Schizophrenia Bulletin vol. 39 no. 4 pp.
754–755, 2013
doi:10.1093/schbul/sbt083
Advance Access publication May 24, 2013
Psychotic Depression: An Underappreciated Window to Explore the Dimensionality
and Pathobiology of Psychosis
John L. Waddington*,1,2 and Peter F. Buckley3
1
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland; 2Cavan-Monaghan Mental Health
Service, Cavan General Hospital & St Davnet’s Hospital, Monaghan, Ireland; 3Medical College of Georgia, Georgia Regents
University, Augusta, GA
*To whom correspondence should be addressed; Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, St Stephen’s
Green, Dublin 2, Ireland; tel: +353-1-402 2129, fax: +353-1-402 2453, e-mail: jwadding@rcsi.ie
In historical context, the classification and consider-
ation of psychotic depression vis-à-vis schizophrenia and
bipolar disorder has long been both unsatisfactory and
contentious. Set against the backdrop of a ­continuum
of depressed mood, from normal reaction to life events
(eg, bereavement) through to severe depression with
marked anhedonia, psychomotor retardation, and
­neurovegetative changes (so-called melancholia), we have
struggled to understand the diversity of mood disorder.
Furthermore, we have struggled to determine whether
we can tease out distinct subgroups of etiological sig-
nificance or, alternatively, whether in reality these reflect
manifestations along a continuum of severity.1 Within
this schema, psychotic depression has long been consid-
ered the most severe form of depressive illness,2 a con-
ceptualization that positions psychotic depression as
distinct and potentially independent of other major psy-
choses, most notably schizophrenia and bipolar disorder.
Thus, psychosis research currently wrestles to reconcile
traditional concepts of categorical diagnosis with con-
temporary evidence favoring a dimensional approach to
nosology, pathobiology, and treatment.
Our field has evolved from classical debates, such as
the relationship between schizophrenia and schizoaffec-
tive disorder, to a contemporary situation where multiple
empirical studies and meta-analytic reviews now focus, at
several levels, on the relationship between schizophrenia
and bipolar disorder. Yet one component of psychotic
illness, despite having the potential to be equally (if not
more) informative on these challenges, is conspicuous in
its neglect: major depressive disorder with psychotic fea-
tures (MDDP). Persons experiencing the emergence of
psychosis on a background of major depressive disorder
reflect most starkly the co-occurrence of categories of
psychotic and affective diagnosis and typify most robustly
the intersection of psychotic and affective dimensions of
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psychopathology. Thus, it remains enigmatic that MDDP
has received so little systematic investigation.
Emergent evidence for underlying neurobiological simi-
larities among psychotic diagnoses, coupled with effort
to understand mental disorders through the framework
of neuroscience,3 now provide a propitious environment
to reconsider the nosological status and pathobiological
implications of MDDP vis-à-vis schizophrenia and bipolar
disorder. Moreover, these deliberations represent some of
the more fundamental challenges and opportunities that
underlie the development of the Diagnostic and Statistical
Manual of Mental Disorders-5 (DSM-5) revision process.4–6
Several important studies are now providing increas-
ing understanding of MDDP in a manner complemen-
tary to the far more numerous studies of schizophrenia
and bipolar disorder. This theme brings together leading
investigators to define our current knowledge on MDDP,
particularly prospective studies following a first psychotic
episode on a background of major depressive disorder,
in terms of epidemiology and clinical characteristics,
genetics, structural and functional neuroimaging, and
treatment. Each author will compare findings at these dif-
fering levels of investigation vis-à-vis current knowledge
of schizophrenia and bipolar disorder, and, as we pre-
pare for DSM-5, synthesize the findings vis-à-vis current
debate as to categorical vs dimensional models.
The authors give careful and thoughtful consider-
ation to these comparisons: Owoeye et  al7 describe the
prospective evaluation of a first psychotic episode on a
background of major depressive disorder, to elaborate
its epidemiology and clinical characteristics; Domschke8
brings together an unforgiving literature on the genetics
of MDDP, in terms of both clinical and molecular genet-
ics; Busatto9 summarizes both structural and functional
brain imaging findings on MDDP; Rothschild10 addresses
the vexing topic of treatment of MDDP, primarily the

relative roles of antidepressants and antipsychotics given
alone or in combination. Collectively, these articles
emphasize the current need and opportunity for a timely
reappraisal of our conceptualization of psychosis by
incorporating MDDP alongside schizophrenia and bipo-
lar disorder. They open an underappreciated window
through which to illuminate further the dimensionality
and pathobiology of psychotic illness.
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