CNS Spectrums (2017), 22, 155–160.

© Cambridge University Press 2017

doi:10.1017/S1092852917000256

REVIEW ARTICLE

Mixed features in major depressive disorder:

diagnoses and treatments
Trisha Suppes1,2* and Michael Ostacher1,2

1
VA Palo Alto Health Care System, Palo Alto, California, USA
2
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California, USA

For the first time in 20 years, the American Psychiatric Association (APA) updated the psychiatric diagnostic system for
mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Perhaps one of the
most notable changes in the DSM-5 was the recognition of the possibility of mixed symptoms in major depression and
related disorders (MDD). While MDD and bipolar and related disorders are now represented by 2 distinct chapters, the
addition of a mixed features specifier to MDD represents a structural bridge between bipolar and major depression
disorders, and formally recognizes the possibility of a mix of hypomania and depressive symptoms in someone who has
never experienced discrete episodes of hypomania or mania. This article reviews historical perspectives on “mixed states”
and the recent literature, which proposes a range of approaches to understanding “mixity.” We discuss which symptoms
were considered for inclusion in the mixed features specifier and which symptoms were excluded. The assumption that
mixed symptoms in MDD necessarily predict a future bipolar course in patients with MDD is reviewed. Treatment for
patients in a MDD episode with mixed features is critically considered, as are suggestions for future study. Finally, the
premise that mood disorders are necessarily a spectrum or a gradient of severity progressing in a linear manner is argued.

Received 31 May 2016; Accepted 7 March 2017

Key words: Atypical antipsychotics, diagnosis, major depression, mixed features, mixed symptoms, mood disorders, treatment.

Introduction concept of mixed symptoms in the setting of MDD, and

Perhaps one of the most notable changes in the
Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-5) was the recognition of the
possibility of mixed symptoms in major depression and
related disorders (MDD).1 For the first time in American
Psychiatric Association nosology, the addition of a mixed
features specifier to MDD represents a structural bridge
between bipolar and major depression disorders. While
debate continues as to the optimal definition for the
mixed features specifier, there has been increased
recognition of the possibility of a mix of hypomania and
depressive symptoms in someone whom has never
experienced hypomania or mania.
The historical context for the development of the
concept of mixed states, as well as differences in
approach, particularly in the European psychiatric
literature, is an important background to our considera-
tion of the “with mixed features” diagnosis. The evolving
* Address for correspondence: Trisha Suppes, MD, PhD, VA Palo Alto
Health Care System, 3801 Miranda Ave. 151T, Palo Alto, CA 94304,
USA. (Email: tsuppes@stanford.edu)
also whether these symptoms should be viewed as a
harbinger to the development of bipolar disorder, have
yet to be fully explored. The implications of this are
clinically significant for treatment and management.
Historical Notes
Historically, there has been a long tradition of discussion
and recognition of what may be broadly termed “mixed
states.” Marenos and Angst have written important
overviews of the development of the concept prior to
the modern era, in particular detailing with both the
ancient recognition and the gradual refinement in
definition through the work of Kraepelin and others in
the 19th century.2,3
In the older literature, the concepts of melancholia
and mania were clearly recognized in the 1800s when
mixed states was conceived as “mid-forms” or “mixtures
of exaltation and depression.”2 There was then greater
focus on this clinical presentation toward the end of the
19th century. In this period, recognition developed of
the range of disease states termed manic depression
illness (which included recurrent unipolar illness), which

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 156 T. SUPPES AND M. OSTACHER
was naturalistically observed by such individuals as
Kraepelin and Weygandt.2,3 The 6 proposed mixed states
as Kraepelin defined them are well-known: depressive or
anxious mania, excited depression, mania with thought
poverty, mania with stupor, depression with flight of
ideas, and inhibited mania.
While there was a limited focus on mixed states in the
mid-20th century, perhaps in part due to greater focus
on psychoanalytic versus biologic considerations, work
by Himmelhoch and others in the 1970s and 1980s
increased awareness that mania and depression did not
exist in only polar isolation, and raised the importance of
assessing mixed states not only as an important modifier
of disease course and treatment response, but as a
distinct subtype of bipolar disorder.4,5 While the DSM-5
recently modified the definition of mixed states, it was
recognized early on that the DSM-IV definition of a
mixed state, as only when a full episode of mania and
depression co-occurred, had limitations that did not
adequately capture clinical experience.6 Debate con-
tinues on the best definition of mixed states, as well as
which definitions should rule the day and are the most
clinically relevant.7–10
DSM-5 and Differential Diagnosis
While DSM-IV made advances in characterizing the mood
disorder range of presentation, including bipolar II
disorder for example, the definition of mixed states was
limited to full mixed episodes, requiring a full manic
episode and a full depressive episode to be simultaneously
present. There was no consideration of the possibility of
more complex and less well-delineated presentations, such
as mixed hypomania or mixed depression in bipolar
disorder—presentations which are quite familiar to clini-
cians but are not formally codified in the nomenclature. No
consideration was formally given to the possibility of MDD
mixed depression, though the European literature has
already included discussion of these more complex
presentations.11–13
More recent publications both before and during the
development of DSM-5 provided a range of evidence
supporting the more frequent presentation of mixed
symptoms over pure euphoria mania in bipolar disorder
and mixed symptoms during depression in patients with
bipolar disorder.14–16 These and other studies clarified not
only that euphoric presentations may be the minority, but
also that in bipolar disorder a mixed presentation may
herald a more severe course of illness.17
During the development of DSM-5, the consideration
was raised that mixed symptoms might also be present
during major depressive episodes in those with MDD but
lacking any history of hypomanic or manic episodes.
Active discussion led to new analyses of older data sets,
such as the National Institute of Mental Health (NIMH)
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Depression Collaborative to identify those with MDD and
some degree of hypomanic symptoms.18 These large data
sets, in concert with new European datasets including the
Bipolar Disorder: Improving Diagnosis, Guidance and
Education (BRIDGE) study, supported the possibility of
MDD depression episodes presented with mixed symp-
toms. Further studies as well as the BRIDGE study, such as
the National Comorbidity Study - Replication (NCS-R) and
the Munich study, and a reanalysis of baseline NIMH
Depression Collaborative Study data, opened the way
to consideration of mixed symptoms during a MDD
episode of depression.10,17–19 The Munich study provided
strong evidence in a somewhat younger population that
subthreshold hypomanic symptoms were present in a
substantial number of MDD episodes without the subjects
necessarily converting to a full bipolar diagnosis over a
10-year observation period.19 In this longitudinal study,
depending on how symptom count was done, based on
1 hypomanic symptom, 40% of the population observed
from an earlier age reported MDEs with some degree of
mixity. While re-examination of the NIMH Depression
Collaborative found that those subjects presenting at
baseline with a depression episode and 3 or more
hypomanic symptoms had a significant likelihood of
converting to bipolar disorder, evidence also suggested
that not all subjects with a degree of subthreshold
hypomania went on to develop bipolar disorder.18 Both
the NCS-R, an epidemiologic replication study, and the
multinational BRIDGE study demonstrated a broad range
of presentations, including subthreshold bipolarity among
many patients with MDD, as well as frank bipolar disorder
often missed.10,17 It should be noted these studies
specifically tested a hypomanic checklist in consideration
of the idea that MDD and BD exist on a continuum.
The confluence of these findings suggests that the
clinical features that distinguish bipolar disorder from
“pure” MDD are very similar to the distinguishing
features for those patients with MDD and a depressive
episode with mixed features. Cross-cultural studies
reinforce findings of increased suicidality, increased
family history of bipolar disorder, and earlier onset of
illness noted for those with MDD in a depressive episode
with mixed features versus a depressive episode without
mixed features.20 Despite the different definitions of
mixed features, these cross-cultural and cross-national
findings overall, given the numbers of patients
described, draw a picture of a potential intermediate
phenotype. This phenotype has yet to be fully defined,
given that a significant percentage fitting this profile
may develop bipolar disorder illness over time.
There has been much discussion differentiating MDD
and bipolar disorder (BD), with mixed features patients
particularly highlighted as those potentially on the road
to developing BD. However, such features as early onset,
increased recurrences, family history, and temperament

have been suggested as distinguishing features for MDD
with and without mixed features.21,22 In particular, the
notion that MDD with mixed features may be less
responsive to antidepressants has not been firmly
established. In one retrospective study (STAR*D), those
patients evidencing at least 2 mixed symptoms actually
were more responsive to antidepressants.23 This,
however, continues to be an active area of debate as to
whether patients exhibiting MDD with mixed features
are more severely ill and less likely to be responsive to
usual antidepressant treatments.24–26
Importantly, the clinical observation of increased
suicidality with mixed symptoms during depressive
episodes has been reported across a range of study
designs.9,10,24,27 While increased suicidality is certainly
not only observed during periods of mixed symptoms,
given the periodic increased energy sometimes seen
during mixed depression and the consequent lower
threshold to action in many cases, caution and careful
observation are warranted.
Diagnosis as Defined by DSM-5
In consideration of developing a specifier that would
apply to patients diagnosed with either bipolar or major
depression and related disorders, what to include or
exclude was reviewed by the DSM-5 committee. In
particular, in the interests of clarity, discussion included
whether to use all of specific symptoms at either pole and
to exclude only those symptoms that often overlap in
depression, hypomania, and mania. These overlapping
symptoms included irritability, agitation, or distractibility.
Given that irritability is a common symptom regardless of
the presence of mixed features, it was viewed as more
nonspecific and therefore more difficult to ascertain if the
irritability related to a mixed picture or simply one of illness
generally. Similar discussion led to the removal of these
overlapping symptoms. This conclusion was also reached in
the recently released position paper on mixed states by the
International Society of Bipolar Disorders.27
While the DSM-5 committee decided to exclude over-
lapping symptoms from the definition of mixed specifiers,
these excluded symptoms are important gateways to
suggest to the clinician that further evaluation for mixed
symptoms should be considered for both the diagnosis and
treatment choices.10,16,17,28–30 In particular, while these
symptoms are present at both poles and across mood
disorders in general, they serve as red flags to look deeper;
recent analyses suggest that when other mixed symptoms
are present, these 3 excluded symptoms, particularly
irritability and agitation, are likely to be present.16,31
The current criteria for major depressive episode with
mixed features are defined as meeting full episode
criteria for a depression episode, and in the last 2 weeks
some degree of the following symptoms at least every day
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MIXED FEATURES IN MAJOR DEPRESSIVE DISORDER 157
and for a noticeable amount of time, though which
symptoms present can vary. Three of the following
symptoms are required:
∙ Elevated or expansive mood
∙ Inflated self-esteem or grandiosity
∙ More talkative than usual or pressure to keep talking
∙ Flight of ideas or subjective sense that thoughts are
racing (This symptom must be distinguished from
anxiety and anxious thoughts.)
∙ Increase in energy or goal-directed activity
∙ Increase or excessive involvement in activities that
have a high potential for painful consequences
∙ Decreased need for sleep
Additional factors would include that the mixed
symptoms are observable to others and represent a
change from usual behavior, and that mixed symptoms
are not better explained by a medical condition or
substance use. (For this second qualifying condition, one
example could be depression with mixed symptoms
attributable to a recent period of using cocaine.)
There is debate as to whether 2 versus 3 symptoms is
the correct threshold to consider for meeting the mixed
features specifier. This issue was considered in the
development of the DSM-5 Mixed Features Specifier,
and it was decided that in the absence of more extensive
prospective data, a conservative decision of requiring 3
non-overlapping symptoms for the specifier should be
made.1,6,12,28 There is a range of views on this topic;
some argue that the bipolar spectrum supports consider-
ing 1 symptom during depression as consistent with a
mixed profile, though there is concern for the precision
and limits of our measurement ability.7,9,10,17 The
requirement of 3 symptoms of a non-overlapping nature
may indeed be too stringent and bias the likelihood of
patients meeting this specifier condition with MDD more
likely to be those who later go on to develop a full
hypomanic or manic episode, thus changing the diag-
nosis to bipolar disorder.18 This debate speaks to the
limits of our notions around mixity, and further
prospective, biologic, and clinical treatment data are
needed to fully inform this debate.
What Do Treatment Reports Suggest About
Mixed Depression?
At this time there are no medications approved by the US
Food and Drug Administration (FDA) for treatment of
MDD depression episode with mixed features. There is
some concern as to the specificity of this diagnosis, and
further studies will be needed to resolve this issue. The
question of whether the medications that patients respond
to during a MDE with mixed features are different than
those for a MDE without mixed features will await future
studies. Such studies are needed to directly address both the
 158 T. SUPPES AND M. OSTACHER
question of specificity of this subcategory of MDD
and to posit a possible approach to distinguishing
differences from BD II or “other specified.” While some
studies suggest no negative impact of antidepressants on
those with MDE with mixed features, others suggest the
opposite. In particular, the question remains whether
greater treatment resistance is conferred by mixed features
as defined by DSM-5.7–9,17,23,26
There is a range of definitions of mixed depression,
including the elements that were viewed as “over-
lapping” in DSM-5, but that are viewed as essential in
the conceptualization and assessment of frequency
during any mixed depression.8,13,25,29,30,32 It is of
interest to consider the 1 study to date that examined
the treatment response of patients with MDD currently
in an episode with mixed features.29
In this study of a newer atypical antipsychotic,
lurasidone, for MDD with mixed symptoms, inclusion
criteria were modified to allow entry and randomization
in this monotherapy, placebo-controlled study based
on 2 or 3 symptoms of the mixed specifier, though
overlapping symptoms of irritability, distractibility, and
agitation were excluded.29 (The study was designed and
undertaken prior to the final version of DSM-5.) The
study found benefit for lurasidone versus placebo for the
defined group over the 6-week study; the authors report
on which symptoms were most frequently observed.
About two-thirds of patients met the entry criteria of
2 mixed symptoms, while the remainder otherwise met
DSM-5 criteria for the mixed feature specifier. Of all
patients (n = 209), about 67% reported flight of ideas,
61% pressured speech, 41% decreased need for sleep,
28% increased energy or activity, 18% elevated or
expansive mood periodically, 16% increase in impulsive
behavior, and 7% inflated self-esteem or grandiosity. By
comparison for overlapping symptoms, 57% reported
irritability, 59% distractibility, and 37% agitation.
This study of a newer atypical antipsychotic provides
the most thorough prospective treatment response data to
date of subjects who approximate the mixed specifier for
MDE in MDD. Of particular note is that the overlapping
symptoms excluded from the mixed features specifier in
DSM-5 occur almost as often as the 2 most frequent
symptoms included in DSM-5: flight of ideas and
pressured speech. Thus, while excluded to bring greater
clarity to the newly proposed specifier bridging MDD and
BD, it is important to note that these symptoms may be
key to alerting the clinician and the patient that further
treatment and assessment are needed beyond the usual
approach to a major depressive episode.
Alternative Considerations for Diagnosis
What are our assumptions about mood disorder spec-
trum, and should we consider whether it really is a
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spectrum? Developing biologic data suggest that our
categories may not reflect what the brain is experiencing
in terms of how symptoms are clumping together in
comparison to the relatively arbitrary categories imposed
by DSM-5 and other similar systems of diagnosis.34
We hope that the developing biological literature will
inform the discussions on mood spectrum from the
purely observational approach currently utilized to
address these questions.1
One of our usual assumptions diagnostically is that the
development of bipolar disorder is a one-way road. The
implication of this is that once a patient has experienced
a hypomanic (or manic) episode, the lifetime diagnosis
changes to bipolar II disorder regardless of future course
of illness, or similarly once a patient has a manic episode,
his or her diagnosis changes to bipolar I and never falls
back to MDD or BDII regardless of future course. The
limitation to this one-way road is that our approach to
treatment changes from “treatment for MDD” to
“treatment for BD.” It has been observed that patients
experiencing MDD who have a MDE with mixed features
respond poorly to antidepressants, though more formal
testing of this hypothesis is needed. On the other end of
this spectrum, no one would advocate more monother-
apy antidepressants in BDI (although it is unclear what
the right treatment is, for example, for a currently
depressed 60-year-old patient whose last manic episode
was at age 22). What, however, is the correct approach to
depression in BPII? There is indication that some
patients with BDII with or without rapid cycling do
nearly as well on antidepressants as on lithium.35–37 Do
these results imply that one group of patients with mixed
features with only to-date subsyndromal hypomania,
such as those with MDD, may not do well on antidepres-
sants, but those potentially seen as further along this
one-way road in fact do fine on antidepressants? What
would these results imply about the concept of the
“spectrum” that is currently the predominant approach
to mood disorders?
There are other unconsidered paradigms besides a
simple spectrum or continuous gradient of severity.
The assumption of a one-way road to modeling
mood disorders probably should be questioned.
If all those with MDD with mixed features do not
in fact develop bipolar disorder over time, and some of
these individuals do less well on antidepressants than
some patients with bipolar II disorder, this argues for
discrete symptoms making up a set of disorders versus a
continuum. Rather than the ongoing assumption that
the only paradigm to model bipolar and major depression
and related disorders is a spectrum, it is to be hoped
that the developing biologic information will more
appropriately define whether this is a continuous or a
discontinuous process requiring other approaches than
a spectrum.

Conclusion
While the concept of mixed states is old, the specific
criteria as set out in DSM-5 are new, and treatment of
patients with MDD with mixed features is clearly lacking, so
there is a critical need to study it as a construct. Even with
such studies, critical questions may be left unanswered. The
current data from epidemiological samples, observational
samples, and subgroup analyses of treatment studies that
may have included patients with mixed features only
suggest that these patients have differential outcomes
compared to patients without such features. These data
do not explain whether prospective studies, randomized for
mixed features, will show the same differential outcomes.
Perhaps standard antidepressants alone would be effective
for them; perhaps other treatments such as monotherapy
or adjunctive antipsychotic medications, or even novel
treatments such as ketamine, would be more effective.
In spite of bipolar disorders and depressive disorders
being in different chapters in DSM-5, the mixed features
specifier remains a natural bridge between them. Depres-
sion in bipolar II disorder is nearly as inadequately studied in
a systematic way as is MDD with mixed features. However, it
is likely that the (apparently low) risk of mania from
antidepressants in bipolar II disorder will not be a barrier to
the treatment of MDD with mixed features, since presum-
ably many such patients have already safely been exposed to
antidepressants in the dozens of existing studies of MDD.
Further consideration should be given to the nature of
the presentations across mood disorders. Should we simply
consider MDD with mixed features a presentation as
inevitably on the path to developing bipolar disorder? Or
is it in fact a legitimate and delineated category distinct
from bipolar II and bipolar disorder other specified?
Certainly a proportion of patients with MDD with mixed
features will go on to develop full-criteria bipolar disorder
(as will patients with MDD alone, as is well-described),18
but only with prospective studies of patients with well-
defined MDD with mixed features—both short- and
intermediate-term in-treatment studies and longer-term
observational ones—can this answer be truly clarified.
Might there be future biomarkers, be they functional (as
in neuroimaging or through cognitive testing), genetic
(such as risk genes or epigenetic phenomena), or others,
taken in combination with studies of treatment response,
that can build a risk model for the identification of and
treatment predictions for subgroups of patients with MDD?
The assiduous use of the mixed features specifier as this is
explored may provide an additional framework in which to
find such answers.
Disclosures
Trisha Suppes reports personal fees and non-financial
support from Astra Zeneca, personal fees and non-financial
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MIXED FEATURES IN MAJOR DEPRESSIVE DISORDER 159
support from A/S H. Lunbeck, grants, personal fees
and non-financial support from Merck and Co., grants,
personal fees and non-financial support from Sunovion
Pharmaceuticals, Inc., personal fees and non-financial
support from Global Medication Education, personal
fees and non-financial support from CMEology, grants
from Stanley Medical Research Institute, grants from
Palo Alto Health Sciences Services, personal fees and
non-financial support from Medscape Education, grants
from Elan Pharma International Limited, personal fees
from Jones and Bartlett, personal fees from UpToDate,
outside the submitted work. Michael Ostacher has the
following disclosures: other consultant work with Sunovion
and Acadia Pharmaceuticals, outside the submitted work.
R E F E R E NC E S :
1. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, 5th ed. Arlington, VA: American
Psychiatric Publishing; 2013.
2. Marneros A. Origin and development of concepts of bipolar
mixed states. J Affect Disord. 2001; 67(1–3): 229–240.
3. Angst J, Marneros A. Bipolarity from ancient to modern
times: conception, birth and rebirth. J Affect Disord. 2001;
67(1–3): 3–19.
4. Himmelhoch JM, Mulla D, Neil JF, Detre TP, Kupfer DJ. Incidence
and significance of mixed affective states in a bipolar population.
Arch Gen Psychiatry. 1976; 33(9): 1062–1066.
5. Akiskal HS, Rosenthal RH, Rosenthal TL, Kashgarian M, Khani MK,
Puzantian VR. Differentiation of primary affective illness from
situational, symptomatic, and secondary depressions. Arch Gen
Psychiatry. 1979; 36(6): 635–643.
6. McElroy SL, Keck PE, Pope HG, Hudson JI, Faedda GL, Swann AC.
Clinical and research implication of the diagnosis of dysphoric or
mixed mania or hypomania. Am J Psychiatry. 1992; 149(12):
1633–1644.
7. Faedda GL, Marangoni C, Rginaldi D. Depressive mixed states:
a reappraisal of Koukopoulos’ criteria. J Affect Disord. 2015; 176: 18–23.
8. Sani G, Napoletano F, Vohringer PA, et al. Mixed depression:
clinical features and predictors of its onset associated with
antidepressant use. Psychother Psychosom. 2014; 83(4): 213–221.
9. Perugi G, Angst J, Azorin J, et al. Mixed features in patients with
a major depressive episode: the BRIDGE-II-MIX study. J Clin
Psychiatry. 2015; 76(3): e351–e358.
10. Angst J, Cui L, Swendsen J, et al. Major depressive disorder with
subthreshold bipolarity in the National Comorbidity Survey
Replication. Am J Psychiatry. 2010; 167(10): 1194–1201.
11. Kukopulos A, Caliari B, Tundo A, et al. Rapid cyclers, temperament,
and antidepressants. Compr Psychiatry. 1983; 24(3): 249–258.
12. Benazzi F, Akiskal HS. Psychometric delineation of the most
discriminant symptoms of depressive mixed states. Psychiatry Res.
2006; 141(1): 81–88.
13. Akiskal HS, Benazzi F, Perugi G, Rihmer. Agitated “unipolar”
depression re-conceptualized as a depressive mixed state:
implications for the antidepressant-suicide controversy. J Affect
Disord. 2005; 85(3): 245–258.
14. Suppes T, Mintz J, McElroy SL, et al. Mixed hypomania in 908
patients with bipolar disorder evaluated prospectively in the Stanley
Bipolar Treatment Network: a sex-specific phenomenon. Arch Gen
Psychiatry. 2005; 62(10): 1089–1096.
15. Goldberg JF, Perlis RH, Bowden CL, et al. Manic symptoms during
depressive episodes in 1380 patients with bipolar disorder: findings
from the STEP-BD. Am J Psychiatry. 2009; 166(2): 173–181.
 160 T. SUPPES AND M. OSTACHER
16. Miller S, Suppes T, Mintz J, et al. Mixed depression in bipolar
disorder: prevalence rate and clinical correlates during naturalistic
follow-up in the Stanley Bipolar Network. Am J Psychiatry. 2016;
173(10): 1015–1023.
17. Angst J, Azorin J, Bowden C, et al. Prevalence and characteristics of
undiagnosed bipolar disorders in patients with major depressive
episode. Arch Gen Psychiatry. 2011; 68(8): 791–799.
18. Fiedorowicz J, Endicott J, Leon A, Solomon D, Keller M, Coryell W.
Subthreshold hypomanic symptoms in progression form unipolar major
depression to bipolar disorder. Am J Psychiatry. 2011; 168(1): 40–48.
19. Zimmermann P, Brückl T, Nocon A, et al. Heterogeneity of DSM-IV
major depressive disorder as a consequence of subthreshold
bipolarity. Arch Gen Psychiatry. 2009; 66(12): 1341–1352.
20. Liu X, Jiang K. Should major depressive disorder with mixed features
be classified as bipolar disorder? Shanghai Arch of Psychiatry. 2014;
26(5): 294–296.
21. Perlis R, Uher R, Ostacher M, et al. Association between bipolar
spectrum features and treatment outcomes in outpatients
with major depressive disorder. Arch Gen Psychiatry. 2011;
68(4): 351–360.
22. Serra G, Koukopoulos A, De Chiara L, et al. Features preceding
diagnosis of bipolar versus major depressive disorders. J Affect
Disord. 2015; 173: 134–142.
23. Perlis R, Cusin C, Fava M. Proposed DSM-5 mixed features are
associated with greater likelihood of remission in out-patients with
major depressive disorder. Psychol Med. 2014; 44(7): 1361–1367.
24. McIntyre R, Soczynska J, Cha D, et al. The prevalence and illness
characteristics of DSM-5-defined “mixed feature specifier” in adults
with major depressive disorder and bipolar disorder: results from the
International Mood Disorders Collaborative Project. J Affect Disord.
2015; 172: 259–264.
25. Smith D, Forty L, Russell E, et al. Sub-threshold manic symptoms in
recurrent major depressive disorder are a marker for poor outcome.
Acta Psychiatr Scand. 2009; 119(4): 325–329.
26. Balázs J, Benazzi F, Rihmer Z, Rihmer A, Akiskal KK, Akiskal HS.
The close link between suicide attempts and mixed (bipolar)
depression: implications for suicide prevention. J Affect Disord.
2006; 91(2–3): 133–138.
Downloaded from https://www.cambridge.org/core. University of New Orleans, on 06 Oct 2017 at 18:00:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000256
27. Swann A, Lafer B, Perugi G, et al. Bipolar mixes states: an
International Society for Bipolar Disorders task force report of
symptom structure, course of illness, and diagnosis. Am J
Psychiatry. 2013; 170(1): 31–42.
28. Koukopoulos A, Sani G. DSM-5 criteria for depression with mixed
features: a farewell to mixed depression. Acta Psychiatr Scand. 2014;
129(1): 4–16.
29. Suppes T, Silva R, Cucchiaro J, et al. Lurasidone for the treatment of
major depressive disorder with mixed features: a randomized,
double-blind, placebo-controlled study. Am J Psychiatry. 2016;
173(4): 400–407.
30. Benazzi F, Koukopoulous, Akiskal H. Toward a validation of a new
definition of agitated depression as a mixed state (mixed
depression). Eur Psychiatry. 2004; 19(2): 85–90.
31. Benazzi F. Reviewing the diagnostic validity and utility of mixed
depression (depressive mixed states). European Psychiatry. 2008;
23(1): 40–48.
32. Benazzi F, Akiskal H. Delineating bipolar II mixed states in the
Ravenna-San Diego collaborative study: the relative prevalence
and diagnostic significance of hypomanic features during major
depressive episodes. J Affect Disord. 2001; 67(1–3): 115–122.
33. Clementz B, Sweeney J, Hamm J, et al. Identification of distinct
psychosis biotypes using brain-based biomarkers. Am J Psychiatry.
2015; 173(4): 373–384.
34. Williams L. Precision psychiatry: a neural circuit taxonomy
for depression and anxiety. Lancet Psychiatry. 2016; 3(5):
472–480.
35. Altshuler L, Sugar C, McElroy S, et al. Switch rates during lithium
monotherapy, sertraline monotherapy and lithium/sertraline
combination therapy for the acute treatment of bipolar II
depression: a randomized double-blind comparison.
Am J Psychiatry. 2017; 174(3): 266–276.
36. Amsterdam J, Shults J. Efficacy and safety of long-term fluoxetine
versus lithium monotherapy of bipolar II disorder: a randomized,
double-blind, placebo-substitution study. Am J Psychiatry. 2010;
167(7): 792–800.
37. Suppes T. Is there a role for antidepressants in the treatment of
bipolar II depression? Am J Psychiatry. 2010; 167(7): 738–740.