers and to consume
more alcohol, and reported lower prevalence of mar-
ried/partnership status. In the most recent measure
of diet before baseline, mean daily caffeine consump-
tion was 218 mg for NHS, 169 mg for NHS II, and
186 mg for HPFS. Contribution of coffee to total
caffeine consumption was 80% for NHS, 71% for
NHS II, and 79% for HPFS.
We documented 277 deaths from suicide among the
208,424 participants, 47 in NHS (rate 4.2/100,000
person-years), 66 in NHS II (rate 5.3/100,000), and
164 in HPFS (rate 20.6/100,000). Adjustment for
smoking had substantial impact on the relationship
between caffeinated coffee (Table II) and caffeine
(Table III) consumption and suicide risk. Trend
toward a lower suicide risk became signifi cant after
adjustment for smoking in the three cohorts, mainly
refl ecting negative confounding by smoking status.
Further adjustment for the other variables in the
multivariate model had a mild confounding effect.
previous questionnaires and a missing indicator vari-
able was included in the models. To test for linear
trends we modeled medians of categories of expo-
sure. Analyses were performed separately in each
cohort and cohort-specifi c estimates were pooled
using random-effect summaries.
Clinical relevance guided the choice of covariates
(Hernan et al. 2002). In the multivariate analysis, we
simultaneously controlled for potential confounders
using updated information at each 2-year question-
naire cycle, including smoking status (never smoked,
past, currently smoke 1 14, 15 24, or 25 cig./day),
high alcohol consumption ( 30 g/day, 30 g/day),
body-mass index ( 25.0, 25.0 29.9, 30.0 kg/m
2
),
physical activity (quintiles), marital status (married/
partnered, widowed, separated/divorced/single), and
reported regular use of antidepressants (yes or no),
and minor tranquilizers such as benzodiazepines
(yes or no). In NHS II, hormonal status (post-
menopausal with or without hormonal therapy, pre-
menopausal or never used hormonal therapy) was
also included. Sensitivity analyses including factors
that can mediate the effects of coffee, such as self-
reported high blood pressure, myocardial infarction
or angina, stroke, diabetes, and cancer (all yes/no)
were preformed. Since caffeine half-life is reduced
by 30 50% in smokers and doubled in women
taking oral contraceptives or other exogenous estro-
gens (Fredholm et al. 1999), we examined effect
modifi cation by these factors of the caffeine/coffee
Table I. Baseline characteristics of study participants by caffeinated coffee consumption.
a
Caffeinated coffee consumption (cups
b
)
Women (NHS, 1992 2008) Women (NHS II, 1993 2007) Men (HPFS, 1988 2008)
1/week
( n 17,049)
1/day
( n 20,134)
4/day
( n 6894)
1/week
( n 41,459)
1/day
( n 11,633)
4/day
( n 8121)
1/week
( n 17,910)
1/day
( n 5646)
4/day
( n 4769)
Age (years)
57.5
7.4 58.6 7.1 57.6 6.7 37.6 4.8 38.3 4.6 39.6 4.3 55.3 9.7 56.0 9.7 54.3 8.6
Physical activity (MET-hr/wk)
19.5 23.6 19.4 23.5 18.1 23.2 20.2 26.0 21.8 27.9 21.2 30.0 30.3 34.6 29.9 32.6 27.9 31.9
Body-mass index (kg/m
2
)
26.4 5.4 26.1 5.0 25.9 4.8 24.9 5.7 24.3 5.1 24.7 5.0 25.3 3.2 25.5 3.2 25.9 3.1
Past smoker (%) 32.1 43.2 36.5 16.0 26.3 26.4 32.2 41.0 45.6
Current smoker (%) 7.4 11.2 32.8 6.6 9.8 35.4 6.0 8.7 20.0
Married/Partnership (%) 71.1 73.5 57.1 73.3 72.8 65.9 70.3 70.4 68.6
Current menopausal
hormones (%)
28.2 29.5 21.7 4.7 4.4 4.6 na na na
Minor tranquilizers (%) 2.7 2.3 1.7 1.7 1.7 1.8 1.0 0.8 0.8
Antidepressants (%) 7.1 6.3 5.4 14.4 14.1 16.9 1.0 1.1 1.3
Diet intake
c
Caffeine (mg/day)
d
81 84 234 159 684 174 80 76 199 58 733 113 53 69 190 56 723 113
Decaffeinated coffee
(cups/day)
0.5 1.0 0.9 1.2 0.4 1.1 0.3 0.8 0.5 0.8 0.2 0.7 0.7 1.2 0.7 1.2 0.3 0.8
Tea (cups/day)
1.1 1.5 0.6 1.0 0.3 0.8 0.8 1.3 0.6
1.0 0.5 1.0 0.5 0.9 0.5 0.8 0.4 0.9
Alcohol intake (g/day)
3.3 7.8 5.5 9.5 5.8 10.4 1.9 4.6 3.5 5.7 4.5 7.8 8.5 13.6 12.0 14.7 15.0 18.8
30 g/day (%)
2.3 3.4 4.6 0.5 0.8 2.3 7.6 11.0 18.0
HPFS, Health Professionals Follow-up Study; NHS, Nurses Health Study; MET, metabolic equivalents of task.
a
Values are reported as mean SD unless otherwise indicated. Means and percentages are standardized to the age distribution of the study population. Coffee
consumption was computed as the cumulative average of intake, but not including changes in intake during the 2-year preceding follow-up periods.
b
One cup 8 oz or 237 ml.
c
Information on diet was obtained in 1990 for the NHS, 1991 for the NHS II, and 1986 for the HPFS.
d
Caffeine was calculated from coffee and non-coffee sources (tea, caffeinated soft drink, chocolate).
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4 M. Lucas et al.
Table II. Relative risks (95% CI) of suicide according to caffeinated coffee consumption.
a
Caffeinated coffee consumption (cups)
1/week 2 6/week 1/day 2 3/day 4/day
P value
for trend
Increment
of 2 cups/day
NHS
No. of cases 16 5 14 8 4
Person-years
RR (95% CI)
257,634 134,745 349,735 294,138 73,749
Age-adjusted
b
1.00 0.63
(0.23, 1.73)
0.69
(0.33, 1.42)
0.40
(0.17, 0.95)
0.67
(0.22, 2.03)
0.19 0.81
(0.54, 1.21)
Age, smoking-
adjusted
c
1.00 0.60
(0.22, 1.66)
0.60
(0.29, 1.25)
0.30
(0.12, 0.71)
0.38
(0.12, 1.20)
0.03 0.66
(0.44, 0.99)
Multivariate
d
1.00 0.67
(0.24, 1.88)
0.62
(0.29, 1.31)
0.35
(0.14, 0.85)
0.35
(0.11, 1.13)
0.03 0.67
(0.45, 1.01)
Sensitivity
e
1.00 0.68
(0.24, 1.92)
0.57
(0.26, 1.24)
0.43
(0.19, 0.99)
0.34
(0.10, 1.08)
0.04 0.70
(0.47, 1.04)
NHS II
No. of cases 24 10 19 9 4
Person-years
RR (95% CI)
532,352 125,576 244,623 276,714 70,755
Age-adjusted
b
1.00 1.74
(0.83, 3.65)
1.64
(0.89, 3.01)
0.67
(0.31, 1.45)
1.11
(0.38, 3.24)
0.45 0.99
(0.71, 1.39)
Age, smoking-
adjusted
c
1.00 1.68
(0.80, 3.52)
1.43
(0.77, 2.64)
0.49
(0.22, 1.07)
0.53
(0.18, 1.61)
0.03 0.76
(0.54, 1.08)
Multivariate
d
1.00 1.63
(0.77, 3.42)
1.38
(0.74, 2.57)
0.46
(0.21, 1.01)
0.55
(0.18, 1.65)
0.03 0.74
(0.52, 1.06)
Sensitivity
e
1.00 1.63
(0.71, 3.72)
1.64
(0.84, 3.18)
0.44
(0.18, 1.07)
0.81
(0.29, 2.26)
0.11 0.86
(0.60, 1.23)
HPFS
No. of cases 73 22 32 29 8
Person-years
RR (95% CI)
306,247 105,251 168,482 163,560 51,166
Age-adjusted
b
1.00 0.82
(0.51, 1.34)
0.79
(0.52, 1.21)
0.78
(0.50, 1.21)
0.67
(0.32, 1.40)
0.18 0.88
(0.70, 1.11)
Age, smoking-
adjusted
c
1.00 0.81
(0.49, 1.31)
0.76
(0.50, 1.17)
0.72
(0.46, 1.12)
0.50
(0.24, 1.07)
0.04 0.81
(0.64, 1.02)
Multivariate
d
1.00 0.81
(0.49, 1.32)
0.74
(0.48, 1.15)
0.65
(0.41, 1.03)
0.49
(0.23, 1.06)
0.02 0.79
(0.62, 1.00)
Sensitivity
e
1.00 0.89
(0.53, 1.48)
0.77
(0.48, 1.23)
0.86
(0.55, 1.35)
0.44
(0.18, 1.04)
0.09 0.83
(0.65, 1.06)
Pooled results
f
RR (95% CI)
Multivariate
d
1.00 0.97
(0.59, 1.58)
0.86
(0.55, 1.34)
0.55
(0.38, 0.78)
0.47
(0.27, 0.81)
0.001
0.75
(0.63, 0.90)
With NHS
1982 2008
follow-up
g
1.00 0.93
(0.65, 1.33)
0.86
(0.64, 1.15)
0.51
(0.37, 0.70)
0.47
(0.30, 0.75)
0.001
0.74
(0.63, 0.86)
CI, confi dence interval; HPFS, Health Professionals Follow-up Study; NHS, Nurses Health Study; RR, relative risk.
a
Cases of suicide were codes E950 to E959 according the Eight Revision International Classifi cation of Diseases (ICD).
b
Adjusted for age (continuous), time interval and indicator variables for missing data on exposure for each questionnaire.
c
Further adjusted for smoking status (never smoked, past, currently smoke 1 14, 15 24, or 25 cig./day).
d
Further adjusted for high alcohol consumption ( 30 g/day, yes or no), body-mass index ( 25, 25 29.9, 30 kg/m
2
), physical activity
(quintiles), marital status (married/partnership, widowed, separated/divorced/single), and reported regular use of minor tranquilizers (yes
or no), and antidepressants (yes or no). For women of NHS II, multivariate model was further adjusted for hormonal status (post-
menopausal with or without hormonal therapy, pre-menopausal or never used hormonal therapy).
e
The same as the multivariate model but using a latency of exposure of 4-year minimum. Number cases were as follow: 47 for NHS, 57
for NHS II, and 149 for HPFS.
f
Results from multivariate models were combined using random-effect model.
g
Results from multivariate models were combined using random-effect model, but the follow-up was 1982 to June 2008 for
NHS (cases 108).
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Coffee, caffeine and suicide risk 5
Table III . Relative risks (95% CI) of suicide according to caffeine consumption.
a
Caffeine consumption (mg/day)
100 100 250 250 400 400 550 550
P value
for trend
Increment
of 300 mg/day
NHS
No. of cases 8 19 8 5 7
Person-years
RR (95% CI)
165,846 322,626 311,137 175,488 134,903
Age-adjusted
b
1.00 1.18
(0.51, 2.71)
0.50
(0.19, 1.34)
0.54
(0.18, 1.66)
0.86
(0.31, 2.39)
0.28 0.81
(0.52, 1.27)
Age, smoking-
adjusted
c
1.00 1.06
(0.46, 2.46)
0.41
(0.15, 1.10)
0.40
(0.13, 1.24)
0.51
(0.17, 1.47)
0.05 0.64
(0.41, 1.02)
Multivariate
d
1.00 0.99
(0.42, 2.31)
0.42
(0.15, 1.15)
0.46
(0.15, 1.45)
0.49
(0.17, 1.42)
0.06 0.66
(0.42, 1.04)
Sensitivity
e
1.00 1.00
(0.43, 2.36)
0.32
(0.11, 0.93)
0.64
(0.22, 1.81)
0.46
(0.16, 1.34)
0.05 0.70
(0.45, 1.08)
NHS II
No. of cases 13 28 14 6 5
Person-years
RR (95% CI)
390,687 373,038 270,719 117,755 97,821
Age-adjusted
b
1.00 2.19
(1.13, 4.23)
1.45
(0.68, 3.09)
1.42
(0.54, 3.75)
1.39
(0.49, 3.92)
0.85 1.05
(0.74, 1.51)
Age, smoking-
adjusted
c
1.00 1.92
(0.99, 3.73)
1.12
(0.52, 2.43)
0.94
(0.35, 2.53)
0.67
(0.23, 1.99)
0.16 0.77
(0.52, 1.12)
Multivariate
d
1.00 1.85
(0.95, 3.59)
1.05
(0.48, 2.27)
0.86
(0.32, 2.31)
0.61
(0.21, 1.80)
0.10 0.73
(0.50, 1.07)
Sensitivity
e
1.00 1.71
(0.82, 3.57)
1.23
(0.54, 2.80)
1.08
(0.39, 3.00)
0.91
(0.32, 2.60)
0.52 0.87
(0.59, 1.28)
HPFS
No. of cases 62 49 35 6 12
Person-years
RR (95% CI)
291,418 210,844 159,937 67,308 65,200
Age-adjusted
b
1.00 1.10
(0.75, 1.61)
1.06
(0.70, 1.62)
0.47
(0.20, 1.10)
0.93
(0.49, 1.74)
0.48 0.91
(0.72, 1.16)
Age, smoking-
adjusted
c
1.00 1.10
(0.75, 1.61)
1.02
(0.67, 1.56)
0.45
(0.19, 1.05)
0.74
(0.39, 1.40)
0.18 0.84
(0.66, 1.07)
Multivariate
d
1.00 1.06
(0.72, 1.56)
0.95
(0.62, 1.47)
0.41
(0.17, 0.97)
0.71
(0.37, 1.37)
0.12 0.82
(0.64, 1.05)
Sensitivity
e
1.00 0.99
(0.66, 1.49)
1.13
(0.73, 1.76)
0.46
(0.20, 1.10)
0.60
(0.29, 1.25)
0.17 0.86
(0.67, 1.12)
Pooled results
f
RR (95% CI)
Multivariate
d
1.00 1.20
(0.85, 1.69)
0.86
(0.57, 1.30)
0.54
(0.30, 0.94)
0.63
(0.39, 1.04)
0.005 0.77
(0.63, 0.93)
With NHS
1982 2008
follow-up
g
1.00 1.07
(0.81, 1.42)
0.79
(0.58, 1.09)
0.45
(0.28, 0.73)
0.55
(0.36, 0.84)
0.001
0.74
(0.63, 0.88)
CI, confi dence interval; HPFS, Health Professionals Follow-up Study; NHS, Nurses Health Study; RR, relative risk.
a
Caffeine was calculated from coffee and non-coffee sources (tea, caffeinated soft drink, chocolate). Cases of suicide were codes E950 to
E959 according the Eight Revision International Classifi cation of Diseases (ICD).
b
Adjusted for age (continuous), time interval and indicator variables for missing data on exposure for each questionnaire.
c
Further adjusted for smoking status (never smoked, past, currently smoke 1 14, 15 24, or 25 cig./day).
d
Further adjusted for high alcohol consumption ( 30 g/day, yes or no), body-mass index ( 25, 25 29.9, 30 kg/m
2
), physical activity
(quintiles), marital status (married/partnership, widowed, separated/divorced/single), and reported regular use of minor tranquilizers (yes
or no), and antidepressants (yes or no). For women of NHS II, multivariate model was further adjusted for hormonal status (post-
menopausal with or without hormonal therapy, pre-menopausal or never used hormonal therapy).
e
The same as the multivariate model but using a latency of exposure of 4-year minimum. Number cases were as follow: 47 for
NHS, 57 for NHS II, and 149 for HPFS.
f
Results from multivariate models were combined using random-effect model.
g
Results from multivariate models were combined using random-effect model, but follow-up was 1982 to June 2008 for NHS
(cases 108).
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6 M. Lucas et al.
suicide risk suggests that caffeine, rather than other
coffee components, contributes to this association.
However, consumption of decaffeinated coffee was
low and we cannot exclude the possibility that an
inverse association with suicide risk could exist for
higher consumption.
After searching the English language medical lit-
erature for articles published before February 2012,
we identifi ed only three cohort studies that have
examined the association between coffee/caffeine
consumption and suicide. Lower suicide risk among
coffee drinkers was fi rst reported in the Northern
California Kaiser Permanente study, a longitudinal
investigation of over 120,000 individuals who were
followed for an average of 8 years (Klatsky et al.
1993). Suicide risk decreased monotonically with
increasing coffee consumption, and was 80% lower
in drinkers of 6 cups (question did not specify
caffeinated coffee) per day as compared to nondrink-
ers. Similarly suicide risk was 72% lower among
women in NHS who drank 4 cups of caffeinated
coffee per day as compared to non-drinkers (decaf-
feinated coffee was not part of the analysis) during
the fi rst 10 years of follow-up (Kawachi et al. 1996).
Finally, a J-shaped association was noted between
daily coffee drinking and suicide risk in a Finnish
population based study comprising over 43,000 indi-
viduals who were followed for an average of 14.6
years (Tanskanen et al. 2000). Compared to those
drinking 1 cup of coffee daily, suicide risk was
lower for moderate coffee consumption (2 3 cups/
day up to 6 7 cups/day), but increased with higher
consumption (8 9 and 10 cups/day). The increased
suicide risk among heavy coffee drinkers was sig-
nifi cant in analyses adjusted for smoking and other
potential risk factors for suicide. The increased risk
among heavy coffee drinkers could not be confi rmed
in our cohorts because only 1.9 2.8% of participants
drank 6 cups of coffee daily. Because individuals
with mental illness may self-medicate with caffeine
(Greden et al. 1978; James and Crosbie 1987), it is
possible that persons with more severe forms of
depression or other mental illness used very high
doses of coffee as a form of self-medication that was,
nevertheless, insuffi cient to improve mood or allevi-
ate dysphoria.
In our study, suicide risk was no further decrease
in the highest level of caffeine intake, which might
suggest that results for caffeine intake are less
convincing than the results for coffee intake. It is
possible that caffeine intake results may be affected
by the contribution of non-coffee sources of caffeine
(20% for NHS, 29% for NHS II, and 21% for
HPFS). Biased RR estimates may also result from
error in assessing caffeine consumption. Overall,
these results suggest that there is little further
After multivariate adjustment, higher coffee con-
sumption was associated with a lower suicide risk in
all cohorts (Table II). Compared to those consuming
1 cup of coffee per week, the pooled multivariate
RR of suicide was 0.55 (95% CI: 0.38, 0.78) for
those consuming 2 to 3 cups per day, and 0.47 (95%
CI: 0.27, 0.81; P for trend 0.001) for those con-
suming 4 cups per day. For each increment of 2
cups of coffee per day, the RR for suicide was 0.75
(95% CI: 0.63 to 0.90). Compared to those in the
lowest ( 100 mg/day) category of caffeine intake,
the pooled multivariate RR of suicide was 0.54 (95%
CI: 0.30, 0.94) for those with intake between 400 to
550 mg/day and 0.63 (95% CI: 0.39, 1.04; P for
trend 0.005) for those with intake 550 mg/day
(Table III). For each increment of 300 mg of caffeine
per day, the pooled multivariate RR for suicide was
0.77 (95% CI: 0.63, 0.93). Results were similar when
NHS follow-up started in 1982 (i.e. including suicide
cases in a previous paper) (Kawachi et al. 1996).
Sensitivity analyses, i.e. using a latency of 4-year
minimum, did not change substantially the multi-
variate model results. Findings remained essentially
unchanged after further adjustment for comorbid
diseases (hypertension, diabetes, cardiovascular dis-
ease, or cancer), other socio-economic variables for
women (education, husband s education, retirement),
or four categories of alcohol intake ( 5 g/day,
5 15 g/day, 15 30 g/day, 30 g/day) (data not
shown). Decaffeinated coffee (Table IV) or tea con-
sumption was not associated with suicide risk (data
not shown). Adjustment for smoking had no effect
on the relationship between decaffeinated coffee and
suicide risk. After further adjustment for cup of caf-
feinated coffee and other covariates, risk of suicide
was not statistically signifi cant with higher consump-
tion of decaffeinated coffee.
The effect of coffee consumption on suicide risk
was not modifi ed by smoking status (current/not
current) (all P 0.16), alcohol use (yes/no) (all
P 0.54), or current menopausal hormone use (yes/
no) (all P 0.41).
Discussion
In these three large prospective cohorts of US men
and women, we observed that suicide risk, which was
similar to that reported in age- and gender-specifi c
US mortality statistics (Rockett et al. 2010),
decreased in a dose-dependent manner with increas-
ing consumption of coffee. As compared with non-
coffee drinkers, the pooled multivariate RR of suicide
was 45% lower among individuals who consumed
2 3 cups of coffee per day, and 53% lower among
individual consuming 4 cups of coffee per day. The
lack of association between decaffeinated coffee and
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Coffee, caffeine and suicide risk 7
Table IV. Relative risks (95% CI) of suicide according to decaffeinated coffee consumption.
a
Decaffeinated coffee consumption (cups)
1/week 2 6/week 1/day 2/day
P Value
for Trend
Increment
of 1 cup/day
NHS
No. of cases 26 8 11 2
Person-years
RR (95% CI)
468,072 369,499 202,131 70,299
Age-adjusted
b
1.00 0.52
(0.23, 1.18)
1.24
(0.59, 2.61)
0.52
(0.12, 2.21)
0.96 1.06
(0.78, 1.44)
Age, smoking-
adjusted
c
1.00 0.57
(0.25, 1.31)
1.25
(0.59, 2.68)
0.47
(0.11, 1.99)
0.82 1.01
(0.74, 1.37)
Multivariate
d
1.00 0.55
(0.23, 1.30)
1.29
(0.59, 2.79)
0.54
(0.12, 2.33)
0.99 1.04
(0.76, 1.43)
Sensitivity
e
1.00 0.56
(0.24, 1.31)
1.07
(0.47, 2.45)
0.70
(0.21, 2.40)
0.91 1.02
(0.74, 1.39)
NHS II
No. of cases 41 20 2 3
Person-years
RR (95% CI)
777,390 323,200 101,075 48,355
Age-adjusted
b
1.00 1.13
(0.66, 1.94)
0.35
(0.08, 1.43)
1.05
(0.32, 3.43)
0.53 0.93
(0.63, 1.35)
Age, smoking-
adjusted
c
1.00 1.28
(0.74, 2.19)
0.36
(0.09, 1.50)
0.96
(0.29, 3.14)
0.47 0.91
(0.63, 1.31)
Multivariate
d
1.00 1.29
(0.75, 2.23)
0.37
(0.09, 1.55)
0.97
(0.29, 3.19)
0.49 0.91
(0.63, 1.31)
Sensitivity
e
1.00 1.10
(0.60, 2.03)
0.42
(0.10, 1.74)
1.08
(0.33, 3.58)
0.69 1.03
(0.73, 1.45)
HPFS
No. of cases 89 41 24 10
Person-years
RR (95% CI)
361,414 257,832 106,582 68,878
Age-adjusted
b
1.00 0.62
(0.42, 0.90)
0.90
(0.57, 1.43)
0.55
(0.29, 1.08)
0.23 0.87
(0.72, 1.05)
Age, smoking-
adjusted
c
1.00 0.61
(0.42, 0.90)
0.90
(0.56, 1.44)
0.53
(0.27, 1.03)
0.19 0.86
(0.71, 1.04)
Multivariate
d
1.00 0.64
(0.43, 0.94)
0.95
(0.59, 1.54)
0.57
(0.29, 1.12)
0.28 0.89
(0.73, 1.07)
Sensitivity
e
1.00 0.66
(0.44, 0.99)
1.03
(0.63, 1.68)
0.56
(0.28, 1.11)
0.29 0.88
(0.73, 1.06)
Pooled results
f
RR (95% CI)
Multivariate
d
1.00 0.79
(0.47, 1.32)
0.95
(0.61, 1.48)
0.63
(0.37, 1.09)
0.26 0.92
(0.80, 1.07)
CI, confi dence interval; HPFS, Health Professionals Follow-up Study; NHS, Nurses Health Study; RR, relative risk.
a
Cases of suicide were codes E950 to E959 according the Eight Revision International Classifi cation of Diseases (ICD).
b
Adjusted for age (continuous), time interval and indicator variables for missing data on exposure for each questionnaire.
c
Further adjusted for smoking status (never smoked, past, currently smoke 1 14, 15 24, or 25 cig./day).
d
Further adjusted for cup of caffeinated coffee (continuous, cup/day), high alcohol consumption ( 30 g/day, yes or no), body-mass index
( 25, 25 29.9, 30 kg/m
2
), physical activity (quintiles), marital status (married/partnership, widowed, separated/divorced/single), and
reported regular use of minor tranquilizers(yes or no), and antidepressants (yes or no). For women of NHS II, multivariate model was
further adjusted for hormonal status (post-menopausal with or without hormonal therapy, pre-menopausal or never used hormonal
therapy).
e
The same as the multivariate model but using a latency of exposure of 4-year minimum. Number cases were as follow: 47 for
NHS, 66 for NHS II, and 164 for HPFS.
f
Results from multivariate models were combined using random-effect model.
benefi t for consumption above 2 3 cups/day or
400 mg of caffeine/day. Therefore, the continuous
estimate should be interpreted with caution.
The results of our study corroborate a lower sui-
cide risk among coffee drinkers, and identify caffeine
as the most likely candidate of any putative protec-
tive effect of coffee. Although the lack of association
between tea and suicide risk seems to contradict this
explanation, caffeine intake from tea may have been
too low for a measurable effect on suicide risk among
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8 M. Lucas et al.
we lack information on dosage and duration of anti-
depressant use. Because the participants were pre-
dominantly non-Hispanic white health professionals,
the generalizability of the observed associations may
be limited to similar populations. In particular, indi-
viduals with substance dependence problems, which
are at high risk of depression and suicide (Martinotti
et al. 2009), are most likely underrepresented in our
cohorts. Further, the personality profi le of the popu-
lation included in the study, health professionals,
may attenuate some putative effects of caffeine,
such as increased impulsiveness and novelty seeking
(Waldeck and Miller 1997; Gurpegui et al. 2007).
On the other hand, a possible protective effect of
caffeine is biologically plausible and deserves serious
consideration. Caffeine has complex effects in the
central nervous system, largely mediated by antago-
nism of adenosine A2a and A1 receptors, including
an increased turnover of several monoamine trans-
mitters, such as serotonin, dopamine, and noradren-
aline (Fredholm et al. 1999; Ferre 2008; Ferre et al.
2008). Therefore, central defi ciency of monoamines
may be improved by caffeine, which enhances dop-
aminergic neurotransmission (Fredholm et al. 1999;
Ferre 2008; Ferre et al. 2008). A defi ciency of central
monoamines is one of the features of depression
(Belmaker and Agam 2008), and several antidepres-
sant drugs are designed to increase monoaminergic
transmission. These pharmacological effects suggest
that caffeine could also act as a mild antidepressant,
a hypothesis that could explain the lower risk of
depression among coffee drinkers in epidemiological
studies (Ruusunen et al. 2010; Lucas et al. 2011).
Caffeine long half-life and possible pharmacoki-
netic interactions with drugs should also be consid-
ered. Peak plasma concentration of caffeine in a cup
of coffee is reached within a range of 1 1.5 h. At
dose lower than 10 mg/kg the caffeine half-life ranges
between 2.5 and 4.5 h, but it is doubled by use of
oral contraceptives or other exogenous estrogens and
reduced 30 50% by smoking (Arnaud 1987). Fur-
ther, because cytochrome P450 1A2 (CYP1A2),
which is the primary enzyme in caffeine metabolism,
is also important in the metabolism of several med-
ications, including antipsychotics, benzodiazopines,
and tricyclic antidepressants (Carrillo and Benitez
2000), changes in caffeine consumption may result
in treatment failure or increased risk of toxicity (Pat-
ton and Beer 2001). Interactions have been reported
also with lithium: caffeine can increase renal lithium
clearance and reduce its blood concentrations, thus
leading to treatment failure (Patton and Beer 2001).
These interactions should be considered when
making recommendations on caffeine consumption
among individuals using psychoactive drugs.
participants in our cohorts. However, our study has
limited ability to distinguish between caffeine and
other components of coffee, and results for decaf-
feinated coffee should be interpreted with caution.
For those who consumed 2 cups/day of decaffein-
ated coffee, the wide confi dence interval included
both the null value and the RR seen for caffeinated
coffee ( 2 cups/day). To avoid contamination by
caffeinated coffee consumption, a more rigorous
analysis of decaffeinated coffee relationship with sui-
cide risk would require the exclusion of subjects
drinking more often caffeinated coffee (e.g. 1 cup/
day). However, we did not have enough cases and
power to perform such analyses.
Unlike previous investigations, we had multiple
assessments of coffee and caffeine intake to obtain a
cumulative average of consumption, thus reducing
random error and accounting for changes in con-
sumption over time. This study also has limitations
and the results should thus be interpreted with cau-
tion. First and foremost, because of the observational
design, neither this nor previous investigations can
prove that coffee or caffeine reduces suicide risk, and
it remains possible that individuals with high intake
of coffee and caffeine have lower suicide risk for rea-
sons other than caffeine/coffee consumption, such as
a lower prevalence of chronic diseases. To minimize
this potential bias, we excluded from the analyses
individuals with history of cancer or cardiovascular
disease at baseline, and conducted sensitivity analy-
ses adjusted for incidence of these diseases or updat-
ing coffee consumption only up to 4 years before
each follow-up interval, thus discounting reductions
in coffee consumption that may have been the con-
sequence of incident events predisposing to suicide.
The robustness of our fi ndings supports, but does
not prove, a protective effect of caffeine.
Caffeine can trigger anxiety and panic attacks in
predisposed individuals (Nardi et al. 2007), and thus
persons with panic attacks and panic disorder often
avoid caffeine. Because anxiety is a risk factor for
attempted suicide (and possibly for completed sui-
cide), the lower suicide risk among coffee drinkers
may be due to a lower prevalence of anxiety disor-
ders in this group (Sareen et al. 2005; Pfeiffer et al.
2009). To address this possibility, we included in the
regression analyses the use of minor tranquilizers, as
a proxy for anxiety disorders. The persistence of an
inverse association between caffeine and suicide in
these analyses is consistent with an effect of caffeine
on suicide risk, but residual confounding cannot be
excluded. Our inverse associations remained even
after adjusting for antidepressant use. However, sui-
cidal person might have been less likely to visit a
physician and be treated for depression. Moreover,
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Coffee, caffeine and suicide risk 9
Staement of interest
The authors have no confl ict of interest to declare.
Supported by research grants P01 CA087969,
U19 CA055075, and R01 CA050385 from the
National Institutes of Health (NIH) for the mainte-
nance and follow-up of the cohorts that provided
data for the study. Dr Ascherio is supported by NIH
Grant R01 NS061858. Dr Lucas received a postdoc-
toral fellowship from Fonds de recherche en sant é
du Qu é bec (FRSQ). The funding source had no role
in the design and conduct of the study, analysis or
interpretation of the data, preparation or fi nal
approval of the manuscript, or the decision to submit
the manuscript for publication.
The contributions of each author were as follows:
all authors had full access to all of the data (includ-
ing statistical reports and tables) in the study and
can take responsibility for the integrity of the data
and the accuracy of the data analysis. Study concept
and design: ML, WCW and AA. Acquisition of data:
WCW and AA. Analysis and interpretation of data:
ML, EJO R, AP, FM, OIO, WCW and AA. Writing
the fi rst draft of the manuscript : ML. Critical revision of
the manuscript for important intellectual content: ML,
EJO R, AP, FM, OIO, WCW and AA. Statistical
analysis: ML, EJO R and AA. Obtained funding:
WCW and AA. Administrative, technical, and material
support: WCW and AA. Study supervision: WCW,
OIO and AA.
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... It has already been documented that caffeine intake is associated with depressive symptoms. Lucas et al. [91] indicated that the risk of depression is associated with the dose of consumed caffeine. They showed that people who drank more than two cups of caffeinated coffee per day were 24% less exposed to depression than those who did not drink coffee. ...
... It is known that caffeinated coffee consumption may be associated with a lower risk of suicide, depending on the amount of coffee consumed daily [99,100]. Lucas et al. [91] analyzed three prospective cohorts of American adults consisting of 43,599 men and 164,825 women, among which caffeine consumption was tested every four years. The authors documented 277 deaths from suicide and showed correlations between caffeine intake and deaths as an inverse relationship [91]. ...
... Lucas et al. [91] analyzed three prospective cohorts of American adults consisting of 43,599 men and 164,825 women, among which caffeine consumption was tested every four years. The authors documented 277 deaths from suicide and showed correlations between caffeine intake and deaths as an inverse relationship [91]. However, in a Finnish population study [101] of over 43,000 people who were followed for an average of 14.6 years, a J-shaped relation was found between daily coffee drinking and the risk of suicide. ...
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Nowadays, caffeine is one of the most commonly consumed substances, which presents in many plants and products. It has both positive and negative effects on the human body, and its activity concerns a variety of systems including the central nervous system, immune system, digestive system, respiratory system, urinary tract, etc. These effects are dependent on quantity, the type of product in which caffeine is contained, and also on the individual differences among people (sex, age, diet etc.). The main aim of this review was to collect, present, and analyze the available information including the latest discoveries on the impact of caffeine on human health and the functioning of human body systems, taking into account the role of caffeine in individual disease entities. We present both the positive and negative sides of caffeine consumption and the healing properties of this purine alkaloid in diseases such as asthma, Parkinson’s disease, and others, not forgetting about the negative effects of excess caffeine (e.g., in people with hypertension, children, adolescents, and the elderly). In summary, we can conclude, however, that caffeine has a multi-directional influence on various organs of the human body, and because of its anti-oxidative properties, it was, and still is, an interesting topic for research studies including those aimed at developing new therapeutic strategies.
... Numerous studies have demonstrated associations between higher levels of coffee intake and a lower risk of suicide and depression [9][10][11][12]. In a pooled analysis of three largescale US-based cohorts of middle-aged men and women (including NHS) [13], each additional two cups/day of coffee consumed was associated with a 25% lower risk of suicide (pooled multivariable RR = 0.75, 95% CI = 0.63, 0.90). A study conducted among over 50,000 NHS women similarly evaluated coffee intake in relation to incident depression over a 10-year period [11]. ...
... In light of prior work indicating that coffee consumption was related to a reduced risk of suicide and depression [13,14], this study sought to determine whether coffee intake was associated with a greater likelihood of sustaining high levels of psychological well-being over time. ...
... The absence of a meaningful relationship is noteworthy because we were able to examine these associations within a large sample, which should increase our ability to detect small but stable effects. Additionally, several prospective studies-including previous investigations conducted in the NHS cohort-have identified a robust relationship between coffee consumption and a reduced risk of both suicide [12,13] and incident depression [11,14]. Taken together, these findings show that while coffee consumption may mitigate depression and suicide risk among middle-age and older women, it does not appear to be appreciably related to psychological well-being over time. ...
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Objective Prior work indicates a robust relationship between coffee consumption and lower depression risk, yet no research has examined links with psychological well-being (e.g., happiness, optimism). This study tested whether coffee intake is prospectively associated with greater psychological well-being over time. Secondarily, associations in the reverse direction were also examined to determine whether initial levels of psychological well-being were related to subsequent coffee consumption.Methods Among women in the Nurses' Health Study, coffee consumption was examined in 1990 and 2002 in relation to sustained levels of happiness reported across multiple assessments from 1992-2000 (N = 44,449) and sustained levels of optimism assessed from 2004-2012 (N = 36,729). Associations were tested using generalized estimating equations with a Poisson distribution adjusted for various relevant covariates. Bidirectional relationships were evaluated in secondary analyses of baseline happiness (1992) and optimism (2004) with sustained moderate coffee consumption across multiple assessments through 2010.ResultsCompared to minimal coffee consumption levels (
... Caffeine, A 2A AR antagonists, and the genetic deletion of A 2A ARs selectively in forebrain neurons abrogate the onset of depressive-like symptoms and can also reverse these symptoms in mice subject to chronic unpredictable stress (Kaster et al., 2015). Accordingly, coffee intake is inversely correlated with the incidence of depression (Grosso et al., 2016;Lucas et al., 2011) and its major consequence suicide (Lucas et al., 2014), and the incidence of major depression is associated with A 2A AR haplotypes . In parallel, the upregulation of A 1 ARs bolsters the resilience toward depressive-like behavior and, conversely, knocking out A 1 ARs increased depressive-like behavior and eliminated the antidepressant effects of sleep deprivation (Serchov et al., 2015). ...
Article
Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011. SIGNIFICANCE STATEMENT: Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists ("biased" or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A2A- and A2BAR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A2AAR antagonist (istradefylline) has been approved as an anti-Parkinson agent.
... Compared with Alzheimer's disease, the benefit of coffee on Parkinson's disease is more substantial not only for reduced risk in healthy people but also for slowing disease progression in patients [32]. Additionally, coffee consumption reduces the risk of depression by 9% in elderly people who drink ≥4 cups of coffee per day Fig. 4 Forest plot of the hazard ratios (HRs) of (A) hemorrhagic stroke and (B) ischemic stroke among the participants in the cohort studies [33] and reduces the risk of suicide by approximately one quarter for each increment of 2 cups/day of coffee according to three large-scale cohort studies of medical professionals [34]. ...
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Background: Stroke is a crucial health threat to adults worldwide. Despite extensive knowledge of risk-factor mitigation, no primary prevention exists for healthy people. Coffee is a widely consumed beverage globally. Health benefit of coffee for several neurological diseases has been identified; however, the association between stroke risk and coffee consumption in healthy people has not been determined. We investigated the effect of coffee on stroke risk by conducting a meta-analysis of prospective cohort studies. Methods: Electronic databases, namely PubMed, BioMed Central, Medline, and Google Scholar, were searched using terms related to stroke and coffee. Articles that described clear diagnostic criteria for stroke and details on coffee consumption were included. The reference lists of relevant articles were reviewed to identify eligible studies not shortlisted using these terms. Enrolled studies were grouped into three outcome categories: overall stroke, hemorrhagic stroke, and ischemic stroke. Results: Seven studies were included and all of them were large-scale, long-term, follow-up cohort studies of a healthy population. Upon comparing the least-coffee-consuming groups from each study, the meta-analysis revealed a reduction in the risk of overall stroke during follow-up (hazard ratio [HR] for overall stroke = 0.922, 95% confidence interval [CI] = 0.855-0.994, P = 0.035). In studies with a clear definition of hemorrhagic and ischemic stroke, coffee consumption reduced the risk of ischemic stroke more robustly than that of hemorrhagic stroke (hemorrhagic, HR = 0.895, 95% CI = 0.824-0.972, P = .008; ischemic, HR = 0.834, 95% CI = 0.739-0.876, P < .001). No obvious dose-dependent or U-shaped effect was observed. Conclusions: Coffee consumption reduces the risk of overall stroke, especially ischemic stroke. Further investigation is required to identify beneficial components in coffee, including caffeine and phenolic acids, to develop preventive medication for stroke.
... Additionally, caffeine, a nonselective adenosine receptor antagonist, prevented depressive-like behavior and synaptic changes induced by chronic unpredictable stress (Kaster et al., 2015). Coherent with preclinical observation, important reviews also sustain that caffeine consumption decreases the incidence of depression and suicide risk in patients (Kawachi et al., 1996;Lucas et al., 2014). In the same way, the selective antagonism of A2a adenosine receptors KW6002 or the A2a genetic inactivation mice model of depression seems key to the antidepressant activity (Yacoubi et al., 2001;Kaster et al., 2004;Yamada et al., 2013;Kaster et al., 2015). ...
... The present study also provides the first demonstration that a prolonged (days) intake of caffeine prevents behavioral modifications caused by repeated restraint stress, as has been observed in other animal models of stress (Pechlivanova et al., 2012;Kaster et al., 2015;Yin et al., 2015;Kasimay Cakir et al., 2017) and in individuals with mood dysfunction, namely depression (reviewed in Grosso et al., 2016;Wang et al., 2016) and suicide ideation (e.g., Lucas et al., 2014;Park et al., 2019). ...
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Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P2X7 receptors (P2X7R) and adenosine A2A receptors (A2AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems work independently, we now investigated a putative interplay between P2X7R and A2AR. Adult rats exposed to restraint stress for 14 days displayed an anxious (thigmotaxis, elevated plus maze), depressive (anhedonia, increased immobility), and amnesic (modified Y maze, object displacement) profile, together with increased expression of Iba-1 (a marker of microglia “activation”) and interleukin-1β (IL1β) and tumor necrosis factor α (TNFα; proinflammatory cytokines) and an up-regulation of P2X7R (mRNA) and A2AR (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the P2X7R-preferring antagonist brilliant blue G (BBG, 45 mg/kg, i.p.) or by caffeine (0.3 g/L, p.o.), which affords neuroprotection through A2AR blockade. Notably, BBG attenuated A2AR upregulation and caffeine attenuated P2X7R upregulation. In microglial N9 cells, the P2X7R agonist BzATP (100 μM) or the A2AR agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the P2X7R antagonist JNJ47965567 (1 μM) and by the A2AR antagonist SCH58261 (50 nM), respectively; notably JNJ47965567 prevented the effect of CGS21680 and the effect of BzATP was attenuated by SCH58261 and increased by CGS21680. These results provide the first demonstration of a functional interaction between P2X7R and A2AR controlling microglia reactivity likely involved in behavioral adaptive responses to stress and are illustrative of a cooperation between the two arms of the purinergic system in the control of brain function.
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Purpose: Uric acid (UA) is thought to exert neuroprotective roles. The purpose of this study was to examine the association of serum UA with suicide attempts (SA) in adolescents and young adults with major depressive disorder (MDD). Patients and methods: We retrospectively recruited 533 participants with MDD aged 13 to 25 years, of which 168 had a history of SA in the past three months and 365 did not have a history of SA. Serum UA levels were measured using the uricase-peroxidase coupling method. In addition to overall serum UA level comparison in MDD individuals with and without SA, a stratified analysis by biological sex was carried out. Results: Compared to MDD individuals without a history of SA, serum UA levels were significantly lower in MDD individuals with SA (P < 0.001). Female MDD, but not male MDD individuals, with SA exhibited lower levels of UA than those without SA (P < 0.01). Importantly, serum UA remained significantly associated with SA in MDD individuals (OR = 0.996, 95% CI: 0.993~0.999, P < 0.01) when controlling for possible confounding variables. Conclusion: This research identifies a relationship between serum UA levels and SA in adolescents and young adults with MDD. UA may represent a biological risk marker for SA, in particular for female MDD individuals.
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Caffeine is the most widely consumed psychoactive compound worldwide. Its mechanisms of action are dose-dependent and when caffeine overdosing occurs, neurologic, cardiovascular and renal systems are mainly affected. Serious toxicities such as seizure and cardiac arrhythmias, seen with caffeine plasma concentrations of 15 mg/L or higher, have caused poisoning or, rarely, death. Caffeine concentrations of 80-100 mg/L are considered lethal. The aim of this systematic review is to summarize data regarding suicides by caffeine administration and analyze the controversial role of caffeine assumption and suicidal risk. We followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) indications in the identification and selection of studies and reviewed a series of fatal cases due intentional intoxication by caffeine. A total of 36 cases have been identified. Our results suggests caffeine seems to be negatively correlated with suicide. Even if some observations suggested that the consumption of caffeine may have beneficial effects against depression, and as a consequence against suicide risk, more in-depth studies are required. Data obtained from our study could support both clinicians and forensic pathologists in identifying possible unrecognized cases.
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Although the majority of the population regularly consume caffeine, there are wide variations between individuals in both daily intake and susceptibility to caffeine's effects. These differences are at least partially genetically determined, possibly via variations in adenosine receptors or caffeine metabolism. Caffeine toxicity is well recognized. Tolerance of its effects and withdrawal symptoms have also been described. Both DSM and ICD-10 recognize caffeine as a potential drug of abuse. Caffeine can induce anxiety, exacerbate psychotic symptoms in some patients with schizophrenia and cause insomnia. It can complicate the management of depression by increasing lithium clearance and can also increase seizure length during ECT. Caffeine can inhibit the metabolism of some psychotropic drugs such as clozapine through the competitive inhibition of CYP 1A2 . Potent inhibitors of CYP 1A2 such as fluvoxamine can precipitate caffeine toxicity. Enquiries about caffeine consumption should be made in all patients who have apparently treatment-refractory illness, or seem unusually sensitive to, or tolerant of, psychotropic drugs.
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Results of case-control studies and of a prospective investigation in men suggest that consumption of coffee could protect against the risk of Parkinson's disease, but the active constituent is not clear. To address the hypothesis that caffeine is protective against Parkinson's disease, we examined the relationship of coffee and caffeine consumption to the risk of this disease among participants in 2 ongoing cohorts, the Health Professionals' Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). The study population comprised 47,351 men and 88,565 women who were free of Parkinson's disease, stroke, or cancer at baseline. A comprehensive life style and dietary questionnaire was completed by the participants at baseline and updated every 2–4 years. During the follow-up (10 years in men, 16 years in women), we documented a total of 288 incident cases of Parkinson's disease. Among men, after adjustment for age and smoking, the relative risk of Parkinson's disease was 0.42 (95% CI: 0.23–0.78; p for trend < 0.001) for men in the top one-fifth of caffeine intake compared to those in the bottom one-fifth. An inverse association was also observed with consumption of coffee (p for trend = 0.004), caffeine from noncoffee sources (p for trend < 0.001), and tea (p for trend = 0.02) but not decaffeinated coffee. Among women, the relationship between caffeine or coffee intake and risk of Parkinson's disease was U-shaped, with the lowest risk observed at moderate intakes (1–3 cups of coffee/day, or the third quintile of caffeine consumption). These results support a possible protective effect of moderate doses of caffeine on risk of Parkinson's disease.