Journal of Affective Disorders 169 S1 (2014) S12–S16

Contents lists available at ScienceDirect

Journal of Affective Disorders

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d

Review

Differential diagnosis of bipolar disorder and major depressive disorder

R.M. Hirschfelda,*
a
Titus H. Harris Chair, Harry K. Davis Professor, Professor and Chairperson, Department of Psychiatry, The University of Texas Medical Branch, Galveston, TX, USA

article info abstract

Article history: Background: Patients with bipolar disorder spend approximately half of their lives symptomatic and
Received 15 May 2014 the majority of that time suffering from symptoms of depression, which complicates the accurate
Received in revised form 8 August 2014 diagnosis of bipolar disorder.
Accepted 3 September 2014
Methods: Challenges in the differential diagnosis of bipolar disorder and major depressive disorder are
Keywords:
reviewed, and the clinical utility of several screening instruments is evaluated.
Bipolar disorder Results: The estimated lifetime prevalence of major depressive disorder (i.e., unipolar depression) is
Major depressive disorder over 3 and one-half times that of bipolar spectrum disorders. The clinical presentation of a major
Depression depressive episode in a bipolar disorder patient does not differ substantially from that of a patient with
Diagnosis major depressive disorder (unipolar depression). Therefore, it is not surprising that without proper
Screening screening and comprehensive evaluation many patients with bipolar disorder may be misdiagnosed
with major depressive disorder (unipolar depression). In general, antidepressants have demonstrated
little or no efficacy for depressive episodes associated with bipolar disorder, and treatment guidelines
recommend using antidepressants only as an adjunct to mood stabilizers for patients with bipolar
disorder. Thus, correct identification of bipolar disorder among patients who present with depression
is critical for providing appropriate treatment and improving patient outcomes.
Limitations: Clinical characteristics indicative of bipolar disorder versus major depressive disorder
identified in this review are based on group differences and may not apply to each individual patient.
Conclusion: The overview of demographic and clinical characteristics provided by this review may
help medical professionals distinguish between major depressive disorder and bipolar disorder.
Several validated, easily administered screening instruments are available and can greatly improve the
recognition of bipolar disorder in patients with depression.
© 2014 Elsevier B.V. All rights reserved.

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S12
2. Consequences of misdiagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S13
3. Identifying bipolar patients in depressed samples. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S13
4. Screening for bipolar disorder and measures of depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S14
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S15
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S15
Funding/support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S15
Contributor’s statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S15
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S16
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S16

1. Introduction strated in a long-term follow-up of 146 patients with bipolar I

disorder, which found that nearly half of the time over 13 years
Although mania and hypomania are the signature and most patients were symptomatic in some fashion, overwhelmingly
recognizable characteristics of bipolar disorder, depression is its with depressive symptoms (Judd et al., 2002). Thus, nearly 40%
most frequent clinical presentation. This is dramatically demon­ of the time over 13 years, individuals with bipolar disorder were
depressed. In contrast, patients were manic or hypomanic less
than 10% of the time and without symptoms about half the time
(Judd et al., 2002). The predominance of depressive compared with
* Corresponding author at: University of Texas Medical Branch, 301 University
Blvd, Galveston, TX 77555-0188, USA. Tel.: +1 409 747 9791; fax: +1 409 747 8300. mood elevation symptoms was even greater when considering
E-mail address: Rohirsch@[Link] (R.M. Hirschfield). patients with bipolar II disorder (Judd et al., 2003).

0165-0327/© 2014 Elsevier B.V. All rights reserved.

 R.M. Hirschfeld / Journal of Affective Disorders 169 S1 (2014) S12–S16 S13

Bipolar patients are much more likely to present to clinicians, Table 1

especially in outpatient settings, when they are depressed Lifetime prevalence of bipolar disorders and major depressive disorder.
(Hirschfeld et al., 2005). However, unipolar depression is more Disorder Prevalence (%)
prevalent than bipolar disorder: the lifetime prevalence of
Bipolar disorder I 1.0
unipolar major depressive disorder is 16.2%, whereas the lifetime Bipolar disorder II 1.1
prevalence of bipolar spectrum disorders is 4.5% (Table 1) (Kessler Subthreshold bipolar disorder 2.4
et al., 2003; Merikangas et al., 2007). The clinical presentation of All bipolar disorders 4.5
a patient with bipolar disorder when depressed may not differ
Major depressive disorder 16.2
from that of a non-bipolar depressed patient. In light of the higher
prevalence of unipolar depression compared with bipolar disorder Data from Kessler, R.C. et al., 2003, JAMA 289 (23), 3095-3105; and
and the similarities in clinical presentation of a depressive episode Merikangas, K.R., et al., 2007, Arch. Gen. Psychiatry 64 (5), 543-552.

in both unipolar and bipolar depression, without appropriate

screening, bipolar patients may be misdiagnosed. Whether the prescription of antidepressants for bipolar patients
Several studies have addressed the prevalence of bipolar causes harm is a subject of considerable debate. Earlier studies
disorder in patients with depressive symptoms. In a general indicated that antidepressants could cause an acceleration of
population sample of 85,358 US adults aged 18 or older, nearly mood cycles and an overall destabilization of patients with bipolar
4% screened positive for bipolar disorder using the Mood Disorder disorder in addition to precipitating a manic or hypomanic episode
Questionnaire (MDQ) (Hirschfeld et al., 2003a). Most of those (Altshuler et al., 1995; Boerlin et al., 1998; Peet, 1994; Wehr et
who screened positive for bipolar disorder had never received a al., 1988). These studies involved the earlier antidepressants,
diagnosis of bipolar disorder, and nearly a third reported having particularly tricyclic antidepressants. More recent studies of the
been diagnosed with unipolar depression (Hirschfeld et al., selective serotonin reuptake inhibitors (SSRIs) do not, in general,
2003a). In a primary care clinic, 21% of patients being treated support destabilization or switch into mania (Sidor and MacQueen,
for depression screened positive for bipolar disorder, and nearly 2011), at least with shorter-term treatment.
two-thirds of those patients reported they had never received The overall conclusion from this research and the use of
a diagnosis of bipolar disorder before (Hirschfeld et al., 2005). SSRI antidepressants in patients with bipolar disorder is that
The figures are somewhat higher for psychiatric samples, where they in general are not particularly effective in terms of treating
estimates suggest that up to more than 49% of depressed patients depression, but they may not be as dangerous as originally
may have bipolar disorder (Benazzi, 1997). This finding strongly believed.
confirms that there are many people suffering from bipolar
disorder in depressed samples, most of whom are not recognized 3. Identifying bipolar patients in depressed samples
as being bipolar, suggesting that the true prevalence, as discussed
above, may not be accurate. The key clinical question at this point is how to identify
patients with bipolar disorder among the patients presenting with
2. Consequences of misdiagnosis symptoms of depression, to ensure that these patients receive
proper treatment. There are several demographic and clinical
There are significant potential consequences of misdiagnosing characteristics that are more commonly observed in bipolar
a bipolar disorder patient experiencing a depressive episode as disorder compared with unipolar depression (Table 2) (Goodwin
having unipolar depression and treating the patient as though he and Jamison, 2007).
or she is suffering from a unipolar depression. In general, standard Patients with bipolar disorder are much more likely to have a
antidepressant therapy has not been shown to be effective in the family history of bipolar disorder (Goodwin and Jamison, 2007).
treatment of depression episodes in patients with bipolar disorder, With regard to clinical course, patients with bipolar disorder
and treatment guidelines recommend using antidepressants only typically have an earlier age of onset than those with unipolar
as adjunct therapy to mood stabilizers for bipolar depression depression. People with bipolar disorder have a mean age of
(Goodwin, 2009; Yatham et al., 2013). onset of 22 years, whereas those with unipolar depression have
Several antidepressants, including paroxetine, imipramine, an average age of onset of 26 years (Goodwin and Jamison, 2007;
sertraline, fluoxetine and bupropion, have been studied as Zisook et al., 2007). Symptoms of bipolar disorder may occur
treatments for depression in bipolar disorder patients adjunctive even earlier in many patients: in one survey, nearly two-thirds
with mood stabilizers. In general, with the important exception of respondents said that they had significant symptoms of the
of fluoxetine in combination with olanzapine (Tohen et al., 2003), disorder prior to age 19 (Hirschfeld et al., 2003b).
adjunctive use of these antidepressants has shown modest efficacy Those with bipolar disorder also are much more likely to have
at best (Nemeroff et al., 2001; Post et al., 2001; Sachs et al., 2007). had a greater number of prior affective episodes and perhaps
In the Systematic Treatment Enhancement Program for Bipolar psychiatric hospitalizations than unipolar depressed patients
Disorder trial, neither adjunctive (added to mood stabilizer or (Goldberg and Harrow, 2004; Goodwin and Jamison, 2007). They
antipsychotic) paroxetine nor adjunctive bupropion was found to are more likely to have a history of treatment-resistant depression.
be more effective than adjunctive placebo in yielding sustained They may have had difficulties with antidepressant treatment,
or transient recovery (Sachs et al., 2007). In a placebo-controlled such as becoming more depressed or irritable or experiencing
study that evaluated monotherapy with paroxetine or quetiapine mood elevation symptoms during antidepressant treatment.
for the treatment of bipolar depression, paroxetine 20 mg/day In fact, they may have even shifted into mania or hypomania
was not found to be more efficacious than placebo, whereas on antidepressants. Patients with bipolar disorder may display
quetiapine 300 mg/day and 600 mg/day was more efficacious marked seasonality, most often experiencing depression during
than placebo (McElroy et al., 2010). Although antidepressants winter months. They may also have had more prior suicide
are widely used in the treatment of such patients (Baldessarini attempts than patients with unipolar depression (Goodwin and
et al., 2008; Baldessarini et al., 2007; Ghaemi et al., 1999), these Jamison, 2007; Rihmer and Kiss, 2002).
research studies do not support the efficacy of antidepressants With regard to clinical presentation, individuals with bipolar
alone or as adjunctive to mood stabilizers in the treatment of disorder are more likely to display mood reactivity rather than
bipolar depression. simply sad mood (Goodwin and Jamison, 2007). There may be
S14 R.M. Hirschfeld / Journal of Affective Disorders 169 S1 (2014) S12–S16

Table 2 Both the MDQ and the HCL-32 are validated, useful screening
Possible indicators of bipolar disorder in depressed patients. instruments for bipolar disorder. The MDQ was introduced
Family history of bipolar disorder earlier and has been more widely used than the HCL-32, and may
Earlier onset of illness (early 20’s) be preferred because it is shorter and can be completed more
Seasonality quickly.
Numerous past episodes
Another widely used self-report instrument that can be
History of psychiatric hospitalization
Mixed states completed very quickly is the Patient Health Questionnaire
Mood reactivity (PHQ‑9). The PHQ-9 is a multi-purpose instrument used for
History of treatment-resistant depression screening, diagnosing, monitoring, and measuring the severity
Switching on antidepressants
of depression (Spitzer et al., 1999). It has 9 questions, some of
History of suicide attempt
which incorporate Diagnostic and Statistical Manual of Mental
Data from Goodwin, F.K., Jamison, K.R., 2007. Manic-Depressive Illness: Disorders, fourth edition (DSM-IV) diagnostic criteria, along with
Bipolar Disorders and Recurrent Depression. 2nd ed. Oxford University Press,
others describing other symptoms of major depressive disorder
New York, NY.
(such as decreased interest or pleasure, loss of appetite, and poor
energy). Each question is graded from zero to 3, depending on the
symptoms associated with mania or hypomania during depressive frequency of a symptom. A total score is calculated by adding the
episodes in this population, particularly increased motor activity, responses to each of the 9 questions, indicating a categorization of
rapid or pressured speech, and grandiose or other delusions. no depression to severe depression (Spitzer et al., 1999).
Patients with bipolar disorder, when depressed, are more likely The most important differences between the PHQ-9 and
to experience “inverse” neuro-vegetative symp­toms, particularly both the MDQ and HCL-32 are the symptoms assessed and
hypersomnia, weight gain, and increased appetite. They also are when these symptoms occurred. The MDQ and HCL-32 focus
more likely to be psychotic (Goodwin and Jamison, 2007) and have on assessing lifelong symptoms of mania and hypomania, while
cognitive impairment (Borkowska and Rybakowski, 2001; Wolfe the PHQ‑9 assesses current depressive symptoms (Angst et al.,
et al., 1987). Conversely, patients with unipolar depression are 2005; Hirschfeld et al., 2000; Spitzer et al., 1999). The PHQ-9 has
more likely to experience typical depressive symptoms including a sensitivity of 88% and a specificity of 88% for major depressive
insomnia, sad mood, and somatic depressive and anxiety episodes (Kroenke and Spitzer, 2002; Kroenke et al., 2001), but
symptoms (Goodwin and Jamison, 2007). does not address the challenge of distinguishing bipolar disorder
from major depressive disorder.
4. Screening for bipolar disorder and measures of depression There are several other instruments available to assess the
occurrence and severity of depressive symptoms. The Beck
Recognition of bipolar disorder in patients with depression Depression Inventory (BDI), developed by Aaron Beck, was
may be improved by using screening instruments (Table 3). The originally published in 1961 (Beck et al., 1961) and revised in
most widely used screening instrument for bipolar disorder is the 1996 to align with DSM-IV diagnostic criteria for major depressive
MDQ, a validated self-rated questionnaire that screens patients disorder (Beck et al., 1996a). The main version consists of 21
for bipolar disorder; however, it is not a diagnostic instrument questions reflecting the symptoms of depression, with responses
(Hirschfeld et al., 2000). ranging from zero to 3 on degree of severity. Examples of questions
The MDQ consists of 15 questions and takes approximately include: “I am sad all the time,” “I am disappointed in myself,”
5 minutes to complete (Hirschfeld et al., 2000). The first and “I am too tired or fatigued to do most of the things I used to
13 questions are designed to identify manic or hypomanic do” (Beck et al., 1996b). These responses are summed to create a
symptoms the patient may have experienced in the past. The last total score, which then will translate into diagnosis of minimal to
2 questions assess symptom clusters and functional impairment. severe depression (Beck et al., 1961). The original BDI and other
Patients who answer yes to at least 7 of the first 13 questions and variations of it have also been used very widely in clinical and
the symptom cluster question, as well as “moderate problem” or research settings.
“serious problem” on the functional impairment question, are The Inventory of Depressive Symptomology (IDS-SR) was
considered to be a positive screen for bipolar disorder. The MDQ developed by John Rush and colleagues to provide a more
had a sensitivity of 0.73 and a specificity of 0.90 in a validation sensitive measure for assessing depression in outpatients than
study of 198 psychiatric outpatients, indicating that the MDQ can the Hamilton Depression Rating Scale (HAM-D) (Rush et al.,
correctly identify almost three-quarters of patients with bipolar 1996). Originally 28 items (Rush et al., 1986), the current version
disorder and will screen out bipolar disorder in 9 of 10 patients is a 30-item self-report scale that includes 2 additional questions
without the condition (Hirschfeld et al., 2000). It has been widely assessing the atypical features included in DSM-IV and was
used throughout the world, having been translated into 19 validated in 1996 (Rush et al., 1996). Details on a 16-item Quick
languages and cited in more than 600 publications. Inventory of Depressive Symptomology (QIDS), also developed
The Hypomania/Mania Symptom Checklist (HCL-32), another by Rush and colleagues, were first published in 2003 (Rush et
validated self-report screening tool for bipolar disorder (Angst al., 2003). Similar to the other self-report inventories, the IDS
et al., 2005), has 2 introductory questions, the first on the and the QIDS include items that assess symptoms of depression
subject’s current emotional state, and the second on the subject’s such as waking up too early, energy level, and thoughts of death
usual level of activity, energy, and mood. Following this are 32 or suicide (Rush et al., 1996; Rush et al., 2003). The IDS and the
questions, most of which address specific symptoms of mania QIDS were developed to provide equivalent weightings for each
and hypomania. Other HCL-32 questions are more general, symptom item (other scales have variable weights), clear anchors
including questions on whether patients get into more quarrels, for symptom frequency and severity, inclusion of all symptoms
drink more coffee or alcohol, or smoke more cigarettes when in the DSM-IV major depressive episode criteria, and to provide
they are in a manic state. A score is calculated by summing the parallel clinician-rated and patient-rated scales (Rush et al., 1996;
number of positive responses to the 32 questions in the third Rush et al., 2003).
section. A score of 14 or greater is considered positive for bipolar The PHQ-9 is probably the best choice for general patient
disorder. The HCL-32 has a sensitivity of 0.8 and a specificity of screening for depression because of its brevity and widespread
0.51 (Angst et al., 2005). use. The BDI is more sensitive to change in clinical state and,
 R.M. Hirschfeld / Journal of Affective Disorders 169 S1 (2014) S12–S16 S15

Table 3
An overview of screening tools for bipolar disorder and depression.

Type of Scale Number of Questions Duration Scoring Algorithm

Bipolar Scales

Mood Disorder Questionnaire Self-report 15 <10 minutes Yes >7 of the first 13 questions and the symptom
(Hirschfeld et al., 2000) cluster question, as well as “moderate problem” or
“serious problem” on the functional impairment
question, = positive screen for bipolar disorder

Hypomania/Mania Symptom Self-report 32 (plus 2 unscored <15 minutes Total score ≥14 = potentially bipolar
Checklist (Angst et al., 2005) introductory items)

Depression Scales

Patient Health Questionnaire Self-report 9 <5 minutes Total score 5–9 = minimal symptoms
(Spitzer et al., 1999) Total score 10–14 = mild depression
Total score 15–19 = moderately severe depression
Total score >20 = severe depression

Beck Depression Inventory-II Self-report 21 <10 minutes Total score 0–9 = minimal depression
(Beck et al., 1996b) Total score 10–18 = mild depression
Total score 19–29 = moderate depression
Total score 30–63 = severe depression

Inventory of Depressive Self-report 30 (IDS) <15 minutes (IDS) Total scores

Symptomology (IDS) and or clinician-rated 16 (QIDS) <7 minutes (QIDS) 0–13 (IDS)/0–5 (QIDS) = none
Quick Inventory of Depressive 14–25 (IDS)/6–10 (QIDS) = mild
Symptomology (QIDS) 26–38 (IDS)/11–15 (QIDS) = moderate
(Rush et al., 1996; 39–48 (IDS)/16–20 (QIDS) = severe
Rush et al., 2003) 49–84 (IDS)/21–27 (QIDS) = very severe

Hamilton Depression Clinician-rated 21 (score 1st 17 only) <20 minutes Total score 0–7 = normal
Rating Scale Total score 8–13 = mild depression
(Hamilton, 1960) Total score 14–18 = moderate depression
Total score 19–22 = severe depression
Total score ≥23 = very severe depression

Montgomery-Åsberg Clinician-rated 10 <15 minutes Total score 0–6 = absence of symptoms

Depression Rating Scale Total score 7–19 = mild depression
(Montgomery and Åsberg, Total score 20–34 = moderate depression
1979; Snaith et al., 1986) Total score 35–60 = severe depression

therefore, may be more useful for monitoring these clinical 5. Conclusion

states in depressed patients. Although the IDS is much less well-
known than the BDI, it is more balanced in terms of symptom Bipolar disorder is highly prevalent in samples of depressed
contributions and may be more sensitive than the BDI to changes patients and can easily be missed, which can have negative
in clinical status. consequences. Careful clinical assessment, including screening
There are 2 clinician-administered rating scales for depression for bipolar disorder by investigating whether there is a history of
that are used in both clinical and research settings: the HAM-D and manic or hypomanic episodes (by using a scale like the MDQ), can
the Montgomery-Åsberg Depression Rating Scale (MADRS). The help substantially with correctly identifying patients with bipolar
HAM-D was developed by Max Hamilton in England more than disorder. Although there are multiple validated instruments to
50 years ago (Hamilton, 1960). It requires a clinically experienced diagnose major depressive episodes, most do not address the
rater to provide numerical ratings on 21 depressive symptoms. bipolar versus unipolar diagnostic challenge.
Examples include depressed mood, feelings of guilt, and agitation
(Hamilton, 1960). There are several different versions of the Conflict of interest
HAM-D with different numbers of items. It is the most widely For the period 10/1/2010 through 9/31/2013, Dr. Hirschfeld has received
royalties from Jones & Bartlett. He also has been a consultant for Grey Healthcare
used assessment instrument for clinician-rated depression in the Group, bioStrategies Group, Merck Manual Editorial Board, and Equinox Group.
world and has been used in many clinical trials. Additionally, he has received honoraria from Physicians Postgraduate Press, Inc,
The MADRS was developed by Montgomery and Åsberg nearly Health and Wellness Partners, Merck Manual Editorial Board, CME Outfitters,
Letters & Sciences, Nevada Psychiatric Association, and CMEology.
40 years ago to be more sensitive to changes in depressed clinical
state than the HAM-D, particularly for use in trials to test the
efficacy of antidepressant medication (Montgomery and Åsberg, Funding/support
Funding for editorial support was provided by Teva Pharmaceuticals, North
1979). It consists of 10 clinician-administered items, each of which Wales, PA. Publication of this manuscript was supported by an independent
may be rated from zero to 6. Items include apparent sadness, medical education grant from Sunovion Pharmaceuticals, Marlborough, MA.
reported sadness, lassitude, and suicidal thoughts (Montgomery
and Åsberg, 1979). The MADRS also has been used very widely in Contributor’s statement
research studies. Robert M.A. Hirschfeld, MD, wrote the initial draft of the manuscript, has
It is important to keep in mind that the PHQ-9, BDI, HAM-D, approved every edit, and has approved the final manuscript. Editorial assistance
was provided by Synchrony Medical LLC, including editorial edits, comments,
and MADRS do not address the bipolar versus unipolar diagnostic and drafting an abstract. Dr Hirschfeld has contributed to and approved the final
challenge. manuscript. Keitha S. Moseley-Dendy, MA, has also provided editorial assistance.
S16 R.M. Hirschfeld / Journal of Affective Disorders 169 S1 (2014) S12–S16

Acknowledgements A.J., Walters, E.E., Wang, P.S., 2003. The epidemiology of major depressive
Dr. Hirschfeld would like to thank Keitha S. Moseley-Dendy, MA, for her disorder: results from the National Comorbidity Survey Replication (NCS-R).
help in preparing the manuscript. Neither Dr. Hirschfeld nor Ms. Moseley- JAMA. 289 (23), 3095–3105.
Dendy received compensation for development of this manuscript. Editorial Kroenke, K., Spitzer, R.L., 2002. The PHQ-9: a new depression diagnostic and
assistance was provided, under the direction of the author, by Synchrony Medical
severity measure. Psychiatric Annals 32 (9), 1–7.
Communications, LLC, West Chester, PA; support for editorial assistance was
Kroenke, K., Spitzer, R.L., Williams, J.B., 2001. The PHQ-9: validity of a brief
funded by Teva Pharmaceuticals, North Wales, PA. Publication of this manuscript
was supported by an independent medical education grant from Sunovion depression severity measure. J. Gen. Intern. Med. 16 (9), 606–613.
Pharmaceuticals, Marlborough, MA. McElroy, S.L., Weisler, R.H., Chang, W., Olausson, B., Paulsson, B., Brecher, M.,
Teva originated the idea and funded the development of this article. The Agambaram, V., Merideth, C., Nordenhem, A., Young, A.H.; EMBOLDEN II
decision to publish this article was solely the responsibility of the author. All (Trial D1447C00134) Investigators, 2010. A double-blind, placebo-controlled
statements, opinions, and content presented in this published article are those of study of quetiapine and paroxetine as monotherapy in adults with bipolar
the author and do not represent the opinions of Teva. Teva provided a medical depression (EMBOLDEN II). J. Clin. Psychiatry 71 (2), 163–174.
accuracy review of this article. Merikangas, K.R., Akiskal, H.S., Angst, J., Greenberg, P.E., Hirschfeld, R.M.,
Petukhova, M., Kessler, R.C., 2007. Lifetime and 12-month prevalence of
bipolar spectrum disorder in the National Comorbidity Survey Replication.
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