Adolescent Anxiety Is Hard to Treat. New Drug-Free Approaches May Help

Adolescence is a remarkable period of development and learning, a time when youths explore and adapt to changes in their social worlds and begin to form a sense of who they are and hope to be. It is a time when they first demonstrate a dramatic adaptability to the unique cognitive, emotional, physical, social and sexual demands placed on them as they transition from dependence on their parents or caregivers to relative independence. It is also, unfortunately, a time when the emergence of most mental health problems peaks.

The most common mental health concerns facing adolescents today are anxiety disorders, and their prevalence has been increasing for the past decade. A survey of tens of thousands of teens showed that this prevalence increased roughly 30 to 40 percent between 2012 and 2018, and based on evidence from teens from Germany, it rose another 70 percent during the first few years of the COVID pandemic. Yet anxiety disorders in young people are largely undertreated.

The only evidence-based behavioral treatments for anxiety are cognitive-behavioral therapies (CBTs). They involve identifying triggers of anxiety and then desensitizing the affected person to them through coping strategies such as positive thought reframing or breathing exercises, along with repeated exposure to the triggers in a safe environment. Although CBT is the most established treatment for adolescent anxiety, not all youths who try it experience relief. Among those who do, many fail to maintain improvements over time. A mere 20 to 50 percent of patients treated for anxiety without medication during adolescence remain in remission six years after initial CBT. The consequences can be long-lasting and severe. Left untreated, anxiety can lead to more serious chronic illnesses such as depression and substance use disorder later in life, greater susceptibility to physical illnesses and, in extreme cases, suicide.

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Fortunately, new discoveries about the adolescent brain are showing promising paths forward for the treatment of anxiety. Current research benefits from rapidly advancing imaging technologies that can reveal patterns of neural activity and exciting potential avenues for intervention. These modalities have already provided access to the inner workings of the developing brain in laboratory animals and teens, and scientists hope they will lead to new approaches in clinical practice that take into account the unique changes in the human brain during adolescence. By focusing on the developing brain and the behaviors it generates early on in life, we may be better able to alter anxiety-related memories, identify cues and situations that help to reduce symptoms, and mitigate the adverse effects of anxiety for young people before they become a more chronic affliction in adulthood.

Brain drawings show that the amygdala and hippocampus are activated at higher levels in adolescents than adults. But the prefrontal cortex, involved in the regulation of emotions, does not achieve peak activity levels until well into adulthood.

In the past two decades we have learned that the adolescent brain undergoes notable changes in structure and function, and these changes are distinct from those observed during early childhood and adulthood. They are localized, meaning certain brain areas change earlier in development than others. Regions involved in emotions, such as the amygdala and the hippocampus, show peak structural and functional changes during the teen years. For example, during adolescence the amygdala’s volume increases (a structural change), and so does the way the amygdala is activated by certain emotional experiences (a functional change). In contrast, brain regions and circuitry associated with the regulation of emotions, thoughts and actions—the prefrontal cortex, for instance—change more gradually, with development continuing well into adulthood. These differences in developmental timing may lead to an imbalance in communication among brain regions, allowing one area to prevail over another in an adolescent’s decision-making. Accordingly, in emotionally charged or threatening situations, early-developing emotional areas “win out” over later-­devel­op­ing ones, driving some of the reactions and responses linked with the behaviors of anxious and volatile teens. These regional differences might have served an evolutionary purpose. They have been linked to heightened sensitivity to emotional and social information that may be essential for reproductive success and the survival of the human species. Unfortunately, these same imbalances have also been associated with increased reactivity to stress and greater susceptibility to anxiety disorders.

A core emotion associated with anxiety disorders is fear. Although fear is an adaptive response to threats and therefore essential for survival, persistent fear long after a threat has been removed can lead to a pathological state of anxiety. People with anxiety disorders have difficulty identifying when previously threatening situations have become safe, and they may overgeneralize by thinking that a negative experience in one situation will recur in other scenarios.

Decades of animal and human research have identified the basic brain circuitry for remembering an acquired fear in adults. The amygdala is key to developing a fear memory, and parts of the prefrontal cortex are involved in decreasing the strength of fear memories—a process known as extinction. Both the amygdala and the prefrontal cortex are highly interconnected with a third region, the hippocampus, which plays a role not only in fear extinction but also in determining how we experience fear in different situations. In particular, the hippocampus provides information about the surrounding environment to help an individual decide whether a given situation is more likely to present a threat (for example, a bear in the woods) or an absence thereof (a bear at the zoo). Much of this circuitry is conserved across different species, enabling the translation of basic animal research to treatments in humans.

Recently researchers have focused attention on fear memory and extinction during adolescence. These studies show that adolescents, like preadolescents and adults, are capable of acquiring a fear memory, but they are less able to extinguish those memories than people in other age groups. After being exposed to a few simple pairings of a neutral stimulus (a colored square) with an aversive stimulus (a loud noise), children, adolescents and adults alike show a fear response, measured by sweat gland activity, to the colored square even when the loud noise no longer happens. When preteen children and adults are then presented repeatedly with the colored square without the loud noise, they begin to see the square not as something predicting the threat of the loud noise but rather as a safe refuge from it—the fear memory is extinguished. Adolescents, however, continue to react fearfully to the colored square.

In cases when fear does get diminished for adolescents, it regularly returns with the passage of time. The finding that adolescents “learn” to extinguish fear less readily than younger or older people has been replicated in studies across species (mice, rats and humans). Most notably, during this developmental period, the amygdala is much more involved in sustaining the fear memory than the prefrontal cortex is in initiating the extinction process. A lower ability to initiate fear-­extinction learning is thought to confer a risk for anxiety. Thus, adolescents may innately be at higher risk.

Graphic compares fear extinction and memory updating scenarios. A reminder cue followed by a delay before fear memory extinction results in a change in the fear memory. A greater reduction in fear is achieved than extinction alone without the cue.

The discovery of differences in fear-extinction behavior and brain circuitry during adolescence has important implications not only for understanding the potential for increased susceptibility to anxiety disorders but also for choosing treatment options. Behavioral therapies such as CBT entail identifying triggers of anxiety, finding coping strategies and undergoing a process of desensitization built on the principles of fear extinction. But during adolescent fear extinction, the involvement of the prefrontal cortex, which is associated with the planning and control of behavior, is diminished—which implies that for adolescents, the effectiveness of conventional exposure-based CBT might also be diminished. Together, these facts raise the question of how we should tailor treatments for the developing brain. Specifically, how might we use what we know about the brain’s fear circuitry and the development of fear learning during adolescence to guide interventions that may be more successful in altering teens’ fear memories?

One strategy involves conceding the delayed maturation of the prefrontal cortex and circumventing the region in treatment. Rather than relying on prefrontal-based extinction learning, we have tested an alternative method called memory reconsolidation updating. Memory reconsolidation is based on the principle that memories are dynamic, not static. Every time a memory is retrieved, it gets modified. Reactivating a fear memory by presenting a reminder of the fear stimulus opens a time-limited window during which the memory itself becomes prone to disruption and change.

Studies in both humans and rodents suggest that fear-­memory updating is mediated by changes to the memory in the amygdala. Unlike the prefrontal circuitry, which continues to show developmental changes into young adulthood, the amygdala undergoes peak maturation during midadolescence.

These findings suggest that one way to help adolescents overcome pathological fear is to introduce what is called a reminder cue to retrieve the memory, followed by a delay before subsequently extinguishing it. In our lab, we tested this idea in both healthy adolescents and adults by comparing their retention of a fear memory after extinction with and without a preceding reminder cue. We found that even though adolescents typically show diminished fear extinction relative to adults, those who were prompted to retrieve the fearful memory several minutes before extinction learning showed a dramatic reduction in fear the next day compared with those who underwent only extinction learning. In fact, those adolescents’ fear memories diminished to the same degree as observed in adults.

Traditionally, extinction learning involves forming a new, competing, safe memory that leaves the original fear memory intact, meaning it is possible for those fearful thoughts to return later. The current findings, however, suggest that with memory reconsolidation updating, the original fear memory is altered. Thus, the reconsolidation approach has the potential to both reduce fear at the time of treatment and lessen the likelihood that it will return.

This research is exciting because it suggests a path to the clinical use of reconsolidation updating. Simple modifications to existing exposure-based CBT techniques might prove effective in reducing triggers of fear and anxiety in adolescent patients. This method could entail a step as simple as the therapist reminding patients why they are there when they arrive for their appointment—the equivalent of the reminder cue and fear-­memory retrieval in the lab setting. Then the therapist could spend several minutes establishing a safe rapport with the patient while waiting for the memory to enter a labile state during the reconsolidation-updating window. Desensitization with exposure therapy could then begin during the time in which the updating process takes place. The current variable efficacy of CBT in adolescents with anxiety disorders may be explained by the fact that some clinicians already use procedures that inadvertently tap into components of reconsolidation updating.

Recent attempts to incorporate reconsolidation-­updating approaches in treating adult patients with anxiety and trauma-related disorders have yielded some success, but to date they have not been used with adolescent patients. The studies in adults show short- and long-term reduction of symptoms, especially for patients with specific phobias and post-traumatic stress disorder. Although more basic and clinical research is needed, this method seems promising.

Another strategy that may help adolescents extinguish a fear memory involves the use of safety cues that signal there is nothing to be afraid of. In an experimental setting, a safety cue can be a simple stimulus—a symbol or a sound—that is distinguishable from and repeatedly contrasted with a fear cue. Outside the lab, safety cues come in many forms and are likely to be a stimulus unique to the individual: a small personal object, a photograph of a loved one, a specific scent. We and others have shown that in humans and rodents alike, safety cues act by recruiting brain regions that show elevated activity during adolescence, including the amygdala and the hippocampus. The anterior part of the hippo­campus in particular shows a strong increase in activity when a safety cue is presented alongside a fear cue; the degree of activity corresponds to the reduction in fear. Furthermore, safety cues rely less on the prefrontal cortex than do other forms of fear regulation, such as extinction, highlighting the possible advantage of using a safety cue–based approach for anxiety during adolescence.

It is not feasible to avoid all triggers of excessive fear and anxiety, so it’s important that patients do not become overly reliant on safety cues to the detriment of learning other coping skills. Safety cues may be a valuable tool for increasing the tolerability of the early stages of treatment so that patients do not drop out. Early treatment sessions could include guidance from the clinician on how to identify and properly deploy a safety cue.

As treatment progresses, cues can give patients a way to reduce their fear response long enough to evaluate the situation and use tools from CBT practice. Although research on integrating safety cues into treatment is in its earliest stages, the method shows great promise, particularly for adolescents. Our group recently demonstrated in mice that intermittently presenting a safety cue during an extinction protocol led to better fear extinction in adolescent mice than observed in either adolescent (28 to 50 days) or adult rodents trained without a safety cue.

The hope for these emerging therapeutic approaches is that we can tailor current anxiety treatments for young people by targeting the developing brain. It is important to be mindful of the fact that the magnitude and intensity of the fear response in people diagnosed with anxiety are probably much greater than the fear evoked by aversive stimuli in lab experiments, which are often mild, narrowly targeted and transient. It is also important to remember that CBT and antidepressants can treat anxiety effectively in many people. Unfortunately, though, for some, these solutions offer only limited or brief benefits. Therefore, the most effective forms of treatment may require a combination of approaches, including desensitization techniques modified to incorporate reconsolidation updating or safety cues, possibly in conjunction with antidepressants.

The ultimate aim is for us to optimize current treatments for youths with anxiety by targeting the brain during a period of development accompanied by intensive learning and, in so doing, improve the quality of life for adolescents both in the immediate future and later in life.

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