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(p. 281) Research Agenda for Anxiety Disorders 

(p. 281) Research Agenda for Anxiety Disorders
(p. 281) Research Agenda for Anxiety Disorders

Edna B. Foa

, Martin Franklin

, Richard J. McNally

, Carmen McLean

, and Daniel Pine

Page of

date: 16 February 2019

(p. 282) The Anxiety Disorders Themselves

What We Know

Much of the research conducted in the last 10 years has explicated in greater detail the complexity of anxiety, which appears more clearly now not to be a unitary construct. Indeed, anxiety is a complex interplay of realistic threat, prior history, conditioning experiences, and anxiety sensitivity. The central role of the amygdala across anxiety disorders has now been clarified, although it also appears that the various anxiety disorders do have distinct biological profiles as well. The field has seen significant advances in terms of the development of a set of cognitive and biological procedures that can be used to aid differential diagnosis; greater methodological consistency across studies will provide increased clarity about the biological and cognitive underpinnings of these conditions. We have also learned that there are genetic contributions to anxiety disorders, although these appear to be modest; here again, methodological consistency across studies will improve our understanding of these contributions across and within the disorders themselves.

What We Do Not Know

The genetic findings that indicate modest effects thus far raise interesting questions about what we do not know, which is how shared and non-shared environmental factors exert their influence over the development and maintenance of pathological anxiety. There is also a great deal to learn about pharmacogenetics and pharmacogenomics, which may elucidate new drug targets based on improved understanding of chromosomal areas of interest. It is widely accepted that extremely large sample sizes are needed to identify a signal and test rather than explore genetic hypotheses, which in turn raises questions about the robustness of such effects. Continuing lack of clarity about the disease states themselves (i.e., the nature and underpinnings of anxiety) continues to hamper our ability to establish anxious phenotypes that will lead to research to improve risk prediction, predict longitudinal course of the various phenotypes, and inform prevention strategies.

Research Priorities

The development of large-scale, multicenter collaborations using shared interview, cognitive, and biological procedures will be necessary to move the research agenda forward, as the complex interactions of interest pose serious challenges when data are derived from smaller, underpowered studies. Such advances will require improvements in data-sharing techniques as well as identification of funding to support the substantial infrastructures needed to support studies on this scale. Team science approaches must also be developed that allow investigators and institutions to work together toward completion of next-stage research studies that have a better chance of addressing the issues that have yet to be explored.

In a recent paper, LeDoux and Pine (2016) suggested that the field will advance further when the distinction is more fully drawn in anxiety between circuits underlying two classes of responses elicited by threat. This conceptualization, which they refer to as the two-system framework, poses two distinct circuits: (1) behavioral responses and accompanying physiological changes in brain and body and (2) conscious feeling states reflected in self-reported fear and anxiety. Accordingly, one would not expect high convergence among the variables across these circuits. Instead, research could focus instead on improving our understanding of how these circuits interact at the behavioral and biological levels of analysis. The hope is that basic knowledge of this sort will inform the development of empirically informed targets for intervention, which could foster improvements in the efficacy of our interventions as well as improved understanding of which forms of intervention are likely to be effective for which patients under which conditions.

(p. 283) Treatment

What We Know

In the last decade what we know about cognitive-behavioral therapy (CBT) and pharmacotherapy has increased substantially. Practicing clinicians, parents, and other professionals who encounter adolescents in their own work now have a solid evidence base that broadly supports the efficacy of these procedures across the anxiety disorders in adolescents. The methodological quality, large sample sizes, and encouraging results of multiple randomized controlled trials support the efficacy of CBT protocols for multiple anxiety disorders, and promote confidence that most patients who complete treatment will likely experience a substantial reduction in anxiety and related symptoms at post-treatment. Moreover, these studies have included, if not focused exclusively on, adolescents, so there is greater certainty that protocols and procedures initially developed for adults are comparably efficacious in adolescents, if not even more so. There is much reason for optimism that CBT protocols that involve some form of exposure to feared stimuli will be helpful in reducing anxiety; multiple studies that tested relaxation or other anxiety management strategies in the last decade also converge in indicating that these procedures, while not entirely inert, are less efficacious than those that encourage “leaning into” fears rather than away from them. As far as medications are concerned, research over the last decade has expanded our knowledge and our confidence that the selective serotonin reuptake inhibitors (SSRIs) are efficacious relative to placebo, but their average response rates often leave patients with clinically relevant residual symptoms. Some research has examined the augmentative effects of CBT and pharmacotherapy in patients already taking SSRIs, but there is still much to be learned about those effects in disorders other than obsessive-compulsive disorder (OCD), where we have the most evidence for the augmentative efficacy of CBT.

We also know that the long-term outcomes for both CBT and pharmacotherapy have been less robust than those observed at posttreatment, and we are now beginning to better understand the patient and therapeutic factors associated with partial response to initial treatment. Immediate and long-term responses to both monotherapies are neither universal nor complete, and these outcomes have spawned efforts at treatment development in order to increase the number of adolescents whose anxiety disorders can be treated effectively and durably.

The last decade also brought important developments in the examination of combined treatments in which CBT and SSRI pharmacotherapy were administered concurrently. Those trials, most notably the Child/Adolescent Anxiety Multimodal Study (CAMS; social anxiety disorder, generalized anxiety disorder, and separation anxiety disorder) and the Pediatric OCD Treatment Study I (POTS I), supported the relative and combined efficacy of CBT and sertraline, but the findings for combined treatment versus the monotherapies were mixed. In CAMS there was a clear combined treatment effect at posttreatment with no caveats; in POTS I the combined treatment effect was moderated by a site effect, whereby combined treatment was more efficacious than CBT alone at one site but both were highly effective and equivalent at the other. Exploration of these effects continues, but suffice it to say now that the evidence base supports starting an anxious adolescent with CBT alone or combined treatment; in the absence of clear moderators of outcome for the most part, clinical judgment at this point can be used to determine which of those regimens would be best as an initial treatment. In the absence of CBT availability, SSRIs are also an efficacious and safe option, as informed by the last decade of large-scale studies that have included adolescents in the sample. The black-box warning for the SSRIs must be taken into consideration, but the data from these large-scale studies in the last decade speak to the safety and tolerability of these medications for anxious teens.

What We Do Not Know

We still need more relative and combined treatment trials across the anxiety disorders, especially those in which comorbid depression is (p. 284) common, such as posttraumatic stress disorder (PTSD). Synergistic effects for combined treatments may be more likely realized in such a context; it is also the case that we have insufficient information to inform treatment sequencing when both CBT and pharmacotherapy options are available. What continues to haunt the treatment field, however, is the search for the “Holy Grail” of moderators of treatment outcome: which treatments, for which patients, under which conditions? Efficacy studies are typically underpowered to detect such effects, though there are a handful of studies now that have at least explored whether patient characteristics (e.g., comorbidity, anxiety disorder diagnosis) influence the likelihood of a positive or negative outcome to specific treatments.

Another major issue that needs to be addressed is the dissemination of empirically supported protocols and methods into the clinical settings where most patients receive care. The last decade’s focus on efficacy studies that emphasize internal validity was certainly necessary given the paucity of information about this crucial topic just 10 years ago. These trees have borne fruit, but trial design decisions that favor internal validity pose threats to external validity. Now that we know much more about the efficacy of CBT and pharmacotherapy for anxious adolescents, the next critical steps must now be taken to examine the effectiveness of empirically supported therapies in clinical settings. An entire subfield known now as implementation science has developed in the last decade, and clinical scientists involved in these endeavors seek to examine the role of therapist, training, clinic variables, and patient variables and their interactions to see whether the treatments developed in the efficacy context can be delivered effectively in settings that are more generalizable to “real-life” clinical practice. This work has begun in earnest already, and we await the outcomes of large-scale studies to inform treatment development and an improved understanding of the complex interactions among all of these factors that can and likely will influence our capacity to deliver effective treatments to all adolescents suffering from anxiety disorders who wish to receive help.

Research Priorities

In keeping with the critical areas in need of further study described above, we advocate for the following:

  1. 1. More efficacy studies of individual anxiety disorders as well as transdiagnostic approaches that cut across our current DSM entities

  2. 2. Increased focus on the relative and combined efficacy of CBT and pharmacotherapies, as well as trials examining varying treatment sequences to determine if there is an optimal way to initiate treatment and to optimize outcomes with augmentative strategies. SMART trials that explore the implications of various decision rules (e.g., whether to switch to an SSRI vs. provide more CBT) would be especially beneficial for treatment providers who currently need to make such complex clinical decisions in the absence of sufficient guiding evidence.

  3. 3. More research connecting the putative biological and behavioral underpinnings of anxiety disorders in youth; engagement of these theoretical targets with methods designed specifically to do so (e.g., response inhibition deficits targeted with training methods) and accompanying symptom reduction would provide crucial information about causality, which at present the field continues to lack.

  4. 4. Identification of new funding sources to support treatment development, examination of efficacy, empirically driven treatment modifications, and dissemination/implementation. Many of the suggested avenues of pursuit listed above are expensive, and shifting priorities within government agencies that have supported the last decade of treatment research make the search for such resources perhaps the most important pursuit of all, since none of the issues identified as still needing exploration can be examined productively without external funding.

(p. 285) Prevention of Anxiety Disorders in Adolescents

What We Know

We know that the ecology of adolescent development and culture involves an expanded network of peer, school, and community affiliations and that this expanded network increases adolescents’ risk for exposure to events and circumstances that have been empirically linked with the development of anxiety disorders. The events and circumstances associated with the development of anxiety disorders include possible high-risk sexual and self-injurious behaviors, smoking and drug use, and exposure to traumatic events (e.g., interpersonal and community violence). Identifying which young people are most at risk to develop anxiety disorders after experiencing negative life events is an important next step toward developing selective treatment and prevention intervention programs.

Specifically, we already know that there are distinct temperamental vulnerabilities to anxiety disorders and anxiety symptoms in some individuals. Moreover, anxiety disorders tend to aggregate in families, and such familial aggregation is due to genetic contributions as well as family environment. A family environment that limits youth independence may particularly put young people at risk. Furthermore, the interactions of children and parents, in which either the child or parent has an anxiety disorder, maintain anxiety and its disorders in young people. Accordingly, one intervention program can involve working directly with the parents to reduce the negative effects of the parent–child interaction. Another individual characteristic, anxiety sensitivity, also serves as a potential risk factor for anxiety disorders, especially panic disorder and PTSD. A third factor, the presence of anxiety symptoms, at a subthreshold level, may also place young people at risk for developing full-blown DSM-5 anxiety disorders.

We know that not all vulnerable children develop anxiety disorders—in fact, relatively few do. Thus, there are factors that protect young people (i.e., children and adolescents) from developing anxiety disorders. Similar to why it is important to know about risk factors, knowledge about protective factors constitutes the building block for developing selective preventive intervention programs that will foster protection from pathological anxiety. In fact, the study of resilience factors has gained traction in recent years.

Specifically, individual characteristics such as child perceived competence, child coping skills and behavior, level of intelligence, and general “resourcefulness” (e.g., knowing how to solve problems and whom to seek out to help solve problems) serve a protective function. Certain environmental resources, such as adequate social support systems (and knowing how to reach out to these systems), and parents who are relatively free of psychopathology and who serve as models of coping also may serve a protective function.

Another fact that is known after decades of clinical trials is that even the best, most well-researched, evidence-based treatments leave at least some youth unresponsive and many still symptomatic. Accordingly, support for research on the anxiety disorders and their treatment must continue to be prioritized.

What We Do Not Know

Although research has informed us some about potential risk and protective factors, we do not know enough about which factors are linked specifically to anxiety disorders rather than being general risk and protective factors that play a role in the development of either internalizing or externalizing disorders in general. Moreover, we do not know how the risk and protective factors differentially affect specific anxiety disorders. This is because the research conducted to date was based on categorical entities rather than continuous measures of psychopathology across a broader range of symptom manifestation. Further, we know much less about protective and risk factors of anxiety disorders in ethnically/racially diverse groups and in socially/economically disadvantaged groups.

Studies of risk and protective factors conducted thus far have primarily used “main effects” models rather than “interactive (p. 286) models.” Consequently, we do not know how risk and protective factors interact with one another and whether they serve to mediate or moderate (or both) anxiety or other psychopathology. We also do not know when in the developmental trajectory of the child potential risk and protective factors have particular influence. Most of the research on risk factors has included either mixed samples of younger and older children (including adolescents), or younger children only. Studies using samples of adolescents only are still rare. We should not presume that potential risk and protective factors operate in similar fashion across developmental stages.

From a selective preventive intervention perspective, we do not know whether targeting of identified risk factors, protective factors, or some combination (or “packages”) of risk and protective factors in certain subsamples of adolescents would in fact lead to a prevention of anxiety disorders. Relatedly, we still do not know enough about whether targeting either particular risk factor(s) (i.e., reducing risk factors), protective factors (i.e., enhancing protective factors), or some combination thereof (i.e., reducing and enhancing risk and protective factors, respectively) would lead to “resilience building” in adolescence. Indeed, no prevention or resilience-building research in the context of anxiety and its disorders has been conducted in adolescents.

We also do not know whether prevention programs aimed at a universal level (in that they target particular facets of the ecology of adolescent development and culture) reduce anxiety disorders in adolescents. For example, does participation in smoking cessation programs reduce or prevent anxiety disorders in teens? If yes, what might be the mediational processes that are operating, and might they be moderated by certain adolescent characteristics? We are not even close to knowing the answers to such questions.

Research Priorities

It is critical that more research be conducted on obtaining basic knowledge about specific risk and protective factors of pathological anxiety in adolescents. This research must carefully consider the context of adolescent development and culture in trying to discern the particular factors and the manner in which these factors interact. Future research should focus on continuous variables related to psychological anxiety rather than on homogeneous samples to evaluate the specificity of these factors to abnormal anxiety. In addition, research needs to focus exclusively on the specificity of protective factors in adolescents. This research needs to consider carefully the role of these factors not only using the “mainstream” population, but using diverse samples that represent the adolescent population.

As with the development of treatment interventions, recognition of the social, biological, cognitive, and emotional changes that emerge during adolescent development should be used to design prevention programs specific for adolescents; thus far this important work has not been done. Given pubertal development and the critical role of the social network for teenagers, programs developed for adolescents should carefully consider how best to provide such interventions in the school setting, and at the same time should take into account the possible issues that arise by implementing interventions in schools (e.g., problems with confidentiality).