applyparastyle "fig//caption/p[1]" parastyle "FigCapt" applyparastyle "fig" parastyle "Figure" Schizophrenia Bulletin doi:10.1093/schbul/sbz141 Downloaded from https://academic.oup.com/schizophreniabulletin/advance-article-abstract/doi/10.1093/schbul/sbz141/5716474 by New York University user on 07 February 2020 Network Analysis Indicates That Avolition Is the Most Central Domain for the Successful Treatment of Negative Symptoms: Evidence From the Roluperidone Randomized Clinical Trial Gregory P. Strauss*,1, Farnaz Zamani Esfahlani2, Hiroki Sayama2, , Brian Kirkpatrick3, Mark G. Opler4, Jay B. Saoud5, Michael Davidson5,6, and Remy Luthringer5 1Department of Psychology, University of Georgia, Athens, GA; 2Department of Systems Science and Industrial Engineering & Center for Collective Dynamics of Complex Systems, Binghamton University, Binghamton, NY; 3Department of Psychiatry and Behavioral Sciences, Reno School of Medicine, University of Nevada, Reno, NV; 4MedAvante-ProPhase, New York, NY; 5Minerva Neurosciences, Waltham, MA; 6University of Nicosia Medical School, Nicosia, Cyprus *To whom correspondence should be addressed; 125 Baldwin St., Athens, GA 30602, US; tel: +1-706-542-030, fax: +1-706-542-3275, e-mail: [email protected] A recent conceptual development in schizophrenia is to view Key words: amotivation/psychosis/treatment/negative its manifestations as interactive networks rather than in- symptoms dividual symptoms. Negative symptoms, which are asso- ciated with poor functional outcome and reduced rates of Introduction recovery, represent a critical need in schizophrenia thera- peutics. MIN101 (roluperidone), a compound in develop- Results of a phase 2b trial indicate that roluperidone, ment, demonstrated efficacy in the treatment of negative a novel cyclic amide derivative with high affinities for symptoms in schizophrenia. However, it is unclear how the 5-hydroxytryptamine 2A, sigma2, and alpha-1 adren- drug achieved its effect from a network perspective. The ergic receptors, exerts a significant improvement on neg- current study evaluated the efficacy of roluperidone from a ative symptoms in schizophrenia patients.1 Although network perspective. In this randomized clinical trial, par- these results provide evidence for efficacy, they do not ticipants with schizophrenia and moderate to severe neg- explain how the drug achieved its effect. Recently, there ative symptoms were randomly assigned to roluperidone has been increasing interest in taking a network approach 32 mg (n = 78), 64 mg (n = 83), or placebo (N = 83). to evaluating psychiatric symptoms to help explain how Macroscopic network properties were evaluated to deter- treatments are effective.2 The underlying theory behind mine whether roluperidone altered the overall density of the this approach is that mental illnesses arise from the inter- interconnections among symptoms. Microscopic properties actions among symptoms in a network, whereby the oc- were evaluated to examine which individual symptoms were currence of one symptom increases the probability that most influential (ie, interconnected) on other symptoms in an interrelated set of symptoms also manifest.3 Symptom the network and are responsible for successful treatment networks are described in terms of their density. Dense effects. Participants receiving roluperidone did not differ networks are highly interconnected and co-activate once from those randomized to placebo on macroscopic proper- symptom exacerbation occurs, forming closely joined ties. However, microscopic properties (degree and closeness clusters of psychopathology that maintain each other and centrality) indicated that avolition was highly central in pa- become self-sustaining. Often, a specific symptom will be tients receiving placebo and that roluperidone reduced this more “central” within a network than others, with strong level of centrality. These findings suggest that decoupling interconnections to other symptoms in the network that the influence of motivational processes from other nega- cause those symptoms to emerge whenever the central tive symptom domains is essential for producing global im- symptom is present. In strongly connected networks, the provements. The search for pathophysiological mechanisms activation of a central symptom may lead to the con- and targeted treatment development should be focused on tinued activation of other symptoms, even after the fac- avolition, with the expectation of improvement in the en- tors which triggered that symptom have disappeared. This tire constellation of negative symptoms if avolition is effec- process may be how symptoms become chronic, whereby tively treated. self-sustaining feedback loops are triggered by a central © The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected] Page 1 of 7 G. P. Strauss et al symptom that leads to the activation of other symptoms, Razor” and proposed that avolition led to the emergence resulting in a global worsening in psychopathology.4 of all other negative symptoms. Specifically, reductions in Downloaded from https://academic.oup.com/schizophreniabulletin/advance-article-abstract/doi/10.1093/schbul/sbz141/5716474 by New York University user on 07 February 2020 It is unclear whether more or less densely connected motivation were proposed to underlie decreased speech symptom networks are most responsive to treatment, as output (alogia), reductions in facial and vocal expression there is evidence for both possibilities.5,6 Densely con- of emotion (blunted affect), diminished pursuit of pleas- nected networks may be difficult to treat because symp- urable activities (anhedonia), and limited engagement toms are closely coupled. In such a network, the treatment in social interactions (asociality). Notably, the capacity must effectively target the most central symptom and to engage in these behaviors may be preserved, but the produce a spreading effect on the global symptom net- level of motivation needed for behavioral initiation was work that yields improvement across other domains. not sufficient to execute them. In a study using network Alternatively, less densely connected networks may be analysis, Strauss et al.10 recently found support for this very difficult to treat because symptoms have little inter- notion, with evidence that avolition was a central nega- action with one another. In this instance, even if a central tive symptom of schizophrenia. This finding may sug- symptom is successfully impacted, the lack of intercon- gest that treatments successfully targeting avolition could nection among symptoms makes it difficult for spreading have a cascading effect, producing global improvements effects to occur because symptoms function as their own in the entire negative symptom cluster once motivation is islands of psychopathology with little interaction. effectively enhanced. Historical difficulties in successfully Determining which domains are most central and treating negative symptoms have made the exploration of driving global negative symptom exacerbation has crit- such possibilities infeasible; however, the recent success ical treatment implications. If this notion is correct, re- of roluperidone offers a unique opportunity to evaluate gardless of which individual symptoms are most central, how successful treatment of negative symptoms occurs it would suggest that the search for pathophysiological from a network perspective. mechanisms and targeted treatment development should In the current analysis, we took a network approach be focused on those key symptoms, with the expectation to evaluating negative symptoms to determine whether of improvement in the entire constellation of negative roluperidone achieved its effect by impacting a spe- symptoms if they are effectively treated. Historically, cific negative symptom domain or the overall density there is precedent to expect avolition (ie, reductions in the of symptom connections. We adopted a standard ap- desire for and initiation of motivated behavior) to be the proach to evaluating symptom networks by calculating most central of the 5 negative symptom domains identi- macroscopic and microscopic network properties.11 fied in the 2005 NIMH Consensus Conference (the others Macroscopic properties (eg, network density, average being alogia, blunted affect, asociality, and anhedonia). clustering coefficient, and average shortest path length) For example, Kraepelin7 attributed considerable impor- provide information about the overall connectedness of tance to avolition, describing schizophrenia patients the network as a whole (see table 1). Networks with a as having: “A weakening of those emotional activities higher density, average clustering coefficient, and lower which permanently form the mainsprings of volition ….” average shortest path length are tightly connected (ie, Bleuler8 also proposed a central role for avolition, pos- symptoms are highly interdependent). In contrast, mi- iting that: “Indifference seems to be the external sign of croscopic properties (eg, degree centrality, closeness their state …. The will (is) . disturbed in a number of centrality) provide information about which individual ways . The patients appear lazy and negligent because symptoms are most influential and interconnected with they no longer have the urge to do anything either of other symptoms in the network. Highly central symp- their own initiative or at the bidding