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Approaches: DSM-ICD
Versus RDoC
Annu. Rev. Clin. Psychol. 2016.12:435-463. Downloaded from www.annualreviews.org
Access provided by Jamia Millia Islamia University on 05/24/18. For personal use only.
Scott O. Lilienfeld and Michael T. Treadway

Department of Psychology, Emory University, Atlanta, Georgia 30322;
email: slilien@emory.edu
Annu. Rev. Clin. Psychol. 2016. 12:435–63 Keywords

First published online as a Review in Advance on diagnosis, classification, comorbidity, dimension, endophenotype
February 3, 2016
The Annual Review of Clinical Psychology is online at Abstract

clinpsy.annualreviews.org
Since at least the middle of the past century, one overarching model of
This article’s doi: psychiatric classification has reigned supreme, namely, that of the Diagnos-
10.1146/annurev-clinpsy-021815-093122
tic and Statistical Manual of Mental Disorders and the International Statistical
Copyright c 2016 by Annual Reviews. Classification of Diseases and Related Health Problems (herein referred to as
All rights reserved
DSM-ICD). This DSM-ICD approach embraces an Aristotelian view of
mental disorders as largely discrete entities that are characterized by dis-
tinctive signs, symptoms, and natural histories. Over the past several years,
however, a competing vision, namely, the Research Domain Criteria (RDoC)
initiative launched by the National Institute of Mental Health, has emerged
in response to accumulating anomalies within the DSM-ICD system. In
contrast to DSM-ICD, RDoC embraces a Galilean view of psychopathol-
ogy as the product of dysfunctions in neural circuitry. RDoC appears to
be a valuable endeavor that holds out the long-term promise of an alterna-
tive system of mental illness classification. We delineate three sets of press-
ing challenges—conceptual, methodological, and logistical/pragmatic—that
must be addressed for RDoC to realize its scientific potential. We conclude
with a call for further research, including investigation of a rapprochement
between Aristotelian and Galilean approaches to psychiatric classification.
435
Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
DSM-ICD and Kraepelin: Hints of a Paradigm Shift . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
DSM AND ICD: ORIGINS AND ASSUMPTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
DSM-ICD Successes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
DSM-ICD Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
DSM-ICD Anomalies: Taking Stock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
RDOC: INTELLECTUAL ANTECEDENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
Laboratory Methods in Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
Early Triumphs in Psychopathology Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
Biological Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
The Slow Progress of Psychopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443

Precision Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
THE BIRTH OF RDOC: FUNDAMENTAL PRESUPPOSITIONS
AND STRUCTURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
An RDoC Primer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445
The Scientific Promise of RDoC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
RDOC: CONCEPTUAL CHALLENGES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Falsifiability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Potential Overemphasis on Biological Dysfunction at the Level of an Individual . . . 448
Biological Predispositions Versus Their Behavioral Manifestations . . . . . . . . . . . . . . . . 449
Challenges Posed by Network Models of Psychopathology . . . . . . . . . . . . . . . . . . . . . . . 450
RDOC: METHODOLOGICAL CHALLENGES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
Neglect of Measurement Error . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
The Limitations of Endophenotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
RDOC: LOGISTICAL/PRAGMATIC CHALLENGES . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
The Dangers of Premature Reification of the RDoC Matrix . . . . . . . . . . . . . . . . . . . . . . 453
Implications for Grant Funding in Non-RDoC Domains . . . . . . . . . . . . . . . . . . . . . . . . . 454
Translating RDoC Findings into a Feasible Classification System . . . . . . . . . . . . . . . . . 455
THE DSM-ICD AND RDOC: QUO VADIS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
INTRODUCTION
I can calculate the motion of heavenly bodies, but not the madness of people.
—Sir Isaac Newton
In a classic article, Lewin (1935) contrasted two approaches to apprehending the state of nature.
The Aristotelian view conceptualizes different entities in the world as underpinned by qualitatively
different essences. Rocks and feathers fall at different rates, Aristotle supposed, because they are
composed of fundamentally different “stuff.” In contrast, the Galilean view regards diverse entities
as underpinned by similar underlying causal forces. For Lewin, the slow but steady march of
science has been characterized by a transition from Aristotelian to Galilean modes of thinking. As
our knowledge of the world has grown, we have come to recognize that similar causal variables
underpin the actions of seemingly disparate phenomena.
The approach enshrined in recent editions of the Diagnostic and Statistical Manual of Mental
Disorders (DSM) and the International Statistical Classification of Diseases and Related Health Problems
436 Lilienfeld · Treadway

(ICD), which we heretofore dub the DSM-ICD model, adopts—at least implicitly—an Aristotelian
model of categorization (Carson 1996). In this approach, which has been dominant in American
psychiatry over at least the past half century, disorders are presumed to constitute largely discrete
entities: They are commonly assumed to differ qualitatively from normality and from each other.
For example, the influential framework for the validation of mental disorders advanced by Robins &
Guze (1970) delineated five criteria for ascertaining whether a diagnostic entity is genuine. Among
them was the “delimitation [of the disorder] from other disorders” (p. 108), the assumption being
that a diagnosis that overlaps extensively with others is of doubtful validity.
DSM-ICD and Kraepelin: Hints of a Paradigm Shift

The reigning DSM-ICD approach is frequently referred to as neo-Kraepelinian (Blashfield
1984) in recognition of the contributions of the German systematist Emil Kraepelin, who ini-
tially believed that superficially similar mental disorders, such as dementia praecox (now termed
schizophrenia) and manic depression (now termed bipolar disorder), could be differentiated by
a detailed documentation of their (a) signs (observable manifestations), (b) symptoms (subjective
reports), and (c) natural history (trajectory over time). Kraepelin, following in the footsteps of Lin-
nean botanists (Compton & Guze 1995), regarded different mental disorders as akin to differing
species or subspecies that could be distinguished largely by their topography.
A key assumption of the neo-Kraepelinian approach is that signs and symptoms are often
sufficient to differentiate mental disorders. Nevertheless, the history of medicine reminds us that
this assumption may be unwarranted. For example, in the early twentieth century, physicians
diagnosed dozens of different fevers—ranging alphabetically from blackwater fever to yellow
fever—and distinguished them on the basis of other co-occurring signs and symptoms (Kihlstrom
2002). Today, physicians recognize that fever is a nonspecific indicator of a plethora of pathologies
rather than a disorder per se, and they attempt to identify the etiology of the fever prior to initiating
treatment.
Despite the enormous impact of the DSM on everyday research and practice, there are growing
indications that its hegemony may at last be beginning to wane. Over the past several years,
rumblings of what some have described as a paradigm shift (Fu & Costafreda 2013) or reboot
(Kendler 2014) in psychiatric classification have become increasingly audible. Ironically, many
scholars appear to have neglected the fact that, late in his career, Kraepelin (1920) expressed
doubts regarding his now familiar distinction between dementia praecox and manic depression
on the grounds that the overlap between these two conditions was too substantial: “We cannot
satisfactorily distinguish between these two diseases. The suspicion remains that we are asking the
wrong questions” (p. 527, italics added; see also Greene 2007).
Among the first responders to the call to ask the right questions, or at least better ones, has
been the National Institute of Mental Health (NIMH) and its Research Domain Criteria initiative
(RDoC; Insel et al. 2010). Though more of a promissory note than a formalized system at present,
RDoC aims to develop a system of psychiatric classification based not on signs, symptoms, and
course, à la Kraepelin, but instead on markers of psychobiological systems linked to adaptive—and
maladaptive—functioning.
DSM AND ICD: ORIGINS AND ASSUMPTIONS

The history of the DSM and its revisions has been recounted in numerous sources (e.g., Lieberman
& Ogas 2015, Lilienfeld et al. 2014, Widiger & Clark 2000, Wilson 1993), so we reprise it only
briefly here. In response to the perceived shortcomings of the first two DSMs, especially their
www.annualreviews.org • DSM-ICD Versus RDoC 437

often vague diagnostic descriptions and the low, or at best modest, interrater reliabilities of their
diagnostic categories, the American Psychiatric Association, with Robert Spitzer at the helm,
released the third edition of DSM in 1980 (DSM-III; Am. Psychiatr. Assoc. 1980). DSM-III was
influenced heavily by the seminal work of the psychiatric group at Washington University in St.
Louis, which had introduced preliminary diagnostic criteria and algorithms (decision rules) for 14
major mental disorders in the early 1970s (Feighner et al. 1972). The more immediate precursor
of DSM-III was the Research Diagnostic Criteria (RDC; Spitzer et al. 1978), which delineated
criteria and algorithms for approximately 20 major diagnostic categories, along with subtypes
within several of these categories.
Like the Feighner and RDC criteria, DSM-III was considerably more neo-Kraepelinian than
its DSM predecessors (Compton & Guze 1995), as it emphasized the differentiation of conditions
on the basis on their signs, symptoms, and natural history. In accord with its neo-Kraepelinian
emphasis, DSM-III provided users with (a) standardized diagnostic criteria and (b) algorithms for
each diagnosis. Rather than merely describing each diagnosis, as DSM-I (Am. Psychiatr. Assoc.
1952) and DSM-II (Am. Psychiatr. Assoc. 1968) had done, DSM-III delineated the specific signs
and symptoms comprising each diagnosis and the method by which they needed to be combined
to establish it. In this way, it almost certainly boosted the interrater reliability of most diagnostic
categories, although some critics have maintained that these increases were modest at best (Kirk &
Kutchins 1992). Although DSM-III-R (Am. Psychiatr. Assoc. 1987) and DSM-IV (Am. Psychiatr.
Assoc. 1994) introduced changes to many diagnoses, they retained DSM-III’s basic structure and
format.
In an effort to accommodate novel evidence that had emerged in the wake of the second
millennium, DSM-5 (Am. Psychiatr. Assoc. 2013), spearheaded by David Kupfer and Darrel
Regier, was published in May of 2013 amid a host of searing criticisms, many of which centered
on alterations to a number of diagnostic categories in the absence of adequate data (see Frances
& Widiger 2012). Although the early phases of planning for DSM-5 were rife with speculations
regarding drastic changes in its content and structure, such as a heightened focus on neuroscientific
markers or the inclusion of a dimensional system for personality disorders (Skodol et al. 2011),
DSM-5 by and large retained the principal format of DSM-IV as well as most of its major diagnoses.
Although DSM-5 is the predominant system of psychiatric classification around the world, chapter
V of the tenth revision of ICD (ICD-10) of the World Health Organization (1992) (which is similar
to the DSM in most important respects) is a neo-Kraepelinian alternative to DSM-5 that has been
adopted in numerous countries outside of the United States. ICD-11 is under construction as of
this writing.
The hue and cry regarding the most controversial changes in DSM-5, such as the deletion of the
bereavement criterion for major depressive disorder (MDD) or the jettisoning of hypochondriasis
as a diagnosis (Frances 2013), may have obscured a deeper point. With the potential exception
of (a) the inclusion of dimensional scales to capture the functioning and impairment associated
with major mental disorders and (b) the inclusion of a hybrid prototype-dimensional model for
personality disorders, both of which appeared in section III (“Emerging Measures and Models”),
DSM-5 was every bit as neo-Kraepelinian as its predecessors.
DSM-ICD Successes
Extreme skeptics of the DSM-ICD system (e.g., Greenberg 2013) have at times argued that this
approach has yielded categories with negligible validity. Similarly, in a widely publicized blog post
announcing the shift of the NIMH toward RDoC, NIMH Director Thomas Insel (2013) wrote
that the DSM’s “major weakness is its lack of validity.”

The assertion that DSM categories lack validity paints with too broad a brush. Many DSM
categories, such as major depression, panic disorder, bipolar disorder, and schizophrenia, display
at least some construct validity, as demonstrated by consistent relations with laboratory indicators,
biological correlates, natural history, and family history. For example, although the DSM diagnosis
of schizophrenia almost surely encompasses a heterogeneous mélange of overlapping conditions,
this diagnosis is associated with certain external correlates, such as smooth pursuit eye movement
dysfunction, ventricular enlargement, a chronic and frequently relapsing course, and a family
history of schizophrenia among biological relatives (e.g., Tsuang et al. 2000).
Moreover, the development of lists of empirically supported therapies—psychological treat-
ments that have been demonstrated to be efficacious for specific disorders (e.g., cognitive-
behavioral therapy for major depression, panic control treatment for panic disorder; Chambless
& Ollendick 2001)—is a testament to the treatment validity (Hayes et al. 1987) of at least some
DSM-ICD categories. If the DSM and ICD were entirely devoid of validity, one could not identify
psychological interventions that are differentially efficacious for different conditions (Garb et al.
2009; but see Inadequate Treatment Validity section). Moreover, by providing researchers and
clinicians with a lingua franca for facilitating diagnostic communication, the DSM has accelerated
scientific progress regarding the correlates, etiology, and treatment of mental disorders (see also
Kendell 1975).
DSM-ICD Anomalies
At the same time, it has become evident that the DSM-ICD approach has been beset by a growing
number of anomalies (Lilienfeld 2014b), many of which have not been adequately resolved across
DSM editions. We touch on the most noteworthy anomalies here.
Scientifically arbitrary diagnostic cut-offs. The DSM is technically agnostic with regard to
whether its conditions are categorical (taxonic) or dimensional in nature. Still, the DSM adopts
a categorical approach as a working model for measurement purposes. This model is debatable
for two major reasons. First, taxometric studies, which allow investigators to ascertain whether
an observed distribution can be decomposed into two or more independent distributions (Meehl
& Golden 1982), indicate that most DSM conditions, including the lion’s share of mood, anx-
iety, eating, personality, and externalizing disorders, appear to be underpinned by one or more
dimensions. The potential exceptions are schizophrenia spectrum disorders, autism spectrum dis-
orders, and some substance use disorders (Haslam et al. 2012). The absence of a point of rarity
(Sneath 1957) demarcating most DSM conditions from normality raises questions regarding the
Aristotelian assumption of discrete conditions. Second, even if some DSM conditions are taxonic,
this would not justify the imposition of a categorical measurement model. Such a model decreases
reliability and validity relative to a dimensional model because it forfeits valuable psychometric
information (Markon et al. 2011). Even for taxonic variables, dimensional measures almost always
provide more sensitive indicators than do categorical measures, as they offer information regarding
individuals’ proximity to the natural cut point.
Heterogeneity. The polythetic model of DSM-III-R and later DSM editions, sometimes derided
as the “Chinese menu” approach, provides criteria that are neither singly necessary nor jointly
sufficient for a diagnosis. This model has generated marked phenotypic heterogeneity. As a partic-
ularly extreme example, in DSM-5 there are 636,120 ways to meet criteria for posttraumatic stress
disorder (Galatzer-Levy & Bryant 2013). Although phenotypic heterogeneity does not necessarily
imply etiological heterogeneity, it seems unlikely that two conditions that overlap minimally in

their expression would stem from similar, let alone identical, causal influences. In addition, such
heterogeneity renders the search for etiological agents more challenging (for a discussion of this
issue with respect to MDD, see Monroe & Anderson 2015).
Comorbidity. An ideal taxonomy yields categories that are largely mutually exclusive (Frances
1980). Yet across its multiple editions, the DSM has been bedeviled by the vexing problem of
comorbidity, a term coined by Feinstein (1970) to denote the co-occurrence of two or more
putatively distinct conditions. For example, in the Australian National Survey of Mental Health
and Well-Being, 21% of participants with one DSM-IV disorder met criteria for three or more
DSM-IV disorders (Andrews et al. 2002); comparable data derive from the United States National
Comorbidity Study (Kessler et al. 1994). In one especially extreme case, a participant in a research
study simultaneously met criteria for all 10 DSM-IV (and DSM-5) personality disorders (Lilienfeld
et al. 2014)!
In the eyes of many authors, the presence of rampant comorbidity is a red flag that the DSM
is not drawing the correct diagnostic borders. Other authors (e.g., Maj 2005) go further, sug-
gesting that such comorbidity reflects the propensity of the DSM to attach different names to
slightly different manifestations of a shared predisposition, an error known as the jangle fallacy
(Block 1995). For example, most personality disorders appear to be complex constellations or
configurations of normal-range personality dimensions (e.g., antagonism, low conscientiousness,
introversion; Widiger & Trull 2007). Hence, it is hardly surprising that many of these conditions,
such as narcissistic and borderline personality disorders, display substantial covariation.
Large number of intermediate cases. An optimal classification system also consists of categories
that yield few intermediate cases (Frances 1980). Yet for most major classes of psychopathology,
one of the most frequent diagnoses is NOS (not otherwise specified), meaning that most patients
with mental disorders do not fit into any extant category (Stein et al. 2000, Westen 2012). Such
patients must be diagnosed by means of a “wastebasket category” that encompasses individuals
who are clearly disordered but whose signs and symptoms do not meet criteria for any extant
diagnosis. For eating disorders, NOS has typically been the modal diagnosis in routine clinical
settings (Fairburn & Bohn 2005); in unstructured interview studies of personality disorders, NOS
is similarly the most frequent diagnosis (Verheul & Widiger 2004).
The high prevalence of NOS diagnoses probably derives from what Hyman (2010) termed
the “problem of overspecification” (p. 166). For diagnoses, the DSM and ICD prescribe strict
criteria and algorithms that almost certainly exclude many individuals who suffer from the same
dysfunction as do most individuals within the category, but who fall barely short of the diagnostic
threshold. For example, an individual in a study who met all criteria for DSM-5 MDD but whose
episode lasted only 12 days (rather than the required two weeks) would be precluded from receiving
a formal diagnosis of MDD. Nevertheless, it is unlikely that this person differs fundamentally from
most people with MDD.
Inadequate treatment validity. As also noted previously, the presence of lists of empirically
supported therapies suggests that at least some DSM categories possess treatment validity and
clinical utility (Garb et al. 2009). Nevertheless, the linkage between diagnosis and treatment is
not nearly as tight in psychiatry as in other domains of medicine. Increasing data suggest that
although at least some treatment specificity exists (Lilienfeld 2014a), common factors—those that
cut across most or all efficacious treatments—account for hefty chunks of variance in therapeutic
outcomes (Laska et al. 2014). More broadly, the DSM era has not borne witness to large-scale
reductions in the morbidity or mortality associated with major mental disorders, nor to decreases

in suicide rates. These sobering facts stand in stark contrast to sharp declines in the death rates
associated with heart disease, stroke, cancer, and many other medical disorders (Insel 2009). It
would be unfair to attribute all of the lack of progress in diminishing psychiatric morbidity and
mortality to our contemporary system of classification. Nevertheless, this state of affairs raises the
distinct possibility that fresh approaches to classification will be needed to achieve intervention
breakthroughs.
Genetic and environmental nonspecificity. If DSM-ICD conditions were largely distinct, as

would be expected from a neo-Kraepelinian framework, one might anticipate that their genetic
and environmental architecture would similarly be largely distinct. Yet the more we learn about
most DSM conditions, the more apparent it becomes that many of the influences impinging on
them are nonspecific. For example, one recent genome-wide association study revealed that many
single nucleotide polymorphisms (SNPs) of small effect contribute to risk for five mental disorders
traditionally deemed to be etiologically disparate, namely schizophrenia, bipolar disorder, MDD,

attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. For instance, the
genetic correlation of SNPs in schizophrenia and bipolar disorder was 0.68 (Cross-Disord. Group
Psychiatr. Genom. Consort. 2013). The genetic overlap in this study is especially striking given
that several of these disorders (e.g., ADHD and schizophrenia) display little overt phenotypic
resemblance.
Similarly, there is compelling evidence for substantial environmental nonspecificity in the eti-
ology of mental disorders. For example, even after controlling statistically for childhood adversity,
childhood sexual abuse has emerged as a modest nonspecific antecedent, and perhaps a causal risk
factor, for a host of different mental disorders, including multiple mood, anxiety, and substance use
disorders (Molnar et al. 2001). Although not undermining the possibility of some disorder speci-
ficity, these findings pose a challenge to the assumption that DSM-ICD conditions are associated
with distinct specific etiologies (for a discussion of specific etiology, see Meehl 1977).
DSM-ICD Anomalies: Taking Stock

The anomalies we have reviewed reveal that all is not well with the scientific health of the DSM.
With each new DSM edition, concerted efforts have been directed to attempting to salvage the
essence of the neo-Kraepelinian framework by invoking a variety of ad hoc maneuvers, such as re-
moving, adding, or revising diagnostic criteria; changing thresholds or age of onsets for diagnoses;
adding new diagnoses or removing others; adding new disorder subtypes; and adding or removing
hierarchical exclusion rules (which prohibit certain conditions from being diagnosed if they appear
to be attributable to another condition). Yet repeated attempts to nibble around the edges of the
DSM anomalies across editions of the manual have met with at best limited success. In the words
of Kendler (2014), the DSM may have found itself in a box canyon: a deep gorge from which it
cannot extricate itself. If so, small-scale revisions to the DSM-ICD, or, in the lingo of Lakatos
(1978), modifications to the auxiliary hypotheses of the DSM-ICD research program, are unlikely
to remedy its core shortcomings. In reacting to the lack of substantial scientific progress in the
DSM-ICD research program, a growing chorus of critics has argued that this approach has failed
to carve nature at its joints, to borrow Plato’s hallowed phrase (see Gangestad & Snyder 1985).
The view that the DSM-ICD model is defective beyond repair is by no means new. In 1989,
British psychiatrist R.E. Kendell (see also Widiger & Trull 2007) wrote:
Ninety years have now elapsed since Kraepelin first provided the framework of a plausible classifi-
cation of mental disorders. Why then, with so many potential validators available, have we made so

little progress since that time? . . . One important possibility is that the discrete clusters of psychiatric
symptoms we are trying to delineate do not actually exist. (Kendell 1989, p. 313)
Ironically, a similar alarm call was sounded 13 years later by the two principal architects of DSM-
5: “Research exclusively focused on refining DSM-defined syndromes may never be successful in
uncovering their underlying etiologies. For that to happen, an as yet unknown paradigm shift may
need to occur” (Kupfer et al. 2002, p. xix). RDoC may be heralding the leading edge of this very
paradigm shift.
RDOC: INTELLECTUAL ANTECEDENTS

Many of the intellectual precursors of RDoC can be traced to early successes in the biomedical
sciences, which unearthed the etiology of what we now recognize as physical disorders masquerad-
ing as mental disorders (Schildkrout 2014). At the same time, many of the enduring failures of
this approach to traditional mental disorders, such as schizophrenia, imparted valuable sobering
lessons that were to inform RDoC.
Laboratory Methods in Medicine

It is easy to forget that by the middle or even the end of nineteenth century, medical diagno-
sis, much like modern-day psychiatric diagnosis, was based almost exclusively on a combination
of careful history taking from patients and a physical examination, an approach known as bed-
side medicine (Ackerknecht 1967). Medical tests began to be introduced in the eighteenth and
nineteenth centuries, with use of the stethoscope, opthalmoscope, and laryngoscope becoming
routine in medical examinations by the 1850s (Kihlstrom 2002). Nevertheless, it was not until the
twentieth century that laboratory tests became de rigueur for diagnosing many medical conditions
(Burke 2000). The examination of cerebrospinal fluid to detect meningitis emerged around the
turn of the twentieth century, and the Wassermann test for the detection of syphilis was devel-
oped in 1906 (Berger 1999). Today, over 3,000 standardized laboratory tests are used in standard
medical practice (Kapur et al. 2012).
Early Triumphs in Psychopathology Research

The laboratory revolution in medicine led to two sensational triumphs in the psychopathology do-
main. Specifically, medical science demonstrated that two conditions long presumed to be largely
or entirely psychogenic, namely general paresis and pellagra, were of purely organic etiology.
General paresis, also called general paralysis of the insane, accounted for 5% to 10% of hospital
admissions around the turn of the century (Tsay 2013). Its primary psychological features in-
cluded delusions, grandiosity, euphoria, concentration difficulties, and poor impulse control. In
1913, Hideyo Noguchi and J.W. Moore isolated the syphilis spirochete (Treponema pallidum) in
the brains of patients with general paresis, demonstrating that the condition was an outcome of ter-
tiary syphilis, in which the bacterium had invaded the central nervous system. Individuals suffering
from pellagra, whose symptoms included irritability, depression, insomnia, paranoia, confusion,
and memory problems, were also common fixtures in inpatient psychiatric hospitals around the
turn of the twentieth century. Research later showed this condition to be a consequence of niacin
deficiency (Sartorius 1993).
The discovery of the medical causes of general paresis and pellagra were justifiably hailed as
triumphs of biomedicine, especially because they promptly led to effective treatments (penicillin

and niacin, respectively). Coming as they did against the backdrop of the discovery of Mendelian
genetics and the germ theory of disease, they encouraged several generations of psychopathology
researchers to believe that other major mental disorders, such as schizophrenia, bipolar disor-
der, and obsessive-compulsive disorder, would similarly be traceable to a single etiological agent
(Kendler & Schaffner 2011). In many respects, however, these successes were misleading. In
the case of schizophrenia, dozens if not hundreds of candidates for the “schizochete” (Neimark
2009)—a presumably unique biological cause of the disorder, such as dopamine hyperactivity, a
dominant gene, or hypofrontality—were proposed over the years. Yet this “single bullet” approach
ultimately failed, almost surely because the causes of these disorders are exceedingly multifactorial
(Kendler 2005). This approach also foundered because these causes are not unique to schizophre-
nia but rather are shared across numerous DSM-ICD disorders. This belated realization was
almost certainly one of many catalysts for the transdiagnostic approach embraced by RDoC.
Biological Markers
The appreciation of multifactorial causality notwithstanding, the 1970s and 1980s saw keen inter-
est in the identification of biological markers for psychopathology (Iacono 1985). Sophisticated
thinkers viewed these markers not as akin to the spirochete that causes general paresis but rather
as fallible but nonetheless useful indicators that could assist in etiological and perhaps diagnostic
efforts. For example, the early 1980s bore witness to the development of the dexamethasone sup-
pression test (DST), an indicator of cortisol reactivity, to assist in the diagnosis of endogenous
depression (Carroll 1982); the discovery of reduced rapid eye movement latency as an indicator
of major depression (Kupfer et al. 1978); and the development of measures of smooth pursuit eye
movement dysfunction (Iacono et al. 1981) as an indicator of schizophrenia.
Nevertheless, the much-vaunted search for biological markers, which continues apace today,
has met with, at best, qualified success. Although some of these putative markers offered fruitful
leads to etiology, no marker displayed sufficiently high levels of both sensitivity and specificity
(as well as positive and negative predictive power) to qualify as proxies for research diagnoses,
let alone as screening or laboratory tests for routine clinical use (Insel 2014, Kapur et al. 2012). For
example, although the DST displayed reasonably high sensitivity for endogenous depression, its
specificity was often poor, reflecting high levels of false positive identifications among patients with
schizophrenia, alcoholism, anxiety disorders, and dementia (Coppen et al. 1983). As a consequence,
a state of disenchantment regarding the DST and other biological markers gradually set in. As of
today, the lone laboratory-based biological tests in the DSM are for a subset of sleep disorders,
such as assay-based measures of hypocretin levels for narcolepsy (Am. Psychiatr. Assoc. 2013), and
even these tests are hardly infallible.
Nevertheless, it has long been unclear whether the failure to detect highly sensitive and specific
markers of mental disorders reflected on the failure of the biological strategy per se rather than
on the gross imprecision of diagnostic phenotypes themselves. As the twentieth century drew to
a close, researchers were increasingly placing their bets on the latter.
The Slow Progress of Psychopharmacology

Another impetus for RDoC has been the lack of progress in the psychopharmacology industry over
the past few decades. The 1950s, which were marked by the explosive growth of psychopharmacol-
ogy, witnessed the discovery of the first tricyclic antidepressant, imipramine (Tofranil), the first
monoamine oxidase inhibitor, iproniazid (Marsilid), the first benzodiazepine, chlordiazepoxide
(Librium), and the first antipsychotic medication, chlorpromazine (Thorazine; see Lopez-Munoz

& Alamo 2009). The next two to three decades were awash in the development of scores of variants
(knockoffs) of these medications.
Yet for reasons that are still poorly understood, progress in psychopharmacology began to slow
to a crawl. Although the advent of selective serotonin reuptake inhibitors in the 1980s and atypical
antipsychotic medications in the 1990s substantially ameliorated the problematic side effect profiles
of major classes of psychiatric drugs, little evidence indicates that these new classes of medications
contributed to marked enhancements in therapeutic efficacy (Anderson 2000, Chakos et al. 2014).
As another example, recent enthusiasm concerning the potential of glutamate antagonists for
schizophrenia gave way to disillusionment in the wake of several failed clinical trials (Zink & Correll
2015). In 2011, two premier drug companies, AstraZeneca and GlaxoSmithKline, announced that
they were terminating their search for new psychiatric medications in light of the bleak outlook for
major discoveries (Cowen 2011), and other firms may soon be following suit. Although some of the
lack of progress may stem from failures of innovation and risk taking in the psychopharmacology
industry, much of it may also derive from the fact that the disorder phenotypes afforded by DSM-
ICD are too crude and heterogeneous to afford effective medication targets.
Precision Medicine
A final intellectual crosscurrent that informed RDoC was the emergence of precision medicine,
sometimes also called personalized medicine, a new branch of medicine that strives to harness
the power of clinical-pathological laboratory measures, such as genetic tests, to tailor treatments
to individuals (Mirnezami et al. 2012). For example, researchers have developed a targeted drug
treatment for a small subset (4%) of patients with cystic fibrosis who possess a specific mutation
(Insel 2014). Similarly, the treatment of breast cancer has been revolutionized by the development
of oncotype testing, permitting physicians to move from a one-size-fits-all intervention approach
to treatment geared to specific genetic profiles (Aftimos et al. 2014). The coming era of precision
medicine has stirred hopes for a similar revolution in psychiatry and clinical psychology.
THE BIRTH OF RDOC: FUNDAMENTAL PRESUPPOSITIONS

AND STRUCTURE
In many ways, RDoC has DSM to thank for its birth. During his tenure as NIMH director, Steven
Hyman expressed his concern at seeing preclinical researchers striving to develop animal models
that mimicked DSM-based diagnostic criteria. As Hyman put it, “The DSM system . . . created
an unintended epistemic prison that was palpably impeding scientific progress. . . . Even animal
studies that purported to develop disease models . . . were often judged by how closely they ap-
proximated DSM disorders” (Hyman 2010, p. 157). Under Hyman’s successor, Thomas Insel, the
NIMH sought to develop a new framework for organizing research that could liberate clinical and
translational researchers from the epistemic prison of DSM criteria. The primary concern was
not that the DSM criteria lacked validity or utility for clinical practice; rather, the issue centered
on whether the de facto wholesale appropriation of DSM criteria by the research community was
impairing the elucidation of pathophysiology. In this sense, the birth of the RDoC initiative can
be seen as inextricably linked to the NIMH’s growing emphasis on translational neuroscience to
guide research priorities.
So-named as an homage to the RDC, the RDoC was formally launched in 2009 as a bold ini-
tiative to transform the current framework of psychiatric classification into an explicitly biological
system (Cuthbert 2014a,b; Insel et al. 2010; Sanislow et al. 2010). RDoC’s aim is ambitious: to
inaugurate nothing short of a paradigm shift in descriptive psychiatry. Rather than base psychiatric

diagnosis on presenting signs and symptoms, as do DSM and ICD, RDoC strives to anchor psy-
chiatric classification and diagnosis in a scientifically supported model of neural circuitry. RDoC
conceptualizes mental disorders as dysfunctions in brain systems that bear important adaptive im-
plications, such as systems linked to reward responsiveness and threat sensitivity (see also Harkness
et al. 2014).
An RDoC Primer
In a widely discussed and controversial blog posting issued several weeks prior to the release of
DSM-5, then-NIMH Director Thomas Insel (2013) staked out a bold claim for RDoC: “NIMH
will be reorienting its research away from DSM categories. Going forward, we will be supporting
research projects that look across current categories—or subdivide current categories—to begin
to develop a better system.” Nevertheless, in subsequent communications, Insel made clear that
NIMH would continue to fund grants that included data on DSM categories, but that it would
prioritize those that emphasized transdiagnostic etiological processes.
At least for the foreseeable future, RDoC is not envisioned as a system of psychiatric classifi-
cation in its own right. Instead, in the near term, RDoC and DSM-ICD are expected to coexist.
Nevertheless, RDoC is intended to provide scaffolding for a large-scale research program that
will ultimately yield an alternative to DSM-ICD (MacDonald & Krueger 2013).
RDoC adopts no a priori stance on what form a new model of classification will eventually
take (Insel 2014). In the words of a recent NIMH director and his colleagues, RDoC is “a vision
for the future” (Insel et al. 2010, p. 749) rather than a fleshed-out proposal. As of this writing,
RDoC is largely fluid in its mission. Such flexibility is probably justifiable in the early phases of
scientific investigation, in which hypothesis generation (the context of discovery) should often
take precedence over hypothesis testing (the context of justification; Kell & Oliver 2004).
Still, the RDoC research program is not entirely open-ended. RDoC provides researchers
with an explicit rubric for guiding investigations. As can be seen in Figure 1, RDoC proposes
that research efforts be conducted within a two-dimensional matrix (Morris & Cuthbert 2012,
Weinberger & Goldberg 2014). This matrix took shape following a series of workshops held over
an 18-month period that involved panels of experts in different domains of neural circuitry. On
the horizontal axis are seven units of analysis organized roughly from more to less “basic”: genes,
molecules, cells, circuits, physiology, behavior, and self-reports (the matrix also includes a column
for paradigms, allowing investigators to indicate which tasks are useful for the research question
at hand). On the vertical axis are five broad domains/constructs that correspond to brain-based
circuits deemed relevant to psychopathology: negative valence systems (e.g., threat, loss), positive
valence systems (e.g., approach motivation, responsiveness to reward), cognitive systems (e.g.,
attention, working memory), systems for social processes (e.g., theory of mind, dominance), and
arousal/regulatory systems.
RDoC rests on several assumptions, four of which are especially crucial (Cuthbert & Insel
2013). First, RDoC is explicitly transdiagnostic in seeking markers of dysfunctional psychobiolog-
ical circuitry that transcend multiple traditional disorder categories; in this respect, it is Galilean in
its presuppositions. Second, RDoC is translational in emphasis, encouraging researchers to apply
the basic science of brain systems and behavior to an understanding of mental disorders. Third,
RDoC adopts a dimensional framework in light of evidence that the activity of most brain circuits,
such as reward and threat systems, is continuously distributed, with few or no clear-cut bound-
aries demarcating normality from abnormality. Fourth, RDoC strives to accord roughly equal
weight to different levels of analysis, including the biological and behavioral (Cuthbert & Insel
2013).

UNITS OF ANALYSIS
Domains/constructs Genes Molecules Cells Circuits Physiology Behavior Self-reports Paradigms
Negative valence systems
Acute threat (”fear”)
Potential threat (”anxiety”)
Sustained threat
Loss
Frustrative nonreward
Positive valence systems

Approach motivation
Initial responsiveness to reward
Sustained responsiveness to reward
Reward learning
Habit
Cognitive systems
Attention
Perception
Working memory
Declarative memory
Language behavior
Cognitive (effortful) control
Systems for social processes

Imitation; theory of mind
Social dominance
Facial expression identification
Attachment/separation fear
Self-representation areas
Arousal/regulatory systems
Arousal and regulation (multiple)
Resting state activity
Figure 1
The provisional matrix for the Research Domain Criteria (RDoC).
Consistent with the view of science as a self-correcting enterprise, RDoC is conceptualized as

provisional and open to revision in light of new scientific data. As a consequence, novel brain-based
constructs may be added to the matrix with the emergence of new neuroscience evidence.
The Scientific Promise of RDoC

As of this writing, there is justifiable excitement in many quarters regarding RDoC’s scientific
potential. RDoC has already begun to loosen the longstanding grip of the DSM-ICD system
over research and grant funding. This hegemony has stifled investigators’ capacity to explore
scientifically promising alternatives to the status quo model of psychiatric classification (see also
Berenbaum 2013, Harkness & Lilienfeld 2013, Markon 2013). Moreover, RDoC’s adoption of a
dimensional approach to psychopathology as a starting assumption accords with the bulk of the
evidence derived from taxometric studies, which suggests that most conditions are underpinned
by dimensions rather than by taxa, that is, natural categories (Haslam et al. 2012). In this respect,
RDoC is more consistent with data on the latent structure of mental disorders than is the DSM.
At the same time, RDoC allows for the possibility of threshold effects (tipping points) or other
categorical effects (Cuthbert & Insel 2013), whereby certain psychopathological phenomena differ
qualitatively rather than quantitatively from normality.

Furthermore, RDoC promises to capitalize on the burgeoning corpus of knowledge concerning

affective and cognitive neuroscience by applying it to the classification of mental disorders. In this
respect, it may ultimately allow for closer linkages between assessment and diagnosis, on the one
hand, and treatment and prevention, on the other. More ambitiously, RDoC may eventually shift
psychiatry and clinical psychology closer to the goal of precision medicine (Insel 2014), or at least
the more modest goal of stratified medicine, in which interventions are tailored to individuals
within well-defined subgroups demarcated by laboratory-based profiles (Kapur et al. 2012). With
the enormous recent influx of research attention and grant funding to RDoC, there is renewed
hope of uncovering laboratory-based assays with high levels of sensitivity and specificity for the
proximal pathological processes that contribute to psychopathological signs and symptoms.
In all of these respects, RDoC appears to be a valuable alternative to the current approach
to classification, especially given that the DSM-ICD’s scientific yield, which has been substantial
despite its noteworthy defects (Regier et al. 2009), appears to be reaching an asymptote. We regard
RDoC as holding out the promise of generating a competing, and ideally more valid, system of
classification relative to that of DSM-ICD. At the same time, RDoC confronts a number of
challenges, many of which have received short shrift in ongoing discussions (but see Berenbaum
2013, Lilienfeld 2014b, Shankman & Gorka 2015).
In the following section, we examine three overarching sets of challenges to RDoC: (a) con-
ceptual, (b) methodological, and (c) practical/logistical (see also Lilienfeld 2014b). Although there
is overlap among these three sets of challenges, we differentiate them for expository purposes.
Given that we intend to be constructive, we devote considerably more space to RDoC’s potential
weaknesses than to its potential strengths. Nevertheless, this differential space allotment should
not be construed as implying that we view RDoC’s weaknesses as outweighing its strengths. To
the contrary, we focus on these weaknesses in the hope that researchers and theorists, including
RDoC’s architects, will pay them greater heed and thereby increase the likelihood that RDoC
will bear scientific fruit. Because we do not perceive any of these challenges as insurmountable,
we hope that our delineation of them plays a role in shaping the future direction of RDoC.
RDOC: CONCEPTUAL CHALLENGES
Falsifiability
Popper (1959) famously argued that for a theoretical model to be scientific, it must be capable
in principle of being proven wrong. Although few contemporary philosophers of science accept
Popper’s premise that falsifiability is the lone demarcation criterion separating science from non-
science (Pigliucci & Boudry 2013), many concur that this feature is one key indicator of a model’s
scientific status. Moreover, Popper maintained that science ideally progresses by means of “severe”
or “risky” tests (see also Meehl 1978), those that place theories at grave risk of falsification.
In the case of RDoC, it is not evident what findings would suggest that it is not mapping
well onto the state of nature, or at least falling considerably short of its avowed goals. Nor is it
entirely clear what would constitute “negative” findings—results that would indicate that RDoC
is a flawed endeavor that is not leading to a feasible alternative model of classification. In our view,
it is incumbent on RDoC’s developers to lay out a set of provisional but explicit benchmarks by
which its progress, or lack of progress, can be gauged.
In a related vein, it will be critical to address the question of whether RDoC, especially once it is
better developed, is superior to the DSM-ICD model in predicting theoretically and pragmatically
relevant external criteria, such as natural history and treatment response. Based on our conversa-
tions with current and would-be RDoC grantees, it is our impression that researchers submitting

proposals within the RDoC framework are being discouraged from pitting RDoC-relevant mark-
ers against DSM diagnoses in their capacity to predict such criteria. Such advice would be ill
conceived, as it could hamper long-term efforts to ascertain whether RDoC is performing as well
as, or ideally better than, the extant system.
A further issue that bears on the falsifiability of RDoC is the distinction between conver-
gent and discriminant validity (Campbell & Fiske 1959, Cole 1987). The lion’s share of RDoC
research focuses on convergent validity, such as demonstrating that presumed markers are predic-
tive of their hypothesized RDoC domains (Shankman & Gorka 2015). For example, it is useful to
demonstrate that fear-potentiated startle is related to intrusive memories, and fear-related mem-
ories are associated with a traumatic event (Norrholm et al. 2014). This finding suggests that
fear-potentiated startle is a valid indicator of the RDoC negative valence domain, especially its
acute threat (fear) subconstruct. Nevertheless, it will be at least equally crucial to demonstrate
that putative markers are not associated with, or at least are less associated with, nonhypothesized
RDoC domains. For example, it will be important to show that fear-potentiated startle is largely
unassociated with markers of the RDoC arousal/modulatory domain, which should theoretically
be largely independent of fear, although it may be predictive of levels of baseline startle.
Potential Overemphasis on Biological Dysfunction at the Level of an Individual

RDoC posits that mental disorders are “disorders of brain circuits” (Insel et al. 2010, p. 749). As
a corollary, RDoC presumes that “The tools of clinical neuroscience . . . can be used to identify
dysfunction in neural circuits” (Morris & Cuthbert 2012, p. 33). At some level, this assumption is
merely a truism given that all psychological disorders, and all psychological phenomena for that
matter, must be mediated by the brain and the remainder of the central nervous system (Kendler
2005). Still, researchers who adopt the RDoC framework must be careful not to confuse biological
mediation with biological etiology.
In the phraseology of Graham (2013), all mental disorders are in the brain, but are not nec-
essarily of the brain. That is, at least some conditions regarded as mental disorders may stem
from neural systems reacting more or less normally to harsh or extreme environmental input.
Such reactions may be acute, such as rapid, overgeneralized fear responses to trauma, or gradual,
such as the slow accumulation of glucocorticoid resistance and chronic inflammation following
prolonged periods of life stress that may result in structural changes to key brain regions involved
in the regulation of mood (Treadway et al. 2015). Similar phenomena are observed in other areas
of medicine: Hypothermia reflects the activity of the body reacting normally to extreme envi-
ronmental input, and some forms of cardiovascular disease may be mediated in part by normal
biological responses to a chronically unhealthy lifestyle. In other cases, biological mediation may
be more akin to a lesion, in which there is a genuine loss of function due to an environmental
insult or a genetic predisposition, or their interaction. Many clinical neuroscience studies neglect
to specify these different classes of hypothesized mechanisms clearly, sufficing to label observed
differences between patient and healthy groups simply as deficits, dysfunctions, or alterations. A
limitation of the RDoC project as currently implemented is that it makes few demands for better
delineation of mechanisms at this level.
Although RDoC does not conflate biological mediation with etiology, it may inadvertently
foster this error by placing considerably less emphasis on psychosocial than on biological variables
(Hershenberg & Goldfried 2015, Lilienfeld 2014b). The RDoC matrix focuses almost exclusively
on intraindividual variables, with little or no explicit coverage of extraindividual variables, such
as the social, developmental, or cultural context (Berenbaum 2013, Shankman & Gorka 2015,
Whooley & Horwitz 2013). This omission is significant given that the phenotypic expression of

biological vulnerabilities may often be constrained by sociocultural factors. For example, religious
beliefs, as well as regional differences in the pricing and availability of alcohol, are associated
with—and probably causally linked to—risk for alcohol use disorder (Kendler 2012). Hence, even
individuals with a potent genetic propensity toward alcohol use disorder may display low rates of
this condition if raised in a socially traditional environment.
Furthermore, five of the seven RDoC units of analysis focus explicitly on biological indicators,
raising concerns that biological levels of analysis may receive undue attention by investigators
(Berenbaum 2013). Although several RDoC publications (e.g., Morris & Cuthbert 2012) have
acknowledged the importance of psychosocial variables and developmental considerations in the
RDoC program, these processes are not explicitly represented in the matrix, an omission that
RDoC may wish to remedy.
Fueling this concern is the fact that some researchers appear to have assumed erroneously
that indicators drawn from one level of analysis (e.g., physiological, behavioral) are necessarily
best suited for detecting abnormalities at that level. For example, in response to Berenbaum’s
(2013) concern that RDoC underemphasizes the role of beliefs, emotions, and other potential
emergent phenomena that are not reducible strictly to neural events (O’Connor, 1994), Cuthbert
& Kozak (2013) wrote that “Berenbaum is right in supposing that research that relies exclusively
on self-report data would fall outside of the RDoC approach” (p. 933). The reasons for this a
priori exclusion are unclear. Such decisions should be adjudicated by data, not by fiat. There is
no inherent reason why self-report measures, which can readily capitalize on aggregation across
indicators of behavior, cognition, and emotion across diverse situations, cannot provide equally—
or more—construct-valid measures of biological systems relative to biological markers of these
systems.
Biological Predispositions Versus Their Behavioral Manifestations

A key distinction that has received little attention in the RDoC literature is that between biological
predispositions to psychopathology and their behavioral manifestations (Lilienfeld 2014b). In this
respect, the distinction between basic tendencies and characteristic adaptations in the personal-
ity literature provides a useful organizing framework (Harkness & Lilienfeld 1997, McCrae &
Costa 1995; for a discussion of the concept of multifinality in developmental psychopathology,
see Franklin et al. 2014). Basic tendencies are personality traits, such as negative emotionality,
whereas characteristic adaptations are the behavioral expressions of these traits, such as an anxi-
ety disorder. Wakefield’s (1992) influential harmful dysfunction framework is broadly consistent
with this distinction; this model posits that the definition of mental disorder is a conjunction
of (a) a failure in, or breakdown of, a naturally selected psychological system (dysfunction) and
(b) impairment (harm) (but see Lilienfeld & Marino 1998 for a critique of aspects of Wakefield’s
framework). This model proposes that the presence of biological dysfunction alone is not sufficient
for psychopathology; this dysfunction must also be manifested in social harm.
The distinction between basic tendencies and characteristic adaptations underscores the point
that certain adaptations to personality traits may be largely unhealthy, whereas others may be
largely healthy. For instance, an individual with high levels of negative emotionality may manifest
this predisposition in an anxiety disorder; alternatively, the individual may manifest it in artistic
productivity, which is associated with high levels of negative emotionality. As another example,
the mean sensation-seeking scores of prisoners are essentially indistinguishable from those of
firefighters (Zuckerman 1994), suggesting that sensation seeking can be manifested in either
socially and personally destructive outlets (e.g., crime, substance abuse) or socially and personally
constructive outlets (e.g., firefighting, law enforcement).

The distinction between basic tendencies and characteristic adaptations highlights the point
that individuals with similar biological predispositions toward psychopathology can manifest these
predispositions in different ways, in part as a consequence of developmental and psychosocial
factors. If so, RDoC may be insufficient as a model for mental disorder, as it may often be unable
to distinguish physiological risk factors for psychopathology from psychopathology per se (see
also Wakefield 2014). If so, RDoC, at least in its present form, may be better suited as a model of
predispositions toward mental illness than of mental illness itself.
Challenges Posed by Network Models of Psychopathology

A growing body of research on network models of psychopathology raises the possibility that
commonly observed covariance patterns among disorder features may be due to causal relations
among signs and symptoms themselves (Borsboom & Cramer 2013). Such relations can complicate
RDoC’s emphasis on dimensionality, as they suggest that multiple patients may arrive at the same
score on an RDoC construct for different reasons. For one patient, a tendency to ruminate may
lead to difficulty sleeping, producing fatigue, which then leads to less energy for social activities,
and ultimately to social isolation and a depressed state. For this patient, symptoms related to
fatigue and depression lie causally downstream of rumination, representing a normal biologic
response to an extreme (internal) environment that is probably mediated by altered default network
function (Pizzagalli 2011). A similar end state may be attained through different pathways: A second
patient may suffer from chronic inflammation, which induces hypodopaminergia and symptoms
of anhedonia and fatigue (Felger & Miller 2014, Miller et al. 2009). RDoC does not explicitly
address this type of heterogeneity underlying common symptom severity.
RDOC: METHODOLOGICAL CHALLENGES
Neglect of Measurement Error

Consistent with the RDoC’s mission, several authors have argued that psychiatric diagnosis should
transition to a laboratory-based approach (Kihlstrom 2002; for a review, see Widiger & Clark 2000)
and thereby bring psychiatry in line with the rest of medicine (Nemeroff et al. 1999). Nevertheless,
this ambitious vision, echoed by RDoC, may be considerably more challenging to achieve than is
commonly appreciated.
Laboratory measures are typically associated with largely unappreciated psychometric weak-
nesses. As Epstein (1980) noted, psychologists have long granted such measures an undeserved
scientific cachet, often giving them a pass with respect to psychometric requirements (see also
Tryon 1973). Laboratory measures of psychological constructs frequently display low levels of
temporal and cross-situational consistency, largely because they contain substantial elements of
situational uniqueness. Performance on such measures can be affected by a plethora of contextual
and situational factors, including the mood and alertness of the participant, time of day, experimen-
tal instructions, nature of the laboratory setting, perceived attitude of the experimenter, demand
characteristics, and idiosyncrasies of the laboratory paradigm itself (Kendler & Neale 2010). These
concerns apply not merely to standard laboratory indices but also to neuropsychological measures.
For example, although many authors treat neuropsychological measures of prefrontal functioning
(e.g., Wisconsin Card Sorting Test, Stroop color-naming task, Tower of Hanoi) as largely
interchangeable, the correlations among these measures are modest (typically below r = 0.25;
Miyake et al. 2000). These relatively low associations stem in part from the task impurity problem
(Miyake & Friedman 2012; see also Abramovitch & Schweiger 2015), the tendency of many neu-
ropsychological measures to detect deficits stemming from multiple psychobiological processes.

In his classic book Personality and Assessment, Mischel (1968) observed that even seemingly
trivial changes in experimental paradigms can lead to dramatic changes in a measure’s inter-
correlations and correlations with other measures. Ironically, Kidd et al. (2013) demonstrated
this point using the very paradigm that Mischel (1974) made famous: the marshmallow test
of delay of gratification in children. They showed that a seemingly trivial alteration in the
experimental set-up—namely, whether an adult who had promised to bring a set of attractive art
supplies to the child immediately prior to the task actually did so—resulted in massive changes in
outcomes. Specifically, children exposed to the “reliable” adult waited an average of 12 minutes,
whereas children exposed to the “unreliable” adult waited an average of only 2 minutes. Kidd
and colleagues interpreted this result as suggesting that children who encounter unpredictable
environments are less likely than other children to delay gratification, as they have ample reason
to doubt whether expected rewards will materialize.
Block (1977; see also Tellegen 1991) similarly noted that T data (test data), that is, data de-
rived from isolated laboratory indicators, are more unreliable and erratic in their relations with
(a) each other and (b) other measures compared with S data (self-report data) and R data (rating
data). Although S and R data possess their own psychometric limitations, these data are typically
aggregated across multiple diverse situations. Such aggregation is often accomplished by sum-
ming items within scales, or in more sophisticated analyses, by creating latent variables using such
techniques as structural equation modeling, which minimizes situational error and yields more
reliable and construct-valid composites of behavior across situations (Epstein 1980, Rushton et al.
1983). In contrast, T data are rarely aggregated across situations, at best being combined only
across multiple trials of the same measure.
These problems may be especially acute in the domain of neuroimaging. Few investigators have
examined the test-retest reliability of measures of functional magnetic resonance imaging (fMRI;
Bennett & Miller 2010), even though this form of reliability is a basic expectation of measures
in other psychological domains. In an analysis of 63 studies, Bennett & Miller (2010) found
that the test-retest reliability of fMRI measures was typically modest, with intraclass correlations
(ICCs) averaging 0.50 (see also Vul et al. 2009). Furthermore, only 29% of activated voxels that
were statistically significant in one study were significant in a second study. Although test-retest
reliabilities for fMRI data were higher with briefer intervals, even back-to-back scans (taken within
one hour) exhibited an average cluster overlap of only 33%.
At the same time, because some of the neural processes examined in these studies may have
been influenced substantially by state variables, these modest test-retest values may reflect inher-
ent short-term fluctuations in the neural processes themselves rather than measurement error.
Scanning can be an unfamiliar experience for many participants, and initial anxiety or discomfort
in the scanner may change over repeated exposures. Moreover, repeated exposures to cognitive
tests will invariably lead to learning, even if only at the level of greater familiarity and fluency.
It would be surprising if these changes were not reflected in differences in neural responses. One
recent study used a relatively large sample to examine how activity in the ventral striatum (VS)
during the feedback phase of a rewarded instrumental conditioning task changed over time as
compared with activity during the anticipation phase (Chase et al. 2015). As would be predicted
by temporal-discounting models of reinforcement learning (Schultz et al. 1997), VS responses
to better-than-expected outcomes during the first scanning session were robust but were nearly
absent during the second session. Conversely, VS responses to anticipation were absent during the
first session but significant during the second. Moreover, the magnitude of feedback-related VS
activity at session 1 predicted the magnitude of anticipatory VS activity at session 2. This outcome-
to-cue transfer in VS activity patterns suggests a change due to learning, but it also contributes to
low interclass correlations when simply comparing the same condition across testing sessions.

These effects may also vary across different types of tasks and conditions. For example, Sauder
et al. (2013) reported that the reliability of fMRI measures of amygdala activation was adequate
in response to fearful faces (ICCs ranged from 0.32 to 0.43) but inadequate in response to angry
faces (ICCs ranged from −0.24 to 0.11). In contrast, structural MRI measures appear to have
considerably higher test-retest reliability (Kendler & Neale 2010). For example, the stability of
measures of cortical thickness as assessed by structural MRI is on the order of r = 0.95 (Wonderlick
et al. 2009).
Even the fMRI research center at which the study is conducted accounts for approximately
8% of the variance in fMRI blood oxygen-level dependent (BOLD) signal results, suggesting that
the laboratory itself is a potential source of error in analyses (Costafreda et al. 2007). Another
investigation revealed that the median ICC of fMRI findings across different imaging centers that
contained identical hardware set-ups was only 0.22 (Friedman et al. 2008).
All of these psychometric limitations may impede the replicability of functional imaging find-
ings unless addressed analytically. Adding to these concerns are findings that the average statistical
power of functional brain imaging studies is only about 0.20, which is considerably lower than
in most domains of psychological and psychiatric research (Button et al. 2013). Low power not
only increases the chances of type II errors (false negative results), but also boosts the likelihood
of overestimating the effect sizes of statistically significant findings, a phenomenon known as the
winner’s curse (Button & Munafo 2016). Replicability concerns are not limited to functional brain
imaging studies. Using a fresh sample of college students as participants, Boekel and colleagues
(2015) attempted to replicate 17 published studies on the relation between structural brain imag-
ing findings and psychological findings derived from self-reported data and other measures (e.g., a
previously reported positive correlation between amygdala gray matter and number of Facebook
friends). Using Bayesian methods, they found minimal support for any of the findings from the
previous 17 studies.
The Limitations of Endophenotypes

Endophenotypes (phenotypes located “beneath the skin”) are a core intellectual progenitor for
RDoC’s conceptualization of brain circuit dysfunction, and many RDoC studies have borrowed
heavily from endophenotype designs. Because they are presumed to be more proximal to genes
than are exophenotypes, endophenotypes should ideally provide purer and more construct-valid
indicators of genetically influenced psychobiological systems (Gottesman & Gould 2003). More-
over, because many endophenotypes cut across traditional disorder categories, endophenotypes
accord with RDoC’s transdiagnostic approach to etiology (Miller & Rockstroh 2013). Neverthe-
less, RDoC is broader than the endophenotype approach, as it does not mandate that candidate
biological markers be heritable.
Despite high initial expectations and provisional successes for certain conditions, such as
schizophrenia (Cannon & Keller 2006, Miller & Rockstroh 2013), the endophenotypes identified
to date have not necessarily proven to be more genetically informative than traditional exophe-
notypes, such as DSM criteria. Flint & Munafò (2007) examined this issue in meta-analyses of
studies of catechol-O-methyltransferase (COMT), an enzyme that metabolizes dopamine (among
other neurotransmitters), and schizophrenia, a disorder associated with dopamine overactivity
in mesolimbic regions. They tested whether the COMT genotype displayed higher effect sizes
with candidate neuropsychological and psychophysiological endophenotypes of schizophrenia,
such as performance on the Wisconsin Card Sorting Test, the N-Back Task, and P300 amplitude
and latency, than with DSM schizophrenia itself. Flint & Munafò (2007) found no evidence
that the ostensible endophenotypes were more highly related to the COMT genotype than

was schizophrenia. Their findings suggest that investigators should not assume that candidate
endophenotypes will necessarily yield higher effect sizes than do exophenotypes in genetic studies
(for a more sanguine view of the status of endophenotypes for schizophrenia, see Tan et al. 2008).
In contrast, Jonas & Markon (2014) reported more encouraging results. They examined the
relation between (a) three polymorphisms in the dopamine and serotonin systems that are poten-
tially relevant to impulsivity and (b) diagnostic (e.g., measures of ADHD), trait (e.g., self-report
measures of impulsivity), neuropsychological (e.g., continuous performance tasks), and neurobio-
logical (e.g., functional imaging indices of right inferior prefrontal activity) phenotypes relevant to
impulsivity. Neurobiological measures were the most highly associated with the genetic markers,
with trait and neuropsychological measures roughly tied for a distant second, and diagnostic mea-
sures last. These analyses suggest that neurobiological measures, such as functional brain imaging
indices, may be promising endophenotypes of impulsivity. Still, as the authors observed, neurobi-
ological studies were characterized by considerably lower statistical power than studies from other
domains, raising the possibility that the effect sizes of the former studies were inflated.
One prominent model of endophenotypes conceptualizes them as intermediate phenotypes,
operating as mediators between genes and exophenotypes. Nevertheless, the evidence that candi-
date endophenotypes mediate the relation between genes and behavioral phenotypes is slim. In a
twin sample, Kendler et al. (1993) found that although neuroticism was associated with elevated
rates of major depression, it did not mediate the association between genetic risk and major de-
pression. Waldman (2005) reported inconsistent findings concerning whether scores on the Trail
Making Test mediate relations between dopamine genes and ADHD, with partial mediation for
Trails A but no significant mediation for Trails B.
Such mediation should not be presumed, as certain putative endophenotypes may lie causally
downstream of the exophenotypes with which they are associated (Kendler & Neale 2010). For
example, P300 amplitude appears to be a valid endophenotype for a broad predisposition toward
externalizing behavior and disinhibition (Patrick et al. 2006). Nevertheless, P300 amplitude is
exquisitely sensitive to attention (Polich 2012). Hence, this marker may be a consequence, not
an antecedent, of the attentional and motivational deficits associated with externalizing disorders,
such as antisocial personality and substance use disorders, which covary extensively with ADHD
(Lilienfeld & Waldman 1990, Torgersen et al. 2006).
One crucial assumption guiding the search for endophenotypes is that the biological indicators
in question are trait rather than state markers, as a measure of a biological vulnerability would
be expected to be stable over time. Again, the trait status of such markers must be demonstrated
empirically rather than assumed (Stoyanov & Kandilarova 2014). For example, motion discrimina-
tion appears to be impaired in both patients with schizophrenia and in their nonaffected relatives,
suggesting that it is a useful trait marker of the disorder. In contrast, motion integration appears to
be impaired in patients with schizophrenia but not in their nonaffected relatives, suggesting that
it is influenced by state variables (Chen et al. 2006). One major challenge for researchers will be
to demonstrate that endophenotypes, as well as other ostensible vulnerability markers of RDoC
domains, are present even between disorder episodes or exacerbations.
RDOC: LOGISTICAL/PRAGMATIC CHALLENGES
The Dangers of Premature Reification of the RDoC Matrix

As noted previously, the RDoC matrix is intended to be provisional. It comprises cells directing
investigators to well-supported neural circuits linked to psychopathology while leaving open the
possibility of modifying extant cells or adding new ones on the basis of new evidence (Cuthbert

& Insel 2013). In this regard, this matrix appears to represent a reasonable compromise between
excessive open-endedness and excessive prescriptiveness.
At the same time, there is a danger of premature reification of the matrix and of the RDoC
endeavor more broadly; it would indeed be unfortunate if the march to freedom from the DSM’s
“epistemic prison” (Hyman 2010, p. 157) led merely to a padded cell in the matrix penitentiary.
A number of scholars have cautioned against such reification in the frequent (mis)interpretation
of DSM categories as settled truths (Kendler 2014), and RDoC must be careful to avoid the same
error. In fairness, the RDoC framers have repeatedly described their intentions for the matrix
to be a working document. Good intentions, however, may afford inadequate protection against
ossification, which can easily insinuate itself through the mundane, bureaucratic activities required
by any large-scale administrative effort. For instance, several recent requests for applications
(RFAs) from NIMH have noted that “Applications must focus on at least one of the constructs
that have been defined in these RDoC workshops” (NIH RFA-MH-14-050; see Shankman &
Gorka 2015). Such wording appears to vitiate RDoC’s avowed goal of being self-correcting, as it
will be difficult or impossible to ascertain whether to add novel cells to the matrix unless these
cells are explicitly investigated. Social cognition research suggests that once mental categories are
set in place, they can quickly become implacable (McCrae & Bodenhausen 2000). To avoid the
error of reification, RDoC should encourage researchers to examine psychobiological constructs
that have the potential to bridge, transcend, or challenge current matrix boundaries, as well as
articulate an explicit process of matrix evaluation and revision. Additionally, RFAs should offer as
much consideration to proposals that seek to explicitly challenge matrix boundaries as they do to
proposals that operate within them.
Although the RDoC matrix was constructed to be broad and flexible, a number of fruitful
hypotheses exist that may be challenging to capture within its framework. For example, some
studies suggest that emotional numbing and alexithymia may be core facets of reduced approach-
related behaviors, but only in the context of response to a traumatic experience, as in posttraumatic
stress disorder (Kashdan et al. 2006). It is not clear, however, how this type of etiology-by-symptom
interaction would be examined within the RDoC framework.
Implications for Grant Funding in Non-RDoC Domains

The RDoC initiative developed from an explicit desire to support translational neuroscience in
mental health research. It is therefore perhaps unsurprising that the RDoC has hastened the
already significant shift in NIMH extramural funding priorities away from psychosocial research,
including research on psychotherapy (Goldfried 2015). Although we welcome the emphasis on
translational neuroscience, there is a legitimate concern that this approach may burn the candle
too far at both ends. On the one hand, as a consequence of RDoC, basic neuroscience efforts
to understand circuit function more generally may be at risk for being underfunded, raising the
concern of insufficient knowledge available for translation. On the other hand, the promise of
neuroscience-guided treatment and diagnosis appears to be on the distant horizon (Frances &
Widiger 2012, Paulus 2015), whereas research devoted to improvements to empirically supported
treatments for psychopathology could alleviate the suffering of thousands in the near term. It would
therefore be beneficial for RDoC to coexist with research programs focused on (a) developing basic
science knowledge without necessarily requiring immediate demonstration of clear translatability
and (b) clinical outcome and process research that can yield important short-term treatment
breakthroughs.

Translating RDoC Findings into a Feasible Classification System

One crucial challenge for RDoC will be to delineate how the large and diverse corpus of find-
ings emanating from its investigations will be meaningfully synthesized into the rudiments of an
alternative model of classification. The RDoC matrix is a heuristic blueprint to guide research,
but it is not a classification system in and of itself, nor is it intended to be. A key unanswered
question, then, is how RDoC findings will be translated into a usable system that can ultimately
guide clinical practice. Although it may too early to address this question, it will be incumbent on
RDoC architects to sketch out an overarching plan for how RDoC research will be used to inform
classification and diagnosis. In the absence of such a rubric, it may be difficult to convert the enor-
mous wealth of data yielded by RDoC investigations into a concrete model that can supplement,
or perhaps eventually substitute for, the DSM-ICD model.
THE DSM-ICD AND RDOC: QUO VADIS?

The DSMs, especially DSM-III and its progeny, were noteworthy achievements in psychiatric
classification, and they brought considerable order and diagnostic reliability to previously dis-
organized territory. In certain respects, the DSM-ICD model has served us well (cf. Greenberg
2013), as it has facilitated epidemiological and etiological research and contributed to the de-
velopment of efficacious interventions that have alleviated the suffering of countless individuals.
Moreover, by mapping onto signs and symptoms, the DSM does a serviceable and face-valid job
of capturing the essence of individuals’ distress and impairment. It is difficult to imagine a compre-
hensive system of psychiatric classification bereft of any reference to the subjective and behavioral
manifestations of people’s psychological suffering.
At the same time, it has become evident that many central features of the DSM-ICD model do
not map adequately onto the state of nature (Sanislow et al. 2010). The high levels of covariation
among putatively distinct categories, the large number of intermediate cases, and the substantial
phenotypic and etiological heterogeneity of numerous diagnostic categories, among other vexing
anomalies, suggest that something is deeply awry with at least some core presuppositions un-
derpinning the neo-Kraepelinian model of psychiatric classification. Moreover, these problems
have proven stubbornly resistant to repeated efforts at amelioration across multiple DSM and
ICD revisions. The shortcomings of the DSM-ICD edifice therefore appear to reflect an inher-
ent deficiency in its architectural floor plan that cannot be fixed merely by adjusting some of its
walls.
The RDoC initiative emerged in the new millennium to address these mounting anomalies
(Insel 2014), and it appears to be a valuable effort to ground psychopathology in well-supported
biological systems that carry important implications for adaptation and maladaptation (Lilienfeld
2014b). In this respect, RDoC has the potential to map more closely than the DSM-ICD onto
psychobiological reality. Moreover, even its critics acknowledge that RDoC has already exerted
one important salutary effect: loosening the stranglehold of the DSM over research and grant
funding. Such hegemony has impeded the investigation of fruitful alternatives to classification
and etiology, and we experience few qualms in bidding it a greatly belated adieu.
In this respect, RDoC must heed some of the lessons of the past. One historical feature shared
by DSM-ICD and RDoC is that neither was intended to become a fixed system in terms of guiding
research priorities. Yet, the DSM system eventually acquired such sovereignty over research that
it became difficult for investigators to examine clinical problems that fell outside of traditional dis-
order boundaries (Hyman 2010). RDoC must make concerted efforts to avoid the same reification
error.

Table 1 A baker’s dozen recommendations for RDoC

1. Lay out explicit benchmarks for ascertaining what findings, or patterns of findings, could falsify the RDoC research framework
or at least suggest that it is not making adequate scientific progress
2. Examine how RDoC is performing relative to the DSM-ICD approach for statistically predicting important external criteria,
such as response to treatment and natural history
3. Explicate alternative models for dysfunction in psychobiological systems (e.g., lesion, hyperactivity, or hypoactivity in the
functioning of these systems; a network model in which there are bidirectional causal relations among diagnostic signs and
symptoms)
4. Accord adequate attention to environmental (e.g., social and cultural context) and developmental influences, and incorporate
such influences explicitly into the RDoC matrix to encourage their investigation
5. Adopt no a priori assumptions regarding what measures will be optimal for detecting individual differences in neural circuitry
relevant to psychopathology, and be guided exclusively by data in this regard
6. Accord adequate attention to the role of measurement error inherent to laboratory measures (T data), and capitalize on the
power of statistical aggregation across indices

7. When conducting research on endophenotypes, test statistical models of pleiotropy and mediation, and do not presume that such
phenotypes are necessarily more heritable or straightforward in their genetic architecture compared with exophenotypes
8. Do not assume that endophenotypes or other candidate biomarkers are more traitlike than statelike; the assertion that such
indicators are stable over time must be demonstrated empirically
9. Remain cognizant of the possibility that psychobiological predispositions can be expressed in a host of diverse behavioral
manifestations
10. Avoid premature reification of the RDoC matrix, and remain open to research that examines cells not explicitly represented in
the current matrix
11. Develop broad guidelines for beginning to translate the growing body of RDoC findings into a usable system of psychiatric
classification
12. Seek ways in which RDoC can coexist with both (a) basic research on neural circuitry and (b) applied research on empirically
supported treatments tied to DSM categories
13. Explore the possibility of a combined system that incorporates both diagnostic signs/symptoms and psychobiological
predispositions
Abbreviations: DSM, Diagnostic and Statistical Manual of Mental Disorders; ICD, International Statistical Classification of Diseases and Related Health Problems;
RDoC, Research Domain Criteria.
As we have noted, RDoC confronts a number of conceptual, methodological, and logistical/

pragmatic challenges, none of which appears to be insuperable (Lilienfeld 2014b). Many of these
challenges have received insufficient discussion in RDoC documents and will require careful
consideration for RDoC to realize its considerable scientific potential. In Table 1, we offer a
baker’s dozen of recommendations for addressing these challenges in the coming years of RDoC
research.
One of the foremost challenges to RDoC’s effort to offer a viable alternative to DSM-ICD
is the fact that psychobiological predispositions can be expressed in a host of diverse behavioral
patterns, some of them largely healthy and others largely unhealthy (Harkness & Lilienfeld 1997).
In this regard, it may be unrealistic to expect RDoC to fully supplant a classification system, such
as the DSM, that provides a remarkably rich compilation of the variegated ways in which human
behavior, both subjective and observable, can break down. Signs and symptoms, their inevitable
shortcomings notwithstanding, will always be necessary for a complete characterization of mental
disorder. Indeed, we suspect that the most informative and construct-valid system of classification
will ultimately necessitate some form of rapprochement between the Aristotelian and Galilean
perspectives afforded by the DSM-ICD and RDoC approaches, respectively. Although we have

heretofore portrayed these two models in bold relief as competing, we are inclined to regard them
as complementary in certain key respects. Each approach is necessary; neither is sufficient.
In our view, the DSM-ICD will never provide a sufficient foundation for a comprehensive clas-
sification system, because psychiatric signs and symptoms, like fever, are inevitably nonspecific
indicators of a host of psychobiological dysfunctions. Conversely, RDoC will never be sufficient for
a comprehensive classification system, because psychobiological dysfunctions can be manifested
in a host of markedly diverse signs and symptoms as a function of innumerable moderating vari-
ables. As a consequence, a full characterization of psychopathology will require the DSM-ICD’s
remarkably astute descriptive observations, informed by the best available research on neural cir-
cuitry relevant to psychopathology. If it attends carefully to the constructive challenges posed here,
RDoC and the fruits of its labor hold the potential to complete the story that Emil Kraepelin, the
Washington University group, and Robert Spitzer started.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
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CP12CH17-Lilienfeld ARI 24 February 2016 11:57

Scott O. Lilienfeld and Michael T. Treadway

Annu. Rev. Clin. Psychol. 2016. 12:435–63 Keywords

The Annual Review of Clinical Psychology is online at Abstract

The Slow Progress of Psychopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443

436 Lilienfeld · Treadway

DSM-ICD and Kraepelin: Hints of a Paradigm Shift

DSM AND ICD: ORIGINS AND ASSUMPTIONS

www.annualreviews.org • DSM-ICD Versus RDoC 437

438 Lilienfeld · Treadway

www.annualreviews.org • DSM-ICD Versus RDoC 439

440 Lilienfeld · Treadway

Genetic and environmental nonspecificity. If DSM-ICD conditions were largely distinct, as

traditionally deemed to be etiologically disparate, namely schizophrenia, bipolar disorder, MDD,

DSM-ICD Anomalies: Taking Stock

www.annualreviews.org • DSM-ICD Versus RDoC 441

RDOC: INTELLECTUAL ANTECEDENTS

Laboratory Methods in Medicine

Early Triumphs in Psychopathology Research

442 Lilienfeld · Treadway

The Slow Progress of Psychopharmacology

www.annualreviews.org • DSM-ICD Versus RDoC 443

THE BIRTH OF RDOC: FUNDAMENTAL PRESUPPOSITIONS

444 Lilienfeld · Treadway

www.annualreviews.org • DSM-ICD Versus RDoC 445

Positive valence systems

Systems for social processes

Consistent with the view of science as a self-correcting enterprise, RDoC is conceptualized as

The Scientific Promise of RDoC

446 Lilienfeld · Treadway

Furthermore, RDoC promises to capitalize on the burgeoning corpus of knowledge concerning

RDOC: CONCEPTUAL CHALLENGES

www.annualreviews.org • DSM-ICD Versus RDoC 447

Potential Overemphasis on Biological Dysfunction at the Level of an Individual

448 Lilienfeld · Treadway

Biological Predispositions Versus Their Behavioral Manifestations

www.annualreviews.org • DSM-ICD Versus RDoC 449

Challenges Posed by Network Models of Psychopathology

RDOC: METHODOLOGICAL CHALLENGES

Neglect of Measurement Error

450 Lilienfeld · Treadway

www.annualreviews.org • DSM-ICD Versus RDoC 451

The Limitations of Endophenotypes

452 Lilienfeld · Treadway

RDOC: LOGISTICAL/PRAGMATIC CHALLENGES

The Dangers of Premature Reification of the RDoC Matrix

www.annualreviews.org • DSM-ICD Versus RDoC 453

Implications for Grant Funding in Non-RDoC Domains

454 Lilienfeld · Treadway

Translating RDoC Findings into a Feasible Classification System

THE DSM-ICD AND RDOC: QUO VADIS?

www.annualreviews.org • DSM-ICD Versus RDoC 455

Table 1 A baker’s dozen recommendations for RDoC

power of statistical aggregation across indices

As we have noted, RDoC confronts a number of conceptual, methodological, and logistical/

456 Lilienfeld · Treadway

www.annualreviews.org • DSM-ICD Versus RDoC 457

458 Lilienfeld · Treadway

Fu CH, Costafreda SG. 2013. Neuroimaging-based biomarkers in psychiatry: clinical opportunities of a