Although the negative effects of substance use disorders on our society are enormous and health care systems have struggled in the effort to integrate prevention, treatment, and recovery services, progress has been made.1 A core challenge to managing substance use disorders is reducing the high rates of relapse, and the ability to identify risk factors for relapse is a major goal of drug addiction research. Individuals receiving treatment for substance use disorders vary widely in their propensity to relapse as well as in the amount of time they remain abstinent after completing treatment. Relapse separates many patients from treatment, even when they are mandated by the criminal justice system to receive treatment. Identifying those at greatest risk and providing treatment that specifically targets modifiable components of that risk would undoubtedly change the landscape of substance abuse treatment, likely attracting more people who need it and perhaps reducing burnout among those who provide it. The study by MacNiven and colleagues2 adds to a limited but growing number of studies that use neuroimaging to identify risk factors for relapse and sustained abstinence. The investigators studied patients with stimulant use disorder receiving early treatment by using functional magnetic resonance imaging (fMRI) to examine whether neural responses to drug cues were associated with future relapse. The study participants were predominantly male users of methamphetamine and/or cocaine (n = 36) and nonaddicted individuals in a control group (n = 40). Patients were initially treated in a 28-day residential treatment program and were subsequently followed up by the research team for up to 6 months after discharge to collect measures associated with relapse.
The researchers focused their fMRI analyses on mesocorticolimbic regions long implicated in drug reinstatement behavior in animal models of addiction: the nucleus accumbens (NAcc), ventral tegmental area, and medial prefrontal cortex. Although all 3 regions showed enhanced fMRI activity in response to drug cues compared with controls, only the drug cue responses in the NAcc were associated with relapse 3 months after discharge. Relapse was characterized both as a binary variable (whereby any use of a stimulant was scored as a relapse) and as a continuous variable (number of days between discharge and any use of a stimulant). Both analyses showed a significant association between NAcc responses to drug cues and these relapse variables at 3 months after discharge. The investigators compared models using fMRI responses with and without other demographic, clinical (eg, depression), and self-report (eg, craving) variables, but the self-report variables did not improve the fit of any models, suggesting that fMRI responses (particularly those in the NAcc) may have significantly greater potential to identify the possibility of relapse. This scenario has been the prevailing argument for biological markers for some time, although the clinical research data are now catching up with the conclusions from animal research.
The study by MacNiven et al2 contributes to an important effort to validate findings from basic science studies with those from clinical research, which informs clinical management more directly. The preclinical literature has established the NAcc as a critical component of the limbic circuits mediating reward-based motivation and arousal, suggesting that neuroadaptations in this region identify the propensity for relapse in humans.3 Animal studies have demonstrated that, for virtually all known drugs of abuse, acute administration enhances mesolimbic activity and release of dopamine in the NAcc. However, dopaminergic effects in preclinical models of long-term stimulant use are more inconsistent with each other than models of short-term use. In this case, clinical studies appear to be more consistent. A recent meta-analysis of human positron emission tomography and single-photon emission computed tomography studies concluded that long-term stimulant users show relatively consistent changes in both the presynaptic and postsynaptic mesolimbic dopaminergic neurons indicative of a generalized downregulation of dopaminergic transmission.4 Thus, despite the much larger animal model body of literature, neuroimaging studies will be vital to translate findings from basic research into clinically useful information.
Studying treatment outcomes in substance abuse research is difficult to do. MacNiven et al2 are to be commended for their success retaining most of the participants for the 3-month and 6-month follow-up visits. However, most of the identification of relapse was done without biological verification. This scenario is less than optimal in the case of stimulants, for which agreement between self-report using timeline follow-back procedures and biological measures may be lower than for other drugs, particularly in patients with psychiatric comorbidities.5 More important, however, given that the participants in the study by MacNiven et al2 were almost entirely men, it will be important to confirm whether the association of NAcc responses to drug cues with relapse extends to women. This confirmation is vital, as women with stimulant use disorders may have more intense craving after drug cessation, and poorer clinical outcomes among women with stimulant use disorders have been reported in multiple studies.6 Nevertheless, if the findings of MacNiven et al2 are generalizable to other substance use disorders, they would have far-reaching implications for identifying risk factors associated with relapse and, potentially, with substance abuse treatment in general.
The promise that neuroimaging will help improve treatment of psychiatric disorders in general and substance use disorders in particular is beginning to be realized. Studies such as the one by MacNiven et al2 make it possible to envision task fMRI (or other biological markers) combined with other measures as an instrument to anticipate relapse in individuals with substance use disorders.7 Moreover, neuroimaging methods, including task and resting-state fMRI, diffusion tensor imaging, and high-resolution structural MRI, are directly informing systematic development of neuromodulation methods, such as repetitive transcranial magnetic stimulation for use in stimulant use disorders.8 Because there are no medications available for stimulant use disorders, these are among the most promising treatments currently in development despite the need for standardized procedures and improved methodological control.9 Among the protocols being tested are those that modulate activity in specific targets within frontal-striatal circuits involved with limbic reward, motivation, and impulsivity, as well as others within the frontal and parietal cortical circuits associated with executive control.8 Although the NAcc findings here might favor transcranial magnetic stimulation protocols that modulate activity in the frontal-striatal circuits, it highlights the need to determine which circuits contribute the most to relapse risk (by evaluating them in parallel) so that optimal neural targets for new treatments can be tested first.
Elucidating robust factors associated with relapse in substance use disorders would allow clinicians and treatment programs to develop prognostic triage strategies to direct high-risk patients to interventions that will improve outcomes and potentially reduce the investment of clinical resources that are less useful. Achieving such a goal is predicated on the development of interventions that reduce relapse rates, increase the time to relapse, and decrease posttreatment substance use in general. Biological markers associated with relapse might then be used to assess treatment response in a clinical setting to optimize management on an individual basis, if necessary.
Published: December 28, 2018. doi:10.1001/jamanetworkopen.2018.6503
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Nierenberg J. JAMA Network Open.
Corresponding Author: Jay Nierenberg, MD, PhD, Center for Biomedical Imaging and Neuromodulation, The Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Bldg 35, Orangeburg, NY 10962 (firstname.lastname@example.org).
Conflict of Interest Disclosures: Dr Nierenberg reported receiving fees for serving as a consultant for Alkermes.
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