Current Medical Research and Opinion

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20

The Rapid Mood Screener (RMS): a novel and

pragmatic screener for bipolar I disorder

Roger S. McIntyre, Mehul D. Patel, Prakash S. Masand, Amanda Harrington,

Patrick Gillard, Susan L. McElroy, Kate Sullivan, C. Brendan Montano, T.
Michelle Brown, Lauren Nelson & Rakesh Jain

To cite this article: Roger S. McIntyre, Mehul D. Patel, Prakash S. Masand, Amanda Harrington,
Patrick Gillard, Susan L. McElroy, Kate Sullivan, C. Brendan Montano, T. Michelle Brown,
Lauren Nelson & Rakesh Jain (2021) The Rapid Mood Screener (RMS): a novel and pragmatic
screener for bipolar I disorder, Current Medical Research and Opinion, 37:1, 135-144, DOI:
10.1080/03007995.2020.1860358

To link to this article: https://doi.org/10.1080/03007995.2020.1860358

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CURRENT MEDICAL RESEARCH AND OPINION
2021, VOL. 37, NO. 1, 135–144
https://doi.org/10.1080/03007995.2020.1860358
Article FT-0790.R1/1860358

ORIGINAL ARTICLE

The Rapid Mood Screener (RMS): a novel and pragmatic screener for
bipolar I disorder
Roger S. McIntyrea, Mehul D. Patelb, Prakash S. Masandc, Amanda Harringtond, Patrick Gillardd,
Susan L. McElroye,f , Kate Sullivang, C. Brendan Montanoh, T. Michelle Browni, Lauren Nelsoni and Rakesh Jainj
a
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada; bAbbVie, Madison, NJ, USA; cGlobal Medical
Education, New York, NY, USA; dAbbVie, Irvine, CA, USA; eLindner Center of HOPE, Mason, OH, USA; fCollege of Medicine, University of
Cincinnati, Cincinnati, OH, USA; gKnoxville Behavioral & Mental Health Services, Knoxville, TN, USA; hCT Clinical Research, Cromwell, CT,
USA; iRTI Health Solutions, Triangle Park, NC, USA; jSchool of Medicine, Texas Tech University – Permian Basin, Midland, TX, USA

ABSTRACT ARTICLE HISTORY

Objective: Depressive episodes and symptoms of bipolar I disorder are commonly misdiagnosed as Received 17 October 2020
major depressive disorder (MDD) in primary care. The novel and pragmatic Rapid Mood Screener Revised 18 November 2020
(RMS) was developed to screen for manic symptoms and bipolar I disorder features (e.g. age of Accepted 3 December 2020
depression onset) to address this unmet clinical need.
KEYWORDS
Methods: A targeted literature search was conducted to select concepts thought to differentiate Rapid Mood Screener;
bipolar I from MDD and screener tool items were drafted. Items were tested and refined in cognitive screening tool; bipolar I
debriefing interviews with individuals with self-reported bipolar I or MDD (n ¼ 12). An observational disorder; major depressive
study was conducted to evaluate predictive validity. Participants with clinical interview-confirmed bipo- disorder; misdiagnosis;
lar I or MDD diagnoses (n ¼ 139) completed a draft 10-item screening tool and other questionnaires. Mood Disorder
Data were analyzed to identify the smallest possible subset of items with optimized sensitivity and Questionnaire
specificity.
Results: Adults with confirmed bipolar I (n ¼ 67) or MDD (n ¼ 72) participated in the observational
study. Ten draft screening tool items were reduced to 6 final RMS items based on the item-level ana-
lysis. When 4 or more items of the RMS were endorsed (“yes”), sensitivity was 0.88 and specificity was
0.80; positive and negative predictive values were 0.80 and 0.88, respectively. These properties were
an improvement over the Mood Disorder Questionnaire in the same analysis sample while using 60%
fewer items.
Conclusion: The pragmatic 6-item RMS differentiates bipolar I disorder from MDD in patients with
depressive symptoms, providing real-world guidance to primary care practitioners on whether a more
comprehensive assessment for bipolar I disorder is warranted.

Introduction depression was cited as the most common misdiagnosis

(60%). As a matter of fact, 1 in 4 patients treated for major
Bipolar I disorder is a chronic and debilitating mental illness
depressive disorder (MDD) may actually have bipolar dis-
that is characterized by a mixture of manic, depressive, and
order, which is a clinical concern given the importance of
subsyndromal symptoms [1]. Although the presence or his-
tory of at least one fully syndromal manic episode is required early intervention and appropriate treatment [5,6]. As timely
for a diagnosis of bipolar I disorder [2], depressive symptoms and accurate diagnoses are precursors of good clinical out-
are the more common presentation. Delayed or missed diag- comes, the high rate of missed bipolar disorder diagnosis is
nosis of bipolar disorder is exceedingly common; the delay a critical unmet need, which provides an incentive for rou-
between the onset of illness and diagnosis of bipolar dis- tine and systematic bipolar disorder screening of all patients
order was reported to be 6–13 years [3,4]. In a large survey who present with depressive symptoms [7].
of individuals with bipolar disorder, 69% of respondents It has been reported that up to 40% of patients with
reported being initially misdiagnosed, with patients receiving bipolar disorder are treated exclusively in primary care [8],
an average of 3.5 misdiagnoses before the correct bipolar suggesting that primary care providers, including nurse
disorder diagnosis was made [4]. Not surprisingly, unipolar practitioners, are uniquely positioned to detect and diagnose

CONTACT Roger S. McIntyre [email protected] Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, MP 9-
325, Toronto ON M5T 2S8 Canada
Supplemental data for this article is available online at https://doi.org/10.1080/03007995.2020.1860358.
ß 2021 AbbVie Inc. Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
www.cmrojournal.com
136 R. S. MCINTYRE ET AL.

the bipolar disorder early in the illness trajectory [9]. In a sur- to screening included uncertainty about when to
vey of primary care providers, respondents reported that screen, insufficient knowledge of bipolar disorder symptoms,
almost one-third of their patients were being treated for a lack of screening tools, and lack of time to screen during a
mental health issue, with depression the most common psy- visit [18].
chiatric condition treated [10]. Further, up to 10% of all visits Using a bipolar I disorder screening tool should help clini-
to primary care are related to depression and as many as cians triage those patients for whom further workup for
64% of all clinical encounters for depression occur in primary bipolar I disorder may be required, thus providing better
care [11]. In a study that reported on the consulting patterns patient care more efficiently. The Rapid Mood Screener
of adults with a positive bipolar disorder screening result, (RMS) for bipolar I disorder is a novel and pragmatic patient-
the most frequently consulted specialty for bipolar disorder reported screening tool that utilizes easily understood
symptoms was primary care (41%); of note, primary care pro- terminology to screen for manic symptoms and bipolar
viders made an incorrect diagnosis or did not identify bipolar depression risk factors in less than 2 min during or outside of
disorder 78% of the time [12]. a clinical visit (e.g. online, via electronic medical record sys-
The importance of timely and accurate diagnosis of bipo- tem, waiting room). Designed to help clinicians identify
lar I disorder cannot be overstated. Untreated bipolar dis- patients with bipolar I disorder, the RMS may be an efficient
order may result in poor outcomes such as persistent and accurate bipolar I disorder screening option that could
symptoms, impaired functioning, recurrences, cognitive
easily be integrated into a busy primary care setting.
impairment, comorbidities, neurobiological changes, and
increased suicidality, while early identification and prompt
treatment have been associated with improved outcomes
across symptomatic and functional domains [13–15]. Methods
Although mania is the hallmark of a bipolar I diagnosis, there
are challenges to quickly identifying prior manic symptoms. Qualitative evaluation
As such, screening for other clinical features that are more Concept selection and item development
likely to be associated with bipolar I disorder than with MDD The RMS was developed in a multistep process beginning
may help clinicians differentiate these diagnoses. For with a targeted literature search to identify concepts that dif-
example, not only are clinical characteristics such as early ferentiate bipolar I disorder from MDD. A search of the litera-
age of depression onset, prior negative response to anti- ture was conducted to identify relevant articles cited in
depressant treatment, and positive bipolar family history PubMed (1 March 2019); results were limited to English lan-
prognostic for bipolar I disorder, they are also likely to be guage articles published in the previous 10 years. Multiple
collected in routine patient evaluation [16]. Differentiating combinations of terms related to bipolar disorder and MDD
bipolar I disorder and MDD is a clinical priority as appropri- indications (e.g. bipolar, unipolar, depression, depressive) and
ate pharmacologic management differs depending on the diagnosis (e.g. differential diagnosis, diagnostic conversion)
disorder. Most importantly, if patients with bipolar I disorder
were searched. Reference lists from retrieved articles were
are treated with a conventional antidepressant as monother-
manually searched for additional articles of interest. Existing
apy, they may be at risk for mood destabilization or treat-
bipolar disorder tools and diagnostic criteria were
ment-emergent mania [17].
also reviewed.
Evidence of frequent misdiagnosis and diagnostic delay
A multidisciplinary group of 6 mental health and psycho-
suggests that the use of a brief, clinically validated, patient-
metric experts then participated in two modified Delphi con-
administered, and easy-to-use screening tool for bipolar I dis-
sensus panels. During Panel 1 (pre-panel online activity and
order would be a welcome addition to clinical practice.
web conference [30 April 2019]), participants reviewed the
Although various bipolar disorder screening tools are avail-
identified concepts and ranked them in order of the ones
able, there are impediments to their use in primary care set-
tings, including length and reliance on screening for manic that would best identify patients with a diagnosis of MDD
symptoms only. Given that office visits in primary care are who may instead have bipolar I disorder. During Panel 2
usually very short, a bipolar I disorder screening tool should (pre-panel online activity and in-person or web conference
ideally have only a small number of easily understood items [20 May 2019]) participants further refined the reduced con-
that can be completed and scored quickly so that results are cept list developed during Panel 1 proceedings and again
immediately informative to the clinician and the patient. ranked them by their potential to differentiate patients with
While screening for MDD appears to be commonplace, with bipolar I disorder from those with MDD. Patient-friendly item
82% of healthcare providers reporting that they currently use wording, and specific thresholds (e.g. age of depression
an MDD screening tool, only 32% reported screening for onset, number of episodes) and variations (e.g. comorbidities,
bipolar disorder (data on file, AbbVie) even though historical family history) were explored and determined for draft
and contemporary screening is recommended to rule out screening tool items. All decisions related to item reduction
bipolar disorder before a diagnosis of MDD is made. For and selection were made based on a consensus from the
example, although most primary care nurse practitioners see majority of participants (i.e. at least 4 of 6). A pool of bipolar
patients with depressive symptoms, only half reported using I disorder screening tool items were drafted for subsequent
a screening tool to assess for bipolar disorder; cited barriers qualitative evaluation.
 CURRENT MEDICAL RESEARCH AND OPINION 137

Cognitive interviews medical, organic, or drug causes [Module O]). A MINI ques-
Two rounds of in-depth qualitative cognitive debriefing inter- tion related to repeated thoughts about death and suicide
views were conducted with adults who were identified from was not administered to minimize emotional risk to study
databases belonging to qualitative research firms. participants and preempt discussion of the topic given the
Participants had a self-reported clinician-provided diagnosis nonclinical study setting. The items of the draft bipolar I dis-
of bipolar I disorder or MDD; individuals with bipolar II dis- order screening tool were administered to participants; more
order were excluded. Participant feedback was used to test clinical information was elicited via self-reported responses
and refine wording as needed to improve draft item clarity to additional questions that provided numeric variations (e.g.
and interpretability. The qualitative interviews also provided number of episodes, age of onset, prior number of antide-
further support for the content validity of the bipolar I dis- pressants) and content permutations (e.g. comorbidities, fam-
order screening tool draft items. ily mental health history) for some draft items. Additional
study measures included the 15-item Mood Disorder
Questionnaire (MDQ) to screen for bipolar disorder [20] and
Quantitative evaluation
the 20-item Center for Epidemiologic Studies Depression
To test the final set of draft screening tool items, a multisite, Scale (CES-D), used to assess the severity of depressive symp-
cross-sectional, observational study was conducted in adults toms over the prior week [21].
with a clinically confirmed diagnosis of bipolar I disorder or MINI diagnostic interviews were conducted by 4 Ph.D.
MDD. The study protocol was approved by the institutional level clinicians, including a licensed clinical psychologist, who
review board (IRB; RTI International IRB) and written informed had participated in training activities to ensure rater accuracy
consent was obtained from participants. Data collected from and consensus; interviewers collaborated throughout the
study participants were used to identify screening tool items interview process to monitor rating agreement and address
that had the greatest potential to optimize the sensitivity discrepancies. All other study measures were partici-
and specificity of the bipolar I disorder screening tool being pant reported.
developed. Based on the totality of item permutations and
numeric thresholds that were evaluated, the best combin-
Statistical analysis
ation of items was identified, with a goal of high accuracy
while using the fewest possible number of items and main- Planned evaluations were conducted using standard psycho-
taining high sensitivity and specificity. metric evaluation techniques. A sample size of 120 partici-
pants was selected to provide adequate precision. To obtain
an analysis sample with approximately equal numbers of
Participants
individuals with MDD and bipolar I disorder (60 each),
Using a standardized recruitment form, medical recruiters
recruitment quotas were established and adjusted based on
selected potential study participants from databases belong-
clinical interview confirmation for each diagnosis throughout
ing to qualitative research firms located in the United States
the recruitment process.
(North Carolina, Texas, Colorado, Florida, and California);
Descriptive statistics were tabulated and summarized by
social network initiatives were also used to recruit partici-
diagnostic subgroup for demographic and clinical character-
pants as needed. In-person interviews were scheduled for
istics, responses to the bipolar I disorder screening tool
people who were eligible and interested.
items, responses elicited from the additional questions, bipo-
At the screening, participants had to be at least 18 years
lar disorder classification based on the MDQ, and CES-D total
of age, with a self-reported clinician-provided diagnosis of
score. Combinations of potential bipolar I disorder screening
bipolar I disorder or MDD, current or past depressive symp-
tool items (and numeric thresholds or item permutations
toms, and current use of an antidepressant, atypical anti-
where applicable) were reviewed collaboratively by the
psychotic, or mood-stabilizing medication. The diagnosis of
screening tool development team to optimize scoring and
bipolar disorder had to be specified as bipolar I disorder or a
test characteristics for the final item set while using the few-
past manic episode of at least 7 days’ duration had to be
est possible number of items. Prediction criteria for multiple
reported. Participants were excluded if they had been hospi-
sets of bipolar I disorder screening tool items with various
talized or admitted to the emergency room due to mental
thresholds elicited from the additional questions (e.g. num-
health issues in the past 30 days, or if they were currently
ber of depressive episodes, age of depression onset)
experiencing a manic episode.
were examined.
Item responses were summed (Yes ¼ 1; No ¼ 0); logistic
Study measures regression was conducted for each set of items tested to
For participants who met inclusion criteria at screening, the provide the summed score that best separated bipolar I dis-
self-reported diagnosis was confirmed by a Mini-International order from MDD. The score that maximized predictive ability
Neuropsychiatric Interview (MINI) structured clinical interview was selected as the total number of items requiring endorse-
[19]. Two MINI modules were administered for diagnostic ment. Because thresholds below and above those in the ori-
purposes (depressive disorder [Module A] and bipolar dis- ginal items were tested, responses to the additional
order [Module C]), and 2 modules were administered to rule questions were used to inform comparisons. Analyses were
out other diagnoses (any psychotic disorder [Module K] and performed using SAS version 9.3 or higher for Windows
138 R. S. MCINTYRE ET AL.

Figure 1. Observational study participants. a6 patients with self-reported depression/MDD had a clinically confirmed diagnosis of bipolar I disorder; 2 patients with
self-reported bipolar depression/manic depression had a clinically confirmed diagnosis of MDD. Abbreviations. MDD, major depressive disorder; MINI, Mini
International Neuropsychiatric Interview.

statistical software (SAS Institute Inc.; Cary, NC; 2012) in a concepts were included in the ranking process. During mul-
nonvalidated personal computer environment. tiple rounds of iterative discussions and concept ranking,
Prediction criteria included sensitivity (the proportion of panelists reduced the initial 72-item list to 6 concepts that
participants who were identified as having bipolar I disorder were considered to be the most discriminative: number of
based on the structured clinical interview who screened posi- prior depressive episodes, comorbidities, age of onset, family
tive for bipolar I disorder); specificity (proportion of partici- history, treatment response, and manic symptoms. Mindful
pants who were identified as having MDD based on the of using patient-friendly terminology, the screening tool
structured clinical interview who screened negative for bipo- development team drafted a pool of 11 screener items
lar I disorder); positive predictive value (PPV; the proportion encompassing the 6 identified concepts for qualitative evalu-
of participants in this sample who screened positive for bipo- ation in cognitive debriefing interviews.
lar I disorder who were identified as bipolar I disorder based The initial draft items were tested and refined for clarity
on the structured clinical interview); and negative predictive and comprehension across 2 rounds of debriefing interviews
value (NPV; the proportion of participants in this sample who in participants with a self-reported diagnosis of bipolar I dis-
screened negative for bipolar I disorder who were identified order or MDD (n ¼ 6 for each round). Based on participant
as MDD based on the structured clinical interview). The con- feedback, minor modifications were made to the draft items
cordance index (C-index; equivalent to the area under the after each round of interviews. After round 2, the pool of 11
receiver operating characteristic curve) was calculated to draft items was reduced to 10 items by combining 2 items
assess overall screening tool performance and accuracy (the that assessed 3 manic symptoms (unusually energetic,
proportion of participants correctly identified as bipolar I dis- unusually happy, unusually outgoing) into 1 item (Item 8) to
order or MDD) was determined. avoid redundancy; 10 draft screener items were retained for
quantitative evaluation. Participants reported that all items
were relevant, not redundant, and easy to interpret
Results
and understand.
From 85 articles identified via targeted literature search, 54
concepts that could differentiate bipolar I disorder from
Quantitative evaluation
MDD were extracted. Clinical experts who participated in
modified Delphi panel activities ranked and refined the con- Observational study participants
cepts based on their capacity to discriminate between bipo- A total of 187 participants were recruited and scheduled for
lar I disorder and MDD; 18 additional panelist-suggested interview sessions; 27 (14.4%) people who were recruited
 CURRENT MEDICAL RESEARCH AND OPINION 139

Table 1. Participant demographic and mood disorder characteristics.

Participant characteristic Bipolar I disorder (n ¼ 67) MDD (n ¼ 72) Overall (n ¼ 139)
Age, years, mean (SD) 44 (12) 47 (14) 46 (13)
Female, n (%) 41 (61) 49 (68) 90 (65)
Race/ethnicity, n (%)
White 48 (72) 41 (57) 89 (64)
Black/African American 7 (10) 16 (22) 23 (17)
Hispanic or Latino 6 (9) 10 (14) 16 (12)
Asian 1 (2) 2 (3) 3 (2)
Other 5 (8) 3 (4) 8 (6)
Mood episode (MINI), n (%)
Participants with lifetime MDE 64 (96) 72 (100) 136 (98)
Participants with current MDE 18 (28) 21 (29) 39 (28)
Participants with lifetime mood disorder with psychotic features 37 (55) 6 (8) 43 (31)
Current Depressive Symptoms (CES-D)
Current CES-D score, mean (SD)a 23 (16) 26 (14) 25 (15)
a
Scores range from 0 to 60, with higher scores indicating greater depressive symptoms.
Abbreviations. CES-D, Center for Epidemiologic Studies Depression Scale; MDD, major depressive disorder; MDE, major depressive episode.

Table 2. Final draft screener items with additional threshold values and concept variations for testing.
Screening tool items Additional questions to elicit threshold or concept variations
1. Have there been at least 3 different periods of time (at least 2 weeks) How many periods of time (of at least 2 weeks) have you felt deeply
when you felt deeply depressed? depressed? ________
2. Did you have problems with depression before the age of 18? How old were you when you first had problems with depression? (even if
you were not yet diagnosed with depression or bipolar
disorder) ________
3. Have you tried at least 3 different antidepressants to treat How many different antidepressants have you tried to treat your
your depression? depression? ________
4. Have you ever had to stop or change your antidepressant because it made …
you highly irritable or hyper?
5. Have you ever been diagnosed with or treated for any of the following: an Have you ever been diagnosed with or treated for any of these conditions?
anxiety-related condition; ADD/ADHD; or problems with drugs or alcohol? w Anxiety or panic attacks
w ADD/ADHD
w Problems with drugs or alcohol

6. Has anyone in your family ever been diagnosed with or treated for any of Has anyone in your family ever been diagnosed with or treated for any of
the following: bipolar disorder; problems with drugs or alcohol; or these conditions?
“nervous breakdown”? w Bipolar disorder
w Problems with drugs or alcohol
w Nervous breakdown
w Anxiety or panic attacks
w Depression
7. Have you ever had a period of at least 1 week during which you were …
more talkative than normal with thoughts racing in your head?
8. Have you ever had a period of at least 1 week during which you felt any Have you ever had a period of at least 1 week during which you were … ?
of the following: unusually happy; unusually outgoing; or w Unusually happy
unusually energetic? w Unusually outgoing
w Unusually energetic
w Unusually irritable
9. Have you ever had a period of at least 1 week during which you needed …
much less sleep than usual?
10. Have you ever been admitted to the hospital for reasons related to your …
mood, emotions, or behavior?
… indicates that no thresholds were tested for this item.
Abbreviations. ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder.

missed their scheduled interview appointments and 160 current depressive symptoms, with mean CES-D scores sug-
interviews were conducted. Among the participants who gesting mild-to-moderate severity in both diagnos-
were interviewed, 21 (13.1%) did not meet diagnostic criteria tic subgroups.
for either bipolar I disorder or MDD based on the MINI clin-
ical interview and were not included in the analysis sample Bipolar I disorder draft screener tool items
(Figure 1). The final dataset included 139 participants with a The 10 draft bipolar I disorder screening tool items and add-
confirmed diagnosis of bipolar I disorder or MDD based on itional questions designed to evaluate various item permuta-
the MINI; most MINI-confirmed diagnoses (n ¼ 131) were con- tions are presented in Table 2; responses to the additional
sistent with the diagnosis reported by the participant at questions were used to inform comparisons among potential
the screening. solutions. Numeric thresholds both above and below the cor-
The mean (SD) age of study participants was 46 (13) responding threshold referenced in the draft screening tool
years; most were female and white (Table 1). Slightly more were evaluated for 3 items (Items 1, 2, and 3). Multiple
than one-quarter of the overall study population were expe- thresholds for each of these items were retained for consid-
riencing a current depressive episode; all participants had eration of potential item sets for the final screener tool.
140 R. S. MCINTYRE ET AL.

Table 3. Rapid Mood Screener final 6-item set. Table 5. RMS and MDQ classification results.
Item Response Clinical interview diagnosis Total
1. Have there been at least 6 different periods of Yes No Bipolar I disorder MDD
time (at least 2 weeks) when you felt n ¼ 58 n ¼ 64
deeply depressed?
2. Did you have problems with depression before Yes No RMS classification results
the age of 18? 6-item response set
3. Have you ever had to stop or change your Yes No Screen positivea True positives: 51 False positives: 13 64
antidepressant because it made you highly Screen negative False negatives: 7 True negatives: 51 58
irritable or hyper? Total 58 64 122
4. Have you ever had a period of at least 1 week Yes No MDQ classification results
during which you were more talkative than 15-Item MDQ
normal with thoughts racing in your head? Screen positiveb True positives: 50 False positives: 14 64
5. Have you ever had a period of at least 1 week Yes No Screen negative False negatives: 8 True negatives: 50 58
during which you felt any of the following: Total 58 64 122
unusually happy; unusually outgoing; or Test characteristics for the RMS and MDQ were based on a sample of 122 of
unusually energetic? 139 participants because 17 participants had a missing value for an additional
6. Have you ever had a period of at least 1 week Yes No question that was used to inform RMS content.
during which you needed much less sleep a
Screening positive requires that at least 4 of the 6 items are endorsed as “Yes.”
than usual? b
Screening positive requires at least 7 “Yes” responses on the 13 mania symp-
# 2020 AbbVie. All rights reserved. Reproduced in part with permission. tom questions (Item 1); “Yes” to Item 2 on the concurrence of mania symp-
toms; and “Moderate” or “Severe” to Item 3.
Abbreviations. MDD, major depressive disorder; MDQ, Mood Disorder
Table 4. Rapid Mood Screener Test performance. Questionnaire; RMS, Rapid Mood Screener.
Threshold Cumulative Sensitivity Specificity PPV NPV Accuracy
percentage ability of the summary score. The highest estimated accuracy
0 6.56 1.00 0.00 0.48 0.00 47.5 was observed with 4 or more “yes” responses; in this case,
1 18.03 1.00 0.13 0.51 1.00 54.1 the sensitivity of the RMS for identifying participants with
2 32.79 0.98 0.33 0.57 0.95 63.9
3 47.54 0.97 0.59 0.68 0.95 77.0 bipolar I disorder was 0.88 and the specificity was 0.80.
4 64.75 0.88 0.80 0.80 0.88 83.6 Three or more “yes” responses also signaled a higher likeli-
5 79.51 0.60 0.88 0.81 0.71 74.6 hood for bipolar I disorder than for MDD (Table 4).
6 100.00 0.34 0.92 0.80 0.61 64.8
Accuracy is percentage of positive correctly predicted events.
Endorsing 4 or more items yielded the best test characteristics.
Abbreviations. NPV, negative predictive value; PPV, positive predictive value.
Rapid mood screener and mood disorder questionnaire:
results in the same analysis population
Test characteristics for participants classified as bipolar dis-
Final rapid mood screener items order by the RMS and the MDQ are presented in Table 5.
After considering various permutations of item combinations, Estimated test characteristics for the RMS were better than
including different individual item thresholds where applic- those estimated for the MDQ in the study population com-
able, the screener development team selected the combin- prising 122 participants with complete RMS information
ation of items that would collectively provide an optimal (Table 6). Predictive criteria for the MDQ in this modified par-
ticipant sample were almost identical to criteria estimated in
balance of specificity and sensitivity for the final RMS while
the full analysis sample (sensitivity ¼ 0.87; specificity ¼ 0.78).
using the smallest possible number of items. Six final RMS
items, 3 that screen for bipolar I disorder risk factors and 3
that screen for manic symptoms, were chosen (Table 3; the Discussion
full version with instructions to healthcare providers is pro-
Screening for bipolar I disorder in patients with depression is
vided in English in Supplemental Material; for certain other
an appropriate and judicious strategy to help primary care
languages (Chinese [Mandarin], Chinese [Cantonese], French,
practitioners identify when a more comprehensive assess-
Spanish [Spain, USA, Mexico], Tagalog [Philippines],
ment for bipolar I disorder is warranted. The RMS was devel-
Vietnamese) please contact [email protected]).
oped with the goal of creating a pragmatic and highly
Based on responses to the additional question for draft
accurate tool that screens for bipolar I disorder using care-
Item 1, improved test characteristics were achieved when the fully constructed items with clear and precise wording. The 6
numeric threshold was revised from “at least 3” to “at least 6” items of the RMS were selected based on multiple considera-
different periods of time feeling deeply depressed, and the tions, including clinical validity, optimized sensitivity and spe-
higher threshold was selected for the final RMS item. cificity, and pragmatism. Item permutations and numeric
The 6 final items of the RMS were summed to yield pre- thresholds tested via the draft screener tool were evaluated
dictive criteria (Table 4). Since Items 1 and 2 were tested to identify the combination of items that provided an opti-
with varying thresholds, responses to additional questions mal balance of test characteristics using the fewest possible
were used to estimate final RMS test characteristics; test per- number of items. To screen for characteristics that are associ-
formance results were calculated in a sample of 122 partici- ated with bipolar I disorder, the RMS asks about the number
pants with complete RMS information (17 participants had of prior depressive episodes (Item 1), the onset of depression
missing responses to an additional question). The C-index before the age of 18 years (Item 2), and discontinuation of
was 0.87 and a score of at least 4 maximized the predictive an antidepressant because it caused the respondent to feel
 CURRENT MEDICAL RESEARCH AND OPINION 141

Table 6. RMS and MDQ test characteristics. Since identifying prior manic symptoms is challenging and
Screener tool Concordance Sensitivity Specificity PPV NPV Accuracy may require robust dialogue to help patients identify past
Index
mood elevation, using the RMS, a screening tool with well-
RMSa 0.87 0.88 0.80 0.80 0.88 83.61 crafted and precisely worded manic symptom items, as well
MDQb 0.82 0.86 0.78 0.78 0.86 81.97
as items that characterize other bipolar I disorder features,
Test characteristics for the RMS and MDQ were based on a sample of 122 of
139 participants because 17 participants had a missing value for an additional may be a distinct clinical advantage for identifying bipolar I
question that was used to inform RMS content. disorder in patients with depressive symptoms.
a
Screening positive requires that at least 4 of the 6 items are endorsed
Although other self-reported bipolar disorder screening
as “Yes.”
b
Screening positive requires at least 7 “Yes” responses on the 13 mania symp- tools are available, reliance on screening for manic symp-
tom questions (Item 1); “Yes” to Item 2 on the concurrence of mania symp- toms only or length may be obstacles to use in the clinic.
toms; and “Moderate” or “Severe” to Item 3.
Abbreviations. MDQ, Mood Disorder Questionnaire; NPV, negative predictive For example, the MDQ, which was also administered in the
value; PPV, positive predictive value; RMS, Rapid Mood Screener. RMS observational study, consists of 15 total items, and
screens for manic symptoms, manic symptoms clusters, and
highly irritable or hyper (Item 3). To screen for past manic level of impairment to identify bipolar I or II disorder. For a
symptoms, the RMS asks if there has ever been a week in positive screen, 7 of 13 MDQ manic symptom items must be
which the respondent was more talkative than normal with endorsed, and in 2 additional items, patients must affirm
racing thoughts (Item 4), felt unusually happy, outgoing, or that several of these symptoms have occurred during the
energetic (Item 5), or needed much less sleep than usual same time period and caused at least moderate impairment.
(Item 6). Based on qualitative feedback, all items were pre- In contrast, the RMS consists of 6 items and requires an
cisely worded to provide easy interpretation and clarity so endorsement of 4 or more of the items to identify patients
respondents could readily identify events that may indicate who may potentially have bipolar I disorder. Other available
past manic characteristics. Since symptoms of bipolar I dis- self-report bipolar screening tools of note include the 48-
order may first present early in life, no timeframe restrictions item Hypomanic Personality Scale (HPS) [23], the 32-item
were used, with the exception of the question designed to Mania/Hypomanic Checklist (HCL-32) [24], the Bipolar
establish the early onset of depression (i.e. before 18 years), Spectrum Diagnostic Scale (BSDS) [25], and the Mood
which is characteristic of bipolar I disorder. While an early Spectrum Self-Report (MOODS-SR) [26]. Obvious disadvan-
life (childhood) mood episode might generate an affirmative tages that may limit the usefulness of the HPS and the HCL-
RMS response that is not related to bipolar I disorder, RMS 32 in clinical practice include length and reliance on hypo-
questions are designed to create an opportunity for compre- manic/manic symptoms. Further, although the BSDS (19
hensive dialogue. Although endorsing 4 or more items items in paragraph form) and MOODS-SR (161 items) include
yielded the best test characteristics signaling a very high like- depressive symptoms, they too are long and potentially
lihood of bipolar disorder, it should be noted that 3 “yes” more complicated than a simple checklist because of their
answers also signaled a higher likelihood for bipolar disorder
scoring and formats. While the General Behavior Inventory
than MDD. A positive screen would be followed up with a
(GBI) also screens for both depressive and manic symptoms
more comprehensive diagnostic evaluation. Based on the
[27–29] and its psychometric properties have been estimated
small number of items and easily interpreted wording, the
in clinical and non-clinical samples [27,30,31], its utility is
RMS is estimated to take less than 2 minutes to complete by
also restricted by length (52–73 items) and multiple versions
a patient.
that provide inconsistent cut-off scores for positive screening,
As many patients with bipolar disorder are treated in pri-
which limits its generalizability.
mary care settings [8] and upwards of half of these patients
Since few studies provide direct comparisons of screener
present with depressive symptoms [16], it is imperative that
tools administered in the same analysis population, RMS and
clinicians have the knowledge and tools to differentiate bipo-
lar I depression from MDD. Misdiagnosis of bipolar I disor- MDQ test properties estimated in the observational study are
ders as MDD is especially concerning given the potential for of particular interest. When 4 or more RMS items were
inappropriate treatment with antidepressant monotherapy endorsed, indicating a positive screen for bipolar I disorder,
and the long attendant delay in receiving appropriate treat- the C-index was 0.87, sensitivity was 0.88, and specificity was
ment. A longer duration of untreated bipolar illness has 0.80. By comparison, when the MDQ screened positive for
been associated with worse outcomes, including a greater bipolar disorder in the same study sample, the C-index was
frequency of episodes and increased risk of hospitalization 0.82, sensitivity was 0.86, and specificity was 0.78. In addition
and suicidality, further supporting the clinical relevance of to these test characteristics, the RMS may also be more con-
timely diagnosis and treatment with an approved pharmaco- venient than the MDQ in a clinical practice setting. Namely,
logical agent [13–15]. The urgent need for timely and accur- the RMS has less than half the number of items than the
ate diagnosis is further highlighted by findings that multiple MDQ, it screens for both bipolar I disorder features and
mood episodes and longer duration illness are associated manic symptoms, it uses a simpler scoring algorithm, and it
with less effective neuroprotective mechanisms and more is estimated to take less time to complete than the com-
apparent harmful biological changes [14]; for example, it has monly cited 5 minute completion time for the MDQ [32–34].
been shown that the incidence of manic episodes was Further, the RMS is precisely worded to better differentiate
related to volume decrease in frontal brain regions [22]. manic symptoms, which is an important consideration since
142 R. S. MCINTYRE ET AL.

it may be difficult to elicit confirmation of a prior manic epi- The RMS is a practical new bipolar I disorder screening
sode from a patient with bipolar I disorder. tool that was developed to help clinicians rapidly identify
The ultimate value of a bipolar I disorder screening tool patients with depressive symptoms who may have bipolar I
depends on a clinician’s willingness to employ it in their disorder instead of MDD. Designed with the objective of
practice. In a survey of 200 HCPs who were asked about combining pragmatism and accuracy, the RMS uses a small
bipolar disorder screening tools (data on file, AbbVie), 85% number of succinctly worded patient-friendly items to min-
of respondents indicated that although they were familiar imize respondent burden and maximize the potential for use
with the MDQ, only 29% currently use it. Most HCPs (81%) in a busy clinical setting. When compared with the MDQ in
reported that they would be more likely to use the RMS the same analysis sample, the RMS had better test character-
than the MDQ, with the RMS significantly outperforming the istics while using 60% fewer items. To the authors’ know-
MDQ across the most valued bipolar disorder screening tool ledge, no prior study evaluating a bipolar disorder screening
attributes (e.g. easily answered questions, practical to use, tool has yielded better collective specificity and sensitivity
easy scoring, the minimal number of questions). Further, than the values estimated for the RMS in this study.
over two-thirds of respondents thought that the RMS was Screening with the RMS is a practical and efficient new way
better than other screening tools and 84% believed that the to help address the all too common problem of misdiagnos-
new RMS would have a positive impact on their practice. Of ing bipolar I disorder as MDD in patients with depressive
particular clinical relevance, almost half of primary care pro- symptoms. Although a screening tool does not provide a
viders indicated that they would screen a greater percentage diagnosis, patients who score 4 or more on the brief self-
of their patients because of the RMS and 76% stated that report RMS questionnaire have a strong probability of bipolar
they would be likely to use it to screen new patients with I, thus alerting primary care physicians that more thorough
evaluation is needed.
depressive symptoms. Overall, survey responses indicated
that the RMS would be a valuable addition to clinical prac-
tice settings, with a majority of primary care providers indi- Transparency
cating that this pragmatic and patient-friendly tool would
encourage them to screen more patients with depres- Declaration of funding
sive symptoms. This manuscript was supported by funding from Allergan (prior to its
Limitations of this study include its reliance on partici- acquisition by AbbVie). The authors had full control of the content and
pants recruited from qualitative research facilities, which may approved the final version.
limit generalizability to real-world samples. Additionally, since
the RMS was designed to identify bipolar I disorder among Declaration of financial/other relationships
patients who may have been misdiagnosed or initially
thought to have MDD, participants with bipolar II disorder R.S. McIntyre has received research grant support from Lundbeck, Shire,
Otsuka, National Institute of Mental Health, Canadian Institutes for
were not included in the study; the RMS is not validated in Health Research, The Brain and Behavior Research Foundation, and the
bipolar II/hypomania. As is the case with any new screening Chinese National Natural Research Foundation. He has also received
tool, additional evaluation of RMS test characteristics is war- speaker/consultant fees from Lundbeck, Pfizer, Janssen, Sunovion,
ranted. Of particular relevance, sensitivity and specificity for Bausch Health, Intra-Cellular, Takeda, Otsuka, Allergan (now AbbVie),
Purdue, Minerva, and Neurocrine. Dr. McIntyre is also CEO and share-
Item 1 (the number of previous episodes of depression) and
holder of Champignon Brands.
Item 2 (age of depression onset) were estimated using P.S. Masand has received research grant support from Allergan (now
responses to additional questions, with these data used to AbbVie). He has received speaker/consultant fees from Acadia, Allergan
inform the selection of the final item set. Further, since Item (now AbbVie), Intra-Cellular Therapies, Lundbeck, Sunovion, and Takeda.
He is also a shareholder of Centers of Psychiatric Excellence (COPE), and
1 was modified from the version administered to participants
Global Medical Education.
during the quantitative evaluation, it has not been adminis- M.D. Patel, A. Harrington, and P. Gillard are employees and share-
tered in its final form. Although the MINI item related to sui- holders of AbbVie.
cidal ideation or thoughts about death was omitted during S.L. McElroy has been a consultant to or member of the scientific
the quantitative evaluation, participants with a current or advisory board of Allergan (now AbbVie), Avanir, Bracket (now Signant
Health), F. Hoffmann-La Roche Ltd., Idorsia, Mitsubishi Tanabe Pharma
past depressive episode met the required criteria for MDD Corporation, Myriad, Naurex, Novo Nordisk, Otsuka, Shire, Sunovion, and
(depressed mood or anhedonia) and had a sufficient number Takeda Pharmaceutical Company Limited (Shire). She has also been a
of other criteria (appetite/weight change, sleep change, psy- principal or co-investigator on studies sponsored and/or funded by
chomotor agitation/retardation, fatigue, guilt/worthlessness, Alkermes, Allergan (now AbbVie), Avanir, Azevan Pharmaceuticals,
Forest, Jazz, Marriott Foundation, Medibio, Myriad, National Institute of
cognitive impairment) so that no diagnoses were reliant on
Mental Health, Naurex, Neurocrine, Novo Nordisk, Otsuka, Shire,
the excluded criteria. Additionally, all participants reported Sunovion, and Takeda Pharmaceutical Company Limited (Shire). She is
that they were on medication to treat MDD or bipolar dis- also an inventor on United States Patent No. 6,323,236 B2, Use of
order, which may limit the ability to generalize the results to Sulfamate Derivatives for Treating Impulse Control Disorders, and along
nonmedicated patients. Future validation studies in larger with the patent’s assignee, the University of Cincinnati, Cincinnati, Ohio,
has received payments from Johnson & Johnson, which has exclusive
clinical samples, racial/ethnic groups, and other settings (e.g. rights under the patent.
inpatient, primary care offices, community mental health cen- K. Sullivan has received consultant and speaker honoraria from
ters, phone/telemedicine administration) are warranted. Allergan (now AbbVie).
 CURRENT MEDICAL RESEARCH AND OPINION 143

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