Acta Psychiatr Scand 2016: 133: 5–22 © 2015 John Wiley & Sons A/S.

2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
All rights reserved ACTA PSYCHIATRICA SCANDINAVICA
DOI: 10.1111/acps.12459

Review
Relationship between prolactin, breast
cancer risk, and antipsychotics in patients
with schizophrenia: a critical review
De Hert M, Peuskens J, Sabbe T, Mitchell AJ, Stubbs B, Neven P, M. De Hert1, J. Peuskens1,
Wildiers H, Detraux J. Relationship between prolactin, breast cancer T. Sabbe1, A. J. Mitchell2,
risk, and antipsychotics in patients with schizophrenia: a critical review. B. Stubbs3, P. Neven4,
H. Wildiers4,5, J. Detraux1
Objective: A recent meta-analysis showed that breast cancer probably is 1
Department of Neurosciences, KU Leuven University
more common in female patients with schizophrenia than in the general Psychiatric Centre, Kortenberg, Belgium, 2Department of
population (effect size = 1.25, P < 0.05). Increasing experimental and Psycho-oncology, Cancer & Molecular Medicine,
epidemiological data have alerted researchers to the influence of prolactin University of Leicester, Leicester, 3School of Health and
(PRL) in mammary carcinogenesis. We therefore investigated the Social Care, University of Greenwich, Greenwich, UK,
possible relationship between antipsychotic-induced hyperprolactinemia 4
Multidisciplinary Breast Center and 5Department of
(HPRL) and breast cancer risk in female patients with schizophrenia. General Medical Oncology, Leuven Cancer Institute,
Method: A literature search (1950 until January 2015), using the University Hospitals Leuven, KU Leuven - University of
MEDLINE database, was conducted for English-language published Leuven, Leuven, Belgium
clinical trials to identify and synthesize data of the current state of
knowledge concerning breast cancer risk (factors) in women with
schizophrenia and its (their) relationship between HPRL and
antipsychotic medication.
Results: Although an increasing body of evidence supports the
involvement of PRL in breast carcinogenesis, results of human
prospective studies are limited, equivocal, and correlative (with risk
ratios ranging from 0.70 to 1.9 for premenopausal women and from
0.76 to 2.03 for postmenopausal women). Moreover, these studies
equally do not take into account the local production of PRL in breast
epithelium, although amplification or overexpression of the local
autocrine/paracrine PRL loop may be a more important mechanism in
tumorigenesis. Until now, there is also no conclusive evidence that Key words: schizophrenia; breast cancer; prolactin;
hyperprolactinemia; antipsychotics
antipsychotic medication can increase the risk of breast malignancy and
mortality. Marc De Hert, UPC KUL campus Kortenberg,
Conclusion: Other breast risk factors than PRL, such as nulliparity, Leuvensesteenweg 517, 3070 Kortenberg, Belgium.
E-mail: marc.de.hert@uc-kortenberg.be
obesity, diabetes mellitus, and unhealthy lifestyle behaviours (alcohol
dependence, smoking, low physical activity), probably are of greater
relevance in individual breast cancer cases within the population of
female patients with schizophrenia. Accepted for publication June 2, 2015

Summations
• Although some studies, examining the relationship between prolactin and breast cancer risk (factors),
suggest that higher circulating prolactin levels may increase breast cancer risk, results are equivocal
and correlative. Therefore, the question of whether or not elevated prolactin levels actually cause
breast cancer remains open to discussion.
• Until now, no causal link between (chronic) administration of antipsychotics and breast tumorigene-
sis in humans has been shown.
• Well-known breast cancer risk factors, of which several are, compared to their healthy counterparts,
more prevalent in women with schizophrenia, probably are of greater relevance than prolactin in this
vulnerable population when considering breast cancer risk and mortality.

5
De Hert et al.

Considerations
• There is a paucity of, particularly high-quality prospective, research investigating the links between
prolactin, breast cancer risk (factors), and antipsychotic medication.
• When looking at the association between prolactin and breast cancer, one has to look beyond endo-
crine prolactin and the cognate view that prolactin receptor signaling can only be triggered by prolac-
tin coming from the bloodstream, as overexpression of the autocrine/paracrine loop of prolactin
within the breast tissue has, based on several observations, been suggested to be an important mecha-
nism in tumorigenesis
• If prolactin increases breast cancer risk, it probably is a factor of (at most) modest magnitude.

PRL levels and decrease tumor size in the major-

Introduction
ity of cases (11).
Prolactin (PRL) is a 23-kDa hormone that is Antipsychotics have a D2R-blocking effect and
mainly synthesized in and released into the blood therefore elevate the secretion of PRL, causing hy-
circulation from lactotroph cells of the anterior perprolactinemia (HPRL) (usually defined as fast-
lobe of the pituitary gland (i.e. the adenohy- ing levels >20 ng/ml in men and >25 ng/ml in
pophysis) (1). Prolactin plays a critical role in women) (1). Although all antipsychotics have the
the cellular growth and differentiation of the propensity to induce HPRL, differences between
mammary gland (2–5). Binding of PRL to its antipsychotic drugs with respect to PRL elevation
receptor activates several signaling pathways (6, are large (1). The highest rates of HPRL are
7), resulting in the enhanced differentiation, pro- consistently reported in association with the
liferation, and survival of breast epithelial cells first-generation antipsychotics (FGAs) and the sec-
(6). Its most important physiological functions ond-generation antipsychotics (SGAs) amisulpride,
include breast enlargement during pregnancy and risperidone, and paliperidone, while the SGAs ari-
the induction and maintenance of milk produc- piprazole and quetiapine have the most favorable
tion during lactation (1, 8). Although typically profile with respect to this outcome (1) (Table 1).
thought of as a pituitary-derived hormone, PRL Increasing experimental and epidemiological
production and secretion is not restricted to the evidence suggests a role for PRL in breast tumori-
pituitary gland. In addition to the adenohypoph- genesis. Like normal mammary gland develop-
ysis, several other extrapituitary sites, including ment, breast carcinogenesis mostly is a hormonally
the mammary gland, physiologically secrete PRL dependent process (12). Therefore, female repro-
(1–3, 7, 9). Thus, PRL reaches the breast both ductive hormones estrogen and progesterone, and
from the systemic circulation and from the local possibly the hormone PRL, can have a major
sources (2, 6). impact on breast cancer risk/growth (6, 12–14).
Prolactin production and secretion is differen- This fact has raised questions about the possible
tially regulated in pituitary and extrapituitary relationship between antipsychotic-induced HPRL
sites (2). Under normal physiological conditions, and breast cancer risk.
pituitary PRL synthesis and secretion is tonically
inhibited by the hypothalamus, mediated by a Table 1. Prolactin side-effect profile of second-generation antipsychotics (1)
number of PRL inhibitory factors of which
Prolactin elevation
dopamine is the most important one (1, 7, 9). A
blockade of dopamine D2 receptors (D2R) coun- Amisulpride +++
teracts the tonic inhibitory effect of dopamine on Aripiprazole 0
Asenapine +
the PRL secretion, resulting in disinhibition of Clozapine +
PRL secretion. The stronger the dopamine D2R Iloperidone +
blockade, the higher the PRL elevation (1). Lurasidone ++
While pituitary PRL is largely regulated by Olanzapine ++
Paliperidone +++
dopamine (1, 2), extrapituitary PRL is not sensi- Quetiapine +/-
tive to this neurotransmitter (2, 9, 10). This Risperidone +++
explains the failure of dopamine agonists, such Sertindole +
as bromocriptine, to affect PRL-dependent breast Ziprasidone ++

tumors in patients (6), whereas in patients with a 0, minimal to no risk; +/-, minimal risk; +, low risk; ++, moderate risk; +++, high
prolactinoma, these agonists normalize pituitary risk.

6

Aims of the study
The aims of this critical review were to address the
lingering question regarding the association
between PRL, breast cancer risk, and antipsychot-
ics, and to describe breast cancer risk (factors) in
patients with schizophrenia, with the purpose to
try to present a full clinical picture. This critical
review has been the result of an intensive collabo-
ration between experts on schizophrenia and
breast cancer.
Material and methods
A systematic search (1950 until January 2015),
using the MEDLINE database, was conducted for
English-language published clinical trials to syn-
thesize the results concerning the current state of
knowledge about breast cancer risk (factors) and
its relationship to HPRL and antipsychotic medi-
cation. For the association between breast cancer
risk and HPRL, we limited ourselves to prospec-
tive studies. Retrospective studies have little scien-
tific value because they assess PRL levels after the
woman had been diagnosed with breast cancer.
For the association between breast cancer risk and
antipsychotic medication, case report studies were
excluded (Fig. 1). The following key words were
used in various combinations: ‘schizophrenia’,
‘breast cancer’, ‘PRL’, ‘prospective’, ‘antipsychotic’,
‘neuroleptic’, ‘risperidone’, ‘olanzapine’, ‘quetia-
pine’, clozapine’, ‘aripiprazole’, ‘amisulpride’, ‘sulpi-
Identification
Screening
Eligibility
Included
Prospective studies on
relationship between
breast cancer and
prolactin (n = 13)
Fig. 1. PRISMA checklist flow
diagram.
Breast cancer, prolactin, and antipsychotics
ride’, ‘paliperidone’, ‘sertindole’, ‘ziprasidone’,
‘lurasidone’, ‘iloperidone’, ‘asenapine’, ‘haloperi-
dol’, ‘phenothiazines’, and ‘butyrophenones’. We
reviewed the reference lists of identified studies and
reviews to detect any additional and potentially
important articles. A comprehensive search, using
the same database, was conducted for English-lan-
guage published clinical trials to provide a succinct
update on the current state of knowledge about
breast cancer risk factors in women with schizo-
phrenia. For this search, the following key words
were used: ‘schizophrenia’, ‘breast cancer’, ‘breast
cancer risk factors’.
Results
Prospective studies on the association between PRL and breast
cancer risk
Until now, two large database and five small pro-
spective studies (15–27) have addressed the associ-
ations between circulating PRL levels and breast
cancer risk in the general population (Table 2).
Those involving small sample sizes (maximum 173
breast cancer cases) (23–27) found no statistical
significant relationship between PRL levels and
breast cancer risk among either pre- or postmeno-
pausal women. Although the larger database
studies [The Nurses’ Health Studies (NHS I/NHS
II) and the European Prospective Investigation
into Cancer (EPIC) study] have shown that higher
circulating PRL levels may increase breast cancer
Records identified through
MEDLINE database searching
(n = 1184)
538 duplicate records removed
94 non-English publications removed
Records assessed for
eligibility (n = 552)
532 articles excluded with reasons
Studies on association breast
cancer, prolactin,
antipsychotic medication
included in qualitative
analysis (n = 7)
7
8
Table 2. Overview of prospective studies on prolactin concentrations and breast cancer risk in premenopausal and postmenopausal women (15–27)

Premenopausal Postmenopausal

Number of cases
Study Study characteristics and controls Results Number of cases and controls Results
De Hert et al.

EPIC database study

Tikk et al. (15) European Prospective Investigation into 512 cases OR = 0.70; 95% 1738 cases OR = 1.29; 95% CI: 1.05–1.58 (top vs. bottom quartile
Cancer Study (1992–2006) 512 controls CI: 0.48–1.03 1738 controls for all postmenopausal women)
(top vs. bottom quartile) OR = 1.11; 95% CI: 0.83–1.49 (top vs. bottom quartile for
OR = 0.70; 95% postmenopausal non-HRT users)
CI: 0.44–1.09 (ER+ cases) OR = 1.45; 95% CI: 1.08–1.95 (top vs. bottom quartile for
(top vs. bottom quartile) postmenopausal HRT users)
OR = 1.29; 95% CI: 1.02–1.63 (ER+ cases) (top vs. bottom
quartile for all postmenopausal women)
OR = 1.12; 95% CI: 0.80–1.57 (ER+ cases) (top vs. bottom
quartile for postmenopausal non-HRT users)
OR = 1.42; 95% CI: 1.01–1.99 (ER+ cases) (top vs. bottom
quartile for postmenopausal HRT users)
NHS database studies
Tworoger et al. (16) Nested case–control study of invasive 241 cases RR = 0.99; 95% 119 cases RR = 1.36; 95% CI: 0.93–1.98) (top vs. bottom quartile)
breast cancer in the Nurses’ Health 214 controls CI: 0.71–1.37) 118 controls
Studies (NHS I/NHS II) (top vs. bottom quartile)
Tworoger et al. (17) Nurses’ Health Studies I (1990–2010) and II PRL collected RR = 1.05; 95% PRL collected <10 years RR = 1.37; 95% CI: 1.11–1.69 (<10 years)
(1999–2009) <10 years before CI: 0.82–1.33 (<10 years) before diagnosis (top vs. bottom quartile)
diagnosis (top vs. bottom quartile) 2468 cases RR = 1.52; 95% CI: 1.19–1.93 (<10 years, ER+ cases)
2468 cases RR = 0.98; 95% 4021 controls (top vs. bottom quartile)
4021 controls CI: 0.73–1.32 (<10 years, PRL collected <10 years RR = 0.93; 95% CI: 0.66–1.33 (>10 years)
PRL collected ER+ cases) (top vs. bottom before diagnosis (top vs. bottom quartile)
<10 years before quartile) 953 cases RR = 0.97; 95% CI: 0.65–1.43 (>10 years, ER+ cases)
diagnosis RR = 1.03; 95% 1339 controls (top vs. bottom quartile)
953 cases CI: 0.68–1.56 (>10 years)
1339 controls (top vs. bottom quartile)
RR = 0.81; 95%
CI: 0.51–1.30 (>10 years,
ER+ cases) (top vs. bottom
quartile)
Tworoger and Pooled analysis of approximately 80% of RR = 1.3; 95% CI: 1.1–1.6 (top vs. bottom quartile). Results were similar for premenopausal
Hankinson (18) the world’s prospective data and postmenopausal women. High PRL levels were associated with a 60% increased risk
of estrogen receptor-positive tumors
Tworoger et al. (19) New analysis RR = 1.3; 95% Pooled analysis of new data RR = 1.3; 95% CI: 1.1–1.7 (top vs. bottom quartile)
377 cases CI: 0.9–1.9 with data sets from the
786 controls (top vs. bottom quartile) NHS I and NHS II cohorts
Pooled analysis of RR = 1.4; 95% 915 cases
new data with data CI: 1.0–1.9 1410 controls
sets from the NHS I (top vs. bottom quartile)
and NHS II cohorts
492 cases
1001 controls
 Table 2. (Continued)

Premenopausal Postmenopausal

Number of cases
Study Study characteristics and controls Results Number of cases and controls Results

Tworoger et al. (20) Prospective nested case–control study 316 cases RR = 1.5; 95% N/A N/A
Nurses’ Health Study II (1996–2003) 633 controls CI: 1.0–2.5
Controlled for number of established (top vs. bottom quartile)
breast cancer risk factors Comparable RR = 1.9; 95%
CI: 1.0–3.7 (ER+/PR+ tumors)
Tworoger et al. (21) Prospective nested case–control study N/A N/A 851 cases RR = 1.34; 95% CI: 1.02–1.76 (top vs. bottom quartile)
Nurses’ Health Study (1989–2000) 1275 controls RR = 1.78; 95% CI: 1.28–2.50 (ER+/PR+ tumors)
Controlled for number of established RR = 0.76; 95% CI: 0.43–1.32 (ER-/PR- tumors)
breast cancer risk factors RR = 1.94; 95% CI: 0.99–3.78 (ER+/PR- tumors)
Hankinson et al. (22) Nurses’ Health Study (1989–1994) N/A N/A 306 cases Multivariate RR = 2.03; 95% CI: 1.24–3.31
Prospective nested case–control study 448 controls (top vs. bottom quartile)
Controlled for number of established
breast cancer risk factors
Other (small) prospective studies
Manjer et al. (23) Swedish cohorts (follow-up varied by N/A N/A 173 cases Adjusted OR = 1.34; 95% CI: 0.83–2.17
cohort) 438 controls (top vs. bottom quartile)
Controlled for number of established
breast cancer risk factors
Kabuto et al. (24) Life Span Study (1970–1983) 46 cases OR = 1.01; 95% 26 cases OR = 6.45; 95% CI: 0.01–43.9. For a log10 unit increase
Controlled for number of established 94 controls CI: 0.02–47.4. For a 56 controls
breast cancer risk factors log10 unit increase
Helzlsouer et al. (25) Washington county cohort (1974–1991) 21 cases RR = 1.1; 95% N/A N/A
Controlled for number of established 42 controls CI: 0.3–4.1
breast cancer risk factors (top vs. bottom tertile)
Wang et al. (26) Guernsey cohort study (1968–1990) 71 cases RR = 1.1; 95% CI: 0.5–2.2 40 cases RR = 1.6; 95% CI: 0.6–4.7 (top vs. bottom quintile)
Controlled for number of established 2596 controls (top vs. bottom quintile) 1180 controls
breast cancer risk factors
Kwa et al. (27) Guernsey cohort study (1968–1975) 22 cases Not statistically 8 cases 8 cases
Controlled for number of established For each women who significant (P = 0.67) For each women who Association between elevated plasma PRL levels and
breast cancer risk factors developed breast cancer, developed breast cancer, subsequent breast cancer is significant (P = 0.04), and on
ten controls satisfying the ten controls satisfying the average, their values were at the 72nd percentile when
matching requirements matching requirements compared to matched controls
were available (in three were available (in three cases,
cases, only nine controls only nine controls were available)
were available)

CI, Confidence interval; EPIC, European Prospective Investigation into Cancer; ER, estrogen receptor; HRT, hormone replacement therapy; N/A, not available; NHS, Nurses’ Health Study; OR, odds ratio; PR, progesterone receptor; PRL, prolactin; RR,
relative risk.
Bold: statistically significant data.

9
Breast cancer, prolactin, and antipsychotics
De Hert et al.
risk, their findings only partially agree. The pooled
analysis of data sets from the NHS I and NHS II
cohorts with new data found a 40% increase in
breast cancer risk (P = 0.05) for premenopausal
women with the highest (= upper level of the nor-
mal range) vs. lowest PRL levels (19). In the EPIC
study, a statistically non-significant association
between PRL levels and breast cancer risk was
observed among premenopausal women (odds
ratio, OR = 0.70; 95% CI: 0.48–1.03) (15). With
respect to postmenopausal women, a 30% increase
in breast cancer risk (P = 0.01) was observed in
the pooled analysis of the NHS cohorts (19). This
association differed by estrogen receptor/proges-
terone receptor (ER/PR) status, as the relative risk
(RR) was found to be significant only for tumors
with ER+/PR+ status (RR = 1.78; 95% CI: 1.28–
2.50) (21). Although the EPIC study equally found
higher serum levels of PRL to be associated with a
statistically significant increase in breast cancer
risk among postmenopausal women (OR = 1.29;
95% CI: 1.05–1.58), this increase in risk seemed to
be confined to women who used hormone replace-
ment therapy (HRT) at blood donation
(OR = 1.45; 95% CI: 1.08–1.95), whereas no sta-
tistically significant association was found for non-
users of HRT (OR = 1.11; 95% CI: 0.83–1.49).
They also found no evidence for heterogeneity of
the PRL–breast cancer risk association by receptor
status (15). Compared to the associations reported
for other endogenous hormones such as estradiol,
with RR estimates up to 2.5 for top vs. bottom ter-
tile levels (28), the observed associations between
circulating PRL and subsequent breast cancer risk,
both in the EPIC and in the NHS studies, are (at
the most) of modest magnitude.
PRL, breast cancer risk, and antipsychotics
The majority of the studies investigating the influ-
ence of antipsychotic medication on breast cancer
risk have considered patients treated with FGAs.
These studies (29–33) have not found an increased
risk of breast cancer, an exception being the cohort
study by Wang et al. (34) These researchers con-
ducted a retrospective cohort study in more than
100 000 women (including psychiatric patients as
well as medical patients and patients from nursing
homes) in which the relationship between FGAs
(including the SGA, risperidone) and breast cancer
was investigated. In this study, 52 819 women on
dopamine antagonists were compared with 55 289
women who were not on this medication. The
authors found that, compared with non-users,
women who used antipsychotic dopamine antago-
nists had a 16% greater risk (adjusted hazard
10
ratio = 1.16, 95% CI: 1.07–1.26) of developing
breast cancer, with a dose–response relationship
between larger cumulative dosages and greater
risk. However, as stated by the authors, the magni-
tude of the observed risk, although statistically sig-
nificant, is small in absolute terms (1239 cases of
breast cancer in the user group vs. 1228 cases in
the non-user group), and they estimated there is
less than a 14% chance that a dopamine antagonist
user who develops breast cancer did so on the basis
of her antipsychotic drug use. Moreover, although
the power was limited, it is noteworthy that breast
cancer risk was statistically significantly increased
in those taking phenothiazines (e.g. chlorproma-
zine, perphenazine), but not butyrophenones (e.g.
haloperidol), despite the fact that both FGA clas-
ses increase PRL by a similar amount (35, 36).
They therefore concluded that their findings ‘do
not warrant changes in patients’ antipsychotic medi-
cation regimens’ (page 1153). Despite this state-
ment, the study by Wang et al. has consistently
been cited to demonstrate that antipsychotic medi-
cations can induce breast cancer, particularly in
female patients with schizophrenia. Hippisley-Cox
et al. (37) tried to determine the risk of six com-
mon types of cancer in patients with schizophrenia
or bipolar disorder (40 441 incident cases with up
to five matched controls per case) and found a
52.2% increase in breast cancer risk in women with
schizophrenia, compared with patients without
mental health problems. However, only a small
association with antipsychotic medication was
found. The increase in breast cancer risk was not
substantially different in subgroups with
(FGAs + SGAs) and without antipsychotic medi-
cation use [adjusted OR = 1.55 (95% CI: 1.08–
2.23) for users and 1.43 (95% CI: 0.68–3.01) for
non-users, both compared with patients without
mental health problems]. Moreover, the authors
state that it is possible that the increased risk of
breast cancer demonstrated in this study was due
to residual confounding by lower parity and other
breast cancer risk factors rather than a true
increase in risk. In a large-scale population-based
cohort study of all residents in a Danish county,
Dalton et al. (29) found no increased risk for
breast cancer among 25 264 FGA users (adjusted
incidence rate ratio = 0.93; 95% CI: 0.74–1.17),
compared with residents of the same Danish
county who did not receive such prescriptions.
However, their inclusion criteria were very broad
(e.g. 8927 included patients had received merely
2–4 prescriptions of antipsychotics and only 8.5%
of female antipsychotic users had a diagnosis of
schizophrenia), meaning that most of the included
patients perhaps did not receive high and/or

chronic doses of antipsychotics. In the first system-
atic review of the literature on the potential pro- or
anticancer activity of antipsychotics, Fond et al.
(38) included 93 studies (in vitro, animal and
human studies) considering the effects of antipsy-
chotic drugs (FGAs + SGAs) on cancer develop-
ment and found that antipsychotics as a class
cannot be considered as a risk factor for breast
cancer in humans.
Although SGAs, as a group and compared to
FGAs, are associated with less PRL elevations,
there are concerns that the SGAs risperidone, ami-
sulpride, and paliperidone, which have been associ-
ated with a high prevalence of HPRL (1)
(Table 1), may increase the risk of breast cancer.
However, results indicate that SGAs equally do
not appear to increase the risk of breast cancer.
Azoulay et al. (39) conducted a retrospective
cohort study (including 106 362 patients pre-
scribed at least one FGA or SGA) and matched all
incident cases of breast cancer up to 10 controls
per case. They found that, compared to patients
who only used FGAs, exclusive users of SGAs
were not at an increased risk of breast cancer
(RR = 0.81, 95% CI: 0.63–1.05). These results
remained consistent after considering specific
SGAs known to significantly increase PRL levels,
such as risperidone (RR = 0.86, 95% CI: 0.60–
1.25). These findings were strengthened by the lack
of any dose–response association, which consid-
ered both cumulative duration of use (patients
were exposed for up to 23 years) and cumulative
dose. Furthermore, no increased risk was observed
in higher risk groups, such as in postmenopausal
women.
Breast cancer risk in female patients with schizophrenia
Breast cancer is one of the most commonly diag-
nosed cancers worldwide (one in eight women will
be diagnosed with breast cancer during their life-
time) and the leading cause of cancer death among
females (40–44). Although the disease occurs in
men as well, male breast cancer is rare (only 0.5–
1% of all breast cancers in the United States occur
in men) (45). Breast cancer is not a single biologi-
cal entity (46), and several molecular subtypes of
breast cancer with a distinctly different survival
and treatment response have been identified (46–
50).
Given that women with schizophrenia have
lower numbers of parity and other known breast
risk factors [obesity, diabetes mellitus (DM), and
unhealthy lifestyle behaviours (alcohol depen-
dence, smoking)], which are, compared with the
general population, more prevalent among these
Breast cancer, prolactin, and antipsychotics
patients (51), one would anticipate higher breast
cancer rates in this population. However, data
are conflicting. Although several studies have
shown an increased breast cancer risk and mor-
tality rate among women with schizophrenia (37,
52–61), other studies have found a decreased
(62, 63) or a non-statistically, significantly
increased risk (29, 54, 64–72). A recent meta-
analysis of observational studies in people with
central nervous system disorders found that
patients with schizophrenia showed a higher co-
occurrence of breast cancer (effect size = 1.25;
95% CI: 1.10–1.42) (73).
Several reasons have been proposed to explain
these inconsistencies. Some authors (74, 75) refer
to methodological issues. However, the discrep-
ancy of results may also be a result of various con-
founding factors that could artificially change the
rates of diagnosed and reported breast cancers in
patients with schizophrenia. For example, people
with schizophrenia are less likely to receive routine
cancer screening (76, 77), meaning that breast can-
cer potentially is under-recognized or only diag-
nosed at a more advanced stage. Furthermore,
patients with schizophrenia have a 10- to 25-year
shorter life expectancy and may die from cardio-
vascular reasons (which are the commonest cause
of death in this population), before reaching the
expected age of death from cancer (51, 78). From a
genetic view-point, we refer to the Fragile X syn-
drome (characterized by a large number of CGG
repeats at the FMR1 gene located on the X chro-
mosome)-related mechanisms in schizophrenia (79,
80), as evidence exists that (breast) cancer risk is
decreased in individuals with this syndrome (81–
83). Thus, taken together, data interpretation con-
cerning the risk of breast cancer in people with
schizophrenia is complex, especially when knowing
that few of the above mentioned studies identified
and adjusted for any putative confounders. There-
fore, larger and methodologically robust studies,
accounting for confounding variables as well as
genes possibly common for schizophrenia and can-
cer, are needed.
Breast cancer risk factors in female patients with schizophrenia
A range of risk factors for the development of
breast cancer have been identified in the literature
(18, 42, 43, 84–89) (Table 3). Factors that are par-
ticularly important for women with schizophrenia
are highlighted in the table and discussed in the
text.
Nulliparity and lack of breast-feeding. Having chil-
dren and breast-feeding are protective factors with
11
De Hert et al.
Table 3. Breast cancer risk factors (18, 42, 43, 84–89)
Age (a woman’s risk of developing the disease increases as she gets older)
Alcohol use
Benign breast disease
Carrying breast cancer susceptibility genes (e.g. BRCA1 and BRCA2 mutations
confer a 60% to 80% lifetime risk for the development of breast cancer)
Delayed childbearing (having a first full-term pregnancy after age 30)
Diabetes mellitus
Early menarche (beginning to menstruate before age 12)
Lack of breast-feeding
Late menopause (starting menopause after age 55)
Low physical activity
Mammographic breast density (having dense breast)
Nulliparity (never having been pregnant/children),
Obesity
Oral contraceptives and hormone replacement therapy (HRT) (also called
menopausal hormone therapy or MHT)
Previous breast biopsy
Personal or family history of breast or ovarian cancer
Race (more often in White women, compared to South Asian and Black women)
Radiation therapy to the breast
Smoking (?)
Bold: Factors of greater relevance in women with schizophrenia, possibly increasing
breast cancer risk in this vulnerable population.
Italic: Factors of lesser relevance in women with schizophrenia, possibly decreasing
breast cancer risk in this vulnerable population.
respect to breast cancer (42, 84, 90, 91). Individuals
with psychotic illnesses are known to have a
reduced fertility, already prior to the onset of psy-
chotic illness (92). Women with chronic schizo-
phrenia, as well as first-episode psychosis, have,
compared to their healthy counterparts, lower
numbers of parity (92–95). Moreover, once having
children, many women with schizophrenia fail to
breast-feed (96). For most antipsychotic drugs, a
firm and evidence-based conclusion about the
safety of their use for the exposed infant during
breast-feeding cannot be reached (97) and product
labeling of antipsychotics (98–104) does not rec-
ommend to breast-feed the infant when the mother
is taking these medications. This has prompted
several clinicians to counsel women with schizo-
phrenia to refrain from breast-feeding (96), who
may as such be deprived of an important protec-
tive factor with respect to breast cancer. Indeed, a
recent meta-analysis showed that in the general
population, breast-feeding could lower this risk by
approximately 10% (42). However, as PRL-elevat-
ing antipsychotics can cause galactorrhea, in both
women and men, one can wonder whether HPRL-
inducing antipsychotics in these cases not rather
constitute a protective factor for mammary cancer.
Interestingly, PRL levels rise during pregnancy
(15–25 9 basal) and breast-feeding (up to 9 30)
and circulate in pregnancy for many months and
in breast-feeding for up to 12 months or more,
without increasing the risk of breast cancer (105).
Moreover, it has been shown that pregnancy and
12
breast-feeding (and accompanying highly elevated
PRL) in patients after breast cancer therapy do not
increase the risk of recurrence or reduce survival
when compared with women who chose not to
become pregnant (105–110), even not in patients
with a BRCA1/2 mutation (111).
Lifestyle risk factors. Obesity. Epidemiological
studies in the general population have shown that
obesity is a contributing factor in both increased
incidence and mortality from breast cancer (112–
114). However, the relation between body weight
and breast cancer risk is critically dependent on
the tumor’s ER/PR and the woman’s menopausal
status. In a meta-analysis, Suzuki et al. (115) noted
a statistically significant 82% increased risk for
ER+/PR+ tumors among postmenopausal women,
when comparing the highest vs. the reference (or
lowest) body weight categories. Estrogen pathways
provide a biological explanation for the relation-
ship between body weight and breast cancer. As
adipose tissue contains high levels of aromatase
enzyme that converts androgens to estrogens,
obesity is linked to increased estrogen levels (116–
118). However, this increase is seen mostly in post-
menopausal, but not in premenopausal, women
(118).
Patients with schizophrenia have, compared to
their healthy counterparts, a 2.8- to 4.4-fold
increased risk of being obese (78), not only because
of a sedentary lifestyle (51, 78, 119, 120) and a high
caloric diet (51, 78), but also because of the intake
of antipsychotic medication as some of these
(clozapine and olanzapine) have a particular pro-
pensity to induce weight gain as well as metabolic
abnormalities (51, 78, 121).
Diabetes mellitus. The combined evidence overall
supports a modest association between type 2 DM
and the risk of breast cancer, which was found to
be more prevalent among postmenopausal women
(42, 122–124). However, metformin (generally the
first-line treatment for DM in obese patients) has
been shown to lower the incidence of breast cancer
(125). The prevalence of type 2 DM in schizophre-
nia is approximately 2–3 times higher than in the
general population and its impact on these patients
more profound (126). Therefore, DM, which is
associated with (particularly central) obesity, phys-
ical inactivity, and antipsychotic medications (with
olanzapine and clozapine having the strongest dia-
betogenic potential), is another potential indepen-
dent risk factor for breast cancer in women with
schizophrenia (42, 51, 78, 126, 127), although the
use of metformin can counteract this effect (127).

Alcohol. Adults with schizophrenia have high
rates of co-occurring substance use disorders
(SUDs) (128–130). Compared with the general
population, persons with schizophrenia are 3–5
times more likely to have a SUD (mainly alcohol)
(131, 132). Approximately every fifth patient with
schizophrenia meets lifetime criteria of alcohol
dependence (133). Alcohol consumption, even at
moderate levels, increases breast cancer risk (84,
134–137). If the observed relationship for alcohol
is causal (with ethanol probably as the main causal
factor) (138), results suggest that about 4–11% of
the breast cancers in developed countries are
attributable to alcohol (137, 139).
Smoking. The relationship between cigarette
smoking and breast cancer risk remains controver-
sial. Considering this potential association, the
hypothesis has been put forward that undeveloped
mammary epithelium before a first pregnancy is
more vulnerable to tobacco carcinogens than the
more differentiated epithelium present after a first
pregnancy. Although one meta-analysis (87) found
active smoking to be associated with increased
breast cancer risk for women who initiate smoking
before first birth (hazard ratio, HR = 1.21, 95%
CI: 1.14–1.28), two other meta-analyses (86, 140)
provided no evidence that breast tissue is more sus-
ceptible to malignant transformation from smok-
ing before the first pregnancy. Another meta-
analysis suggested that subgroups of women, char-
acterized by a genetic predisposition, may be at
higher risk of breast cancer if they are exposed to
tobacco smoke (141). If smoking elevates breast
cancer risk, this will be of particular importance in
people with schizophrenia given the extremely high
levels of smoking in these individuals (142, 143).
Oral contraceptives and HRT. One of the treatment
options for women with breast cancer includes
hormone therapy (also called antihormone ther-
apy), keeping the cancer cells from getting or using
the natural hormones (estrogen and progesterone)
they need to grow (84). This means that medica-
tion or treatment that contains estrogen [oral con-
traceptives (OCs) (before menopause) and HRT
(around menopause)] may elevate the risk of breast
cancer. Although the current consensus is that par-
ticularly combination HRT (estrogen combined
with progesterone) increases breast cancer risk
(118), there is much less agreement about the role
of OCs.
Several meta-analyses, systematic reviews, and
studies identified HRT as a factor increasing breast
cancer risk and mortality in the general population
(42, 144–150). One of these analyses (35 527 cases
Breast cancer, prolactin, and antipsychotics
and 180 318 controls) suggested that ever users of
HRT have a 23% (pooled OR, OR = 1.23; 95%
CI: 1.21–1.25) higher risk of breast cancer when
compared with non-users (42).
A number of studies suggest that current use of
OCs slightly increase the risk of breast cancer,
especially among younger women (42, 151–160).
Other studies show that OCs do not raise breast
cancer risk (161–166). A recent meta-analysis even
showed a statistically non-significant association
(OR = 1.21; 95% CI: 0.93–1.58) between OC use
and breast cancer among high-risk women (carri-
ers of a BRCA1/2 mutation) (167). Thus, although
the National Cancer Institute (84) mentions OCs
as a modest breast risk factor, studies remain
inconsistent. This inconsistency is likely due to dif-
ferent dosages of the individual estrogen and pro-
gestin components and formulation of used OCs
(118). For example, the first generations of birth
control pills contained approximately five times
more estrogen and four times more progestin than
the latest OCs (118, 168).
The effect of estrogen and progesterone hor-
mones on breast cancer risk/relapse is very com-
plex. As the conjugated equine estrogen/
medroxyprogesterone acetate (CEE/MPA) arm of
the Women’s Health Initiative trial showed (in
contrast to the CEE-alone arm) an increase in
breast cancer risk (144, 145), a number of investi-
gators suggested that continuous use of MPA
(related in chemical structure to progesterone) in
the CEE/MPA arm may have played a role in the
increased risk of breast cancer (169–173). Several
studies showed that recent use of depo-MPA
equally is associated with an increased risk of
breast cancer (174–177). Moreover, paradoxically,
several studies revealed that estrogens adminis-
tered in high doses may have antitumor effects in
(highly refractory metastatic) patients with breast
cancer (118, 178–181). Thus, it seems that mainly
the associated progesterone increases the risk.
Despite all this, contraceptive usage seems to be
low in women with severe mental illness (182): The
majority, for a variety of possible reasons, does
not use OCs (183). Two large-scale (n ≥ 1000)
studies (184, 185) found that, respectively, only
7.8% and 17% of women with schizophrenia use
OCs. This risk factor therefore may be less impor-
tant for these patients.
Relationship between PRL and breast cancer risk factors
A number of studies have evaluated the association
between PRL levels and several well-established
breast cancer risk factors. Only the associations
between nulliparity and hormone therapies (OCs
13
De Hert et al.
and HRT) have been firmly confirmed. Data have
demonstrated that women that have given birth
one or more times have 15–50% lower PRL levels
than nulliparous women, with the majority of this
decrease following the first full-term pregnancy
(18, 186, 187). Some reports have demonstrated a
positive association between PRL levels and OC
(4, 187) or HRT use (15). Overall, the associations
between higher circulating PRL levels and other
breast cancer risks than nulliparity and hormone
therapies have mostly been negative for both pre-
and postmenopausal women, even after adjusting
for parity (4, 15, 18, 186–188).
Discussion
Data interpretation concerning the risk of breast
cancer in women with schizophrenia, as well as the
association between breast cancer risk (factors)
and PRL, is complex. Results of studies examining
breast cancer risk in women with schizophrenia are
conflicting: Several studies have shown an
increased breast cancer risk and mortality rate
among women with schizophrenia (37, 52–61, 73),
while other studies have found a decreased (62, 63)
or a non-statistically, significantly increased risk
(29, 54, 64–72). Although people with schizophre-
nia are at elevated risk of experiencing several of
the established factors that increase the likelihood
of breast cancer in the general population (e.g.
obesity, DM, alcohol, inactivity), there is a paucity
of high-quality prospective research investigating
these links. Results of prospective studies consider-
ing the effect of pituitary PRL on breast cancer
risk are inconsistent and only partially agree. In
studies evaluating the relationship between pitui-
tary PRL levels and breast cancer risk factors, only
the associations between nulliparity and hormone
therapies (OCs and HRT) have been confirmed.
Moreover, as the available data are correlative, the
question of whether or not elevated PRL levels
actually cause breast cancer remains open to dis-
cussion.
Studies investigating the relationship between
PRL levels and breast cancer risk have predomi-
nantly focused on circulating PRL levels. How-
ever, PRL functions not only in an endocrine
manner, where it is secreted by the pituitary and
acts on distant tissues such as the mammary gland,
but also in an autocrine/paracrine [i.e. locally pro-
duced PRL from mammary (tumor) cells that acts
directly on the cell itself (autocrine) or neighboring
cells (paracrine)] fashion (2, 4, 9). There is increas-
ing evidence that autocrine/paracrine PRL may
play a role in human breast cancer as animal and
in vitro data show that PRL stimulates breast can-
14
cer cell proliferation, survival, and migration via
binding to the cell-surface PRL receptor (2, 4, 7,
10, 14, 167, 189). The exact mechanisms whereby
this occurs, however, remain poorly understood.
Therefore, a further understanding of the actions
of the autocrine/paracrine loop of PRL (which is
not dopamine sensitive), the interactions of endog-
enous PRL with its receptor, as well as the inter-
play of PRL with other factors (such as estrogen
and progesterone) implicated in mammary tumori-
genesis is necessary.
Several lines of evidence suggest that PRL can
have ‘protective’ attributes. It has been shown that
PRL can act as invasion/metastasis suppressor
hormone in breast cancer (190). The 16-kDA PRL
isoform, which is a PRL fragment of the full-
length 23-kDA PRL hormone, has been shown to
have anti-angiogenic effects in vivo (191). Angio-
genesis or blood vessel formation is indispensable
for breast cancer development and progression,
and PRL can act as a stimulatory (the unmodified,
full-length 23-kDA PRL hormone) or inhibitory
(the proteolytic PRL fragments ranging from 14 to
18 kDA, also known as vasoinhibins) factor on
growth, dilatation, and remodeling of blood ves-
sels. In its (anti-)angiogenic function, PRL can act
both as a circulating hormone and in an autocrine/
paracrine fashion (192, 193). In breast cancer, the
role of PRL could depend on the production of va-
soinhibins, which can be generated from systemic
PRL or from PRL produced and secreted by
human breast cancer cells. Reduced levels of vaso-
inhibins (due to low levels of protease activity) cre-
ate a more favorable angiogenic condition for
tumor progression (193). This supports the com-
plex role of PRL and puts forward the concept that
PRL may possess a dual role in breast carcinogen-
esis, acting as a growth and survival factor (pro-
oncogenic) as well as suppressor hormone.
Another way to address the question whether
circulating levels of PRL are important for the
development of mammary carcinogenesis is to
study patients with a tumor secreting PRL (prolac-
tinoma). Due to delays in diagnosis, these patients
often have been exposed to increased PRL levels
for months or even years and therefore are an
interesting population to investigate the associa-
tion between HPRL and breast cancer risk.
Although there is a paucity of such data, two large
cohort studies (11, 194) of patients treated for idio-
pathic HPRL or prolactinomas did not find any
increased risk of breast cancer. Another interesting
approach to explore the contentious issue of possi-
ble carcinogenic effects of PRL is to look at
patients with Parkinson’s disease (PD) who have
low dopamine levels (195, 196). On the basis of this

observation, one would expect to find high PRL
levels and a positive association between PD and
breast cancer. However, results are inconsistent
(195, 197, 198).
Considering the possible association between
antipsychotic medication, PRL, and breast cancer
risk, further well-conducted research is needed to
assess the extent, if any, to which antipsychotics
contribute to the increase of breast cancer risk in
women with schizophrenia or other people using
antipsychotics, over and above other breast cancer
risk factors, of which several (such as nulliparity
and obesity) are more prevalent in patients with
schizophrenia. The story about the possible rela-
tionship between antipsychotic-induced HPRL
and breast cancer risk can get even more complex
when considering the findings of several reports
suggesting that HPRL in schizophrenia is not nec-
essarily only caused by antipsychotic medication,
but might already be present in antipsychotic-na€ıve
first-episode patients and even in prodromal stages
(1, 199). One of these studies on PRL levels in anti-
psychotic-free patients with schizophrenia found
HPRL in 23.8% of antipsychotic-na€ıve patients
with an at-risk mental state for psychosis and in
33.3% of antipsychotic-na€ıve patients with first-
episode psychosis (200). This finding is in accor-
dance with the results of the European First Epi-
sode Schizophrenia Trial (EUFEST) study,
showing HPRL in 71% of first-episode patients of
whom approximately half had never been exposed
to antipsychotic treatment (201), as well as with
other studies of drug-na€ıve patients (202–204).
Nevertheless, on the basis of the available data, it
can be concluded that the evidence concerning the
assumed risk of breast cancer resulting from expo-
sure to PRL-elevating dopamine antagonists is too
limited and that no causal link between (chronic)
administration of antipsychotics and breast tumor-
igenesis in humans has been shown. Moreover,
several reports describe mechanisms of cancer pro-
tection with antipsychotic medication. Certain an-
tipsychotics, such as phenothiazines, pimozide, or
penfluridol, can inhibit the growth of human can-
cer cells (205–214). Considering breast cancer, it
has been shown in vitro that the (PRL-elevating)
phenothiazines (e.g. thioridazine and chlorproma-
zine) may be promising antihormone therapy sen-
sitizing compounds for enhancing the effect of
tamoxifen, a first-line adjuvant treatment for
breast cancer patients, in tamoxifen-resistant
human breast cancer cells (215, 216). A recently
conducted study demonstrated a conceivable reso-
lution of tamoxifen-induced side-effects when
using the PRL-elevating compound risperidone,
without interfering the efficacy of tamoxifen
Breast cancer, prolactin, and antipsychotics
against breast cancer in both in vitro and in vivo
models (217).
In 2008, a panel of, almost exclusively, UK
experts in psychiatry, medicine, toxicology, and
pharmacy, undertaking a critical examination of
the available clinical evidence, agreed that there is
insufficient evidence to warrant routinely advising
patients that the risk of breast cancer might be ele-
vated when using antipsychotic medication (218).
Whereas sexual dysfunctions and osteoporosis are
reported as important consequences of antipsy-
chotic-induced HPRL in the recently published
updates of the World Federation of Societies of
Biological Psychiatry guidelines, breast cancer is
not recognized as a potential adverse outcome
(219). These recommendations, together with
results of studies concerning antipsychotics and
breast cancer risk in women with schizophrenia,
should provide some reassurance to both psychia-
trists and their patients on the (long-term) safety of
these agents. If antipsychotic-induced HPRL
[which is not mentioned by the National Cancer
Institute (84) and currently not an established pre-
dictor in the management of breast cancer (220)] is
a risk factor for breast cancer in women with
schizophrenia, one has to consider that, compared
to the associations reported for other hormones
such as estrogen, it is probably a factor of (at
most) modest magnitude. Moreover, it is only one
factor beside many others of which several (partic-
ularly the ones associated with lifestyle and repro-
ductive status) are, compared with the general
population, of greater relevance in this vulnerable
population.
Despite this, several experts (218, 220), as well as
the product labeling of most (the exceptions being
aripiprazole and clozapine) antipsychotics advise,
one has to be careful to use PRL-elevating antipsy-
chotics in patients with breast cancer or patients
with a past history or family history of breast can-
cer. Therefore, clinicians must weigh, as with any
case, the potential benefits and risks. In fact, it
may be more reasonable to use these drugs in
patients with breast cancer when there are strong
clinical reasons to prescribe such medications; for
example, in patients where schizophrenia is life-
threatening and/or very debilitating or the risk of
seriously exacerbating the disease by avoiding anti-
psychotic treatment may outweigh the possible risk
of elevated PRL levels. Using or, if possible,
switching to another, PRL-sparing, antipsychotic
may be a valuable alternative. However, one may
not forget that metabolic side-effects (such as DM
and obesity) with particularly the PRL-sparing an-
tipsychotics clozapine and olanzapine, possibly
may be associated with a higher incidence of breast
15
De Hert et al.
cancer as these factors play a role in breast cancer
survival rates. Having little effect on weight and as
a partial D2R agonist, adjunctive aripiprazole
treatment may be a safer option for patients suffer-
ing from both psychosis and HPRL (1, 78, 221). A
recent meta-analysis of five randomized controlled
trials (n = 639) comparing the safety and efficacy
of adjunctive aripiprazole vs. placebo for antipsy-
chotic-induced HPRL found adjunctive aripipraz-
ole to be both safe and effective as a reasonable
choice treatment for patients with antipsychotic-
induced HPRL. Adjunctive aripiprazole was asso-
ciated with a 79.11% PRL level normalization
rate. The appropriate dose of adjunctive aripipraz-
ole may be 5 mg/day (222). However, the add-on
effects of aripiprazole in reversing antipsychotic-
induced HPRL depend on the pharmacological
properties of the preexisting antipsychotic; adjunc-
tive aripiprazole treatment reverses effectively
HPRL induced by risperidone and olanzapine, but
seems to be less effective for that induced by benza-
mide antipsychotics (amisulpride and sulpiride)
(223, 224). Adding a dopamine agonist may be
another option, although this will not lower the
dopamine-insensitive breast PRL. Further research
is needed before solid conclusions and recommen-
dations can be made. Last but not least, it is advis-
able that the oncologist and clinician be involved
together with the patient to arrive at an informed
decision.
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