The symptoms of schizophrenia are extremely heterogeneous and span a wide spectrum of psychopathology, both in terms of inter-individual variance and course variance. There have been successive attempts over time at better integrating and classifying this significant heterogeneity by creating different diagnostic classifications, starting with the dementia praecox1 and continuing into present times with a succession of classifications2 in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)3 and the International Statistical Classification of Diseases and Related Health Problems, tenth edition (ICD-10).4 These classification systems were in part derived from careful clinical, research-based longitudinal observations, and more recently based on consensus decisions by expert panels. The fact that these classification systems have changed over time points to their potential lack of reliability and scientific validity among some of the many contributing factors. This has also been demonstrated by a review of meta-analyses reporting an overlap of symptom features that found transnosological overlap of symptom features across major diagnostic categories, such as psychotic features of mood disorders overlapping with psychotic features of patients with schizophrenia, or cognitive deficits in patients with schizophrenia overlapping with some cognitive features in patients with bipolar disorder.5
A particular challenge to traditional diagnostic classifications is psychiatric comorbid presentations. In the case of schizophrenia, the DSM-5 considers comorbid symptoms as part of another diagnosis that is occurring alongside schizophrenia.3 In this scenario, the patient has two major conditions; these have co-occurred (perhaps for some etiological reason common to both disorders), and one of the two disorders is a primary condition. However, if no primacy disorder can be determined, then mixed labels are used, such as schizo-affective disorder or schizo-obsessive subtype of schizophrenia. Taken together, it is clear that psychiatric diagnoses do not have explanatory power and do not capture the complex causal relationships within and between the genetic, neurophysiological, and behavioral features that characterize mental illness. This makes the delineation of clear boundaries for comorbid conditions difficult, and also makes it challenging for research applications when investigators study specific comorbid behavioral domains and their underlying neurophysiological pathogenesis.
There may be a need for alternative strategies in understanding the heterogeneity of schizophrenia symptoms and comorbid conditions. Particularly in the context of research investigations, there is a need for a new symptom domain approach that is free of traditional diagnostic “attachments.” One that is transnosological and allows for the study of comorbidities within diagnostic categories as well as for more specific investigations into underlying neurocircuitry pathophysiology and treatment approaches. This would mean applying the same study methodology across entire nosological systems and, in particular, to comorbid manifestations. Such a new approach may be offered by the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC).6,7 This article presents the potential impact of using the RDoC in the study of behavioral domains within schizophrenia and specifically for comorbid manifestations by posing the following questions: Can the RDoC criteria be used for better behavioral understanding of comorbidity in schizophrenia? Is the RDoC classification helpful in the biological understanding of comorbidity in schizophrenia? Can the RDoC criteria be helpful in formulating biological treatment approaches for comorbidity in patients with schizophrenia?
What is the RDoC Framework?
Related to the increased emphasis on neurodevelopmental underpinnings of diverse illness manifestations, the RDoC framework encourages investigators to think differently about comorbidity. The co-occurrence of disorders and symptoms has been the focus of extensive empirical study; however, due to the longstanding and traditional use of categorical diagnostic distinctions in psychiatry research, comorbidity among psychiatric disorders has often been treated as experimental “noise” and nuisance.8,9 For readers less familiar with the concept of RDoC and its matrix, we briefly review its innovative aspects.
The RDoC is a dimensional system because it relies on 5 dimensions that “span the range from normal to abnormal.”7 Each of these five constructs is envisioned to function along a continuum from normal to pathological.10 Whereas conventional diagnostic systems incrementally revise and build on their pre-existing paradigms, RDoC is “detached from current disorder categories.”7 Also, rather than “starting with an illness definition and seeking its neurobiological underpinnings, RDoC begins with current understandings of behavior-brain relationships and links them to clinical phenomena.”7 Unlike conventional diagnostic systems, which typically rely on self-report and behavioral measures alone, the RDoC framework has the “explicit goal” of allowing investigators access to a wider range of data, including genetic, molecular, cellular, circuits, and neurophysiological data. In addition to self-report measures and measure of behavior, RDoC also incorporates units of analysis beyond those found in the DSM-5,3 allowing RDoC to be informed by insights into genes, molecules, cells, circuits, physiology, and large-scale paradigms.7
The five RDoC domain constructs include:
Negative valence systems: fear, anxiety, loss, frustrative, nonreward;
Positive valence systems: reward learning, reward valuation, habits;
Cognitive systems: attention, perception, declarative memory, working memory, cognitive control;
Systems for social processes: attachment formation, social communication, perception of self, perception of others;
Arousal/modulatory systems: arousal, circadian rhythm, sleep and wakefulness.
RDoC criteria can help researchers develop valid biomarkers and endophenotypes that ultimately may yield more precise and validly defined disorders.7 The RDoC approach also overcomes one of the inherent problems with the categorical approach, which assumes the notion of a unitary diagnostic entity that has a numerical value with a variance for all its measures.8 Findings of group differences, then, imply that all patients are impaired compared with normal controls on some measure, which may not be accurate because at least some patients may not be so impaired, and it would be important to know why. On the less-impaired side of the severity continuum, one would find patients with “forme fruste” conditions, which are proportionately less severe, and excluding these patients obscures an explication of potentially relevant dimensions and also obviates attention to clinically relevant dysfunction.8
The Application of RDoC Criteria to Comorbid Conditions in Schizophrenia
Can the RDoC classification be helpful in the biological understanding of comorbidity in schizophrenia? The main comorbid conditions in schizophrenia include schizo-affective, schizo-obsessive, and schizo-aggressive disorders, as well as schizophrenia with substance use. To examine a specific comorbid function, such as depression, across various diagnostic categories may first appear to be unproductive to advance our understanding of the underlying biological mechanisms. However, as the circuits and measurements of depression and depressive behaviors are better understood, it may eventually help to recognize that these circuits have common features and underlying genetic pathogenesis, which in turn will help us better understand whether or not depression is present as a comorbid syndrome in schizophrenia.11 Currently, we are struggling to understand whether such symptoms are due to depression pathology or schizophrenia pathology.9 However, measures that have been validated to assess relevant circuit functions in depression (whether in cognition, reward circuit activity, or arousal systems) may provide a fruitful methodology to move forward in addressing such important questions. Another value the RDoC can bring to biological research of comorbid conditions, such as depression, is the use of the RDoC matrix (Figure 1). For example, it allows researchers to extract information from the matrix to answer a specific neurobiological question or to understand a clinically relevant psychopathological construct, such as depression. For this purpose, simple exploration of RDoC's matrix provides a bird's-eye view of how aspects of human behavior are encompassed as the composite of five dynamically maintained domains, each animated by a cluster of associated psychological constructs.9,12
The Research Domain Criteria matrix. Reprinted from the National Institute of Mental Health7 (in the public domain, permission not required).
Another example of an application of the RDoC concept is in the understanding of substance use disorder as a comorbid condition of schizophrenia. Clearly, substance use disorders are transnosological and add a serious negative prognosis to all psychiatric disorders, and specifically to the course of patients with schizophrenia. The precise understanding of its underlying biological neurocircuitry, particularly involving the dopamine reward circuitry, will open up new treatment approaches for this comorbid condition. It may be possible to compare the effects of clozapine and risperidone on cannabis-craving pathways (ie, chronic craving, attentional bias, and cue-elicited craving) in patients with schizophrenia or schizophrenia-like disorders and co-occurring cannabis abuse or dependence, and then examine the associated brain activation patterns with functional magnetic resonance imaging. Outcome measures can be structured to follow RDoC recommendations to link behavioral assessments with hypothesized underlying cognitive changes. This may contribute to better understanding of clozapine's hypothesized superior anticraving effects for cannabis use.13,14
Can the RDoC criteria be used for better behavioral understanding of comorbidity in schizophrenia? The RDoC approach suggests that behavioral domains, such as depression, substance use, aggression, and obsessive-compulsive features, should be studied unlinked from their diagnostic attachments. In addition, there may be more scientific advantage to study these comorbid behavioral domains across diagnostic classifications. In other words, it may be more productive to investigate obsessive-compulsive features across bipolar disorder, schizophrenia, and obsessive-compulsive disorder because the behavioral presentations are similar. Another example of this more recent approach has been the recognition that cognitive deficits, which have been traditionally attributed to schizophrenia, are now also seen to be significantly associated behavioral features of bipolar disorder.5 This approach fulfills two specific recommendations of the RDoC approach. The first is the study of a behavioral domain across different degrees of severity and the postulate of a shared, genetically determined influence on neurodevelopment. The author's group15 published a study of the shared psychotic symptom domains of patients with bipolar disorder compared to patients with schizophrenia. We found similarities in psychotic symptom domains, as measured by the Positive and Negative Syndrome Scale, in patients with bipolar mania and schizophrenia.15
The other specific application of the RDoC concept is the study of the longitudinal stability of a behavioral domain, which has always been more challenging when studying the changing course of traditional diagnostic entities.16 This is particularly applicable in the study of some comorbid conditions, such as schizo-affective disorder. Characterization of patients with both psychotic and mood symptoms either concurrently or at different points during their illness has always posed a diagnostic challenge and has resulted in the poor reliability, low diagnostic stability, and questionable validity of schizo-affective disorder as defined in DSM-5.17
Can the RDoC criteria be helpful in formulating treatment approaches for comorbidity in schizophrenia? The RDoC approach offers a more inclusive set of clinical considerations than traditional approaches, which might contribute not only to a better overall definition of the severity status of a given behavioral domain, but might also contribute to a more differentiated treatment approach.18 This may be particularly advantageous for the treatment of comorbid conditions, in which a systematic RDoC-based assessment of the specific behavioral comorbid domain can expand the traditional diagnosis-based problem list and help formulate more specific treatment approaches.18 Yaeger and Feinstein18 in fact have suggested to enrich DSM-5 diagnoses by RDoC features, together with the use of a hybridized “multi-axial” clinical portrait.
The introduction of the RDoC can also allow for a much more precise study of predictors of treatment response if a particular neurocircuit has been linked to a specific behavior, leading to the identification of a biomarker. It is hoped that such genetic, neuroimaging and other physiological biomarkers will have predictive value for treatment response to pharmacological and/or psychotherapeutic treatments. An example of such an approach would be to examine the functional 5-HTTLPR/rs25531 genotype, anterior cingulate cortex function, and cardiovascular flexibility as treatment-response predictors of the RDoC-defined behavioral domain of depression in patients with a schizo-affective disorder. Preliminary evidence was found for these biomarkers to modulate treatment outcome in patients with depression.19
The RDoC criteria will not displace the ICD/DSM diagnostic systems, at least not in the near future. However, they are useful in psychiatric research as they allow investigators to focus on 1 of 5 defined behavioral paradigms and on the systematic underlying molecular, genetic, cellular, and neurophysiological underpinnings of the chosen behavior and stay free of traditional diagnostic categories. This may be particularly advantageous for the study of comorbid disorders.
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- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
- World Health Organization. The International Statistical Classification of Diseases and Related Health Problems. 10th ed. Geneva, Switzerland: World Health Organization; 1992.
- Bortolato B, Miskowiak KW, Köhler CA, Vieta E, Carvalho AF. Cognitive dysfunction in bipolar disorder and schizophrenia: a systematic review of meta-analyses. Neuropsychiatr Dis Treat. 2015;11:3111–3125. doi:10.2147/NDT.S76700 [CrossRef].
- Insel T, Cuthbert B, Garvey M, et al. Research Domain Criteria (RDoC): toward a new classification framework for research on mental disorders. Am Psychiatry. 2010;167:748–751. doi:. doi:10.1176/appi.ajp.2010.09091379 [CrossRef]
- National Institute of Mental Health. Research Domain Criteria (RDoC); 2013. https://www.nimh.nih.gov/research-priorities/rdoc/index.shtml. Accessed November 8, 2018.
- Cuthbert BN. The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology. World Psychiatry. 2014;13(1):28–35. doi:. doi:10.1002/wps.20087 [CrossRef]
- Morris SE, Cuthbert BN. Research Domain Criteria: cognitive systems, neural circuits, and dimensions of behavior. Dialogues Clin Neurosci. 2012;14(1):29–37.
- Elmer GI, Brown PL, Shepard PD. Engaging Research Domain Criteria (RDoC): neurocircuitry in search of meaning. Schizophr Bull. 2016;42(5):1090–1095. doi:. doi:10.1093/schbul/sbw096 [CrossRef]
- Siris SG. Depression in schizophrenia: perspective in the era of “atypical” antipsychotic agents. Am J Psychiatry. 2000;157(9):1379–1389. doi:. doi:10.1176/appi.ajp.157.9.1379 [CrossRef]
- National Institute of Mental Health. Important notes on the matrix. https://www.nimh.nih.gov/research-priorities/rdoc/constructs/rdoc-matrix.shtml. Accessed November 8, 2018.
- Machielsen M, Schelt A, Beduin E, Dekker NGenetic Risk and Outcome of Psychosis (GROUP) Investigators. Differences in craving for cannabis between schizophrenia patients using risperidone, olanzapine or clozapine. J Psychopharmacol. 2012;26(1):189–195. doi:. doi:10.1177/0269881111408957 [CrossRef]
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- Lindenmayer JP, Bossie CA, Kujawa M, Zhu Y, Canuso CM. Dimensions of psychosis in patients with bipolar mania as measured by the positive and negative syndrome scale. Psychopathology. 2008;41(4):264–270. doi:. doi:10.1159/000128325 [CrossRef]
- Keshavan MS, Ongur D. The journey from RDC/DSM diagnoses toward RDoC dimensions. World Psychiatry. 2014;13(1):44–46. doi:. doi:10.1002/wps.20105 [CrossRef]
- Malaspina D, Owen MJ, Heckers S, et al. Schizoaffective disorder in the DSM-5. Schizophr Res. 2013;150(1):21–25. doi:. doi:10.1016/j.schres.2013.04.026 [CrossRef]
- Yager J, Feinstein RE. Potential applications of the National Institute of Mental Health's Research Domain Criteria (RDoC) to clinical psychiatric practice: how RDoC might be used in assessment, diagnostic processes, case formulation, treatment planning, and clinical notes. J Clin Psychiatry. 2017;78(4):423–432. doi:. doi:10.4088/JCP.15nr10476 [CrossRef]
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