1079597

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PPSXXX10.1177/17456916221079597HagertyPerspectives on Psychological Science

ASSOCIATION FOR
PSYCHOLOGICAL SCIENCE

Perspectives on Psychological Science

Toward Precision Characterization and 1­–19

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DOI: 10.1177/17456916221079597
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Forward and Integrative Framework of the www.psychologicalscience.org/PPS

Hierarchical Taxonomy of Psychopathology

and the Research Domain Criteria

Sarah L. Hagerty1,2
1
Mental Illness Research Education and Clinical Center (MIRECC), Veterans Affairs Palo Alto Health Care System,
Palo Alto, California, and 2Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine

Abstract
A critical mission of psychological science is to conduct research that ultimately improves the lives of individuals
who experience psychopathology. One important aspect of accomplishing this mission is increasing the likelihood
that treatments will work for each person. I contend that treatment prognosis can be improved by moving toward
a precision-medicine model. I advance a principle-driven framework for working toward these objectives. First, I
synthesize the Hierarchical Taxonomy of Psychopathology and the Research Domain Criteria and demonstrate how
integrating these models facilitates precision characterization of psychopathology. Second, I outline and demonstrate
a systematic process for approaching treatment selection by leveraging precisely characterized representations of
psychopathology. Finally, I advocate the research and clinical applications of this framework. Although clinical and
psychological scientists are conducting exciting, multidisciplinary, and methodologically rigorous research in their
respective domains, the impact of these pursuits will be maximized in the context of a unifying theoretical framework
that supports a clear guiding mission.

Keywords
Hierarchical Taxonomy of Psychopathology, HiTOP, Research Domain Criteria, RDoC, precision medicine, precision-
treatment selection, psychiatric nosology

I suggest that one of the ultimate imperatives for psy-
chological science is to improve the human condition.
One way of realizing this goal is by optimizing treat-
ment prognosis for psychopathology given that approx-
imately one third of patients with a psychiatric diagnosis
currently do not respond to treatment (Gloster et al.,
2020). Consistent with a precision-medicine approach, I
contend that treatment prognosis could be improved for
each person if treatment selection is targeted and precise.
I argue that precision-treatment selection requires (a)
characterizing psychopathology with a high degree of
precision and (b) using a principle-driven process to
select treatments using precise characterizations of psy-
chopathology. These two objectives represent the com-
ponent parts of my precision-characterization-and-treatment
framework.
The Diagnostic and Statistical Manual of Mental
Disorders (DSM) continues to be the most widely used
system for delineating categories of psychological dys-
function. However, novel perspectives have emerged
over the past decade that are pushing the field to recon-
sider how forms of psychopathology could be defined
and differentiated. The Hierarchical Taxonomy of Psy-
chopathology (HiTOP) and the Research Domain Criteria
(RDoC) have emerged as frameworks for conceptualizing
Corresponding Author:
Sarah L. Hagerty, Mental Illness Research Education and Clinical
Center (MIRECC), Veterans Affairs Palo Alto Health Care System, Palo
Alto, California Department of Psychiatry and Behavioral Sciences,
Stanford University School of Medicine
Email: shagerty@stanford.edu
2 Hagerty
Table 1. Objectives and Steps Involved in Precision Characterization and Case Formulation
Framework objective Step in objective
Objective 1: precision Step 1
characterization
Step 2
Step 3
Objective 2: leveraging Step 1
precision characterization Step 2
Step 3
Note: HiTOP = Hierarchical Taxonomy of Psychopathology; RDoC = Research Domain Criteria.
and researching psychopathology. The HiTOP model has
led to advances in mapping the covariation of psychiatric
symptoms with a high degree of quantitative rigor,
whereas RDoC has been influential at guiding research
on the neurobiological processes that underlie the con-
tinua of mental health. Ultimately, research findings
guided by these models could inform novel classification
schemes and treatment paradigms for mental health.
Although HiTOP and RDoC each stand to make mean-
ingful contributions independent from one another, their
contributions would be maximized in the context of a
unifying theoretical model that is built around an over-
arching guiding objective. Consistent with my assertion
that RDoC and HiTOP can have the greatest impact
through synergy, I believe my framework for precision
characterization and treatment selection leverages the
integration of HiTOP and RDoC (see Table 1).
HiTOP and RDoC have different origins and are
designed to accomplish different objectives. The RDoC
framework was born out of a National Institute of Men-
tal Health initiative and represents a research framework
designed to facilitate investigation of psychological and
biological constructs that underlie the continua of men-
tal health. HiTOP is an investigator-led initiative focused
on delineating and measuring empirically derived
dimensions of manifest psychopathology. Holding in
mind these different origins and purposes, in this article,
I propose a framework that draws on a synergy of
HiTOP and RDoC. Throughout the article, strengths and
shortcomings of HiTOP and RDoC are discussed relative
to objectives delineated in the proposed framework.
Briefly, in the context of the objectives of the proposed
framework, HiTOP’s strength is in delineating specific
dimensions of manifest psychopathology in a way that
reflects an empirical organization of complex human
experiences. RDoC’s strength is in delineating neurobio-
logically oriented constructs that represent potential
mechanisms underlying manifest psychopathology. The
Description of step
Classify symptom-level manifestations of complex
human experiences that are implicated in manifest
psychopathology with a high degree of specificity
(i.e., HiTOP dimensions)
Identify relevant neurobiologically oriented constructs
(i.e., RDoC constructs)
Map the linkages between symptom-level classifications
and neuropsychophysiological constructs
Identify target classification dimensions
Identify constructs that represent levers of change
Target identified constructs with treatment
proposed framework aims to capitalize on these syner-
gistic strengths to achieve one possible form of precision
characterization of psychopathology that could be lever-
aged to inform precision-treatment paradigms.
I justify, outline, and demonstrate the proposed frame-
work in four sections. First, I discuss the state of the field
relative to the current ability to precisely characterize
psychopathology and offer a solution for how to integrate
HiTOP with RDoC to achieve precision characterization
(see Table 1, Objective 1). Second, I outline a principle-
driven process for leveraging precision characterization
to guide treatment selection (see Table 1, Objective 2).
Third, I discuss how this framework could be applied in
clinical-science and clinical-practice domains. Fourth, I
highlight limitations, potential criticisms, and further
questions associated with the framework.
My focus on precision is consistent with a movement
toward precision medicine across physical-health,
mental-health, and policy domains (Collins & Varmus,
2015; Fernandes et al., 2017; Hamburg & Collins, 2010).
Accordingly, an explicit focus over the past decade has
been to move psychiatry and psychology toward a
precision-medicine model, which holds the promise of
improving treatment outcomes and reducing the burden
of mental health (Insel, 2014). Here, I focus on the aim
of precision-treatment selection by way of precision
characterization as a particular aspect of precision
medicine.
Key Terms Defined
This article relies on several terms, for which I present
definitions here (for a glossary of terms, see Table 2).
Disorder refers to an abnormality that persists over an
intransient period of time and causes impairment and
disability in an individual. Disease refers to a disorder
with known cause or causes and course. Patients are
afflicted with disorders and diseases, whereas diagnoses
Perspectives on Psychological Science XX(X) 3

Table 2. Glossary of Terms Defined in Relation to Precision Characterization of Psychopathology

Term Definition
Disorder An abnormality that persists over an intransient period of time and causes
impairment and disability in an individual
Disease A disorder with known cause or causes and course
Diagnosis The label that clinicians and researchers place on diseases and disorders;
a particular type of classification entity
Classification system A broad term that refers to an organizational structure under which entities
are catalogued according to a set of criteria
Classification entity A single organizational unit in a classification system
Classification dimension A particular type of organizational unit (i.e., one that is measured on a
continuum) in a classification system
Neuropsychophysiological construct Phenomena with origins in the brain and other body systems that may be
causally (e.g., as underlying determinants/mechanisms) and noncausally
(e.g., co-occur) associated with manifestations of psychopathology
Reliability The degree of reproducibility of a classification
Validity The degree to which a given classification captures the true disorder or
disease state that it seeks to encapsulate
Psychopathology and psychological Psychological states that cause distress and/or have deleterious impacts on
dysfunction an individual’s ability to function
Precision The accuracy with which manifestations of psychopathology and their
determinants are characterized and treated
Stratified medicine The identification of meaningful subgroups of patients who may
collectively benefit from a treatment that is tailored according to the key
shared characteristic or characteristics that define the subgroup
Personalized medicine Tailoring treatment at the level of an individual person according to
individual characteristics

refers to the labels that clinicians and researchers place
on diseases and disorders. A classification system is a
broad term that refers to an organizational structure
under which entities are catalogued according to a set
of criteria. A classification entity is a single organiza-
tional unit in a classification system. A diagnosis is a
specific type of classification entity, as is a dimension.
Neuropsychophysiological constructs refers to phenom-
ena with origins in the brain and other body systems
that may be causally (e.g., as underlying determinants/
mechanisms) and noncausally (e.g., co-occur) associ-
ated with manifestations of psychopathology. As it
relates to classification of disorders and diseases, reli-
ability refers to the degree of reproducibility of a clas-
sification, and validity refers to the degree to which a
given classification captures the true disorder or disease
state that it seeks to encapsulate. Throughout the arti-
cle, I refer to psychopathology and psychological dys-
function, which I use interchangeably throughout to
refer to psychological states that cause distress, have
deleterious impacts on an individual’s ability to func-
tion, or create barriers to an individual’s quality of life.
In the context of precision medicine for mental disor-
ders, I define precision as the accuracy with which
manifestations of psychopathology and their determi-
nants are characterized and treated.
“Precision medicine” is often used interchangeably
with both stratified medicine (i.e., identifying meaning-
ful subgroups of patients who may collectively benefit
from a treatment that is tailored according to the key
shared characteristic or characteristics that define the
subgroup) and personalized medicine (i.e., tailoring
treatment at the level of an individual person on the
basis of individual characteristics; Fernandes et al.,
2017). Many methods, measurement modalities, and
approaches are implicated in precision medicine,
including mapping genetic profiles, applying artificial
intelligence to large medical data sets to identify key
individual difference factors, introducing systematic
measurement of symptoms and physiology into the
clinic, and studying the most proximal biological deter-
minants of pathology (e.g., how brain circuitry relates
to psychopathology).
Here, I use “precision” as an umbrella term that refers
to using various forms of measurement to understand and
treat the neuropsychophysiological (i.e., the combined
psychological, physiological neural) causes, conse-
quences, and manifestations of psychopathology. Com-
mensurate with existing methodological tools and
research findings to date, precision-treatment selection
for psychopathology is, at this point, largely limited to
deriving precision insights from sample-level findings.
4 Hagerty
However, as clinical science evolves and requisite
subgroup-level and person-level data become available,
these updates can be incorporated into the framework.
Precision Characterization
of Psychopathology
Precision characterization defined
I suggest that precision characterization of psychopa-
thology can be achieved in three steps: (1) Classify
symptom-level manifestations of complex human expe-
riences that are implicated in manifest psychopathology
with a high degree of specificity, (2) identify relevant
neurobiologically oriented constructs, and (3) map the
linkages between symptom-level classifications and
constructs (see Table 1, Objective 1, Steps 1–3). The
product of this three-step process is a representation
of symptom classifications, neurobiologically oriented
constructs, and their interrelationships (referred to
hereafter as a characterization map). These character-
ization maps can be used to represent precise charac-
terizations of psychopathology.
Current classification systems
in clinical science and practice
The issue of organizing manifestations of psychological
dysfunction under classification schemes has been a
long-standing dilemma for the field. Here, I provide an
overview of key systems relevant to the evolution of
psychiatric classification and discuss the strengths of
these systems relative to the goal of precision charac-
terization of psychopathology.
The DSM. The DSM, currently in its fifth edition (DSM-5;
American Psychiatric Association [APA], 2013), has been
the prevailing system for classifying psychopathology in
research and clinical practice for the past several decades.
Some historical accounts suggest that following a period
in which clinicians indiscriminately treated patients with
psychiatric medications, clinicians observed that appar-
ent effectiveness of certain medications depended on the
nature of the patient’s psychiatric presentation (Kendell,
1971). Thus, clinicians realized that some individuals were
being treated incorrectly, which prompted the need for
the delineation psychopathology typologies. With the pub-
lication of its first edition in 1952, the DSM became the
first prominent system to address these needs and impose
an organizational structure on manifestations of psycho-
logical dysfunction.
In its current form, the DSM-5 (APA, 2013) includes
a list of mental disorders that are each defined by a set
of diagnostic criteria. Given that the criteria that form
DSM diagnoses are symptoms and not underlying
causes, it is fair to say that the DSM classifies disorders
rather than diseases. The intention of the DSM has been
to advance a common language among members of the
field such that manifestations of psychopathology are
consistently referred to by the same diagnostic label by
clinician consensus. In other words, the DSM has been
designed to maximize reliability and not necessarily
validity of disorders. The classifications outlined in the
DSM serve as a starting point in the evolution toward
increasingly valid representations of disorders and dis-
ease states (Regier et al., 2009).
HiTOP
HiTOP is an alternative classification system that aims
to empirically classify symptom-level manifestations of
psychiatric dysfunction and complex human experi-
ences with a high degree of specificity. Per the HiTOP
model (Kotov et al., 2017, 2021), complex human expe-
riences associated with psychopathology (a) are dimen-
sional in their nature, (b) can be empirically grouped
according to co-occurrence of features, and (c) are
dimensions of psychopathology organized hierarchi-
cally from narrow to broad dimensions. Because HiTOP
is grounded in the need for quantifiable symptom con-
structs, measurement of HiTOP dimensions implicates
scales and self-report questionnaires. Here, I discuss
these aspects of the HiTOP system and comment on
how HiTOP can be leveraged toward achieving preci-
sion characterization of psychopathology.
In the context of psychopathology, dimensions refer
to continua of maladaptive characteristics (Kotov et al.,
2017). The HiTOP model is built on the premise that
manifestations of psychopathology exist on a contin-
uum rather than as discrete categories. This assumption
is supported by both clinical observation and empirical
research studies. In fact, no psychiatric disorders have
been empirically established as discrete categorical
entities (Markon & Krueger, 2005; Wright et al., 2013).
Furthermore, diagnoses are less reliable when arbitrary
categories are imposed onto dimensional phenomenon
(Chmielewski et al., 2015; Markon, 2013). Thus, by hon-
oring the dimensional nature of psychopathology, the
HiTOP classification dimensions capture the true nature
of psychological dysfunction and benefit from enhanced
reliability.
The quantitatively derived classification dimensions
in the HiTOP model are organized in a hierarchical
structure that comprises multiple levels (substructures).
The syndrome substructure is the lowest-order level,
the superspectra substructure is the highest-order level,
Perspectives on Psychological Science XX(X)
and intermediary substructures (i.e., spectra, subfac-
tors, components) are specified in between. The clas-
sification dimensions in each substructure become
progressively narrower down the hierarchy, from high-
est-order to lowest-order substructures. Thus, the hier-
archical structure allows researchers and clinicians to
flexibly classify psychopathology at varying degrees
of specificity depending from which substructure or
substructures dimensional classifications are selected.
For example, classification at higher-order substruc-
tures can help capture the most salient general features
of a person, whereas classification that uses dimen-
sions from narrower, lower-order substructures can
capture more specific features of a person’s clinical
presentation.
Members of the HiTOP consortium suggest that
quantitative nosology is poised to address the faults
associated with traditional taxonomies (Kotov et al.,
2018). Validation studies have lent empirical support to
the HiTOP model. Specifically, since the seminal HiTOP
article was published in 2017, the externalizing and
psychosis superspectra have been empirically validated
(Kotov et al., 2020; Krueger et al., 2021). In addition, a
large meta-analysis found strong support for the overall
HiTOP model (Ringwald et al., 2021). Over the past half
decade, the HiTOP consortium has grown, evolved, and
published high-impact HiTOP-conformant research. At
present, the consortium is made up of a number of
workgroups, each of which is tasked with studying the
HiTOP model, updating the model as indicated by
research results, and assessing its clinical utility.
In summary, the HiTOP model uses a quantitative
nosology approach that can be used to classify symp-
tom-level manifestations of psychopathology with a
high degree of specificity. The model achieves classifi-
cation specificity in two key ways: (a) It includes clas-
sification dimensions that are specific with regard to
the type of psychopathology (i.e., delineates empiri-
cally derived classification dimensions that comprise
relatively homogeneous manifestations of psychological
dysfunction), and (b) it allows for classification that is
specific regarding the magnitude of psychological dys-
function (i.e., dimensional nature of classification enti-
ties capture degree of dysfunction).
The RDoC framework. The RDoC is a research frame-
work for investigating the pathophysiology of psychopa-
thology with origins in basic neuroscience and an emphasis
on neurocircuitry. The focus of RDoC is on understanding
how biological mechanisms generate behaviors and symp-
toms (Cuthbert, 2014; Cuthbert & Insel, 2013). Like HiTOP,
RDoC assumes that constructs are dimensional and does
not assume the boundaries created by DSM categories.
Recall that diseases are defined as a disorder with a known
5
cause or course. Thus, it can be argued that an implicit
objective of RDoC is to move the field toward a disease
model. Realizing a disease model ultimately requires the
field to adopt a classification system that delineates diag-
noses based on underlying pathophysiological etiology.
The current prevailing classification system for psychopa-
thology (i.e., DSM) does not explicitly delineate diagnoses
based on underlying pathophysiology, and thus the cur-
rent system is not optimally valid as a classification system
of diseases. Thus, for RDoC to move the field toward a
disease model, research inspired by RDoC should contrib-
ute to the development and refinement of a classification
approach that delineates diagnoses based on underlying
pathophysiological etiology. In this context, I suggest that
goals of RDoC-inspired research include understanding
etiology and enhancing the validity of classification, both
of which contribute toward the overarching objective of
moving the field toward a disease model.
Thus, realizing RDoC’s mission of moving the field
toward a disease model is poised to benefit the validity
of classification. Throughout medicine, issues arise when
descriptive diagnostic systems are specified without sen-
sitivity to underlying pathophysiological determinants.
Specifically, heterogeneous pathophysiological pathways
can appear as a homogeneous disorder at the symptom
level, as is the case with diabetes mellitus (e.g., destruc-
tion of islet cells vs. insulin resistance causal pathways).
Conversely, a single etiology can manifest in multiple
forms at the symptom level, as demonstrated by the
myriad of COVID-19 symptom presentations caused by
the SARS-CoV-2 virus. For example, in physical medicine,
classifications derived from expression of superficial
symptoms alone may fail to capture typologies of psy-
chopathology, which compromises validity.
Although RDoC is a research framework, research
and reclassification efforts informed by RDoC could
have substantial impacts on clinical-treatment outcomes
if leveraged effectively. Despite decades of progress,
treatments for many of the most prevalent and disabling
psychiatric disorders remain only modestly effective,
including for depression (Cuijpers et al., 2020). One
possible contributing factor of these suboptimal rates
of treatment efficacy is that the disorder-based diagno-
ses generated by the DSM may not be optimal guides
for treatment. Some have suggested that treatments that
target underlying determinants hold greater promise.
For this reason, proponents of RDoC have argued that
progress toward improved treatment prognosis is predi-
cated on the field transitioning toward a model of diag-
nostic classification that is based on underlying
pathophysiology and neurocircuitry (Insel, 2014).
The RDoC framework is represented by a matrix in
which the rows delineate a host of constructs (e.g.,
reward responsiveness) that are organized hierarchically
6 Hagerty
in broad functional domains (e.g., positive valence), and
the columns designate different levels of analysis (e.g.,
genes, molecules, circuits, and self-report). Each matrix
coordinate specifies types of data that could be
employed to measure the respective construct relative
to the respective unit of analysis. The constructs and
domains in the RDoC framework encompass the full
variable range of human functioning. That is, there is
nothing inherently abnormal or pathological about the
constructs or domains themselves. Thus, RDoC explicitly
encourages dimensional measurement of the constructs
and domains included in the framework.
Overall, RDoC provides a framework for guiding
research on the continua of mental health, including
underlying determinants of psychopathology. I suggest
that a greater understanding of underlying determinants
is a key component of precision characterization of
psychopathology. Thus, RDoC research insights could
play a key role in contributing to more precise charac-
terizations of psychopathology.
Precision characterization of
psychopathology: evaluating existing
models and frameworks
Above, I discussed the DSM, HiTOP, and RDoC, which
are three prominent approaches to researching, under-
standing, and classifying the continua of mental health.
Although each of these tools have their strengths, nei-
ther DSM, RDoC, nor HiTOP independently facilitates
precision characterization of psychopathology as
defined by the proposed framework (Table 1, Objective
1, Steps 1–3).
Although the DSM represents a seminal advancement
toward reliability of psychiatric diagnoses, it was not
designed to maximize validity of classification entities.
Because the DSM relies on categorical disorders, the diag-
noses found in the DSM do not capture the magnitude
of dysfunction with a high degree of specificity. Symptom
heterogeneity in diagnostic categories and relative insen-
sitivity to the magnitude of dysfunction hinder the DSM’s
ability to classify symptom-level manifestations of psy-
chopathology with a high degree of specificity (i.e., does
not accomplish Step 1). In addition, the DSM delineates
diagnoses based on clinician consensus of symptom clus-
ters and does not explicitly incorporate underlying patho-
physiological determinants into diagnostic criteria (i.e.,
does not provide infrastructure to accomplish Steps 2 and
3). Thus, as a system for precision characterization of
psychopathology, the DSM leaves room for improvement
for all three of the proposed steps.
The classification dimensions outlined in the HiTOP
model classify symptom-level manifestations of psycho-
pathology with a high degree of specificity relative to
the DSM. This enhanced specificity is achieved by reduc-
ing the heterogeneity of symptoms in each classification
entity via quantitative approaches. In addition, HiTOP’s
dimensional approach enhances specificity by capturing
the magnitude of pathology in each classification dimen-
sion. Because of its contribution to specificity, the
HiTOP model could be applied toward accomplishing
Step 1.
Authors of the HiTOP model acknowledged that
HiTOP falls short of comprehensively characterizing psy-
chopathology given that the HiTOP classification dimen-
sions are not necessarily derived according to underlying
pathophysiology (Kotov et al., 2017). Consequently,
additional approaches are needed to further validate the
descriptive HiTOP dimensions and classify psychological
dysfunction comprehensively and accurately. Kotov and
colleagues (2017) suggested that even comprehensively
grouping signs and symptoms with a high degree of
quantitative rigor and specificity may result in omitting
disorders that are etiologically coherent but have mul-
tiple clinical manifestations or erroneously assuming that
a given phenotype is a unitary classification dimension
when in fact it emanates from multiple, distinct, etiologi-
cal pathways. Each of these scenarios has important
implications for characterizing psychopathology and
facilitating precision-treatment selection. Mapping the
underlying pathways between classification dimensions
and underlying determinants is needed, and the tools to
do so are missing from the HiTOP model. Therefore, the
HiTOP model falls short of facilitating Steps 2 and 3 of
precision characterization.
RDoC is not in itself a system for classifying psycho-
pathology (Insel et al., 2010), and therefore, the RDoC
framework does not specify entities under which mani-
festations of psychopathology can be classified. Thus,
RDoC does not accomplish Step 1. The RDoC frame-
work does, however, provide a structure for character-
izing neuropsychophysiological constructs that may
serve as underlying determinants of psychopathology.
Within RDoC, these potential mechanisms are opera-
tionalized by dimensional constructs and organized
under functional domains. Therefore, RDoC facilitates
Step 2.
A solution for precision
characterization: integrating HiTOP
and RDoC
Between RDoC and HiTOP, two of the three steps of
precision characterization of psychopathology are facil-
itated. That is, Step 1 of precision characterization can
be met by classifying symptom-level manifestations of
psychopathology with HiTOP dimensions, and Step 2
can be accomplished by identifying relevant constructs
Perspectives on Psychological Science XX(X)
from the RDoC matrix. An interface between HiTOP
and RDoC (i.e., mapping the linkages among HiTOP
dimensions and RDoC constructs) could accomplish
Step 3 of precision characterization. Therefore, integrat-
ing RDoC and HiTOP could facilitate Steps 1 through
3 of precision characterization (for a summary, see
Table 1, Objective 1, Steps 1–3).
Others have noted that an interface between RDoC
and HiTOP could further advance psychiatric nosology
and deepen the understanding of the neurobiological
bases of psychopathology (Latzman & DeYoung, 2020).
Consistent with this recognition, Stanton and colleagues
(2020) advanced guidance for how to measure and link
HiTOP classification dimensions with RDoC constructs,
which suggests that an interface between HiTOP and
RDoC is methodologically feasible. In addition, a host of
existing literature suggests that linkages between HiTOP
classification dimensions and RDoC functional domains
indeed exist (for a summary, see Michelini et al., 2021).
Michelini and colleagues (2021) comprehensively sum-
marized empirical literature relevant to drawing linkages
between RDoC constructs and HiTOP dimensions. Their
synthesis of existing literature serves as a starting point
for mapping linkages between HiTOP dimensions and
RDoC constructs, which can be further developed as
additional research emerges. Next, I demonstrate how
HiTOP, RDoC, and an integration of these two systems
can be used to accomplish precision characterization.
Precision characterization:
a demonstrative clinical example
To demonstrate the proposed three-step approach, con-
sider the following clinically motivated example: the
co-occurrence of symptoms associated with the DSM-5
(APA, 2013) diagnoses of posttraumatic stress disorder
(PTSD) and major depressive disorder (MDD).
PTSD and MDD co-occur at a rate much higher than
would be expected by chance alone (Kessler et al.,
1995). Per the HiTOP model (Kotov et al., 2017), the
distress subfactor is comprised by several components.
Many of the DSM-5 (APA, 2013) diagnostic criteria for
both PTSD and MDD are reflected in the components
in the distress subfactor. Therefore, under the HiTOP
classification model, PTSD and MDD largely fall under
the internalizing spectra and, more specifically, in the
distress subfactor. Accordingly, per Step 1 of precision
characterization (see Table 1, Objective 1, Step 1), the
co-occurrence of symptoms associated with PTSD and
depression could be classified under the distress sub-
factor of HiTOP.
Using the HiTOP structure to classify symptom-based
syndromes that were previously thought of in terms of
DSM diagnoses requires translation between HiTOP and
7
the DSM. Determining how to map DSM criteria to
HiTOP components is not immediately obvious in all
circumstances and requires deep clinical knowledge of
the constructs and symptoms (for interpretation of
DSM-5 [APA, 2013] PTSD and MDD diagnostic criteria
in the context of the HiTOP distress subfactor compo-
nents, see Table 3). Adopting a HiTOP-classification
approach to organizing observable symptoms through
the lens of a DSM perspective requires this type of
translation at the component level of HiTOP. Thus, in
my summary depiction of the framework-based char-
acterization of co-occurring PTSD and MDD (see Fig.
1), I show the components of the distress subfactor,
and Table 3 serves as a guide for translation between
DSM criteria and HiTOP distress components. To further
demonstrate the translation between the DSM and
HiTOP, I also included the fear subfactor and associated
components in the depiction of co-occurring MDD and
PTSD. A side-by-side comparison of the components
in fear and distress helps elucidate the distinction
between these two HiTOP subfactors. Without the con-
text that comes from examining components, it would
be reasonable for someone to assume that the DSM
diagnosis of PTSD might be classified under the fear
subfactor because PTSD involve fear-like responses.
However, in looking at the components of fear, it
becomes more apparent that the fear subcomponent of
HiTOP is more closely aligned with symptoms consis-
tent with phobias, obsessive compulsive disorder, and
panic disorder and that distress is a more appropriate
classification dimension for capturing the majority of
symptoms associated with the shared symptom-level
features of PTSD and depression.
Steps 2 and 3 of precision characterization are some-
what interdependent. Step 2 calls for identification of
relevant constructs (e.g., neuropsychophysiological
processes), and in Step 3, links are mapped between
these constructs and the classification dimensions iden-
tified in Step 1. Accordingly, a “relevant” construct may
be one that demonstrates an empirical association with
the classification dimension or dimensions of interest.
In the context of the demonstrative example, a number
of RDoC constructs and subconstructs have been associ-
ated with the distress subfactor (Michelini et al., 2021).
To demonstrate the framework’s approach with clarity
and simplicity, I focus on mapping the RDoC constructs
in the negative-valence system and the distress subfac-
tor using the synthesis of empirical literature summa-
rized by Michelini and colleagues (2021). Figure 1
summarizes these linkages. Again, to continue the dif-
ferentiation between the distress subfactor from the fear
subfactor, the fear subfactor and corresponding RDoC
negative valance linkages are also displayed. Three
RDoC negative-valence constructs, including “potential
8 Hagerty

Table 3. Translation Between HiTOP Components and DSM Diagnostic Criteria

HiTOP distress Corresponding DSM Corresponding DSM

component symptoms of MDD symptoms of PTSD
Dysphoria Depressed mood Intense, prolonged psychological distress at
exposure to internal or external trauma
cues; persistent and exaggerated negative
beliefs or expectations about oneself,
others, or the world; persistent negative
emotional state; persistent inability to
experience positive emotions
Anhedonia Diminished interest of pleasure Markedly diminished interest or
participation in significant activities
Insomnia Insomnia (or hypersomnia) Sleep disturbance
Suicidality Recurrent thoughts of death, recurrent
suicidal ideation, a suicide attempt, a
specific plan for committing suicide
Agitation (Psychomotor) agitation Marked physiological reactions to internal
or external trauma cues
Retardation (Psychomotor) retardation
Appetite loss/gain Decrease or increase in appetite
Dissociation Dissociative reactions (e.g., flashbacks) in
which the individual feels or acts as if the
traumatic events were recurring
Reexperiencing Dissociative reactions, recurrent involuntary
and intrusive memories, recurrent
distressing dreams
Avoidance Avoidance of/efforts to avoid distressing
memories, thoughts, or feelings about/
associated with trauma, including external
reminders (e.g., people, places, activities)
Irritability Irritable behavior and angry outbursts
Hyperarousal Hypervigilance
GAD symptoms Excessive anxiety and worry, restlessness Problems with concentration
or feeling keyed up or on edge, being Sleep disturbance
easily fatigued, difficulty concentrating Irritable behavior and angry outbursts
or mind going blank, irritability,
muscle tension, sleep disturbance

Note: HiTOP distress component = relevant components from the HiTOP distress subfactor (Kotov et al., 2017); corresponding
DSM symptoms of MDD/PTSD = diagnostic criteria taken from the fifth edition of the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5; American Psychiatric Association, 2013); only HiTOP distress components with DSM symptom
counterparts per my translation analysis are shown; DSM = Diagnostic and Statistical Manual; HiTOP = Hierarchical Taxonomy of
Psychopathology; MDD = major depressive disorder; PTSD = posttraumatic stress disorder; GAD = generalized anxiety disorder.

threat,” “sustained threat,” and “loss,” have been linked
to distress (Michelini et al., 2021).
Ultimately, the proposed three-step approach to pre-
cision characterization can be represented as a charac-
terization map made up of classification dimensions,
neuropsychophysiological constructs, and connections
among the dimensions and constructs. These charac-
terization maps can be generated by synthesizing a host
of empirical studies, as exemplified in the above para-
graphs and summarized by Figure 1.
Precision-Treatment Selection
In the first section, I discussed and demonstrated preci-
sion characterization of psychopathology (Table 1,
Objective 1). Ultimately, I concluded that an interface
between HiTOP classification dimensions and RDoC
constructs serves as a system for precision characteriza-
tion of psychopathology. In this section, I discuss
Objective 2 of the proposed framework—using preci-
sion characterization to inform treatment selection.
First, I highlight the importance of a principle-driven
approach to precision-treatment selection by discussing
the shortcomings of existing treatment-selection prac-
tices. Second, I outline the proposed principle-driven
approach for leveraging precision characterization to
inform treatment selection (see Table 1, Objective 2,
Steps 1–3) and highlight the ways in which a principle-
driven approach could enhance the accuracy and reli-
ability of treatment selection for psychopathology.
Perspectives on Psychological Science XX(X) 9

Internalizing

Distress Fear
• Dysphoria • Avoidance • Retardation • Blood-Injection-Injury • Interactive Anxiety
• Lassitude • Hyperarousal • Appetite Loss • Physiological Panic • Performance Anxiety
• Anhedonia • Numbing • Appetite Gain • Psychological Panic • Public Places
• Insomnia • Dissociation • (Low) Well-Being • Cleaning • Enclosed Spaces
• Suicidality • Irritability • GAD Symptoms • Rituals • Animal Phobia
• Agitation • Pure Obsessions • Reexperiencing • Checking

Potential Sustained Potential Acute

Loss
Threat Threat Threat Threat

Fig. 1. Characterization map portraying the interface between Hierarchical Taxonomy of Psychopathology (HiTOP) subfactors relevant to
major depressive disorder (MDD) and posttraumatic stress disorder (PTSD; solid outline boxes) and Research Domain Criteria (RDoC) nega-
tive valence constructs (dashed outline boxes). Linkages based on comprehensive analysis of empirical literature (Michelini et al., 2021). Note
that the co-occurrence of symptoms associated with MDD and PTSD are best classified under the distress subfactor, and the fear subfactor
is portrayed to draw contrast and aid in the translation between HiTOP and the Diagnostic and Statistical Manual of Mental Disorders. GAD =
generalized anxiety disorder.

Key components and existing
treatment-selection practices
Treatment selection is a core component of precision
medicine. I argue that in the context of precision medicine,
a treatment should be selected by applying a method that
reliably predicts—with accuracy—which treatment is most
likely to adaptively modify the target concern. To maximize
the accuracy of treatment selection, available specifics
about the causes and manifestations of dysfunction should
be incorporated. To maximize the reliability, the selec-
tion method should be based on specific criteria or a
principle-driven process. I argue that existing treatment-
selection practices do not simultaneously maximize accu-
racy and reliability of treatment selection. Here, I discuss
two commonly employed treatment-selection practices
and their shortcomings in this context.
Diagnosis-driven treatment. Evidence-based clinical-
practice guidelines suggest that treatments should be
selected according to DSM diagnoses. This practice fol-
lows from an established translational research pipeline
in which treatments are developed and tested among
patient populations who meet criteria for particular diag-
noses. This process results in treatments being designated
as “evidence-based” for their effectiveness at treating par-
ticular DSM disorders. Selecting treatments according to
DSM diagnostic status is a reliable method because DSM
diagnostic status is a concrete, reliable criterion on which
to base treatment selection.
However, there is reason to believe that diagnosis-
based treatment selection may not be the most accurate
treatment-selection method. Although some interven-
tions demonstrate high levels of effectiveness for treating
specific DSM disorders, no treatment is effective at treat-
ing all instances in the diagnostic category for which it
is considered an evidence-based treatment. For example,
behavioral activation (BA) is an evidence-based interven-
tion for depression that is highly effective at treating
depression relative to control conditions (g = –.74 in a
large meta-analysis; Ekers et al., 2014). Although this
effect size is large, BA does not improve symptoms
among all individuals who meet DSM criteria for depres-
sion (Ekers et al., 2014). In addition, the effectiveness of
some treatments does not seem to follow DSM diagnostic
categories because some treatments demonstrate effec-
tiveness at treating more than one disorder. For example,
selective serotonin reuptake inhibitors (SSRIs) are a class
of medications that demonstrates effectiveness at treating
MDD (Cipriani et al., 2009) and anxiety disorders
( Jakubovski et al., 2019). These examples suggest that
using DSM diagnoses as treatment-selection criteria may
not be the method that yields maximally accurate predic-
tions about treatment efficacy.
10
Symptom-driven treatment. In practice, outside the
context of tightly controlled clinical-treatment trials, treat-
ment decisions often do not follow diagnosis-based clinical-
practice guidelines and instead are made according to
symptom profiles (Cabana et al., 1999; Mellman et al.,
2001). This tendency may be due to three interrelated
factors. First, many psychiatric treatments demonstrate
transdiagnostic effectiveness and are therefore imple-
mented across diagnostic categories. For example, recall
that some medications are found to be effective across
different disorders that share common symptoms. Spe-
cifically, SSRIs were once classified as antidepressants but
are now commonly prescribed for anxiety disorders
(Gardarsdottir et al., 2007), and a substantial proportion
of patients with anxiety disorders are treated with anti-
psychotics (Weber et al., 2016). One empirical study ana-
lyzed the link between DSM diagnoses and providers’
pharmacotherapy-prescription practices. Findings sug-
gest that each diagnosis was treated with multiple medi-
cation classes, and most medications were prescribed for
multiple disorders (Waszczuk et al., 2017).
Second, assessment practices may be another reason
why treatment decisions do not align with categorical
diagnoses. In clinical-practice settings, it is uncommon
for providers to consistently assess patients with com-
prehensive diagnostic-assessment protocols that yield
diagnostic labels ( Jensen-Doss & Hawley, 2011). Rather,
clinicians often use unstructured diagnostic interviews
to identify salient symptoms or symptom clusters.
Third, symptoms in diagnostic categories are hetero-
geneous, and some evidence suggests that providers
tailor treatment approaches to symptom-level manifesta-
tions of dysfunction in diagnoses. In fact, an empirical
analysis of practitioners’ prescribing tendencies suggests
that psychiatric medications were prescribed in line with
symptom profiles rather than DSM diagnoses (Waszczuk
et al., 2017). As one example, patients diagnosed with
depression that present with somatic and pain symp-
toms are less likely to be treated with antidepressants
compared with depressed patients who present with
cognitive symptoms (Menchetti et al., 2009).
For these three reasons and other others, symptom-
driven treatment selection is a common approach used
in clinical practice. Symptom-driven treatment selection
may result in greater treatment-selection accuracy (i.e.,
result in selecting the treatment that is tailored to the
specific concern). However, symptom-driven treatment
selection may not be an optimally reliable treatment-
selection method because the current status quo process
of symptom assessment may be less reliable than the
assessment of diagnoses. Although there is an agreed-on
process for assessing psychiatric diagnoses (i.e., assess-
ing DSM diagnostic criteria), there has not been a com-
parable “gold-standard” guide for the assessment of
Hagerty
broad-based symptoms. Indeed, there are highly reliable
and well-validated measures of specific symptom dimen-
sions, but the field lacks a reliable, principle-driven
approach for the process of assessing symptom profiles
and matching such symptom profiles to treatments. This
is consistent with the finding that treatment decisions
made in psychiatry are often based on clinical judgment
and heuristics (Hsin et al., 2016), which may maintain
biases that prevent patients from receiving optimal care
(Tversky & Kahneman, 1974). HiTOP provides a process
for reliably assessing a broad range of symptoms, and
thus HiTOP could serve as a way to enhance the reli-
ability of symptom assessment.
Shortcomings of existing practices. In summary, one
could consider accuracy to be the degree to which the
treatment-selection method predicts which treatment is
most likely to adaptively modify the target concern. One
could consider reliability to be the degree to which the
treatment-selection method yields consistent, reproduc-
ible predictions that are based on criteria or principles.
With these definitions in mind, diagnosis-driven treat-
ment selection is a relatively reliable approach because
diagnoses serve as reliable criteria on which treatment
selection can be based but compromises accuracy of
treatment selection because diagnoses may not be the
most helpful treatment-effectiveness guides. On the other
hand, symptom-driven treatment selection may be rela-
tively more accurate because it tailors treatment selection
to specific manifestations of pathology but may be less
reliable because this approach—as it is currently imple-
mented in clinical practice—often relies on clinicians’
observations and judgments in the absence of standard-
ized assessments for broad-based symptom profiles or
reproducible processes for matching symptom profiles
with treatments. Thus, the question remains what a
treatment-selection approach that maximizes both accu-
racy and reliability would look like. Below, I outline a
principle-driven treatment-selection approach that aims
to maximize accuracy and reliability.
A principle-driven approach
to precision-treatment selection
Precision characterization is a necessary but not suffi-
cient component of an accurate and reliable treatment-
selection method. Precision characterization could
enhance the accuracy of predictions about which treat-
ment may be most effective by identifying key con-
structs that are associated with particular manifestations
of psychological dysfunction. These constructs could
then serve as treatment targets. In turn, treatment selec-
tion could be made according to the extent to which a
given treatment influences the identified treatment
Perspectives on Psychological Science XX(X)
targets. I outline the proposed principle-driven approach
for precision-treatment selection in Table 1, Objective
2. I suggest that leveraging precision characterization
to inform treatment selection could be accomplished
in a three-step process: (1) identify target classification
dimensions, (2) identify constructs that represent the
most powerful levers of change, and (3) target identi-
fied constructs with corresponding intervention
approach (see Table 1, Objective 2, Steps 1–3).
To demonstrate this approach, consider the precision-
characterization example discussed in the first section.
As shown in Figure 1 and summarized in the first sec-
tion above, three negative valence constructs are associ-
ated with “PTSD” and “depression” symptom clusters
(i.e., specific HiTOP distress components). These con-
structs serve as possible treatment targets because they
may be key mechanisms that underlie the manifestation
of “PTSD,” “depression,” and the co-occurrence of these
symptom clusters. The first step in the proposed frame-
work suggests identifying the dimensions on which
change is desired. Given the emphasis on precision, I
suggest that a reasonable strategy is to target classifica-
tion dimensions from the lowest order (i.e., narrowest,
most specific) strata on which the clinical picture is
characterized. Thus, it would be reasonable to identify
the HiTOP distress subfactor as a target for treatment
(Table 1, Objective 2, Step 1).
The second step prompts identification of constructs
that represent potential levers for change on the target
classification dimensions identified in Step 1. Revisiting
the clinically motivated example, a host of constructs
is associated with distress (see Fig. 1). Given the varia-
tion in structure of these characterization maps, it is
difficult to offer highly specific, prescriptive criteria
regarding how to identify constructs at this step. In this
case, three constructs (sustained threat, potential threat,
and loss) may be key constructs involved in the mani-
festation of distress. Any one of these three constructs
could therefore represent viable treatment targets in the
context of this precision-characterization map.
According to Step 3, treatment selection should be
based on whether a given treatment is likely to adap-
tively modify the constructs identified in Step 2. For
example, in the context of the clinically motivated
example, exposure therapy is an evidence-based inter-
vention that has been shown to adaptively modify
sustained threat, which can be behaviorally operation-
alized as avoidance (Cuthbert, 2014). That is, exposure-
therapy targets sustained threat through a process of
eliminating avoidances by promoting extinction learn-
ing via engagement in approach behaviors (Culver
et al., 2012; Foa, 2011). Given that sustained threat is
one of the three RDoC constructs linked to the distress
classification dimension, selecting exposure therapy
11
would be consistent with the principle-driven precision-
treatment-selection framework. As further support
for the selection of exposure therapy in the context
of this characterization map, exposure therapy has
been shown to adaptively modify components within
the distress subfactor, including those that are jointly
associated with PTSD and MDD. For example, pro-
longed exposure, a particular form of exposure
therapy, has been shown to reduce symptoms of co-
occurring PTSD and depression (Powers et al., 2010;
van Minnen et al., 2015). The evidence-informed theo-
rized effects of exposure therapy on distress compo-
nents via sustained threat are shown in Figure 2. As
demonstrated by this example, precision characteriza-
tion can help guide and justify selection of a treatment
that is best tailored to specific manifestations of
psychopathology.
Per the proposed framework, the utility of RDoC
toward improved treatment prognosis rests on the
assumption that targeting etiological processes is a
helpful heuristic for selecting effective treatments. This
assumption is consistent with the disease model, which
emphasizes the importance of incorporating an under-
standing of underlying pathophysiology into treatment.
As discussed above, the constructs represented in the
RDoC matrix represent biologically oriented patho-
physiological processes that can be measured across a
range of modalities (i.e., “units of analysis”). Although
RDoC does not specify particular measures in each
modality, the constructs provide a content map from
which investigators can operationalize constructs in
specific choices of measures. For example, functional
MRI is commonly used to operationalized function
within the “circuit” unit of analysis and is a proximal
measure of neurobiological processes, whereas symp-
tom questionnaires are commonly used to operational-
ize in the “self-report” unit of analysis.
In the clinical example, the sustained-threat con-
struct is discussed in terms of behavior (i.e., behavioral
avoidance), and the suggested treatment modality is
also behavioral (i.e., exposure therapy). In this exam-
ple, I suggest that exposure therapy be considered
because exposure therapy is a “gold-standard” interven-
tion for avoidance in the context of anxiety and threat
dysregulation. Although exposure therapy is a “gold-
standard” first-line intervention for targeting avoidance
(i.e., sustained threat), it may be the case that pharma-
cological interventions could be used as a stand-alone
treatment or to augment therapy in cases of significant
threat dysregulation. For example, ketamine is thought
to enhance extinction learning by facilitating memory
reconsolidation and enhancing learning. In fact, a num-
ber of preliminary studies have suggested that augment-
ing prolonged exposure therapy with ketamine is both
12 Hagerty

Dysphoria
Insomnia
Agitation
Anhedonia
GAD Symptoms
Increase in Shared Features of
“PTSD” & “Depression”
Within the Distress Dimension Exposure Therapy
(Inhibitory Learning via
Toleration of Distress)
Sustained Threat
(Behavioral Avoidance)

Accessibility and Retrievability of

Dysphoria Nonthreat Associations Facilitating
Insomnia Engagement in Approach Behaviors
Agitation Thus Reducing Avoidance,
Anhedonia Decreasing Threat Responses, and
GAD Symptoms Improving Mood

Amelioration of Shared
Features of “PTSD” & “Depression”
Within the Distress Dimension

Fig. 2. Evidence-informed depiction of precision characterization informing treatment

selection for a clinically motived example. The sustained-threat Research Domain Criteria
(RDoC) construct is theorized to underlie features of posttraumatic stress disorder (PTSD)
and depression that are represented in the Hierarchical Taxonomy of Psychopathology
distress dimension. Exposure therapy is theorized to target behavioral avoidance and ame-
liorate PTSD/depression symptoms by promoting new learning of non-threat associations,
which facilitates approach behaviors, reduces avoidance, decreases threat response, and
improves mood. GAD = generalized anxiety disorder.

feasible (Shiroma et al., 2020) and effective at treating
PTSD (Duek et al., 2019). More research is needed to
determine who might benefit most from this kind of
pharmacological intervention and/or augmentation.
One hypothesis is that individuals with relatively more
exaggerated threat responses could benefit most from
augmentation.
In addition to ketamine, various other pharmacologi-
cal agents and neuromodulatory interventions may
be beneficial for targeting transdiagnostic features
of pathology. For example, vagus-nerve stimulation
(George et al., 2008) and transcranial magnetic stimula-
tion are two neuromodulatory interventions that have
shown transdiagnostic promise in the treatment of anxi-
ety, PTSD, and depression (Cirillo et al., 2019; Clarke
et al., 2019; George et al., 2008). In addition, experi-
mental therapies, such as 3,4-methylenedioxymetham-
phetamine, have shown promise for augmenting
psychotherapy for the treatment of PTSD. The pro-
posed framework can guide research on whether and
for whom cognitive-behavioral interventions and/or
pharmacotherapies and/or neuromodulatory interven-
tions are effective.
Application of Framework
Applications in clinical science
Are treatment outcomes better when treatment selection
is tailored to precise characterizations of pathology? This
is one of the questions that must be answered to estab-
lish the merits of a precision-medicine model for psy-
chopathology. This framework can be used to generate
hypotheses and inform study designs that test the effec-
tiveness of precision-treatment selection. In the sections
above, I discussed and exemplified the dual process of
characterizing presentations of psychopathology with a
high degree of precision and applying a principle-driven
strategy for identifying targeted treatments. Studies can
be designed to test whether treatments that are selected
according to this process are associated with clinical
improvements over and above usual care. Specifically,
Perspectives on Psychological Science XX(X)
precision-characterization maps can be specified accord-
ing to existing research and theory, as I demonstrated
in the first section, and a precision-treatment selection
could be hypothesized, as I demonstrated in the second
section. In the context of a clinical trial, patients could
be assessed on the dimensions and constructs relevant
to a given precision-characterization map. Patients
could then be divided into groups according to the
degree to which their clinical profile at baseline matches
the typology represented by the characterization map
of interest (such individuals could be considered typol-
ogy+). Patients could then be randomly assigned to
receive either usual care or a precision treatment. Vari-
ous specific questions could be answered with this type
of research process and design, including whether
precision-treatment matching (i.e., typology+ individu-
als who received the precision treatment) outperforms
usual care. Findings from these types of studies could
inform clinical care and guide future precision-treatment
research.
In addition to evaluating the effectiveness of preci-
sion-treatment selection, the proposed framework
could guide research questions related to refining
clinical-research outcomes. For example, measuring
and studying symptoms (i.e., classification dimensions)
and underlying mechanisms (i.e., RDoC constructs)
could encourage clinical scientists to explore questions
such as the following: What does it mean to get better?
How should treatment success be operationalized?
Reductions in target symptoms? Amelioration of under-
lying pathophysiology? Both?
Finally, this framework can inform research that con-
tributes to the refinement of nosological systems of
psychopathology. As discussed regarding the RDoC
model (Insel et al., 2010), mapping relationships
between underlying pathophysiological constructs and
manifestations of psychopathology can help advance
reliable and valid classification schemes. The links
between classification dimensions and pathophysiologi-
cal constructs found in the characterization maps gener-
ated by implementing the framework (Table 1, Objective
1) represent testable hypotheses, which could be vali-
dated by targeted studies. Results of such studies could
help refine the understanding of how dimensions of
functioning relate to underlying mechanisms, and this
information could be applied toward refining psychi-
atric nosologies.
Applications in clinical practice
In addition to serving as a theoretical guide for testing
precision-treatment-selection models and informing
clinical-science research more broadly, this framework
can serve as scaffolding for applying RDoC and HiTOP
13
in clinical practice in the relative immediacy. Recogniz-
ing that much research still needs to be done before
these systems are fully ready for translational use, I
suggest that withholding their use in clinical contexts
until they are fully explicated carries the consequence
of maintaining a status quo that continues to yield sub-
optimal clinical results. Therefore, there may be benefit
to integrating this framework into clinical practice and
iteratively evaluating its scientific merit and clinical util-
ity. This could help refine the framework and its com-
ponent parts (i.e., HiTOP and RDoC) and may benefit
clinical care in parallel.
With this in mind, clinicians can use this framework
to guide assessment and inform case conceptualization.
Doing so is feasible because clinicians could use exist-
ing measures and tools to assess patients on HiTOP
classification dimensions and RDoC constructs. In fact,
work from the HiTOP consortium suggests that HiTOP
can indeed be integrated into clinical practice (Ruggero
et al., 2019) because a variety of existing validated scale
measures that map onto HiTOP dimensions can be
readily administered to patients (Wendt et al., 2021). In
addition, efforts are underway to develop a compre-
hensive measure of the HiTOP model (Simms et al.,
2022). Other work suggests that approaching psycho-
therapy informed by a HiTOP assessment is clinically
feasible (Hopwood et al., 2020; Mullins-Sweatt et al.,
2020). Likewise, it is feasible—although not yet straight-
forward (see the following section)—to measure RDoC
constructs in clinical settings. The RDoC matrix pro-
vides guidance on how to operationalize each construct
and subconstruct across units of analysis. In the context
of the current status quo, self-report and behavioral-
measurement modalities could be most easily incorpo-
rated into clinical practice because of resource
constraints. That is, most clinical environments are not
equipped with MRI scanners, wet lab facilities, and so
on. However, resources permitting, incorporating
assessments from across units of analysis could add
valuable insights about treatment targets.
Assessment of HiTOP dimensions and RDoC domains
could be done comprehensively, or clinicians could
target a subset of dimensions and constructs to assess
depending on the patient’s presentation. Once a patient
is assessed on HiTOP dimensions and RDoC constructs,
clinicians and care teams could integrate results from
these assessments following the principle-driven pro-
cess to inform their case conceptualization and treat-
ment selection. Applying this framework in clinical
settings does not represent an unrealistic departure
from the status quo of clinical case conceptualization
and treatment selection. As discussed above, clinicians
commonly conceptualize and treat patients according
to presenting symptoms. Thus, this framework would
14
be a way of enhancing the reliability of existing prac-
tices by providing a principle-driven, systematic struc-
ture for guiding assessment, conceptualization, and
treatment selection.
Potential Criticisms, Limitations,
and Further Considerations
With this framework, I have advanced a principle-
driven structure for integrating symptom-level manifes-
tations of psychopathology (i.e., the HiTOP dimensional
classification scheme) and neurobiologically oriented
constructs (i.e., components of the RDoC matrix). Con-
ducting research that characterizes these linkages is
essential toward refining psychiatric classification
schemes and developing precision-treatment approaches.
Although this framework represents progress toward
these goals, it should be considered in the context
limitations and further considerations. Below, I high-
light key limitations and further considerations and
preemptively address some potential criticisms of the
proposed framework.
Addressing potential criticisms
of framework
Isn’t linking neurobiological processes to symp-
toms already accomplished by RDoC? RDoC has
been established as a research framework for investigat-
ing underlying dimensions of psychopathology that spans
circuits to behavior and self-report. Characterizing the
continua of mental health across units of analysis such
that manifestations of psychopathology are linked to
neuropsychological processes is an idea that is consistent
with the RDoC research framework. Objective I of the
proposed framework involves linking symptom-level
manifestations that are implicated in manifest psychopa-
thology to relevant neurobiologically oriented constructs.
Thus, some readers may perceive RDoC and Objective I
of the proposed framework to be overlapping in scope.
However, I argue that Objective I of the proposed
precision-characterization framework complements rather
than overlaps with RDoC. That is, I suggest that RDoC
may not be designed to optimally capture broad-based,
empirically derived, symptom-level manifestations of
complex human experiences with a high degree of speci-
ficity. The constructs that make up the RDoC matrix are
organized from a perspective that is oriented toward neu-
robiological processes. Although the RDoC framework
implies that these processes manifest behaviorally and
psychologically, RDoC constructs may best capture expe-
riences that occur throughout phylogeny (e.g., threat
response) and may not optimally capture complex expe-
riences, such as delusions of persecution. In addition, the
Hagerty
RDoC constructs do not necessarily reflect the empirical
structure of manifest psychopathology. Thus, RDoC may
be best suited to delineate neurobiologically oriented
constructs, and another model could complement RDoC
by offering a way to classify symptom-level dimensions
of manifest psychopathology. Accordingly, I suggest that
the empirically derived dimensions delineated by HiTOP
may be well suited to characterize a wide range of com-
plex symptom-level manifestations of psychopathology
with a high degree of specificity. Given these comple-
mentary strengths of HiTOP and RDoC, I suggest that an
integration of HiTOP and RDoC could offer a means of
linking underlying neurobiological processes with spe-
cific symptom-level manifestations of pathology that rep-
resent complex human experiences.
HiTOP might provide insight into neurobiological
processes, so why is RDoC needed, too? HiTOP has
evolved since its initial conception in 2017. The consor-
tium has adopted a robust organizational structure,
including workgroups that address various facets of the
HiTOP model. One such workgroup is the Neurobiologi-
cal Foundations Workgroup, which is tasked with under-
standing how quantitative models of psychopathology
(e.g., HiTOP) interface with neurobiologically oriented
approaches (Perkins et al., 2020). Indeed, a recent review
published by members of the HiTOP Neurobiological
Foundations Workgroup suggests that a synergy between
HiTOP and RDoC may be an effective means by which to
understand the neurobiological bases of manifest psy-
chopathology. The article suggested that the dimensions
that result from quantitative structural investigations (e.g.,
HiTOP dimensions) can serve as clinical endpoints of
neurobiological variation (RDoC constructs). The authors
went on to comprehensively review links between HiTOP
targets and RDoC constructs using the available literature
(Michelini et al., 2021). Michelini and other members
of the HiTOP Neurobiological Foundations Workgroup
(Michelini et al., 2021) proposed that a strength of HiTOP
is in identifying the endpoints of manifest psychopathol-
ogy and that a strength of RDoC is in identifying con-
structs that represent meaningful sources of neurobiological
variation. In developing the present framework, I drew on
these complementary strengths when considering how
HiTOP and RDoC may be integrated.
Limitations of framework
Pragmatic challenges with linking HiTOP dimen-
sions and RDoC constructs. Despite the strengths asso­
ciated with synergy, it does indeed introduce a source of
complication to integrate two systems rather than rely on
one internally consistent model. Although it is outside
the scope of the current article to provide comprehensive
Perspectives on Psychological Science XX(X)
guidance on translational application of this framework,
it is worth highlighting some key issues that are impor-
tant to attend to when approaching the application of
this framework, particularly with respect to integrating
RDoC and HiTOP. First, determining measurement strate-
gies that facilitate the operationalization of HiTOP dimen-
sions and RDoC domains is one challenge that must
be resolved to apply this framework. Deciding on mea-
sures in this context is complicated because measuring
RDoC constructs and HiTOP dimensions such that link-
ages between the two can be detected requires careful
consideration of assessment framing with respect to time.
That is, each HiTOP dimension can be measured through
the lens of traits (dispositional constructs that reflect per-
sistent tendencies) or symptoms (relatively transient fea-
tures of psychopathology that manifest during a specific
time period), with the difference being the time frame
over which the dimension is assessed (DeYoung et al.,
2022). Likewise, the constructs found in the RDoC matrix
differ with respect to intraindividual changes over time. In
addition, measurement modalities that operationalize
constructs in the RDoC matrix differ with respect to their
sensitivity to detecting meaningful changes in the con-
structs over time in an individual. Moreover, even more
complicated is the issue of aligning assessments of RDoC
constructs and HiTOP dimensions in relation to each
other with respect to time frame. For example, suppose a
true relationship exists between the fear HiTOP dimen-
sion and the acute threat RDoC construct. Detecting this
link requires framing the assessments of the fear dimen-
sion and the acute threat construct over time frames that
are sensitive to how this pair of phenomena interact.
Operationalizing and measuring RDoC constructs
and HiTOP dimensions. Another key issue that bears
relevance to the application of this framework is that of
measure selection and availability. The RDoC matrix is
designed to provide a structure for guiding research on
transdiagnostic constructs implicated in psychopathol-
ogy. Toward this end, the RDoC framework prompts
researchers to consider how constructs can be measured
across units of analysis, from circuits to self-report and
behavior. RDoC was not designed to provide prescriptive
guidance regarding measure selection for RDoC con-
structs. Thus, researchers who conduct RDoC-inspired
studies make measurement decisions according to their
best interpretation of the constructs of interest, and
researchers who conduct RDoC-inspired research often
retrofit existing self-report scales to cover constructs of
interest. Presently, there is a relative lack of consensus
among the field on how to operationalize RDoC constructs
at the level of self-report. To my knowledge, there does
not yet exist a comprehensive self-report measure that
provides broad coverage of the RDoC matrix. Scalable
15
assessment of RDoC constructs could benefit from the
development of reliable and valid self-report measures
that are specifically designed to operationalize RDoC
constructs.
Regarding HiTOP, the HiTOP consortium is actively
developing comprehensive measures of HiTOP for use
in clinical and research settings (Simms et al., 2022). In
the meantime, several existing scale measures can be
combined to achieve nearly comprehensive coverage
of HiTOP, which is referred to as the HiTOP Digital
Assessment Tracker.
The framework is principle-driven and not pre-
scriptive. The proposed framework is principle-driven
and not prescriptive. The field is not yet at a point at
which treatment-selection decisions can be generated
algorithmically at the sample or individual level. Accord-
ingly, the process outlined in this framework should be
interpreted as a tool for integrating RDoC constructs and
HiTOP domains in a structured, principle-driven way
rather than as a prescriptive algorithm. At this stage, the
framework serves as a guide for approaching the process
of characterizing psychopathology and treatment selec-
tion in a way that maximizes precision and reliability
given the tools available in clinical science.
Further considerations
Establishing an understanding of causal patterns.
Although a growing body of research links HiTOP dimen-
sions with RDoC domains (Michelini et al., 2021), the
causal patterns among symptom-level dimensions and
pathophysiological constructs have yet to be robustly
characterized. The ultimate goal of the proposed frame-
work is to characterize typologies of psychopathology in
a way that elucidates precisely tailored, actionable treat-
ment targets. To realize this goal, it is important to under-
stand whether, how, and under which conditions RDoC
constructs exert causal influence over symptom-level
dimensions and vice versa. As highlighted by the demon-
strative clinical example, the framework assumes a causal,
mechanistic role of RDoC constructs on HiTOP dimen-
sions. Although this assumption has theoretical ground-
ing (Cuthbert & Insel, 2013), it will be important to
integrate results of research that characterize patterns of
causality into the application of this framework. Although
this framework is based on causal assumptions, I have
intentionally referred to RDoC domains as “constructs”
rather than “mechanisms” or “underlying determinants”
in how the framework is presented because the causal
roles of RDoC constructs have yet to be comprehensively
determined with empirical research. A related challenge
will be agreeing on criteria for how to measure symptom-
level dimensions and neurophysiological constructs.
16
Selecting treatments and evaluating treatment
effective­ness. Furthermore, existing treatments for psy-
chological conditions were not developed to match this
framework. Specifically, interventions have been devel-
oped and tested in relation to DSM diagnoses, not RDoC
constructs and HiTOP dimensions. Therefore, the exist-
ing pool of treatments may not map onto the treatment
targets identified via the proposed characterization strat-
egy, and it may not be immediately clear which inter-
ventions target which constructs. In a sense, deriving
treatment-selection insights using the proposed frame-
work requires retrofitting existing DSM-based treatments
to this type of model. Thus, this framework may expose
the need to develop additional treatments or treatment-
augmentation methods, in which case, this framework
can serve as a starting point for developing mechanisti-
cally grounded therapies.
Moreover, it remains an open question how to mea-
sure treatment success in the context of this framework.
The proposed framework posits that RDoC constructs
play a key role in the manifestation of symptom-level
dimensions of psychological dysfunction. This intro-
duces complexity about how to measure and opera-
tionalize treatment response. For example, would an
effective treatment have to modify the underlying con-
structs, symptom-level dimensions, or both? How
should a characterization map be updated if symptoms
are reduced without ameliorating the hypothesized
underlying constructs?
Addressing the assumption of treatment utility of
assessment. One key assumption of the proposed frame­
work is that the assessment of symptom dimensions and
other constructs will have clinical utility. I have specified
a theoretical framework aimed at maximizing the reliabil-
ity and validity of assessment-driven characterization of
pathology. I suggest that leveraging assessment to char-
acterize pathology precisely may reveal specific, action-
able, treatment targets. Ultimately, I argue that this process
of assessment will yield maximally effective treatment
prognoses. The extent to which assessment guided by
the proposed framework has a beneficial impact on treat-
ment outcomes is a question that should be tested empir-
ically. The literature on the Treatment Utility of Clinical
Assessments (see Kamphuis et al., 2021) suggests that the
evidence is mixed regarding whether and how assess-
ment improves clinical outcomes. These inconsistent
findings suggest that some forms or applications of
assessment might demonstrate clinical benefit, whereas
others do not. Future research should test whether and
how the assessment process embedded in this frame-
work benefits clinical outcomes over and above standard
clinical-assessment practices.
Hagerty
Concluding thoughts
These limitations and outstanding questions notwith-
standing, the proposed precision-characterization and
-treatment framework is poised to inspire research that
can address these issues and can flexibly integrate
advances in clinical science as they emerge. In addition,
the proposed framework can be implemented relatively
immediately in clinical settings to guide case concep-
tualization and treatment selection.
Transparency
Action Editor: Joshua Hicks
Editor: Laura A. King
Declaration of Conflicting Interests
The author(s) declared that there were no conflicts of
interest with respect to the authorship or the publication
of this article.
ORCID iD
Sarah L. Hagerty https://orcid.org/0000-0002-1082-5511
Acknowledgments
I thank Leanne Williams for her contributions to early versions
of the article as my primary mentor in the Mental Illness
Research Education and Clinical Center advanced fellowship
at the Veteran Affairs Palo Alto.
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