The impact of a virtual mind–body program on symptoms of depression and anxiety among international English-speaking adults with neurofibromatosis
Abstract
The neurofibromatoses (NFs) are a set of incurable genetic disorders that predispose individuals to nervous system tumors. Although many patients experience anxiety and depression, there is little research on psychosocial interventions in this population. The present study examined the effects of a mind–body intervention on depression and anxiety in adults with NF. This is a secondary analysis of the Relaxation Response Resiliency Program for NF (3RP-NF), an 8-week virtual group intervention that teaches mind–body skills (e.g., relaxation, mindfulness) to improve quality of life. Participants were randomized to 3RP-NF or the Health Enhancement Program for NF (HEP-NF) consisting of health informational sessions and discussion. We evaluated depression (PHQ-9) and anxiety (GAD-7) at posttreatment, 6 months, and 12 months. Both groups improved in depression and anxiety between baseline and posttest, 6 months, and 12 months. The 3RP-NF group showed greater improvements in depression scores from baseline to 6 months compared with HEP-NF and with lower rates of clinically significant depressive symptoms. There were no between-group differences for anxiety. Both interventions reduced distress and anxiety symptoms for individuals with NF. The 3RP-NF group may be better at sustaining these improvements. Given the rare nature of NF, group connection may facilitate reduced distress.
1 INTRODUCTION
The neurofibromatoses (NFs)—NF1, NF2-related schwannomatosis (NF2), and schwannomatosis—are a set of incurable, progressive genetic disorders that predispose individuals to tumors of the nervous system (Jouhilahti et al., 2011). All NF subtypes are associated with significant impairments and reductions in quality of life as a result of symptoms including cutaneous tumors (Jouhilahti et al., 2011), gait problems, facial weakness, hearing loss (NF2; Evans, 2023), and chronic pain (schwannomatosis; Merker et al., 2012), resulting in increased healthcare utilization (Wang et al., 2012). Given their impairing and incurable nature, it is unsurprising that the NFs are associated with psychological sequelae. Individuals with NF have higher rates of psychological symptoms than individuals with other serious illnesses, such as cancer (Fishbein et al., 2022), including heightened depression and anxiety. Between a quarter and a half of patients report clinically significant depressive and anxiety symptoms (Fishbein et al., 2022), at levels much higher than population norms (Wang et al., 2012).
Although the NFs are associated with heightened emotional distress, there is little research on psychosocial interventions to improve psychological functioning in this population. Individuals with NF show deficits in coping skills (e.g., relaxation, assertiveness, and optimism) needed to deal with the impairing nature of their disorder (Fishbein et al., 2022). To address this need, we developed the Relaxation Response Resiliency Program for NF (3RP-NF), an 8-week virtual intervention that teaches mind–body skills to improve quality of life (QoL; Vranceanu et al., 2018). Our 3RP-NF intervention was adapted from the original 3RP program, designed to elicit the “relaxation response” (RR), a state of calm awareness, through relaxation and mindfulness skills. Like other mindfulness-based interventions (Marino et al., 2021; Sanada et al., 2017), the 3RP program has demonstrated ability to improve health indicators and well-being for a number of health conditions but required adaptation to suit the unique needs of individuals with NF (Bhasin et al., 2013; Denninger et al., 2014; Kuo et al., 2015; Vranceanu et al., 2013, 2014). In the first fully powered single-blinded randomized controlled trial of a psychosocial NF intervention, 3RP-NF demonstrated sustained improvements in QoL compared with a dose-matched health education control (the Health Enhancement Program for NF, HEP-NF; Vranceanu et al., 2023). In particular, we found that QoL improved in both groups but that individuals in the 3RP-NF group were better able to maintain and grow these improvements by 12-month follow-up.
The present secondary analysis aims to examine the effects of 3RP-NF on secondary outcomes of depression and anxiety symptoms compared with HEP-NF. We hypothesized that participants in the intervention group would demonstrate greater reductions in both depression and anxiety at postintervention and that treatment effects would be maintained at 6-month and 12-month follow-ups.
2 MATERIALS AND METHODS
2.1 Editorial policies and ethical considerations
Study procedures were reviewed and approved by the Massachusetts General Hospital institutional review board (Protocol no. 2017P000143). Informed consent was obtained from all participants prior to data collection.
2.2 Study design
This two-arm, single-blinded randomized control trial compared the 3RP-NF intervention to a health education control (HEP-NF).
2.3 Study participants
Participants were recruited globally through the NF Registry sent from the Childhood Tumor Foundation (CTF) and similar email listserv services. The study was advertised as a Stress Management Program to maintain the single-blind study design. Interested participants met with study staff virtually to review eligibility criteria, consent, and the safety protocol. Inclusion criteria were (1) diagnoses of NF1, NF2, or schwannomatosis by a medical professional, (2) ≥18 years of age, (3) ability to provide informed consent and remain in compliance with study procedures, (4) English literacy equivalent to a 6th-grade reading level or above, (5) self-reported stress and difficulties coping with NF symptoms; (6) score ≥6 on the Perceived Stress Scale-4 items (Cohen, 1988; Cohen et al., 1983; McGregor et al., 2015). Exclusion criteria were (1) severe psychopathology (e.g., untreated schizophrenia) that would interfere with study procedures, (2) change in antidepressant medication in the past 3 months, (3) past 3 months participation in cognitive behavioral or relaxation therapy, (4) significant mental health conditions necessitating immediate treatment based on self-report and observation during screening, and (5) being unwilling or unable to participate in virtual group sessions. Participants were enrolled between October 2017 and January 2021. The final follow-up outcome assessment was completed in February 2022.
2.4 Randomization
Participants were randomly assigned to the 3RP-NF or HEP-NF groups following completion of consent and baseline assessments. Randomization was stratified by disease type (NF1, NF2, and schwannomatosis) using a preset REDCap function.
2.5 Study interventions
The 3RP-NF intervention consisted of 8 weeks of group sessions (90 min/session) conducted over Zoom with a clinical psychologist. Groups were made up of 3–8 participants, depending on the number of eligible participants in each cohort. Each session included group discussions about techniques and skills to promote adaptive coping in response to NF-related stress.
The 3RP-NF combines relaxation and mindfulness skills, adaptive coping skills, and positive psychology to increase QoL, all tailored to address the unique needs of adults with NF to support them in managing stress and NF symptom burden. Examples of session skills include body awareness, meditation, setting SMART goals, guided imagery, mindful breathing, and identifying negative automatic thoughts.
Sessions additionally included in-session practice using RR exercises. 3RP-NF participants received weekly homework assignments and audio recordings to practice and track mind–body techniques delivered during the sessions. Session 8 included a comprehensive review of prior skills to promote long-term retention.
The HEP-NF comparison program was also an 8-week 90-min group intervention consisting of educational information and group discussion. Modules included NF-related stress, sleep, nutrition, exercise, healthcare management, and communication, with session 8 comprising a review of program material.
2.6 Data collection
Assessments were conducted at baseline, posttest (8 weeks), 6 months, and 12 months. Participants received a unique REDCap link to complete the surveys online. Participants did not receive compensation for completing study assessments.
2.7 Measures
2.7.1 Anxiety
The General Anxiety Disorder-7 is a 7-item self-report to assess how frequently participants experience various problems related to anxiety over the last 2 weeks. Example items include “Feeling nervous, anxious, or on edge,” “Worrying too much about different things,” and “Feeling afraid, as if something awful might happen.” GAD-7 items are scored on a 0 (not at all) to 3 (nearly every day) scale. Higher total scores indicate greater anxiety. The GAD-7 is reliable and valid in clinical populations (Spitzer et al., 2006). Cronbach's alpha in the present sample was 0.89. The minimally clinically important difference (MCID) in cancer patients is 3.0 (Kroenke et al., 2016; Livingston et al., 2022).
2.7.2 Depression
The Patient Health Questionnaire-9 is a 9-item self-report to assess depression severity over the last 2 weeks. Example items include “Feeling down, depressed, or hopeless,” “Feeling tired or having little energy,” and “Little interest or pleasure in doing things.” PHQ-9 items are scored on a 0 (not at all) to 3 (nearly every day) scale. A final item asks participants to rate the degree of functional impairment associated with depression. Higher total scores indicate greater depression. The PHQ-9 is reliable and valid in clinical populations (Sun et al., 2020). Cronbach's alpha in the present sample was 0.90. The MCID in cancer patients is 2.0 (Toussaint et al., 2020).
2.8 Data analytic strategy
We employed SAS version 9.4 and adhered to the intention-to-treat principle by including all randomized participants in our analyses. To evaluate the impact of treatment on depression and anxiety outcomes, we employed a linear mixed model with a completely unstructured covariance structure across up to four repeated measurements, including baseline, posttest, and 6- and 12-month follow-ups. The mixed model accounts for all available data, including participants who did not complete evaluations or were lost to follow-up, and imputes missing data through the estimated covariance among repeated measurements, leading to unbiased estimates. We calculated the differences between 3RP-NF and HEP-NF in changes from baseline to posttreatment and 6- and 12-month follow-up times by utilizing linear contrasts of least-square means. We presented the point estimates with unadjusted 95% confidence intervals for PHQ-9 and GAD-7 total scores. Finally, we compared differences between 3RP-NF and HEP-NF in the rates of clinical levels of anxiety and depressive symptoms at posttest, 6-month follow-up, and 12-month follow-up among the subgroup of patients who reported clinical levels of these symptoms at baseline. Clinical levels of anxiety and depression were defined as scores above 5 on the GAD-7 and PHQ-9, respectively (Kroenke et al, 2001; Spitzer et al., 2006). We restricted these analyses only to those with clinical levels of symptoms, as these were the participants who had room to demonstrate improvement.
3 RESULTS
3.1 Study flow
Of the 228 randomized participants, in each condition n = 83 had NF1, n = 16 had NF2, and n = 15 had schwannomatosis. Two hundred seven (95.18%) of the 228 enrolled individuals finished the program by attending at least six of the eight sessions and submitting the posttreatment evaluations.
The study flow and treatment compliance have been covered in other places (Vranceanu et al., 2018, 2023). There were no significant variations in baseline measurements or demographic factors between the 3RP-NF and HEP-NF groups, the completers, and noncompleters at any time point (ps > 0.05).
3.2 Depression
Within groups, participants in both the 3RP-NF and HEP-NF conditions showed statistically significant improvement in the PHQ-9 total score between baseline and posttest (3RP-NF Mdifference = −3.06; 95% CI, −3.99 to −2.12; p < 0.001; HEP-NF Mdifference = −3.21; 95% CI, −4.13 to −2.29; p < 0.001) with differences above the MCID. Improvements were also observed between baseline and 6-months (3RP-NF Mdifference = −2.75; 95% CI, −3.65 to −1.84; p < 0.001; HEP-NF Mdifference = −1.40; 95% CI, −2.29 to −0.52; p = 0.002) and baseline and 12-months (3RP-NF Mdifference = −2.01; 95% CI, −3.08 to −0.93; p < 0.001; HEP-NF Mdifference = −1.59; 95% CI, −2.64 to −0.54; p = 0.003). Between groups, the 3RP-NF group showed significantly greater improvement compared with the HEP-NF group in the PHQ-9 total score from baseline to 6 months (Mdifference = −1.34; 95% CI, −2.54 to −0.15; p = 0.03). There was no significant between group difference in the PHQ-9 total score from baseline to posttest and from baseline to 12 months (Table 1).
| Symptom outcome | Baseline to posttreatment | Baseline to 6 month post | Baseline to 12 month post | |||
|---|---|---|---|---|---|---|
| Mean difference (95% CI) | p-value | Mean difference (95% CI) | p-value | Mean difference (95% CI) | p-value | |
| PHQ-9 total score | ||||||
| Within 3RP-NF | −3.06; −3.99 to −2.12 | <0.001 | −2.75; −3.65 to −1.84 | <0.001 | −2.01; −3.08 to −0.93 | <0.001 |
| Within HEP-NF | −3.21; −4.13 to −2.29 | <0.001 | −1.40; −2.29 to −0.52 | 0.002 | −1.59; −2.64 to −0.54 | 0.003 |
| Between | 0.15; −1.04 to 1.34 | 0.80 | −1.34; −2.54 to −0.15 | 0.03 | −0.42; −1.85 to 1.01 | 0.57 |
| GAD-7 total score | ||||||
| Within 3RP-NF | −2.94; −3.87 to −2.00 | <0.001 | −2.65; −3.64 to −1.66 | <0.001 | −2.72; −3.74 to −1.71 | <0.001 |
| Within HEP-NF | −3.09; −4.01 to −2.17 | <0.001 | −2.38; −3.35 to −1.42 | <0.001 | −2.15; −3.14 to −1.16 | <0.001 |
| Between | 0.16; −1.01 to 1.32 | 0.79 | −0.26; −1.54 to 1.01 | 0.68 | −0.57; −1.90 to 0.75 | 0.40 |
Among the subgroup of patients who reported clinical levels of depressive symptoms at baseline, the between-group comparisons showed significantly lower rates of clinical levels of depressive symptoms in the 3RP group at the 6-month (3RP-NF = 70.6%, HEP = 90.9%, p < 0.001) and 12-month (3RP-NF = 67.9%, HEP = 84.1%, p = 0.016) follow-ups, but not at posttest (Table 2).
| Symptom outcome | HEP-NF | 3RP-NF | |
|---|---|---|---|
| Depression | |||
| Posttest | 68/94 (72.3%) | 62/92 (67.4%) | Value = 0.54 DF = 1 p = 0.46 |
| 6-month follow-up | 80/88 (90.9%) | 60/85 (70.6%) | Value = 11.56 DF = 1 p < 0.001 |
| 12-month follow-up | 69/82 (84.1%) | 53/78 (67.9%) | Value = 5.79 DF = 1 p = 0.016 |
| Anxiety | |||
| Posttest | 56/81 (69.1%) | 52/79 (65.8%) | Value = 0.20 DF = 1 p = 0.65 |
| 6-month follow-up | 51/73 (69.9%) | 46/73 (63.0%) | Value = 0.77 DF = 1 p = 0.38 |
| 12-month follow-up | 50/68 (73.5%) | 48/68 (70.6%) | Value = 0.15 DF = 1 p = 0.70 |
3.3 Anxiety
Within groups, participants in both the 3RP-NF and HEP-NF groups showed statistically significant reductions in the GAD-7 total score between baseline and posttest (3RP-NF Mdifference = −2.94; 95% CI, −3.87 to −2.00; p < 0.001; HEP-NF Mdifference = −3.09; 95% CI, −4.01 to −2.17; p < 0.001), with differences above the MCID. Improvements were also observed between baseline to 6-months (3RP-NF Mdifference = −2.65; 95% CI, −3.64 to −1.66; p < 0.001; HEP-NF Mdifference = −2.38; 95% CI, −3.35 to −1.42; p < 0.001) and baseline to 12 months (3RP-NF Mdifference = −2.72; 95% CI, −3.74 to −1.71; p < 0.001; the Mdifference = −2.15; 95% CI, −3.14 to −1.16; p < 0.001) (see Table 1). No between-group differences for the changes in anxiety from baseline to posttreatment and 6 month and 12-month post were observed. There were no significant between-group differences in improvements in GAD-7 total score between 3RP-NF and HEP-NF from baseline to posttest, 6 months, and 12 months (see Table 1).
Among the subgroup of patients who reported clinical levels of anxiety symptoms at baseline, the between-group comparisons showed no significant differences in the rates of clinical levels of anxiety symptoms at posttest and the two follow-up time points (Table 2).
3.4 Durability of treatment effects
For the PHQ-9 total score, the between-group comparisons of the durability of treatment effects from posttreatment to 6 months post favored 3RP-NF (1.49; 95% CI, 0.34–2.65; p = 0.01; lower one-sided 95% confidence bound = 0.422), with 3RP-NF showing maintenance while HEP-NF demonstrated reduction of symptoms (see Table 3 and Figure 1). However, no differences were observed in terms of the durability of treatment effects from posttreatment to 12-month post, with both groups showing a deterioration in depressive symptoms (see Table 3 and Figure 1).
| Symptom outcome | Posttreatment to 6-month post | Posttreatment to 12-month post | ||
|---|---|---|---|---|
| Mean difference (95% CI) | p-value | Mean difference (95% CI) | p-value | |
| PHQ-9 total score | ||||
| Within 3RP-NF | 0.31; −0.52 to 1.14 | 0.46 | 1.05; 0.16 to 1.94 | 0.02 |
| Within HEP-NF | 1.80; 0.99 to 2.61 | <0.001 | 1.62; 0.76 to 2.47 | 0.002 |
| Between | 1.49; 0.34 to 2.65 | 0.01 | 0.57; −0.66 to 1.80 | 0.36 |
| GAD-7 total score | ||||
| Within 3RP-NF | 0.29; −0.66 to 1.24 | 0.55 | 0.21; −0.71 to 1.13 | 0.65 |
| Within HEP-NF | 0.71; −0.21 to 1.63 | 0.13 | 0.94; 0.06 to 1.83 | 0.04 |
| Between | 0.42; −0.90 to 1.74 | 0.53 | 0.73; −0.54 to 2.01 | 0.26 |
For the GAD-7 total score, none of the between-group comparisons of the durability of treatment effects from posttreatment to 6 months and from posttreatment to 12 months were significant. While both groups showed maintenance of symptoms from posttreatment to 6-months post, it was only the 3RP-NF group that showed this maintenance from posttreatment to 12 months, with deterioration of symptoms in the HEP-NF group (0.94; 95% CI, 0.06–1.83; p = 0.04; lower one-sided 95% confidence bound = 0.422).
4 DISCUSSION
The present study is the first analysis of the effects of a psychosocial intervention for NF on depression and anxiety outcomes. We found that both the 3RP-NF and HEP-NF groups showed significant improvements in depression and anxiety between baseline and posttest, above the minimally significant clinical cutoffs for both depression and anxiety symptoms. There were reduced rates of clinical levels of depressive symptoms at 6 and 12-month follow-ups for those in the 3RP-NF group who had clinically elevated depressive symptoms at baseline. Both groups also saw improvements from baseline to 6 months and baseline to 12 months. Individuals who participated in 3RP-NF additionally showed greater improvements in depression scores from baseline to 6 months compared with HEP-NF, suggesting that participants better sustained improvements in the 3RP-NF group following the intervention. However, this difference did not persist at 12 months. Further, there were largely no between-group differences for the reductions in anxiety seen in both groups.
The 3RP-NF intervention was designed to address heightened stress and difficulties coping with NF symptoms by teaching relaxation, mindfulness, adaptive coping, assertiveness, optimism, and mindfulness skills. Its effectiveness in reducing depression and anxiety is consistent with research demonstrating the effects of mind–body interventions in reducing psychological distress (Schumer et al., 2018). However, the largely equivalent results between the two groups suggests that specifically for symptoms of depression and anxiety, the group intervention format was beneficial to individuals with NF regardless of whether the content contained these mechanistic treatment targets or educational information. One possibility is that the group-based format of both interventions was a crucial treatment component: because of the rare nature of NF, participants had perhaps not previously interacted with a group of people who understood and shared their condition and experience. Social connection is associated with improvements in both depression (Leskelä et al., 2006; Sarwar et al., 2022; Scardera et al., 2020) and anxiety (Hart & Hittner, 1991; Rueger et al., 2010; Scardera et al., 2020) and social support improvements have been shown to mediate the effects of psychosocial treatments even for individual therapy (Dour et al., 2014).
These findings are promising given that we observed clinically significant improvements in both interventions. There is an absence of psychosocial treatment research, especially with fully-powered, large sample trials like the present study, as well as clinical options for patients with NF. These conditions are often disabling and progressive, resulting in a need for frequent emotional adjustment to new obstacles throughout the treatment course (Compas et al., 2012; Jordan & Plotkin, 2022). Participants in both groups showed short-term (baseline to post), mid-term (baseline to 6 months), and long-term (baseline to 12 months) improvements in psychological symptoms. However, the 3RP-NF program demonstrated some improved ability to sustain effects in the short-term, particularly with regard to sustaining reductions in depressive symptoms at 6 months. The present study highlights a crucial need for psychosocial support for individuals with NF given the high rates of anxiety and depression in this population.
Several limitations of the present study warrant consideration and offer directions for future research. This study was conducted in a predominantly white and female sample, consistent with research suggesting that women are more likely than men to participate in psychosocial research (Knox et al., 2022). Future studies should evaluate whether similar effects are observed in more diverse samples. Enrollment occurred during the middle of the COVID-19 pandemic, which may have impacted the extent to which social support and connection were valued and resulted in greater effects of social connection on depression and anxiety in the two groups. Additionally, the ease of using live video conferencing could have resulted in higher attendance and compliance across groups. Finally, the 3RP-NF intervention was didactic-intensive, with multiple skills delivered in the course of a single session, and each skill was only presented once in the intervention. As a result, there was less time for building mastery over skills use, trouble-shooting skills practice, and flexibly attending to the needs of the individual participants, which is a key component of skills-based group therapies (Chapman, 2006). Future skills training interventions should evaluate whether reducing the amount of material per session and increasing repetition of skills content results in greater mastery and larger effects on depression and anxiety outcomes in this population. Finally, it will be important to evaluate whether the group format of the present interventions—and the connection it offered—was the impetus for reductions in anxiety and depression. If so, it may be beneficial for future interventions to more directly target social connection, including building emotional intimacy (Aron et al., 1997).
The present study offers promise for the impact of psychosocial interventions on depression and anxiety in individuals with NF. Both mind–body skills training and health education interventions were successful, with the 3R-NF group showing particular promise in sustaining improvements in psychological outcomes. Mind–body skills may offer some limited ability to sustain improvements but results largely suggest that improvements are possible regardless of intervention content. Increasing access to psychosocial group care for patients with NF is of crucial importance for limiting the negative psychological effects of these often disabling and isolating conditions.
AUTHOR CONTRIBUTIONS
Katherine McDermott: Wrote the introduction and discussion, revised the methods and results, and oversaw the compilation and submission of the manuscript. Jafar Bakhshaie: Conducted the data analyses and wrote the results. Julie Brewer: Contributed to the writing of the methods and discussion and completed the tables and references. Ana-Maria Vranceanu: Secured funding and oversaw the design and execution of the study and the manuscript.
FUNDING INFORMATION
This study was funded by the U.S. Department of Defense (DOD) grant no. W81XWH-17-1-0121 awarded to Ana-Maria Vranceanu.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
PATIENT CONSENT STATEMENT
Informed consent was obtained from all participants prior to initiation of data collection.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03406208. Registration was submitted on December 6, 2017, first patient enrolled in October 2017.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
