PSYC 8741 Yale University Basics of The Nervous System Psychopharmacology Study Guide

  

Description

Please complete the attached study guide using the attached resources of book chapters and articles. I will also be sending lecture powerpoints.

Answers should be clear and well explained.

Psychopharmacology
Exam 1 Study Guide
Exam 1 will cover chapters 1, 2, 3, and 13 in Sinacola as well as articles assigned to date and lecture handouts.
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basics of the nervous system, including associated functions (i.e., the PNS and CNS and associated systems and their general
functions)
lobes of the brain and associated functions (broadly)
what a neuron is
the basic structure of a neuron
what dopamine pathways are associated with (in a general sense)
what serotonin pathways are associated with (in a general sense)
how neural communication occurs within and between neurons
what is meant by depolarization and hyperpolarization
what ions are and the most common ones (NA+, K+, Cl-, Ca++)
excitatory versus inhibitory messages
what an action potential is
what long-term potentiation refers to
the process of reuptake
common neurotransmitters including dopamine, norepinephrine, serotonin, GABA, glutamate, acetylcholine, epinephrine,
glycine
what neurotrophins are
the routes of drug administration and related rates of absorption
how drugs are commonly distributed and metabolized
drug half-life
what lipid solubility refers to
therapeutic dose, toxic dose, therapeutic index
what tolerance refers to
what withdrawal refers to
what discontinuation syndrome is
what potentiation refers to
what synergism refers to
what placebo refers to
what “prn” means
chemical dependency and common co-morbid disorders
the dopamine hypothesis
common types of treatment for chemical dependency
the CAGE questionnaire
which medications are commonly prescribed for patients with a dual diagnosis and which are usually avoided
drugs commonly used in treatment of alcohol dependence
drugs commonly used in treatment of opioid dependence
drugs commonly used in treatment of cocaine dependence
drugs commonly used in treatment of nicotine dependence
issues with AA and NA as treatment for substance use
long-term effects of drug use
the effects of different drugs (e.g., alcohol, nicotine, amphetamine, cocaine) on neurons/neurotransmission
Page 1 of 1
Hanley and Mintzes BMC Pregnancy and Childbirth 2014, 14:242
http://www.biomedcentral.com/1471-2393/14/242
RESEARCH ARTICLE
Open Access
Patterns of psychotropic medicine use in
pregnancy in the United States from 2006 to
2011 among women with private insurance
Gillian E Hanley1,2 and Barbara Mintzes1,3*
Abstract
Background: Psychiatric disorders are equally common during pregnancy as among non-pregnant women, and
many of these conditions are treated with psychotropic medicines. Relatively little is known about patterns of use
of many these agents during pregnancy, and specifically of how rates may have shifted during the last decade. We
aimed to quantify the rate of pregnancy related exposures to categories of psychotropic medicines stratified according
to the primary indication for use (antidepressants, antipsychotics, anxiolytics, and psychostimulants), trimester of
pregnancy, trends over time and region, and indication for use.
Methods: We conducted a retrospective cohort study of pregnancies among women in the Truven Health MarketScan
database (source population 70 million Americans), which captures person-specific clinical use and includes detailed
information on filled prescriptions, hospitalizations and outpatient visits for all privately insured employees and their
dependents. We classified psychotropic medicines of interest using ATC level 3 accordingly: antipsychotics (N05A);
anxiolytics (N05B); antidepressants (N06A); psychostimulants, agents used for ADHD and cognitive enhancement
(N06B). We also examined temporal and regional trends in use.
Results: We included 343,299 women who had a live birth between Jan 1, 2006 and Dec 31, 2011, of whom 10.3%
were dispensed one or more psychotropic medicines during pregnancy. This rate varied from 6% to 15% between
states. The rate of use of psychotropic medicines was relatively stable between 2006 and 2011. The most
commonly used psychotropic medicines were selective serotonin reuptake inhibitors (5.1%) and benzodiazepine
or benzodiazepine-like medicines (3.9%). Among psychotropic users, the most commonly associated psychiatric
diagnosis was depression (25.0%), followed by anxiety disorders (24.4%). Approximately 1.6% of women used
more than one category of psychotropic medicine in pregnancy, most commonly an antidepressant and an
anxiolytic medicine (1.2%).
Conclusions: Given this relatively high rate of use, the lack of evidence that the most frequently used medications
improve birth outcomes and the safety concerns associated with both early and late pregnancy use for many
frequently-used medications, there is a need for further study of factors driving psychotropic medication use during
pregnancy.
Keywords: Pregnancy, Prescription drugs, Psychiatric conditions in pregnancy, Psychotropic medicines,
Administrative data, Depression, Anxiety
* Correspondence: Barbara.mintzes@ti.ubc.ca
1
School of Population and Public Health, University of British Columbia,
Vancouver, BC, Canada
3
Therapeutics Initiative, University of British Columbia, #307, 2176 Health
Sciences Mall, Vancouver, BC V6T 1Z3, Canada
Full list of author information is available at the end of the article
© 2014 Hanley and Mintzes; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public
Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this
article, unless otherwise stated.
Hanley and Mintzes BMC Pregnancy and Childbirth 2014, 14:242
http://www.biomedcentral.com/1471-2393/14/242
Background
In North America, there is evidence that use of psychotropic medicines during pregnancy, especially antidepressants, became increasingly prevalent in the early
2000’s [1]. Pregnancy was historically considered protective
against mental health disturbances. More recent commentaries highlight pregnancy as a high-risk period [2]. Neither
appears to be the case, with the most reliable estimates
suggesting no significant difference in the rates of the
most commonly diagnosed psychiatric disorders between
pregnant and non-pregnant women of childbearing age,
after adjustment for ethnicity, social class, age, health status and stressful life events [3-5]. The principal psychiatric
disorders encountered during pregnancy include major
depressive disorder, anxiety disorders, bipolar affective
disorder, and schizophrenia [6]. These conditions are
often treated with psychotropic medicines, and little is
known about patterns of use of many these agents during
pregnancy, and specifically of how rates may have shifted
during the last decade.
While patterns of use during pregnancy of some categories of psychotropic medicines, most notably selective
serotonin reuptake inhibitor (SSRI) antidepressants, have
been well studied, estimates of the rate of use vary widely.
For example, studies from the Nordic countries have reported that fewer than 2% of women use antidepressants
during pregnancy [7], whereas one study in a Medicaid
population in Tennessee reported use in 13.4% of all pregnancies [1]. Rates of use have also changed considerably
over time [8-10]. This suggests that both temporal and
geographic factors are important in understanding use
of psychotropic medicines during pregnancy. These
differences may reflect a range of factors, including
underlying prevalence, rates of diagnosis and care seeking,
and proportions with drug versus non-drug treatment.
The way that psychotropic medicines are prescribed has
also shifted over time. For example, use of antipsychotics
has increased, and the approved indications for antipsychotic drugs have expanded beyond psychotic disorders to include bipolar, major depressive, and anxiety
disorders [11]. Previous research also suggests that the
rate of antipsychotic use during pregnancy has been
increasing [12]. ADHD is increasingly being diagnosed
among adults as well as children [13]. Diagnosis and
treatment of more than one mental health disorder at a
time is not uncommon, and depression and anxiety disorders are often diagnosed as comorbid conditions [14-16].
A common methodological limitation to all studies
examining outcomes of prescription drug use during pregnancy is confounding by the underlying indication for the
medicine use and other systematic differences at baseline
affecting both treatment decisions and outcomes. This is
likely to be especially important for women who have
multiple mental health disorders, as their outcomes may
Page 2 of 12
be confounded by their comorbid condition, and they may
be exposed to more than one psychotropic medication.
Thus, examining the use of one category of psychotropic
medicine during pregnancy is unlikely to present a
complete picture of the pharmacologic exposure of the
infant or the mental health of the pregnant woman.
Risks to the infant may also be higher with exposure to
more than one class of psychotropic medicine. Oberlander
et al. found higher risks of congenital heart defects among
infants whose mothers were using both SSRI antidepressants and benzodiazepines during pregnancy [9]. Thus,
understanding the complete picture of exposures to psychotropic medicines during pregnancy is important.
In this study we aim to quantify the rate of pregnancy
related exposures to categories of psychotropic medicines
stratified according to the primary indication for use
(antidepressants, antipsychotics, anxiolytics, and psychostimulants), trimester of pregnancy, trends over time and
region, and indication for use. We are especially interested
in the proportion of women using different classes of
drugs who initiate use during pregnancy, versus ongoing
exposures among established users. We also examined the
use of medicines from more than one category during
pregnancy (e.g. an antidepressant and an anxiolytic). Defining how commonly psychotropic medicines are used
during pregnancy, which psychotropic medicines are most
often prescribed, what conditions are most commonly
treated with psychotropic medicines, and how psychotropic
conditions are managed during pregnancy will help define
new research priorities in this field.
Methods
We conducted a retrospective cohort study of pregnancies
among women in the Truven Health MarketScan database
(source population 70 million), which captures personspecific clinical use and includes detailed information on
filled prescriptions, hospitalizations and outpatient visits
for all insured employees and their dependents. These
data come from a selection of large employers, health
plans and government and public organizations (approximately 100 payers) across multiple states in the
United States. Ethics approval was obtained from the
Behavioral Research Ethics Board at the University of
British Columbia.
Study cohort
We included data from the first pregnancy for each
mother that ended in a live birth in hospital between Jan
1, 2006 and Dec 31, 2011. Our data set includes primiparous and multiparous women, the latter with live births
prior to 2006. Pregnancies were captured in the inpatient
and outpatient data using ICD-9 diagnostic codes indicating delivery in the maternal hospital record and outpatient
record. To ensure complete capture of prescription drugs
Hanley and Mintzes BMC Pregnancy and Childbirth 2014, 14:242
http://www.biomedcentral.com/1471-2393/14/242
used before and during pregnancy, we only included
women who were enrolled continually during pregnancy and the three months pre-conception with no
more than a one-month gap in their health insurance
enrollment. As gestational age varied, the total number
of months in which the women needed to be enrolled
in the health insurance plan varied with it.
Page 3 of 12
account for the possible overestimation that might result
from including psychotropic medicines filled only once in
the first trimester, we also present conservative numbers
of exposures during pregnancy where we have removed
women who filled only 1 prescription during the first trimester of pregnancy, as these might represent prescriptions filled prior to knowledge of the pregnancy and not
used once the woman became aware she was pregnant.
Definitions of pregnancy periods
Maternal hospital records provided the date of admission
for each in-hospital birth, but not the date of birth. We assumed that the date of admission was equal to the delivery
date. The pregnancy period was built using the algorithm
developed by Li et al., which was shown to correctly
classify medication exposure status in most live born
deliveries with a sensitivity and positive predictive value
of ≥95% and a specificity and negative predictive value
of almost 100% [17]. Using the gestational age (in days)
calculated from the algorithm we estimated a date of
conception by subtracting gestational days from the admission date. From this estimated conception date, we
built several time periods for analysis of psychotropic drug
exposures: 1) weeks 1 to 13 of gestation (first trimester);
2) Weeks 14 to 26 of gestation (second trimester), 3) week
27 of gestation to delivery (third trimester), 4) 6 months
prior to conception (preconception) and, 5) six months
postpartum (postpartum).
Psychotropic drug use in pregnancy
Outpatient prescription drug claims include prescriptions
dispensed to women at eligible pharmacies either through
a mail-order or card program prescription drug claim,
capturing all prescriptions dispensed that are covered by
her insurance plan. We classified psychotropic medicines
of interest using ATC level 3 accordingly: antipsychotics
(N05A); anxiolytics (N05B); antidepressants (N06A);
psychostimulants, agents used for ADHD and cognitive
enhancement (N06B). Additional file 1 outlines all medicines in each category that were dispensed to a woman
in our cohort during pregnancy. We excluded the caffeine and caffeine combinations that were included in
N06B. We did not remove medicines that we suspected
were being prescribed for non-psychological indications,
such as the typical antipsychotics that appear to be used
primarily as antiemetics, as these prescriptions still represent exposures to a psychotropic medicine from one of
the relevant drug classes. We also present frequencies of
women who filled prescriptions from more than 2 categories of psychotropic medicines during the perinatal
period, and the use of 2 or more different antidepressant
medicines during the perinatal period.
We defined exposure to a psychotropic medicine during
pregnancy and according to trimester if a prescription was
filled on a date within the relevant pregnancy period. To
Patterns of prescription drug exposure
We defined prevalent users of psychotropics during
pregnancy as women for whom the psychotropic was
dispensed in the 6 months prior to pregnancy and then
again in pregnancy. In contrast, incident users were
those with no prescription for the psychotropic in the
6-months before pregnancy. Again we also present
conservative estimates by removing the women who
only filled one prescription for the psychotropic of interest
in the first trimester from both groups. Finally we present
incident use of psychotropic medicines in the postpartum
period, defined as initiation of use during the 180 days
following delivery. These women had no prescription for
the psychotropic agent before or during pregnancy.
Description of associated conditions
Medical conditions associated with use of psychotropics
were identified using the International Classification of
Diseases, Ninth Revision diagnosis codes in the patient’s
hospital and outpatient records between 180 days before
our estimated conception date and delivery. Additional
file 2: Table S1 outlines the diagnostic codes used. The
frequency of these conditions was determined in (1) all
patients exposed to psychotropics agents during pregnancy
(2) patients exposed to each category of psychotropic
medicine (3) according to incident or prevalent use of psychotropic medicines and for the two most commonly used
categories of psychotropic medicines, antidepressants and
anxiolytics and (4) among women who did not fill prescriptions for psychotropic medicines in pregnancy.
Temporal and regional trends in psychotropic medicine
use during pregnancy
We examined the trends in exposure to any psychotropic
medicine during pregnancy and to each category of psychotropic medicines annually from 2007 to 2011 according to
the year of delivery. We examined regional variations
in psychotropic prescribing by examining frequency of
exposure to psychotropic medicines, antidepressants
and anxiolytics by state.
Statistical analyses
All analyses were descriptive of this commercially insured
population. The results are parameters for this particular
population rather than estimates based on a sample and
Hanley and Mintzes BMC Pregnancy and Childbirth 2014, 14:242
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Page 4 of 12
thus we present the results without confidence intervals. All
analyses were performed using either Stata version 13.0 (College Station, TX) or SAS version 9.3 (SAS Institute, Cary, NC).
than one category of psychotropic medicine during pregnancy, and most of these women were using a combination of antidepressants and anxiolytics (4,068, 1.2%).
Results
There were 343,299 live births between Jan 1, 2006 and
Dec 31, 2011 that met our enrollment criteria (not missing
more than one month of enrollment for the 3 months
prior to conception and during the pregnancy). The mean
age of the women at the time of delivery was 30.3 years
with a standard deviation of 5.6 years (median 30 and
interquartile range 27 to 34); 4,895 (1.4%) pregnancies
were multiple gestations, 29,733 (8.7%) were preterm
deliveries. Overall 35,303 women (10.3%) were prescribed
a psychotropic medicine during pregnancy (this number
drops to 6.8% when we remove women who only filled
one prescription during the first trimester of pregnancy).
24,776 (7.2%) women filled a prescription for a psychotropic medicine during the first trimester, 15,883 (4.6%)
during the second trimester and 18,161 (5.3%) during the
third trimester. The most common category of psychotropic
medicine use during pregnancy was antidepressants, with
22,275 (6.5%) women filling an antidepressant during pregnancy (conservative estimates are 15,097 (4.4%)), followed
by anxiolytics which were filled by 14,535 (4.2%) of pregnant
women in our cohort (conservatives estimates are 9,235
(2.7%)). Antipsychotics and stimulants were used during
pregnancy by 2,373 (1.1%) and 2,062 (0.6%) respectively
(Table 1). There were 5,423 (1.6%) women using more
Patterns of prescription drug exposure
Rates of use of all psychotropic medicines were higher in
the 6 months preconception than in the first trimester
and decreased further in the second trimester, likely
reflecting women who stopped medicines after becoming
aware of their pregnancy. This pattern was consistent
across all categories of psychotropic medicine except for
typical antipsychotics, which were used considerably more
in the first trimester of pregnancy, likely as an antiemetic.
The most common class of antidepressants dispensed
during pregnancy were SSRIs which were dispensed to
17,410 (5.1%) of women followed by selective norepinephrine reuptake inhibitors (dispensed to 2,382 or 0.8%
of women). Table 2 lists the most common psychotropic
medicines among each category and includes all medicines
that were used by at least 0.1% of the study population.
Among SSRIs the most commonly dispensed medicines
were sertraline, fluoxetine, and escitalopram with 8,432
(2.5%), 3,605 (1.1%), and 3,481 (1.0%) of women filling
a prescription for these medicines during pregnancy
respectively. Nearly all of the anxiolytics prescribed
were benzodiazepines or benzodiazepine-like medicines
(n = 13,486, 3.9%), the latter including zaleplon, zolpidem,
and eszopiclone. The most common benzodiazepine or
benzodiazepine-like medicines prescribed were zolpidem
Table 1 Summary measures of psychotropic prescription drug use before, during and after pregnancy
N = 343299
6 months preconcept
n (%)
1st trimester
n (%)
2nd trimester
n (%)
3rd trimester
n (%)
Pregnancy
total n (%)
Pregnancy total
with >1 Rx n (%)
Any psychotropic
33,995 (9.9)
24776 (7.2)
15883 (4.6)
18161 (5.3)
35303 (10.3)
23261 (6.8)
Antidepressant
23,083 (6.7)
17214 (5.0)
12235 (3.6)
11937 (3.5)
22275 (6.5)
15097 (4.4)
SSRI
16524 (4.8)
12881 (3.8)
9773 (2.9)
9751 (2.8)
17410 (5.1)
12278 (3.6)
SNRI
3170 (0.9)
2175 (0.6)
973 (0.3)
805 (0.2)
2382 (0.8)
1075 (0.3)
Tricyclic
1222 (0.4)
611 (0.2)
236 (0.07)
209 (0.06)
784 (0.2)
308 (0.1)
Other
4390 (1.3)
3085 (0.9)
1875 (0.6)
1634 (0.5)
4019 (1.2)
1026 (0.3)
≥ 2 antidepressants
2776 (0.8)
2132 (0.6)
889 (0.3)
676 (0.2)
3521 (1.0)
1613 (0.5)
12969 (3.8)
7503 (2.2)
3881 (1.1)
7002 (2.0)
14535 (4.2)
9235 (2.7)
Anxiolytic
Benzo or benzo-like*
12231 (3.5)
6840 (2.0)
3391 (1.0)
6686 (2.0)
13486 (3.9)
8613 (2.5)
Other
950 (0.3)
809 (0.2)
549 (0.2)
377 (0.1)
1375 (0.4)
757 (0.2)
Antipsychotic
1344 (0.4)
1728 (0.5)
808 (0.2)
503 (0.1)
2373 (1.1)
1015 (0.3)
Atypical
899 (0.3)
604 (0.2)
315 (0.1)
301 (0.1)
742 (0.2)
388 (0.1)
Typical
357 (0.1)
1072 (0.3)
464 (0.1)
160 (0.05)
1573 (0.5)
995 (0.3)
2798 (0.8)
1982 (0.6)
498 (0.1)
325 (0.1)
2062 (0.6)
545 (0.2)
Stimulant/ADHD
≥ 2 categories of psychotropic**
5423 (1.6)
3339 (1.0)
1431 (0.4)
1519 (0.5)
5423 (1.6)
2390 (0.7)
Antidepressant + anxiolytic
4195 (1.2)
2293 (0.7)
1064 (0.3)
1247 (0.36)
4068 (1.2)
1630 (0.5)
*Includes benzodiazepines as well as eszopliclone, zolpiedem, and zaleplon.
**defined as prescriptions for ≥ 1 class of psychotropic medicine during pregnancy e.g. a benzodiazepine and an antidepressant; does not include women who
used ≥ 1 medicine within the same class (e.g. two antidepressants).
Hanley and Mintzes BMC Pregnancy and Childbirth 2014, 14:242
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Table 2 Most common psychotropic exposures (not exhaustive of all drug exposures—only medicines that were used
by ≥ 0.1% of the study population)
Drug class
Number exposed
during pregnancy
Conservative number exposed
during pregnancy*
Number who filled more
than 1 Rx during pregnancy
SSRI
17414 (5.1)
13379 (3.9)
11142 (3.3)
Sertraline
8432 (2.5)
6936 (2.0)
5360 (1.6)
Fluoxetine
3605 (1.1)
2694 (0.8)
2300 (0.7)
Escitalopram
3481 (1.0)
2310 (0.7)
1951 (0.6)
Citalopram
2295 (0.7)
2310 (0.7)
1246 (0.4)
13486 (3.9)
9399 (2.7)
4304 (1.3)
Zolpidem
8239 (2.4)
7238 (2.1)
2676 (0.8)
Alprazolam
2654 (0.8)
1288 (0.4)
893 (0.3)
Diazepam
1884 (0.6)
384 (0.1)
178 (0.05)
1233 (0.4)
634 (0.2)
302 (0.1)
4019 (1.2)
2658 (0.8)
2164 (0.6)
Benzodiazepines (and benzo like)
Lorazepam
Other antidepressants
Bupropion
3399 (1.0)
2351 (0.7)
1925 (0.6)
Trazodone
602 (0.2)
270 (0.1)
189 (0.1)
2382 (0.7)
1474 (0.4)
1377 (0.4)
Venlafaxine
1398 (0.4)
936 (0.3)
875 (0.3)
Duloxetine
795 (0.2)
449 (0.1)
416 (0.1)
Desvenlafaxine
210 (0.1)
100 (0.03)
96 (0.03)
Typical antipsychotics
1573 (0.5)
712 (0.2)
274 (0.1)
Prochlorperazine
1527 (0.4)
682 (0.2)
250 (0.1)
SNRIs
Other anxiolytics
Buspirone
Scopolamine
1375 (0.4)
820 (0.2)
375 (0.1)
745 (0.2)
520 (0.2)
288 (0.1)
535 (0.2)
248 (0.1)
56 (0.02)
Amphetamine
1291 (0.4)
657 (0.2)
633 (0.2)
Cyclic antidepressants
784 (0.2)
385 (0.1)
272 (0.1)
490 (0.1)
239 (0.1)
162 (0.05)
Amitriptyline
Nortriptyline
Atypical antipsychotics
Quetiapine
173 (0.1)
75 (0.02)
56 (0.02)
742 (0.2)
465 (0.1)
397 (0.1)
363 (0.1)
228 (0.1)
191 (0.06)
*Removes women who only filled one prescription in the first trimester.
(n = 8,239, 2.4%), alprazolam (n = 2,654, 0.8%), diazepam
(n = 1,884, 0.6%) and lorazepam (n = 1,233, 0.4%).
The majority of typical antipsychotic prescriptions
during pregnancy were for prochloperazine (n = 1527,
0.4%), and nearly half of these prescriptions occurred
only during the first trimester. The conservative number
of women exposed, excluding women with a single prescription in the first trimester, drops to 682 (0.2%). If
prochloperazine was primarily being used as an antiemetic, women may have filled a single prescription for
short-term relief of first trimester nausea. As we could
not distinguish between this situation and women who
discontinued drug use when they knew they were pregnant,
we retained the same definition of conservative use as with
other medications. Only 17% of women with prescriptions
for typical antipsychotics during pregnancy refilled their
prescription (n = 274, 0.1%). The most commonly used
atypical antipsychotic was quetiapine, which has been approved to treat major depressive disorder. However, use of
quetiapine in pregnancy was uncommon (n = 363, 0.1%).
Table 3 shows the mean, median and interquartile
range for the cumulative numbers of days supply during
the pregnancy among the patients dispensed each category
of psychotropic medicine. The median duration of antidepressant use during pregnancy was 90 days with a mean
duration of 125.3 days, reflecting exposure for nearly half
the pregnancy. This duration of exposure was similar
among women using SSRIs and slightly shorter among
women using SNRIs (median 60 days, mean 111.1) and
other antidepressants (median 60 days, mean 100.0 days).
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Table 3 For psychotropic medicines dispensed during pregnancy, number of days exposure during pregnancy by type
Any psychotropic
Antidepressant
Median
25th percentile
75th percentile
Mean ± SD
60
30
160
104 ± 118.2
90
30
210
125.3 ± 103.2
SSRI
90
30
180
118.9 ± 91.4
SNRI
60
30
180
111.1 ± 98.6
Cyclic
30
30
80
69.1 ± 72.5
Other
60
30
150
100.0 ± 90.3
Anxiolytic
30
10
40
43.2 ± 65.6
Benzo or benzo-like
29
10
40
41.8 ± 64.0
Other
30
12
40
46.7 ± 59.7
Antipsychotic
14
7
30
46.4 ± 81.7
Atypical
60
30
150
103.8 ± 102.5
Typical
8
5
15
14.7 ± 24.4
49
30
90
79.8 ± 89.9
Stimulant/ADHD
Anxiolytic exposure was much shorter with a median exposure of 30 days and a mean of 43.2 days. The shortest
duration of exposure was among the typical antipsychotics,
including prochlorperazine (97% of use in this class),
amitriptyline, chlorpromazine, fluphenazine, haloperidol,
loxapine, perphenazine, thioridazine, and trifluoperazine.
Typical antipsychotics were used for a median of 8 days
and a mean of 14.7 days. Stimulants had median exposure
duration of 49 days (mean 79.8).
Table 4 outlines psychotropic medicine use during
pregnancy according to whether the use represents prevalent or incident use in pregnancy. Most use of antidepressants during pregnancy represents prevalent use
(n = 15,253, 4.4%; Table 4). In contrast, anxiolytics (primarily benzodiazepines and benzodiazepine-like medicines)
were most often initiated during pregnancy (n = 9,215, 2.7%
incident users versus n = 4271, 1.2% prevalent users). Typical antipsychotics were also used primarily by incident
users in pregnancy (Table 4).
Description of associated conditions
Table 5 shows the relevant mental health conditions in
patients with and without psychotropic medicine use
during pregnancy. Of the 35,303 psychotropic medicine
users during pregnancy, just under half had a relevant
diagnosis (49.7%) at any time during pregnancy or in the
six months pre-conception. Of these, the most common
diagnoses were depressive disorders (25.0%) and anxiety
disorders (24.4%); 31.5% of antidepressant users had been
diagnosed with anxiety compared to 35.3% diagnosed with
a depressive disorder. Just under half of all users of stimulants had a diagnosis of ADHD (49.6%) and 72.3% of all
stimulant users had a diagnosis of at least one mental
health disorder. Women who were using more than one
psychotropic during pregnancy were most likely to have at
least one relevant psychiatric diagnosis (73.9%). There
were 11,181 women with a diagnosis of depression and
14,102 women with a diagnosis of an anxiety disorder
who did not use psychotropic medicines during pregnancy
Table 4 Prevalent and incident use of psychotropic medicines during the perinatal period
N = 343,299
Antidepressants
SSRI
Prevalent use
in pregnancy
Prevalent use in
pregnancy; > 1 Rx*
Incident use in
pregnancy
Incident use in
pregnancy > 1 Rx*
Incident use
postpartum
15253 (4.4)
11588 (3.4)
7,022 (2.1)
5353 (1.6)
15652 (4.6)
10998 (3.2)
8300 (2.4)
6,416 (1.9)
5079 (1.5)
14625 (4.3)
Anxiolytics
4574 (1.3)
2992 (0.9)
9961 (2.9)
7100 (2.1)
7583 (2.2)
Benzo**
4271 (1.2)
2742 (0.8)
9,215 (2.7)
6657 (1.9)
7319 (2.1)
Antipsychotic
559 (0.2)
365 (0.1)
1814 (0.5)
854 (0.3)
773 (0.2)
Typical antipsychotic
27 (0.01)
14 (0.00)
1546 (0.5)
698 (0.2)
326 (0.1)
Atypical antipsychotic
480 (0.1)
307 (0.09)
262 (0.1)
158 (0.05)
447 (0.1)
1741 (0.5)
886 (0.3)
321 (0.1)
135 (0.04)
604 (0.2)
ADHD
*Removes women who only filled one prescription in the first trimester.
**benzodiazepine or benzodiazepine like product.
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Table 5 Diagnosed maternal conditions in the year prior to or during pregnancy, stratified by exposure to
psychotropic medicines
Diagnoses, n (%)
Any psychotropic Antidepressant Anxiolytic Stimulants for Antipsychotic No psycho-tropic More than
N = 35303
N = 22275
N = 14535 ADHD N = 2062 N = 2373
use N = 307996
one N = 5423
Bipolar disorder
1637 (4.6)
1225 (5.5)
581 (4.0)
499 (24.2)
98 (4.1)
1747 (0.6)
634 (11.7)
Major depressive disorder
8814 (25.0)
7874 (35.3)
2414 (16.6) 488 (23.7)
218 (9.2)
11861 (3.9)
2036 (37.5)
Anxiety
8611 (24.4)
7006 (31.5)
3188 (21.9) 487 (23.6)
213 (9.0)
14102 (4.6)
2127 (39.2)
Adj/Acute stress‡
3176 (9.0)
2335 (10.5)
1261 (8.7)
179 (8.7)
211 (8.9)
8041 (2.6)
725 (13.4)
Schizophrenia
48 (0.1)
28 (0.1)
11 (0.1)
35 (1.7)
1 (0.04)
34 (0.01)
22 (0.4)
Personality disorder
143 (0.4)
116 (0.5)
40 (0.3)
27 (1.3)
3 (0.1)
141 (0.05)
38 (0.7)
Sleep disorder
1799 (5.1)
1130 (5.1)
1033 (7.1)
75 (3.6)
34 (1.4)
3255 (1.1)
472 (8.7)
ADHD
1347 (3.8)
546 (2.5)
292 (2.0)
1023 (49.6)
73 (3.1)
1119 (0.4)
469 (8.6)
13655 (61.3)
5786 (39.8) 1490 (72.3)
1086 (45.8)
25707 (8.3)
4007 (73.9)
At least one relevant diagnosis 17561 (49.7)
‡
A diagnosis of adjustment reaction and/or acute stress.
representing 57% and 62% of women in our data set with
these diagnoses, respectively. Of the 11,217 women diagnosed with acute stress or adjustment disorder, 3176
(28%) were prescribed a psychotropic drug, most often an
antidepressant.
Table 6 shows diagnoses for mental health disorders
according to prevalent and incident use of psychotropic
medicines, antidepressants and anxiolytics (as well as
conservative prevalent and incident use). The rate of users
with a relevant diagnosis is nearly double for prevalent
users of psychotropic medicines compared with incident
users (63.1% versus 31.1% respectively).
Temporal and regional trends
Figure 1 shows psychotropic medicine use during pregnancy across each year of study. The figure indicates
remarkable consistency in exposure to psychotropic
medicines during the study period. There was a slight
decrease in antidepressant use between 2010 and 2011
from 6.7% to 6.4%, and the use of stimulants increased
from 0.4% in 2007 to 0.9% in 2011. Figure 2 shows the
rate of psychotropic exposure during pregnancy by
state. Significant regional differences are observed with
the lowest rates of psychotropic use being observed in
New York (6.44%) and California (6.99%) and the highest
rates of use in Idaho (15.41%), Louisiana (14.94%), Utah
(14.80%), West Virginia (14.44%), and South Carolina
(14.17%). A number of the Southern states had higher
than average rates, with Alabama, Arkansas, Kentucky,
Louisiana, North and South Carolina, Indiana, Tennessee
and West Virginia all having rates above 12%.
Discussion
In this analysis of nearly 350,000 pregnancies among
women with private health insurance from across the
United States, we found that at least one psychotropic
medicine was dispensed to 1 in 10 pregnant women
during pregnancy. The most commonly used medicines
during pregnancy were antidepressants (selective serotonin
reuptake inhibitors specifically) and anxiolytics (benzodiazepine and benzodiazepine-like medicines). We also report
that 1.6% of women were using two or more different categories of psychotropic medicines during pregnancy, most
often an antidepressant and an anxiolytic. The median
duration of exposure was 60 days, ranging from 29 to
90 days for all categories of medications except for typical
antipsychotics, which are often used as antiemetics. Relatively few women received atypical antipsychotics (1.1%)
or stimulants or other drugs for ADHD (0.6%). We found
very little variation in the rate of exposure over the study
period, with approximately 10% of pregnant women using
a psychotropic medicine during pregnancy in each year
between 2007 and 2011.
The most common psychiatric diagnoses in this cohort
in the period from six months pre-pregnancy to the end
of pregnancy was anxiety (n = 22,713) followed by depression (n = 20,675), with 37.9% and 42.6% of those with each
diagnosis, respectively, receiving psychotropic medications
in pregnancy. The latter is similar to the 40.3% rate of
antidepressant use among women with a relevant diagnosis in a national US study of over one million pregnant
low-income women covered by Medicaid from 2000 to
2007 [18]. Among women taking antidepressants, anxiety
diagnoses (31.5%) were nearly as prevalent as depression
diagnoses (35.3%), and there were twice as many antidepressants users with an anxiety diagnosis than anxiolytic
users with an anxiety diagnosis (7,006 compared with
3,176).
What do these findings mean for maternal and infant
health and well-being? While the evidence in this area is
complex and often contradictory, and a full evidence
review is beyond the scope of this article, a few areas of
concern merit discussion in order to provide necessary
context for our results. Pregnant women with depression
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Table 6 Diagnoses by prevalent and incident use of psychotropics, antidepressants and anxiolytics
Prevalent use
during pregnancy
Conservative
prevalent use*
Incident use
in pregnancy
Conservative
Incident use*
Psychotropic users
N = 20481
N = 15689
N = 14822
N = 10798
Bipolar disorder
1294 (6.3)
1105 (7.0)
342 (2.3)
278 (2.6)
MDD
6724 (32.8)
5680 (36.2)
2084 (14.1)
1730 (16.0)
Anxiety
6450 (31.5)
5266 (33.6)
2153 (14.5)
1651 (15.3)
Sleep disorder
1360 (6.6)
1076 (6.9)
439 (3.0)
319 (3.0)
ADHD
1208 (5.9)
877 (5.6)
139 (1.0)
86 (0.8)
Adj/acute‡
2098 (10.2)
1652 (10.5)
1078 (7.3)
800 (7.4)
Any relevant diagnosis
12921 (63.1)
10400 (66.3)
4640 (31.3)
3567 (33.0)
Antidepressant users
N = 15253
N = 11588
N = 7022
N = 5353
Bipolar disorder
895 (5.9)
721 (6.2)
329 (4.7)
250 (4.7)
MDD
5858 (38.4)
4789 (41.3)
2010 (28.6)
1629 (30.4)
Anxiety
5176 (33.9)
4118 (35.5)
1822 (26.0)
1372 (25.6)
Sleep disorder
844 (5.5)
637 (5.5)
286 (4.1)
210 (3.9)
ADHD
402 (2.6)
315 (2.7)
144 (2.1)
104 (1.9)
Adj/acute‡
1623 (10.6)
1241 (10.7)
712 (10.1)
532 (9.9)
Any relevant diagnosis
9967 (65.3)
7896 (68.1)
3688 (52.5)
2821 (52.7)
Anxiolytic users
N = 4574
N = 2993
N = 9961
N = 7099
Bipolar disorder
325 (7.1)
240 (8.0)
255 (2.6)
181 (2.6)
MDD
1181 (25.8)
826 (27.6)
1227 (12.3)
886 (12.5)
Anxiety
1609 (35.2)
1075 (35.9)
1571 (15.8)
1016 (14.3)
Sleep disorder
596 (13.0)
407 (13.6)
437 (4.4)
294 (4.1)
ADHD
166 (3.6)
119 (4.0)

126 (1.3)
102 (1.4)
Adj/acute‡
506 (11.1)
332 (11.1)
755 (7.6)
524 (7.4)
Any relevant diagnosis
2753 (60.2)
1858 (62.1)
3033 (30.5)
2080 (29.3)
*Removes women who filled 1 prescription in the first trimester.
‡
A diagnosis of adjustment reaction and/or acute stress.
Figure 1 Psychotropic medicine use during pregnancy by year.
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Figure 2 Psychotropic medicine use during pregnancy by state.
have worse birth outcomes, on average, than women
without a psychiatric diagnosis, and this is often used as
a rationale to support drug treatment in pregnancy [19].
However, the evidence on depression and pregnancy
outcomes has been criticized for inadequately addressing
confounding [20], including socio-economic factors
[19,21], psychiatric diagnoses [22] and pregnancy complications [23,24], and it is often unclear whether
depression and anxiety diagnoses precede or follow
pregnancy complications [25]. More importantly, to
date there is no evidence that antidepressants for
depression or anxiolytics for anxiety mitigate poorer
health outcomes among women with depression or
anxiety-related diagnoses [26-28]. The medicines used
to treat these mood disorders have been associated
with poorer birth outcomes [29,30]. Selective serotonin
use in pregnancy has been associated with a number of
adverse health outcomes, including a higher rate of
miscarriage [31], pre-term birth [32], congenital heart
malformations with first trimester exposure [33], and
persistent pulmonary hypertension of the newborn
[34]. The extent to which poorer health outcomes with
antidepressant exposure are a result of unmeasured
confounding by the underlying maternal depression or
anxiety remains an open question [9]. There is less inconsistency with respect to postnatal adaptation syndrome, a
syndrome that generally presents as a transient combination of respiratory distress, jitteriness, abnormal tone,
tremors, restlessness, convulsions, jaundice, rigidity, and
hypoglycaemia [35-38], and occurs in approximately 1/3rd
of newborns exposed to SSRIs in utero [39]. The evidence
on safety of use of atypical antipsychotics is sparse but
tends to suggest an increased risk of NICU admission
among exposed infants; however, the population of
antipsychotic users tends to have much higher rates of
many adverse conditions, which likely confounds this
association [40,41]. There is some evidence from case–
control studies of an increased risk of cleft palate with
benzodiazepine use in the first trimester [42], and a
neonatal withdrawal syndrome following third trimester
use [42,43]. A research study from Taiwan has suggested
that zolpidem, the most frequently used anxiolytic in
our cohort, is associated with poorer infant outcomes;
however, unmeasured confounding is again a very real
problem in this literature [44].
Our results were not consistent with earlier studies
reporting a trend of increased use of psychotropic medicines during pregnancy. Cooper et al. examined a publicly
insured American Medicaid population in Tennessee and
reported that antidepressant use more than doubled between 1999 and 2003 from 5% to 13% [1]. A more recent
national study of women covered by Medicaid from 2000
to 2007 found that 8.1% were dispensed antidepressants in
pregnancy [18]. They also found that antidepressant use
declined following an FDA warning in 2003 on increased
risk for suicidality in children and adolescents [18]. Although largely irrelevant to use in pregnancy, this may
have led to greater overall caution. The higher rate
reported (8.1% versus our rate of 6.7%) may reflect greater
exposure among women of lower socio-economic status;
however, there is only one year of overlap in the two analyses, and although we found no difference in exposure
rate from 2007 to 2011, an earlier shift in rate of drug use
may have occurred. Our results regarding higher rates of
use of psychotropic medicines in Southern states is consistent with regional variation in depression diagnoses
among adults reported in US epidemiological surveys
[45]. Our study also indicates higher than average rates in
Hanley and Mintzes BMC Pregnancy and Childbirth 2014, 14:242
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some Mid-Western and Western states, a finding that
differs from disease surveillance surveys but should be
interpreted with caution, as we have some small numbers in some of these states (e.g. Idaho n = 785; Kansas
n = 2,833)
We found little use of atypical antipsychotics (0.2%).
Other research has reported an increasing trend in offlabel use of antipsychotics in the general US population,
including, for example, prescribing of quetiapine for
insomnia [11]. While we reported a high rate of use of
typical antipsychotics in the first trimester, given the
median prescription length (8 days) and frequent incident
use in the first trimester, we expect that this represents
use as antiemetics. Prochlorperazine, the most commonly
prescribed typical antipsychotic in our cohort, is indicated
in the U.S. for severe nausea and vomiting. However, the
drug’s label warns against use in pregnancy, “except in
cases of severe nausea and vomiting that are so serious
and intractable that, in the judgment of the physician,
drug intervention is required and potential benefits outweigh possible hazards” [46].
Our study is subject to some limitations. Our data are
drawn from a large private insurance claims database
that includes women from across the United States (44
states are represented). However, a large proportion of
births in the US occur to women who are covered by
Medicaid [47], and it is unclear whether our findings
generalize to these women. The same applies to our
state-specific prescribing patterns, which only reflect
prescribing patterns of this commercially insured population. However, the general regional trends we present
are consistent with previous studies of prescription drug
use during pregnancy [1,48]. We were also unable to
identify pregnancies that ended in spontaneous abortions,
or therapeutic abortions, a population which may have
higher exposure to psychotropic medicines [31]. Any bias
created through these omissions is likely to be in the direction of underestimating exposure.
Our measure of exposure is based on pharmacy dispensing of medication, and does not directly measure
medication use by the pregnant women. To account
for this limitation, we provide conservative estimates that
remove women who filled only one prescription in the
first trimester, as these women seem most likely to
have filled prescriptions that might not have been used.
Finally, we had to impute last menstrual period based on
claims for labor and delivery, which provide information
on preterm birth. Although this approach has been shown
to be valid [17], some degree of misclassification is likely.
We are also limited in our ability to detect diagnosed
mental health conditions. While ICD-9 codes are helpful
in identifying conditions, they do not reflect a goldstandard diagnosis and a preferable measure would be a
diagnostic interview undertaken by a trained health care
Page 10 of 12
provider. We also report that only half of our psychotropic
medicine users had a relevant mental health diagnosis.
While this may reflect some missing diagnostic information due to one-month lapses in coverage, it is also consistent with results from the US National Ambulatory
Medical care surveys indicating the lack of psychiatric
diagnosis noted at two-thirds of primary care consultations at which an antidepressant was prescribed [49].
The fact that many of these medicines are commonly
prescribed for other indications may also be a relevant
factor, as our rates of diagnoses were higher among
women using categories of medicines with less off-label
use (e.g. stimulants to treat ADHD).
Conclusions
In summary, approximately 10% of privately-insured
women in the United States are dispensed one or more
psychotropic medicine during pregnancy, with important
regional variation, around 6% to 15%. The most commonly
used psychotropic medicines are selective serotonin reuptake inhibitors and benzodiazepine or benzodiazepinelike medicines. The most commonly associated psychiatric
diagnosis was depression, followed by anxiety disorders,
which were mainly treated with antidepressants. Approximately 1.2% of women use both an antidepressant and an
anxiolytic medicine during their pregnancy. Given these
relatively high rates of use, the lack of evidence that the
most frequently used medications improve birth outcomes,
and the safety concerns raised both by early and late pregnancy use for many frequently-used medications, there is
a need for further study of factors driving use of these
medicines during pregnancy. For depression and anxiety
disorders, alternative treatment options are available. One
question raised by these findings is the extent to which
pregnant women, and women of reproductive age who
may be planning pregnancy, have equivalent access to
non-drug as to drug options for common mental health
concerns.
Additional files
Additional file 1: Generic names of all psychotropic medicines
prescribed during pregnancy to women in our cohort.
Additional file 2: Table S1. Mental health ICD-9 codes.
Competing interests
The authors declare they have no competing interests.
Authors’ contributions
GEH participated in devising the analytical plan, carried our data analysis and
drafted the manuscript. BM participated in devising the analytical plan, and
edited the draft. Both authors read and approved the final manuscript.
Acknowledgments
We would like to thank Dr. Anat Fisher for her help with data cleaning and
preparation and Mr. Greg Carney and Dr. Colin Dormuth for their help with
data acquisition. Dr. Fisher and Mr. Carney are funded by the University of
Hanley and Mintzes BMC Pregnancy and Childbirth 2014, 14:242
http://www.biomedcentral.com/1471-2393/14/242
Victoria Centre on Aging, and Dr. Carney and Dr. Dormuth by the Drug
Safety and Effectiveness CNODES network. We would also like to
acknowledge our funders. G. Hanley is supported by the Canadian Institutes
for Health Research, the Michael Smith Foundation for Health Research,
Women’s Health Research Institute and Neurodevnet. B. Mintzes holds a
Michael Smith Health Research Foundation Scholar Award. This study was
supported by the Canadian Institutes of Health Research [Grant # 263768].
The funders were not involved in any part of the study.
Author details
1
School of Population and Public Health, University of British Columbia,
Vancouver, BC, Canada. 2Child & Family Research Institute, Vancouver, BC,
Canada. 3Therapeutics Initiative, University of British Columbia, #307, 2176
Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
Received: 24 April 2014 Accepted: 8 July 2014
Published: 22 July 2014
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medicine use in pregnancy in the United States from 2006 to 2011
among women with private insurance. BMC Pregnancy and Childbirth
2014 14:242.
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Placebos without Deception: A Randomized Controlled
Trial in Irritable Bowel Syndrome
Ted J. Kaptchuk1,2*, Elizabeth Friedlander1, John M. Kelley3,4, M. Norma Sanchez1, Efi Kokkotou1,
Joyce P. Singer2, Magda Kowalczykowski1, Franklin G. Miller5, Irving Kirsch6, Anthony J. Lembo1
1 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Osher Research Center, Harvard Medical School,
Boston, Massachusetts, United States of America, 3 Psychology Department, Endicott College, Beverly, Massachusetts, United States of America, 4 Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 5 Department of Bioethics, National Institutes of Health, Bethesda, Maryland, United
States of America, 6 Department of Psychology, University of Hull, Hull, United Kingdom
Abstract
Background: Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that
response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and nonconcealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment
of irritable bowel syndrome (IBS).
Methods: Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic
center, involving 80 primarily female (70%) patients, mean age 47618 with IBS diagnosed by Rome III criteria and with a
score $150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills
presented as ‘‘placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce
significant improvement in IBS symptoms through mind-body self-healing processes’’ or no-treatment controls with the
same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary
measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL).
Findings: Open-label placebo produced significantly higher mean (6SD) global improvement scores (IBS-GIS) at both 11day midpoint (5.261.0 vs. 4.061.1, p,.001) and at 21-day endpoint (5.061.5 vs. 3.961.3, p = .002). Significant results were
also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR,
p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day
endpoint (p = .08).
Conclusion: Placebos administered without deception may be an effective treatment for IBS. Further research is warranted
in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with
informed consent.
Trial Registration: ClinicalTrials.gov NCT01010191
Citation: Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, et al. (2010) Placebos without Deception: A Randomized Controlled Trial in Irritable
Bowel Syndrome. PLoS ONE 5(12): e15591. doi:10.1371/journal.pone.0015591
Editor: Isabelle Boutron, University Paris Descartes, France
Received August 24, 2010; Accepted November 13, 2010; Published December 22, 2010
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public
domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Funding: This study was partially supported by grant K24 AT004095, R01 AT00402-01 and R01AT004662 from National Center for Complementary and
Alternative Medicine-NIH and in part from a gift from The Bernard Osher Foundation. The opinions expressed by the authors are their views alone and do not
reflect the official views or policy of the National Center for Complementary and Alternative Medicine, National Institutes of Health, Public Health Service or the
U.S. Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the
manuscript.
Competing Interests: AJL has worked as a consultant for Ironwood, GSK, Salix, Alkermes, and Ardelyx. These companies have had no relationship to this study.
All other authors report no competing interest or appearance of competing interest.
* E-mail: ted_kaptchuk@hms.harvard.edu
widespread belief that beneficial responses to placebo treatment
require concealment or deception. [3] This belief creates an ethical
conundrum: to be beneficial in clinical practice placebos require
deception but this violates the ethical principles of respect for patient
autonomy and informed consent. In the clinical setting, prevalent
ethical norms emphasize that ‘‘the use of a placebo without the
patient’s knowledge may undermine trust, compromise the patientphysician relationship, and result in medical harm to the patient.’’
[4] Nevertheless, a recent national survey of internists and
rheumatologists in the US found that while only small numbers of
Introduction
Placebo treatment can have a significant impact on subjective
complaints. [1] Furthermore, recent studies have shown measurable
physiological changes in response to placebo treatment that could
explain how placebos alter symptoms. [2] A critical question is
establishing how physicians and other providers can take optimal
advantage of placebo effects consistent with their responsibility to
foster patient trust and obtain informed consent. Directly harnessing
placebo effects in a clinical setting has been problematic because of a
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and from referrals from healthcare professionals. During the
telephone screening, potential enrollees were told that participants
would receive ‘‘either placebo (inert) pills, which were like sugar
pills which had been shown to have self-healing properties’’ or notreatment. Participants were adults ($18 years old) meeting the
Rome III criteria for IBS [17] with a score of $150 on the IBS
Symptom Severity Scale (IBS-SSS). [18] The diagnosis of IBS was
based on typical symptoms and exclusion of patients with alarm
symptoms. [19,20] was confirmed by a board certified gastroenterologist (AJL) or a nurse practitioner (EF) experienced in
functional bowel disorders. Patients were excluded if they had
any unexplained alarm features (i.e. weight loss .10% body
weight, fevers, or blood in stools, or had family history of colon
cancer, or inflammatory bowel disease). Patients with a history of
pelvic floor dyssynergia, the need to use manual maneuvers in
order to achieve a bowel movement, surgery of the colon at any
time, abdominal surgery within 60 days prior to entry into the
study, or laxative abuse were excluded from the study. Patients
with other medical conditions (e.g., neurological disorders,
metabolic disorders, or other significant disease), or pretreatment
laboratory or ECG findings believed to impair their ability to
participate in the study were also excluded. Any surgery within the
past 30 days, pregnancy, breast-feeding, or participation in
another clinical study within 30 days prior to the start of the
study were also disqualifying factors.
Patients were allowed to continue IBS medications (e.g., fiber,
anti-spasmodics, loperamide, etc.) as long as they had been on
stable doses for at least 30 days prior to entering the study and
agreed not to change medications or dosages during the trial.
Patients were asked to refrain from making any major life-style
changes (e.g., starting a new diet or changing their exercise
pattern) during the study.
US physicians surreptitiously use inert placebo pills and injections,
approximately 50% prescribe medications that they consider to
have no specific effect on patients’ conditions and are used solely as
placebos (sometimes called ‘‘impure placebos.’’) [5] Many other
studies confirm this finding. [6] Given this situation, finding effective
means of harnessing placebo responses in clinical practice without
deception is a high priority.
Irritable bowel syndrome (IBS) is one of the top 10 reasons for
seeking primary care and with a world-wide prevalence of
approximately 10 to 15%. [7,8] It is a chronic functional
gastrointestinal disorder characterized by abdominal pain and
discomfort associated with altered bowel habits. [9] The symptoms
of IBS not only adversely affect a person’s health-related quality of
life (QOL), [10,11] but are associated with a substantial financial
burden of reduced work productivity and an over 50% increase in
the use of health-related resources. [11,12] While many therapies
are commonly used to treat individual IBS symptoms such as
constipation or diarrhea, few therapies have been shown to be
effective and safe in relieving the global symptoms of IBS. [11,13]
Previous research has demonstrated that placebo responses in IBS
are substantial and clinically significant. [14,15] Furthermore, data
from our previous qualitative study of IBS patients being treated
single-blind with placebos indicated that patients can tolerate a
high degree of ambiguity and uncertainty about placebo treatment
and still benefit. [16] In view of these considerations, we selected
IBS as a suitable condition to test the widespread belief that
placebo responses are neutralized by awareness or knowledge that
the treatment is a placebo.
The objectives of this study were to assess the feasibility of
recruiting IBS patients to participate in a trial of open-label
placebo and to assess whether an open-label placebo pill with a
persuasive rationale was more effective than no-treatment in
relieving symptoms of IBS in the setting of matched patientprovider interactions.
Interventions
Patients were randomly assigned either to open-label placebo
treatment or to the no-treatment control. Prior to randomization,
patients from both groups met either a physician (AJL) or nursepractitioner (EF) and were asked whether they had heard of the
‘‘placebo effect.’’ Assignment was determined by practitioner
availability. The provider clearly explained that the placebo pill
was an inactive (i.e., ‘‘inert’’) substance like a sugar pill that
contained no medication and then explained in an approximately
fifteen minute a priori script the following ‘‘four discussion points:’’
1) the placebo effect is powerful, 2) the body can automatically
respond to taking placebo pills like Pavlov’s dogs who salivated
when they heard a bell, 3) a positive attitude helps but is not
necessary, and 4) taking the pills faithfully is critical. Patients were
told that half would be assigned to an open-label placebo group
and the other half to a no-treatment control group. Our rationale
had a positive framing with the aim of optimizing placebo
response. It was emphasized that each group was critical for the
trial. All patients were told that they would receive educational
recommendations for their IBS at the end of the study. After
completion of the physical examination and assessments, patients
were then randomized using a sequentially numbered opaque
sealed envelopes that contained treatment assignments drawn
from a computer-generated random number sequence. Until this
point, the patient-provider interaction — including delivering the
persuasive rationale and the explanation of the importance of both
groups – was similar for all participants. At this point, during the
last moments of the interview, they were told their assignments.
Patients randomized to the open-label placebo group were given a
typical prescription medicine bottle of placebo pills with a label
clearly marked ‘‘placebo pills’’ ‘‘take 2 pills twice daily.’’ The
Methods
Design
A three week randomized controlled trial (RCT) comparing
open-label placebo to no-treatment controls was conducted
between August 2009 and April 2010 in a single academic
medical center. Written informed consent was obtained from each
patient prior to participation on the study. The Beth Israel
Deaconess Medical Center Institutional Review Board approved
the design and informed consent.
Patients who gave informed consent and fulfilled the inclusion
and exclusion criteria were randomized into two groups: 1)
placebo pill twice daily or 2) no-treatment. Before randomization
and during the screening, the placebo pills were truthfully
described as inert or inactive pills, like sugar pills, without any
medication in it. Additionally, patients were told that ‘‘placebo
pills, something like sugar pills, have been shown in rigorous
clinical testing to produce significant mind-body self-healing
processes.’’ The patient-provider relationship and contact time
was similar in both groups. Study visits occurred at baseline (Day
1), midpoint (Day 11) and completion (Day 21). Assessment
questionnaires were completed by patients with the assistance of a
blinded assessor at study visits. (The protocol for this trial and
supporting CONSORT checklist are available as supporting
information; see Checklist S1 and Protocol S1.)
Patients
Participants were recruited from advertisements for ‘‘a novel
mind-body management study of IBS’’ in newspapers and fliers
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placebo pills were blue and maroon gelatin capsules filled with
avicel, a common inert excipient for pharmaceuticals (Bird’s Hill
Pharmacy, Needham, MA). Patients in the no treatment arm were
reminded of the importance of the control arm. All visits were in
the context of a warm supportive patient-practitioner relationship.
The midpoint 11 day visit was brief (approximately 15 minutes)
and included an opened question regarding adverse events,
concomitant medications and a brief physical examination. After
the examination, a treatment-blind researcher administered
questionnaires. Patients receiving placebos received a short
reminder regarding the ‘‘four discussion points.’’ In the no
treatment arm, patients were encouraged and thanked for helping
make a successful study.
Before the study began the providers practiced the trial
procedures on simulated and real patients. Once a month, the
two providers (AJL, EF) and a third researcher (TJK) met to
discuss fidelity to the protocol and any other problems. AJL and
EF consistently reported that they had no problem holding the
entire initial interview process to approximately 30 minutes and
the mid-point to 15 minutes.
our main outcome measure (IBS-GIS at 21-day endpoint), we
planned an independent samples t-test. We estimated a priori that a
total sample size of 80 would provide 94% power to detect a large
effect (d = .8) and 60% power to detect a medium effect (d = .5). For
IBS-SSS and IBS-QOL, we computed change scores from baseline
and then conducted independent samples t-tests. We used chi
square tests of independence for IBS-AR. Per protocol analyses
were also conducted, but they produced no substantive differences
from our planned intent-to-treat analyses and are not reported here.
Results
As shown in Figure 1, 92 patients were screened, and 80 eligible
patients were randomized into the two arms (43 into no-treatment
and 37 into open-label placebo). There were missing outcome data
for 13 patients at midpoint (16%; 6 no-treatment control, 7 openlabel placebo), and for 10 patients at endpoint (13%; 4 notreatment control, 6 open-label placebo). As noted above, missing
data was replaced using the last observation carried forward
method. Table 1 shows baseline data.
As shown in Figure 2 and Table 2, patients treated with openlabel placebo had significantly greater scores than the notreatment control on the main outcome measure, Global
Improvement Scale (IBS-GIS), at both the 11-day midpoint
(5.261.0 vs. 4.061.1, p,.001, d = 1.14) and the 21-day endpoint
(5.061.5 vs. 3.961.3, p = .002, d = 0.79). In addition, there were
statistically significant differences at both time points on reduction
on in symptom severity (IBS-SSS) and adequate relief (IBS-AR),
and a trend toward significance at the 21-day endpoint on
improvement in quality of life (IBS-QOL).
Forty-three patients saw the male physician for all three visits,
20 patients saw the female nurse-practitioner for all three visits,
and 17 patients saw a combination of the two or missed a
treatment session. Given that the two treatment providers differed
by gender and discipline (MD vs. NP), we tested for differences in
treatment outcomes. No significant differences were found
between providers on the primary outcome measure, IBS-GIS
(p = .57 at midpoint, and p = .51 at endpoint). Similarly, there
were no significant differences between providers on any of the
secondary outcome measures.
Adverse events were reported by only three placebo-treated
patients (8%) at midpoint and five patients (14%) at endpoint. The
most common adverse events that patients reported were upper
respiratory infection (N = 3) and pain (N = 2); other events
included rash, runny stools, and a sty on the eye.
The detailed results of the qualitative check-out questionnaire
will be reported elsewhere. However, responses to two questions
seemed especially relevant to the interpretation of this quantitative
report. Specifically, 1) did patients in the open-label arm
understand that they were taking a placebo (‘‘What did you think
was in the placebo pills?’’) and 2) were patients in the no treatment
arm disappointed (‘‘Were you disappointed to be in the treatment
as usual arm?’’) To answer these questions two researchers (TJK,
MK) independently extracted the responses to these questions. A
third researcher (JPS) compared these extracted responses and a
discussion settled two occasions where handwriting that was
difficult to interpret. TJK categorized the data using the iterative
and emergent methodology of grounded theory. [25,26] When
participants in the placebo arm were asked: ‘‘ What did you think
was in the placebo pills?’’ of the 29 who responded, 16 wrote
‘‘sugar’’ (12), ‘‘flour’’ (3) or ‘‘calcium’’ (1),’’ 6 responded ‘‘nothing,’’
5 responded ‘‘did not know,’’ 1 responded ‘‘symbolic reminder,’’
and 1 responded ‘‘possible test medication.’’ When participants in
the no-treatment arm were asked: ‘‘Were you disappointed to be
Assessment
Our primary outcome measure was the IBS Global Improvement Scale (IBS-GIS) which asks participants: ‘‘Compared to the
way you felt before you entered the study, have your IBS
symptoms over the past 7 days been: 1) Substantially Worse, 2)
Moderately Worse, 3) Slightly Worse, 4) No Change, 5) Slightly
Improved, 6) Moderately Improved or 7) Substantially Improved.[21,22] Other measures included: the IBS-SSS measure,
which contains five 100-point scales, that assess the severity of
abdominal pain, the frequency of abdominal pain, the severity of
abdominal distention, dissatisfaction with bowel habits, and
interference with quality of life, [18] All 5 components contribute
to the score equally yielding a theoretical range of 0–500, with a
higher score indicating greater symptom severity. The IBSAdequate Relief (IBS-AR) is a single dichotomous (yes or no)
item that asks participants ‘‘Over the past week have you had
adequate relief of your IBS symptoms?’’ [23] The IBS-QoL is a
34-item measure assessing the degree to which IBS interferes with
patient quality of life. Each item is rated on a 5-point Likert scale
and a linear transformation yields a summed score with a
theoretical range of 0 to 100, with a higher score indicating better
quality of life. [24] Side effects were recorded at each assessment.
A pill count was taken at visits two and three. Given the
unprecedented nature of the study, at the completion of the trial
patients were given a short qualitative open-ended check-out
questionnaire and asked for written responses. The questions were
different for each group. Those in the placebo treatment arm were
asked four questions: What do you think of about the idea of
taking placebo? Did you expect it to work or were you skeptical?
What did you think was in the placebo pills? Any further
comments? Those in the no-treatment were asked three questions:
Were you disappointed to be in the treatment as usual arm? What
did you like most and least about the trial? Any further comments?
All assessments were performed by a researcher who was blind to
treatment assignment.
Statistical Analysis
All tests were two-tailed with alpha set at .05. All results are
reported as mean 6SD unless otherwise noted. All analyses were
intent-to-treat, and missing data were replaced using the last
observation carried forward method. Since IBS-GIS and IBS-AR
are change scores and are not assessed at baseline, we carried
forward scores for patients who had at least one follow-up visit. For
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Placebos without Deception
Figure 1. Enrollment Flowchart.
doi:10.1371/journal.pone.0015591.g001
in the treatment as usual arm?’’ of the 38 who responded, 29 said
‘‘no’’ and only 9 said ‘‘yes’’ or ‘‘a little’’. We then looked at the
responses of the nine who expressed disappointment, to see how
they responded to: ‘‘What did you like most and least about the
trial?’’ All gave uniformly positive answers such as ‘‘I liked that my
feeling about the intensity of the problem was validated and was
taken seriously…and was able to discuss my IBS,’’ ‘‘the doctor and
the nurse were wonderful and accommodating,’’ ‘‘I liked the oneon-one attention with the MD, able to ask questions about IBS
with a person trained in the illness; this MD is very kind’’
(underling in the original). This qualitative data seemed to indicate
that, in general, patients understood they were taking placebo and
were not overly disappointed in being in the no-treatment arm.
Discussion
We found that patients given open-label placebo in the context
of a supportive patient-practitioner relationship and a persuasive
Table 1. Demographics and Baseline Characteristics.
Demographics and Baseline Characteristics
No Treatment
(N = 43)
Open Placebo
(N = 37)
Age
46618
47618
Female – no. (%)
32 (74)
24 (65)
White – no. (%)
36 (84)
26 (70)
IBS Type – no. (%)
Diarrhea Predominant
16 (37)
10 (27)
Constipation Predominant
14 (33)
16 (43)
Mixed
13 (30)
11 (30)
13611
16612
IBS Duration in Years
Symptom Severity (IBS-SSS)
297658
310682
Quality of Life (IBS-QOL)
59621
55621
Upper GI Symptoms (GERD & Dyspepsia) – no. (%)
18 (42)
11 (30)
Taking Medications for IBS – no. (%)
15 (35)
20 (54)
Taking Antidepressants – no. (%)
7 (16)
9 (24)
Note: All values are means 6SD, unless otherwise noted. Group differences were examined using independent t-tests for continuous measures and chi square test for
categorical measures.. IBS = irritable bowel syndrome; IBS-SSS = IBS Symptom Severity Scale; IBS-QOL = IBS Quality of Life Scale; GI = Gastrointestinal; GERD =
Gastroesophageal Reflux Disease.
doi:10.1371/journal.pone.0015591.t001
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Figure 2. Outcomes at the 21-Day Endpoint by Treatment Group.
doi:10.1371/journal.pone.0015591.g002
rationale had clinically meaningful symptom improvement that
was significantly better than a no-treatment control group with
matched patient-provider interaction. To our knowledge, this is
the first RCT comparing open-label placebo to a no-treatment
control. Previous studies of the effects of open-label placebo
treatment either failed to include no-treatment controls [27] or
combined it with active drug treatment. [28] Our study suggests
that openly described inert interventions when delivered with a
plausible rationale can produce placebo responses reflecting
symptomatic improvements without deception or concealment.
Table 2. Treatment Outcomes.
No Treatment
(N = 43)
Open Placebo
(N = 37)
p-value
Midpoint (11 Days)
Global Improvement (IBS-GIS)
4.061.1
5.261.0
,.001
Adequate Relief (IBS-AR) – no. (%)
10 (23)
18 (49)
.02
Symptom Severity Reduction (IBS-SSS)
28666
75687
.008
Quality of Life Improvement (IBS-QoL)
4.468.9
8.3611.6
.10
Endpoint (3 Weeks)
Global Improvement (IBS-GIS)
3.961.3
5.061.5
.002
Adequate Relief (IBS-AR) – no. (%)
15 (35)
22 (59)
.03
Symptom Severity Reduction (IBS-SSS)
46674
92699
.03
Quality of Life Improvement (IBS-QoL)
5.4613.8
11.4616.6
.08
Note: All values are means 6SD except where noted. IBS = irritable bowel syndrome; IBS-GIS = IBS Global Improvement Scale; IBS-AR = IBS Adequate Relief;
IBS-SSS = IBS Symptom Severity Scale; IBS-QoL = IBS Quality of Life Scale.
doi:10.1371/journal.pone.0015591.t002
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Our results challenge ‘‘the conventional wisdom’’ that placebo
effects require ‘‘intentional ignorance.’’ [29] Our data suggest that
harnessing placebo effects without deception is possible in the
context of 1) an accurate description of what is known about
placebo effects, 2) encouragement to suspend disbelief, 3)
instructions that foster a positive but realistic expectancy, and 4)
directions to adhere to the medical ritual of pill taking. It is likely
our study also benefited from ongoing media attention giving
credence to powerful placebo effects.
Both treatment arms were given in a context of a warm patientprovider relationship. It is possible that this relationship had a
positive benefit for the patients, and indeed, the no-treatment arm
showed improvement. Given that patients in both treatment arms
experienced the same frequency and duration of contact time and
the content of the interaction was very similar, we believe that the
incremental improvement in our open-label arm was due to the
addition of open-label placebo treatment. The magnitude of
improvement reported by those on open-label placebo treatment
was not only statistically significant but also clinically meaningful.
The effect size for the primary outcome, calculated as the
standardized mean difference (d) between the open-label-placebo
and no-treatment groups, was 0.79 at endpoint, which is
conventionally interpreted as a large effect. [30] At endpoint, we
also observed medium sized effects for the differences between
placebo and control groups on symptom severity (d = 0.53) and
quality of life (d = 0.40). An improvement from baseline of 50
points on the IBS-SSS reliably indicates meaningful symptomatic
improvement. [18] The open-label group improved by 92 points
on this measure; in addition, the improvement shown by the openlabel placebo group exceeded that shown by the no-treatment
group by 46 points. Similarly, an increase of 10 points on the IBSQoL indicates a clinically meaningful improvement, and we
observed an increase of 11 points on this measure for the openlabel group. [24] Finally, the percentage of patients reporting
adequate relief during the preceding 7 days at the 21-day endpoint
(59%) is comparable with the responder rates in clinical trials of
drugs currently used in IBS. [31,32] A recent meta-analysis of
double-blind, placebo-controlled trials of alosetron in IBS
estimated that 51% of patients treated with alosetron had
adequate relief as compared to 38% of patients treated with
placebo. [33] Our results were remarkably similar (59% for openplacebo; 35% for no-treatment control), suggesting that open-label
placebo in the context of a persuasive rationale may show
comparable efficacy to established IBS treatments.
The placebo response in this trial (59% on IBS-AR) was
substantially higher than typical reported placebo responses of 30–
40% in double-blind IBS pharmaceutical studies. [15] This finding
seems counterintuitive. We speculate that it is an indication of the
credibility of our open-label rationale. Patients in our study
accepted that they were receiving an active treatment, albeit not a
pharmacological one, whereas patients in double-blind trials
understand that they have only a 50% chance of receiving active
treatment. It may be that one hundred percent certainty that one
is receiving the ‘‘treatment of interest’’ (in this case open-label
placebo) is more placebogenic than a fifty percent probability of
receiving an inactive control.
It may be worthwhile to interpreted our study in light of the
2001 landmark meta-analysis of placebo effects and its 2010
expanded and updated version. [34,35] In the recent analysis, the
authors found 202 randomized trials in 60 medical conditions that
included placebo and no-treatment groups. When meta-analytically combined, in general, little evidence of clinically meaningful
effects of placebo beyond no treatment was found. The metaanalysis, however demonstrated a significantly larger placebo
PLoS ONE | www.plosone.org
effect for a subset of 28 studies with a specific aim of investigating
the placebo effect. Perhaps this subset is most relevant to our study
which was also specifically examined placebo effects. Further
prospective research will be necessary to clarify under what
circumstances and in what conditions one can expect or not expect
to find robust placebo responses.
There are intimations in the placebo literature that providers
with greater perceived expertise or authority (e.g., physician versus
nurse, dentist versus technician) will elicit greater placebo
responses. [36,37] In our study, we found no evidence for
significant differences between male physician and female nursepractitioner.
In addition to its clinical significance, our study has important
ethical implications. As mentioned above, evidence indicates that
physicians continue to use placebo treatment without transparent
disclosure to patients [5,6] Our results suggest that the placebo
response is not necessarily neutralized when placebos are
administered openly. Thus our study points to a potential novel
strategy that might allow the ethical use of placebos consistent with
evidence-based medicine. Minimally, open-label placebo may
have potential as a ‘‘wait and watch’’ strategy before prescriptions
drugs are prescribed. Further studies of open placebo are merited
not only for IBS but for illnesses primarily diagnosed by subjective
symptoms and introspective self-appraisal. In sum, our study
suggests that for some disorders it may be appropriate for
clinicians to recommend that patients try an inexpensive and safe
placebo accompanied by careful monitoring before and after
prescribing medication. Clearly replication and further research is
essential before such a practice could be implemented.
Limitations
This RCT has several limitations. Most importantly, our sample
size was relatively small and the trial duration was too short to
obtain estimates of long-term effects. Therefore, the trial could be
described as a ‘‘proof-of-principle’’ pilot study. Obviously,
replication with a larger sample size and a longer follow-up is
needed before clear clinical decisions could be made based on our
data.
Other potential limitations of our study may be the issue of
report bias (e.g., ‘‘wishing to please the experimenter’’). However,
given the impossibility of double-blind assessment of open placebo
versus no-treatment control, the effects of report bias cannot be
eliminated. Another related limitation is that patients assigned to
no-treatment may have been disappointed, thus inflating the
differences between open-label placebo and no-treatment control
groups. Importantly, our qualitative check-out data found the notreatment group experiencing positive support, with 76% of them
reporting that they were not disappointed with their assignment.
This argues against disappointment being a significant factor. A
further possible limitation is that our results are not generalizable
because our trial may have selectively attracted IBS patients who
were attracted by an advertisement for ‘‘a novel mind-body’’
intervention. Obviously, we cannot rule out this possibility.
However, selective attraction to the advertised treatment is a
possibility in virtually all clinical trials. In any case, patients in
clinical practice are ultimately given choices and it may turn out
that open-label placebo will be helpful only for those who elect to
try this option. Finally, it could be argued that IBS is a poor illness
to study placebo effects because it lacks objective measures.
However, there are many serious conditions for which primary
outcomes are primarily subjective (e.g. depression, anxiety and
chronic pain), and the preponderance of evidence indicates that
placebo treatments are most effective for such patient-centered
complaints. [1]
6
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Placebos without Deception
Protocol S1
In summary, our study suggests that patients are willing to take
open-label placebos and that such a treatment may have
salubrious effects. Further research is warranted in IBS and
perhaps other illnesses to confirm that placebo treatments can be
beneficial when provided openly and to determine the best
methods for administering such treatments.
(DOC)
Author Contributions
Conceived and designed the experiments: TJK JMK EK FGM IK AJL.
Performed the experiments: AJL EF JMK MNS JPS MK. Analyzed the
data: JMK AJL IK TJK MK JPS. Wrote the paper: TJK AJL JMK FGM
IK EK.
Supporting Information
Checklist S1
(DOC)
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