While COVID-19 infection is usually associated with a brief illness followed by recovery within weeks, many people experience prolonged symptoms months after acute infection (Liu et al., Reference Liu, Jayasundara, Pye, Dobbins, Dore, Matthews and Spokes2021a). Prolonged symptoms after an acute COVID-19 infection have been given a number of names, including long COVID, post-COVID syndrome, and COVID long haulers (Raveendran, Jayadevan, & Sashidharan, Reference Raveendran, Jayadevan and Sashidharan2021). Long COVID is associated with a wide variety of symptoms, including fatigue, headaches, shortness of breath, loss of sense of smell, ‘brain fog’, cognitive impairment, neuropathy, muscle pain, sleep disturbance, and other multi-system symptoms, along with reduced mental health and impaired quality of life (Crook, Raza, Nowell, Young, & Edison, Reference Crook, Raza, Nowell, Young and Edison2021; Malik et al., Reference Malik, Patel, Pinto, Jaiswal, Tirupathi, Pillai and Patel2022; Maury, Lyoubi, Peiffer-Smadja, de Broucker, & Meppiel, Reference Maury, Lyoubi, Peiffer-Smadja, de Broucker and Meppiel2020; Sudre et al., Reference Sudre, Murray, Varsavsky, Graham, Penfold, Bowyer and Steves2021).
A meta-analytic estimate of the pooled prevalence of long COVID indicates that, around the world, some 43% of those who contract COVID-19 experience long-term symptoms (Chen et al., Reference Chen, Haupert, Zimmermann, Shi, Fritsche and Mukherjee2022). Risk factors include female sex, pre-existing asthma, older age, obesity, comorbidities, and more severe acute COVID-19 symptoms (Cabrera Martimbianco, Pacheco, Bagattini, & Riera, Reference Cabrera Martimbianco, Pacheco, Bagattini and Riera2021; Chen et al., Reference Chen, Haupert, Zimmermann, Shi, Fritsche and Mukherjee2022; Sudre et al., Reference Sudre, Murray, Varsavsky, Graham, Penfold, Bowyer and Steves2021). Social isolation, decreased physical activity, changed lifestyles, and pandemic-related social and economic insecurities may contribute to developing the physical and psychological symptoms of long COVID (Cabrera Martimbianco et al., Reference Cabrera Martimbianco, Pacheco, Bagattini and Riera2021; Marshall, Bibby, & Abbs, Reference Marshall, Bibby and Abbs2020). For some, long COVID may become a protracted, debilitating, multi-systemic disability (Alwan, Reference Alwan2021; Brown & O'Brien, Reference Brown and O'Brien2021).
The COVID-19 pandemic has had substantial mental health repercussions (Jenkins et al., Reference Jenkins, McAuliffe, Hirani, Richardson, Thomson, McGuinness and Gadermann2021a), as the public health restrictions that aim to reduce the spread of the virus have disrupted many protective factors for mental health and wellness (Heinsch et al., Reference Heinsch, Wells, Sampson, Wootten, Cupples, Sutton and Kay-Lambkin2022; Hoare, Milton, Foster, & Allender, Reference Hoare, Milton, Foster and Allender2016; Silva, Loureiro, & Cardoso, Reference Silva, Loureiro and Cardoso2016). Depression, anxiety, and distress have increased among the general population during the pandemic (Aknin et al., Reference Aknin, Neve, Dunn, Fancourt, Goldberg, Helliwell and Amor2022), as social interaction, pro-social activities, physical activity, and everyday life have been radically transformed. The research on mental health in long COVID remains scant (Vannorsdall & Oh, Reference Vannorsdall and Oh2021). However, it appears that long COVID can be accompanied by anxiety, depression, and post-traumatic stress disorder, as well as neurocognitive issues (Raveendran et al., Reference Raveendran, Jayadevan and Sashidharan2021); these, in turn, can be complicated by the physiological and neurological symptoms that prevent people from returning to their previous level of functioning (Aiyegbusi et al., Reference Aiyegbusi, Hughes, Turner, Rivera, McMullan, Chandan and Calvert2021). People with long COVID are at risk of combining the mental health impacts of long COVID with those associated with population-level pandemic response strategies (Brüssow & Timmis, Reference Brüssow and Timmis2021). Unfortunately, as mental healthcare needs have increased, the mental healthcare system has also been disrupted (Mann, Chen, Chunara, Testa, & Nov, Reference Mann, Chen, Chunara, Testa and Nov2020). A shift to virtual care has exacerbated the digital divide and changed willingness to seek services (Hoyer et al., Reference Hoyer, Ebert, Szabo, Platten, Meyer-Lindenberg and Kranaster2021), compromising access to timely mental health support.
The National Institute for Health and Care Excellence (NICE) has issued clinical practice guidelines for the treatment of long COVID, in which they recommend integrated and interdisciplinary models of care to meet the wide range of long-term needs with which these individuals may present (International Foundation of Integrated Care, 2020). As part of integrated treatment models, it is critical that we combine physical healthcare with social services, mental health supports, cognitive rehabilitation, and psychiatric treatments when indicated (Aiyegbusi et al., Reference Aiyegbusi, Hughes, Turner, Rivera, McMullan, Chandan and Calvert2021). Given the complexity of the physical, cognitive, psychological, and social impacts of long COVID in the context of the ongoing pandemic, there is a need for multi-facetted, complex interventions that are adapted to the individual and the local context. This intervention complexity requires appropriate evaluation, ideally following the Medical Research Council's framework for evaluating complex interventions (Skivington et al., Reference Skivington, Matthews, Simpson, Craig, Baird, Blazeby and Moore2021).
Interventions that support mental health and psychological wellbeing have been shown to help people with physical health challenges (Ferrier et al., Reference Ferrier, Ski, O'Brien, Jenkins, Thompson, Moore and Castle2021; Gilbert et al., Reference Gilbert, Chamberlain, White, Mayers, Pawsey, Liew and Castle2012; Jenkins et al., Reference Jenkins, Tan, O'Flaherty, Knowles, Thompson, Ski and Gock2021b). By building resiliency in vulnerable populations, it is possible to build positive mental health that supports disease management and improves quality of life. Pharmacological interventions are also sometimes indicated for mental health problems secondary to physical health diagnoses (National Collaborating Centre for Mental Health, 2010). It is therefore important to consider such interventions within multi-component, integrated models of care for long COVID. However, since long COVID is an emerging clinical entity, effective interventions for this complex condition constitute a critical gap in the literature. To advance research agendas in this area, it is important to understand the current state of the research, even at this early stage, in the absence of a large body of published evidence.
This systematic review aims to support the rigorous planning of research agendas by synthesizing the currently registered trials examining interventions for mental health, cognition, and psychological wellbeing in long COVID.
Methods and analysis
This systematic review of registered trials follows the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) (Page et al., Reference Page, McKenzie, Bossuyt, Boutron, Hoffmann, Mulrow and Moher2021).
Trial retrieval
An electronic search was conducted of two large, international registries for clinical trials: clinicaltrials.gov, a trial registry by the United States National Library of Medicine, and the International Clinical Trials Registry Platform, an aggregator of international trial registries by the World Health Organization. The search was conducted on 4 January 2022 and updated on 31 May 2022, covering the first 5 months of 2022.
Recognizing that this is a new, emerging literature, multiple search strategies were piloted to identify keywords. Based on the relatively small number of trials on the topic, it was decided not to use intersecting search terms, to balance risk of missing trials v. over-screening. Therefore, search terms were long COVID, OR post COVID, OR post-acute COVID, OR long haul*, OR COVID sequelae, OR sequelae of COVID, OR COVID survivor, OR post-SARS-COV-2. There were two filters: (1) the date-of-registration of the trial had to be between 1 January 2020 and 31 December 2021 or between 1 January 2022 and 31 May 2022 for the update; (2) only interventional trials were included (filter available on clinicaltrials.gov only). All trials found with these search parameters were uploaded into Covidence systematic review software (Veritas Health Innovation, 2021), where duplicates were automatically deleted and visually confirmed. For records in the final record set, published articles with outcome data were manually sought in MEDLINE and PsycINFO using the study ID and lead researcher names.
Eligibility criteria
From a PICO (population, intervention, control, outcomes) perspective (Richardson, Wilson, Nishikawa, & Hayward, Reference Richardson, Wilson, Nishikawa and Hayward1995), studies were eligible if they addressed individuals with long COVID, used any intervention, with or without a comparison group, and had either a primary intervention aim or primary outcome specific to mental health, cognition, or psychological wellbeing. Studies with quality of life as a primary outcome were included only if the quality of life measure contained a mental health or psychological wellness subscale, ensuring that a mental/psychological component is to be included in the outcomes rather than limiting the outcome to physical health-related quality of life. Each study's own definition of long COVID was accepted, provided that the record referred to the concept of long COVID and recruited individuals at a minimum of 1 month after acute COVID-19. Records could originate from any country and could report on participants of any age group and with any sociodemographic characteristics. Excluded were trials registered prior to 2020 (i.e. before the pandemic) or after 31 May 2022, non-interventional trials, and trials that did not focus on mental health, cognition, or psychological wellbeing.
Study selection
The initial search yielded a total of 912 records, among which 150 duplicates were automatically removed by Covidence (Veritas Health Innovation, 2021), for an initial search of 762 records. The update produced an additional 158 records, including 18 duplicates, for a total of 902 records. These records were reviewed first at the title and project summary level based on inclusion and exclusion criteria. After a training and calibration review of 25 records by a research lead and a research staff, the research staff and lead both independently screened 152 records (152/762 = 20%), achieving 92.8% agreement, with an inter-rater agreement of κ = 0.74 [substantial agreement (Sim & Wright, Reference Sim and Wright2005)]. Any conflicts were resolved by consensus. The research staff independently screened the remaining records, with open discussion of any uncertainties. An additional 30 duplicates were removed manually during screening. Records that were retained were then screened at the full record level by both the research lead and research staff for 21 initial records (21/100 = 21%), with 90.5% agreement [κ = 0.74, substantial agreement (Sim & Wright, Reference Sim and Wright2005)]. The research staff screened the remaining records at the initial search and all records at the updated search independently, bringing any uncertainties to the project lead for discussion and resolution by consensus. The final record set was reviewed and confirmed by the research lead.
Data extraction and synthesis
Data were extracted into an Excel spreadsheet by the study staff, with ongoing discussion. Data extraction included descriptive information about the (1) trial as a whole (i.e. the study ID, funder/sponsor, date of registration, country of the principal investigator, countries of recruitment, scientific title), (2) intervention (i.e. name, type, description, delivery mode, dose, frequency, length), (3) study design (i.e. allocation, model, masking, arms, recruitment status, start, and expected end date), (4) sample (i.e. long COVID definition if available, age, sample size, inclusion, exclusion criteria), and (5) outcome measures (i.e. primary outcome(s), secondary outcome(s), measures, timing of measurement). Data were synthesized and summarized in narrative and table format based on the type of intervention.
Quality assessment
The Cochrane Risk of Bias 2.0 (Higgins, Savović, Page, Elbers, & Sterne, Reference Higgins, Savović, Page, Elbers, Sterne, Thomas, Higgins, Chandler, Cumpston, Li, Page and Welch2021) guidelines were used to examine study quality. Since the review was conducted on registered trials rather than publications presenting outcomes, only minimal variables were available. Of the five domains in the Cochrane guidelines, domain 1 (randomization process) was partially reviewed for randomization and allocation concealment; domain 2 (deviations from the intended intervention) was partially reviewed for participant and care provider masking only; domain 3 (missing outcome data) was not reviewed, since no outcome data are available; domain 4 (outcome measurement process) was fully reviewed. Domain 5 (reported results) was not reviewed, since no results have been reported. A partial risk-of-bias determination was made, based on the retained domains. The risk-of-bias assessment was conducted collaboratively, with the study lead and a study staff member completing 11/28 (39.3%) of the initial studies together, and the staff member completing the remaining alone, bringing any questions forward for discussion. Results of the partial risk-of-bias assessment are narratively reported.
Results
Of a total of 902 identified records, 42 were eligible for inclusion; see the PRISMA diagram in Fig. 1 (Page et al., Reference Page, McKenzie, Bossuyt, Boutron, Hoffmann, Mulrow and Moher2021). Associated with the selected trials, one published protocol was found (Gao et al., Reference Gao, Zhong, Quach, Davies, Ash, Lin and Baker2021); publications presenting outcome data were not available for any of the trials. General trial characteristics are described in Table 1 and detailed trial information is provided in Table 2. The 42 records report on trials of psychological interventions, cognitive or neurorehabilitation interventions, pharmacological and other medical interventions; herbal, nutritional, or natural supplements; and physiotherapy or physical rehabilitation interventions.
Fig. 1. PRISMA flow chart for trials identified in the systematic review.
Table 1. Characteristics of the 42 trials included in the systematic review
Table 2. Complete summary of the 42 trials included in the review
QOL, quality of life; PTSD, post-traumatic stress disorder; TAU, treatment as usual; N/A, not available; RCT, randomized-controlled trial; ACT, acceptance and commitment therapy; CBT, cognitive-behavioral therapy; m, month.
a These are feasibility or pilot trials not intended to produce complete unbiased outcomes.
The trials are targeting a total target sample size of 5814 participants (median: 65; range: 10–1500). The trials are geographically distributed across 14 countries. Most are described as either randomized efficacy controlled trials (23, 54.8%) or randomized-controlled feasibility/pilot trials (12, 28.6%). All trials are being conducted among adults, and the majority are also including geriatric populations. Trials list an average of 2.8 primary outcomes (s.d. = 3.0, range 1–12), which are being measured using an average of 3.5 primary outcome measures (s.d. = 4.8, range = 1–21). They list an additional average of 5.0 secondary outcomes (s.d. = 3.6, range 0–14) and 6.1 secondary outcome measures (s.d. = 5.1, range 0–23). Nine (21.4%) identified mental health (i.e. depression, anxiety, distress) as among their primary outcomes, while 18 (42.9%) listed cognition, and 17 (40.5%) listed psychological wellbeing.
Psychological interventions
Eleven trials are examining psychological interventions: five self-management programs (Blázquez, Reference Blázquez2022; Busse & Potter, Reference Busse and Potter2022; Chantal, Hiyam, & Karen, Reference Chantal, Hiyam and Karen2021; Collette, Willems, Cabello, & Lesoinne, Reference Collette, Willems, Cabello and Lesoinne2022; Culos-Reed & Twomey, Reference Culos-Reed and Twomey2021; Martin & Lynall, Reference Martin and Lynall2022), three cognitive-behavioral therapy interventions (Acartürk & Öztürk, Reference Acartürk and Öztürk2021; Håkansson, Hartman, & Cronhjort, Reference Håkansson, Hartman and Cronhjort2021; Martin & Lynall, Reference Martin and Lynall2022) (one with components of acceptance and commitment therapy and one using peer support), two meditation interventions (Croghan, Hurt, Fokken, & Currie, Reference Croghan, Hurt, Fokken and Currie2022; Subramaniam, Reference Subramaniam2021), one psychoeducational intervention (Collette et al., Reference Collette, Willems, Cabello and Lesoinne2022), and one case-management intervention (Hatcher, Ward, & Edgar, Reference Hatcher, Ward and Edgar2021). Components of multidisciplinary care are present in several; for example, a cognitive-behavioral therapy intervention includes stretching exercises (Acartürk & Öztürk, Reference Acartürk and Öztürk2021), while other interventions include psychoeducation across cognition, diet, breathing, and other spheres of life (Blázquez, Reference Blázquez2022; Busse & Potter, Reference Busse and Potter2022; Culos-Reed & Twomey, Reference Culos-Reed and Twomey2021; Martin & Lynall, Reference Martin and Lynall2022). However, none are fully integrated models of care. Intervention durations range from 3 weeks to 3 months. Eight trials are randomized, including three randomized-controlled feasibility or pilot trials. The interventions target primary and secondary outcomes such as depression, anxiety, distress, self-efficacy, cognition, and quality of life, as well as study feasibility variables and other long COVID symptoms. Two have mental health-specific inclusion criteria, i.e. clinical distress or a positive screen for clinical depression or anxiety (Acartürk & Öztürk, Reference Acartürk and Öztürk2021; Håkansson et al., Reference Håkansson, Hartman and Cronhjort2021), another includes cognitive impairment as an inclusion criterion (Collette et al., Reference Collette, Willems, Cabello and Lesoinne2022), and one lists quality-of-life impairments as a requirement to participate (Hatcher et al., Reference Hatcher, Ward and Edgar2021). Six trials exclude individuals with severe or acute mental illness, or a history of mental illness (Acartürk & Öztürk, Reference Acartürk and Öztürk2021; Blázquez, Reference Blázquez2022; Collette et al., Reference Collette, Willems, Cabello and Lesoinne2022; Croghan et al., Reference Croghan, Hurt, Fokken and Currie2022; Håkansson et al., Reference Håkansson, Hartman and Cronhjort2021; Subramaniam, Reference Subramaniam2021), and two exclude individuals with substance use disorders (Acartürk & Öztürk, Reference Acartürk and Öztürk2021; Collette et al., Reference Collette, Willems, Cabello and Lesoinne2022); severe cognitive deficits are an exclusion criterion for three trials (Collette et al., Reference Collette, Willems, Cabello and Lesoinne2022; Hatcher et al., Reference Hatcher, Ward and Edgar2021; Håkansson et al., Reference Håkansson, Hartman and Cronhjort2021).
Pharmacological and other medical interventions
Five interventions are testing pharmacological and other medical treatments for long COVID. Pharmacological agents include the selective serotonin reuptake inhibitor vortioxetine (McIntyre & Subramaniapillai, Reference McIntyre and Subramaniapillai2021), a C1 esterase inhibitor (recombinant) (Melamed, Collins, & Palm, Reference Melamed, Collins and Palm2021), and atorvastatin (Anderson & Carcel, Reference Anderson and Carcel2021). Other medical treatments include portable oxygen concentrator (Glezer, Reference Glezer2022), and a one-time marrow stromal cell infusion (Alderman, Montemayor, & Savitz, Reference Alderman, Montemayor and Savitz2022). The trials focus on improving cognitive functioning, mood, or functioning more broadly. None describe integrated models of care. Intervention duration ranges from one-time treatment to 6 months. All five trials are randomized and the majority are at least partially blinded, and three are placebo controlled (Alderman et al., Reference Alderman, Montemayor and Savitz2022; McIntyre & Subramaniapillai, Reference McIntyre and Subramaniapillai2021; Melamed et al., Reference Melamed, Collins and Palm2021). None of the studies have any mental health or wellbeing-specific inclusion criteria. Two trials require self-reported cognitive deficits to participate (Glezer, Reference Glezer2022; McIntyre & Subramaniapillai, Reference McIntyre and Subramaniapillai2021). Severe mental illness and dementia are among the exclusion criteria for three (Anderson & Carcel, Reference Anderson and Carcel2021; McIntyre & Subramaniapillai, Reference McIntyre and Subramaniapillai2021); one excludes individuals with substance use disorders (McIntyre & Subramaniapillai, Reference McIntyre and Subramaniapillai2021).
Herbal, nutritional, or natural supplement interventions
Five trials are investigating herbal, nutritional, or natural supplements. These trials are diverse, examining cannabidiol-dominant medicinal cannabis (Iveson, Lynskey, & Thurgur, Reference Iveson, Lynskey and Thurgur2021), a dietary replacement and weight management program (Blane, Combet, & the ReDIRECT Study Team, Reference Blane and Combet2021), niagen (vitamin B3) (Guzman-Velez, Gutiérrez-Martínez, González-Irizarry, & Gerber, Reference Guzman-Velez, Gutiérrez-Martínez, González-Irizarry and Gerber2021), a homeopathic medicinal combination (Rice & Jacobs, Reference Rice and Jacobs2021), and a mixed herbal supplement (Karosanidze & Panossian, Reference Karosanidze and Panossian2021). A sixth trial is examining a Chinese herbal medicine intervention integrated with physical rehabilitation (Gao et al., Reference Gao, Zhong, Quach, Davies, Ash, Lin and Baker2020), which is described in the physical rehabilitation section below. The other five trials are not described as examining integrated models of care.
Intervention duration ranges from 2 weeks to 5–6 months in the four of five studies reporting a duration. Four of five trials are randomized, three with placebo control groups and one with a waitlist control group. The medicinal cannabis study is a single-group pilot trial (Iveson et al., Reference Iveson, Lynskey and Thurgur2021). Primary and secondary outcomes include depression and anxiety, cognitive function, quality of life, fatigue, long COVID symptoms in general, and a variety of physical health metrics. None of the studies require that individuals have impairments to mental health or wellbeing to participate, but one study requires cognitive deficits (Guzman-Velez et al., Reference Guzman-Velez, Gutiérrez-Martínez, González-Irizarry and Gerber2021). Four trials list severe, chronic, or pre-existing mental illness as an exclusion criterion (Blane et al., Reference Blane and Combet2021; Guzman-Velez et al., Reference Guzman-Velez, Gutiérrez-Martínez, González-Irizarry and Gerber2021; Iveson et al., Reference Iveson, Lynskey and Thurgur2021; Rice & Jacobs, Reference Rice and Jacobs2021), and three exclude individuals with substance use disorders (Guzman-Velez et al., Reference Guzman-Velez, Gutiérrez-Martínez, González-Irizarry and Gerber2021; Iveson et al., Reference Iveson, Lynskey and Thurgur2021; Rice & Jacobs, Reference Rice and Jacobs2021). None list any cognitive impairment factors as exclusion criteria.
Cognitive and neurorehabilitation interventions
Nine trials are examining cognitive and neurorehabilitation interventions, using cognitive training or brain stimulation. Five interventions focus on cognitive rehabilitation therapies with diverse approaches and techniques, from using digital devices (Flöel, Reference Flöel2021; Gunning, Oberlin, & Victoria, Reference Gunning, Oberlin and Victoria2021; Ownby & Davenport, Reference Ownby and Davenport2022; Taub & McKay, Reference Taub and McKay2020), adapting elements of cognitive therapy (Taub & McKay, Reference Taub and McKay2020), or incorporating breathing, meditation, and neurolinguistic programming (Liira & Arokoski, Reference Liira and Arokoski2022). Four trials are examining the effectiveness of neuromodulation and neurostimulation technologies such as transcranial direct current stimulation, cranial electrotherapy stimulation, or transcutaneous vagus nerve stimulation (Eryilmaz, Andreou, & Pax, Reference Eryilmaz, Andreou and Pax2021; Koczulla & Schneeberger, Reference Koczulla and Schneeberger2021; Neri & Barcessat, Reference Neri and Barcessat2021; Zheng, Wang, & Fullmer, Reference Zheng, Wang and Fullmer2022). One trial combines brain stimulation and intensive cognitive training (Flöel, Reference Flöel2021); however, none of the trials indicate integrated, multidisciplinary care. Intervention length ranges from 10 days to 10 weeks. The majority of the studies are randomized-controlled trials with placebo or waitlist control groups receiving sham stimulation or treatment as usual. Two out of nine trials are feasibility non-randomized studies with no comparison group (Ownby & Davenport, Reference Ownby and Davenport2022; Zheng et al., Reference Zheng, Wang and Fullmer2022). For six trials, primary outcomes focus on cognitive function; one trial identifies anxiety as the primary outcome (Koczulla & Schneeberger, Reference Koczulla and Schneeberger2021). Other primary and secondary outcomes include quality of life, fatigue, daily functioning, depression, and other symptoms associated with long COVID. Six of the nine trials require some degree of cognitive impairment to participate (Eryilmaz et al., Reference Eryilmaz, Andreou and Pax2021; Flöel, Reference Flöel2021; Gunning et al., Reference Gunning, Oberlin and Victoria2021; Ownby & Davenport, Reference Ownby and Davenport2022; Taub & McKay, Reference Taub and McKay2020; Zheng et al., Reference Zheng, Wang and Fullmer2022) and one lists anxiety as an inclusion criterion (Koczulla & Schneeberger, Reference Koczulla and Schneeberger2021). Four exclude individuals with pre-existing severe cognitive impairment (Flöel, Reference Flöel2021; Gunning et al., Reference Gunning, Oberlin and Victoria2021; Ownby & Davenport, Reference Ownby and Davenport2022; Taub & McKay, Reference Taub and McKay2020). Six exclude those with mental illness or substance use disorders (Eryilmaz et al., Reference Eryilmaz, Andreou and Pax2021; Flöel, Reference Flöel2021; Gunning et al., Reference Gunning, Oberlin and Victoria2021; Liira & Arokoski, Reference Liira and Arokoski2022; Ownby & Davenport, Reference Ownby and Davenport2022; Taub & McKay, Reference Taub and McKay2020).
Physiotherapy and physical rehabilitation-based interventions
Twelve trials are examining physiotherapy or physical rehabilitation-based interventions, focusing on respiratory or cardio-respiratory rehabilitation (Bileviciute-Ljungar & Borg, Reference Bileviciute-Ljungar and Borg2021; Edgell, Reference Edgell2022; Gao et al., Reference Gao, Zhong, Quach, Davies, Ash, Lin and Baker2020; Greenspan et al., Reference Greenspan, Walsh-Messinger, Mackles, Debidda, Kaner, DePalo and Chin2021; Nogueira, Silva, & Nogueira, Reference Nogueira, Silva and Nogueira2021; Sanchez-Ramirez, Reference Sanchez-Ramirez2021; Wheatley & Shea, Reference Wheatley and Shea2021), exercise and strength training (Asimakos & Katsaounou, Reference Asimakos and Katsaounou2021; Gao et al., Reference Gao, Zhong, Quach, Davies, Ash, Lin and Baker2020; Gilliland & Driver, Reference Gilliland and Driver2022; Mustafaoğlu & Yasacı, Reference Mustafaoğlu and Yasacı2022; Sanchez-Ramirez, Reference Sanchez-Ramirez2021), hyperbaric oxygen therapy (Zilberman-Itskovich, Reference Zilberman-Itskovich2020), and symptom cluster-based rehabilitation (Koczulla & Gloeckl, Reference Koczulla and Gloeckl2022). Some multidisciplinary integration of treatments is reported. One trial includes mindfulness, relaxation, and psychotherapeutic components (Bileviciute-Ljungar & Borg, Reference Bileviciute-Ljungar and Borg2021), another refers to psychological and dietary supports (Asimakos & Katsaounou, Reference Asimakos and Katsaounou2021), while one study combined individualized exercises with cognitive training (Gilliland & Driver, Reference Gilliland and Driver2022). One trial integrates cardiorespiratory rehabilitation with a combination of Chinese herbal medicines (Gao et al., Reference Gao, Zhong, Quach, Davies, Ash, Lin and Baker2020). Intervention duration ranges from 3 to 12 weeks. Most of the studies are randomized-controlled trials, with sham treatment, waitlists, or active control groups. Primary and secondary outcomes are varied, including depression, anxiety, cognition, quality of life, and a range of physiological and functional outcomes. None of the 12 trials list any mental health variables as inclusion criteria; one requires cognitive deficits (Zilberman-Itskovich, Reference Zilberman-Itskovich2020) and two require negative impacts on quality of life (Asimakos & Katsaounou, Reference Asimakos and Katsaounou2021; Zilberman-Itskovich, Reference Zilberman-Itskovich2020). Two trials exclude individuals with severe cognitive deficits or dementia (Asimakos & Katsaounou, Reference Asimakos and Katsaounou2021; Sanchez-Ramirez, Reference Sanchez-Ramirez2021), and two exclude those with substance use disorders (Bileviciute-Ljungar & Borg, Reference Bileviciute-Ljungar and Borg2021; Zilberman-Itskovich, Reference Zilberman-Itskovich2020). Three exclude individuals with mental illness (Bileviciute-Ljungar & Borg, Reference Bileviciute-Ljungar and Borg2021; Gao et al., Reference Gao, Zhong, Quach, Davies, Ash, Lin and Baker2020; Sanchez-Ramirez, Reference Sanchez-Ramirez2021), two only if the mental illness is untreated or uncontrolled (Bileviciute-Ljungar & Borg, Reference Bileviciute-Ljungar and Borg2021; Gao et al., Reference Gao, Zhong, Quach, Davies, Ash, Lin and Baker2020).
Limited risk-of-bias assessment
Overall risk-of-bias assessment is reported in Table 2.
Randomization
Most of the registered trials report randomization (35, 83.3%), a low risk-of-bias indicator. However, only four records confirm that they will implement allocation concealment (9.5%); information about the randomization process is missing for all other records.
Masking
Fifteen studies (35.7%) report that participants and/or treatment providers are masked, lowering the risk of bias.
Outcome measurement
Nineteen trials (45.2%) achieved a low risk-of-bias rating, with appropriate masked measurement processes that would not be expected to be influenced by bias. Four trials (9.5%) are associated with some concern, and 19 trials (45.2%) have a high risk-of-bias rating, generally due to open label designs and possible interviewer or self-report biases in outcome assessments.
Discussion
Given the rapid emergence and global spread of COVID-19, it has taken time to move from identifying long COVID to testing treatments for it. A small international body of research is assessing interventions for mental health, cognition, and psychological wellbeing in long COVID. Several psychological interventions are being tested, but few full-scale psychotherapeutic interventions are being trialed to date. Only a few interventions with pharmacological and other medical treatments were found, complemented by a similar number of herbal, nutritional, or natural supplement interventions. Several physical and cognitive rehabilitation interventions are also being examined. Randomized-controlled trials and randomized-controlled feasibility trials dominate the trial landscape.
We laud researchers who have quickly registered trials and begun testing interventions for this new clinical entity. At the same time, we highlight that the number, size, and quality of trials and the breadth of interventions are limited. Given the potential long-term disability associated with long COVID (Alwan, Reference Alwan2021; Brown & O'Brien, Reference Brown and O'Brien2021), we call on funders to support research in this area at a level commensurate with symptomatic burden. We also call on interventionists to rapidly pursue large-scale, rigorous, high-quality clinical trials on interventions that address the full range of long COVID symptoms, including mental health, cognition, and psychological wellbeing (Crook et al., Reference Crook, Raza, Nowell, Young and Edison2021; Malik et al., Reference Malik, Patel, Pinto, Jaiswal, Tirupathi, Pillai and Patel2022; Maury et al., Reference Maury, Lyoubi, Peiffer-Smadja, de Broucker and Meppiel2020; Sudre et al., Reference Sudre, Murray, Varsavsky, Graham, Penfold, Bowyer and Steves2021). Adaptive trials may be the most promising design approach to address the mental health symptoms of long COVID, in the context of an evolving pandemic and emerging knowledge base (Janiaud, Hemkens, & Ioannidis, Reference Janiaud, Hemkens and Ioannidis2021). Given the urgent need to build a new evidence base, juxtaposed with typically high rates of non-publication of clinical trials (Lee, Bacchetti, & Sim, Reference Lee, Bacchetti and Sim2008), researchers are encouraged to publish their findings – positive or negative – at the earliest possible date (Mlinaric, Horvat, & Supak Smolcic, Reference Mlinaric, Horvat and Supak Smolcic2017). Likewise, publishers and peer reviewers are encouraged to welcome both positive and negative findings to accelerate the construction of a balanced and comprehensive evidence base in this new domain.
NICE guidelines recommend integrated, interdisciplinary treatments for long COVID (International Foundation of Integrated Care, 2020), but the current trials demonstrate limited service integration. Integrated, interdisciplinary models of care that directly address a broad range of symptoms are needed, and they should be rigorously evaluated using methodologies appropriate for complex interventions (Skivington et al., Reference Skivington, Matthews, Simpson, Craig, Baird, Blazeby and Moore2021). Many of the registered trials are broadly scanning for outcomes in an integrated manner, across biological and psychological spheres, which is also important to continue. The ongoing use of virtual service features will provide important advancements for the evidence base on virtual healthcare interventions (Torous, Jän Myrick, Rauseo-Ricupero, & Firth, Reference Torous, Jän Myrick, Rauseo-Ricupero and Firth2020).
While many of trials currently registered are addressing mental health in some way, comparatively few trials focus explicitly on mental health, v. cognition and psychological wellbeing. Importantly, interventions targeting individuals with severe mental illness or pre-existing mental illness are absent, and a number of trials explicitly identify mental illness as an exclusion criterion. Not only can long COVID be associated with the emergence of new mental health challenges (Aiyegbusi et al., Reference Aiyegbusi, Hughes, Turner, Rivera, McMullan, Chandan and Calvert2021), but some long COVID patients will have pre-existing mental illness, which is a risk factor for long COVID (Gebhard et al., Reference Gebhard, Sütsch, Bengs, Deforth, Buehler, Hamouda and Gebhard2021) and may affect the experience of long COVID. Similarly, substance misuse is a very common comorbidity among people with mental illness (Lai, Cleary, Sitharthan, & Hunt, Reference Lai, Cleary, Sitharthan and Hunt2015), yet none of the registered trials mentioned substance misuse, except as an exclusion criterion. We therefore call on interventionists to develop and evaluate interventions that integrate evidence-based treatments for mental illness and substance misuse with treatments for the physiological symptoms of long COVID, while also addressing the potential interaction between mental and physical health.
Given the novelty of this clinical entity, it is unsurprising that trials are recruiting from the general population of patients with long COVID. A next, critical step is to test interventions adapted to vulnerable subpopulations. With a focus on equity, diversity, and inclusion, interventions should attend to individuals with different sociodemographic characteristics, including youth and seniors, and subgroups of people who are facing challenges with various social determinants of health, physical and mental health comorbidities, limited access to digital technologies, and other treatment access barriers. While doing so, attending to generalizability within interventions and trial designs may provide gains for other disorders with overlapping symptomatology (Wong & Weitzer, Reference Wong and Weitzer2021). Researchers are encouraged to reflect on additional knowledge gaps and opportunities, from their unique disciplinary perspectives, and to move forward with addressing them in a timely manner.
We further call on the research community to engage patients in the research and service design process to address long COVID, from a pragmatic, patient-oriented research perspective (Allemang, Sitter, & Dimitropoulos, Reference Allemang, Sitter and Dimitropoulos2022; Canadian Institutes of Health Research, 2019). Only two of the registered trials refer to patient-engaged research processes (Busse & Potter, Reference Busse and Potter2022; Martin & Lynall, Reference Martin and Lynall2022). However, patients first identified long COVID as a clinical entity (Callard & Perego, Reference Callard and Perego2021), demonstrating their important insights into their lived experience and their ability to advocate for themselves to drive change. Through co-creation, patients can make meaningful contributions to research and service design (Canadian Institutes of Health Research, 2019; Hamilton et al., Reference Hamilton, Hoens, Backman, McKinnon, McQuitty, English and Li2018).
This review has a number of limitations. Notably, the pace of COVID-19 research is extremely rapid (Liu et al., Reference Liu, Nie, Li, Chen, Cao, Ren and Xia2021b). This review is limited to trials registered by 31 May 2022; any trials registered after this date, or not registered, are not included. Given the limited amount of information available in trial registries, only a partial quality appraisal was possible. Due to the lack of trial results to date, a meta-analytical report was not possible. Researchers are encouraged to register their trials, consult the trial registries for studies aligning with their area of work, and report their results rapidly to members of the scientific and clinical care communities, many of whom are eagerly awaiting their findings.
Conclusions
An emerging body of research has begun to test interventions for mental health, cognition, and psychological wellbeing in long COVID. However, this review highlights that the scope of the associated intervention research currently in progress is not yet commensurate with the scope of this important new clinical entity. Despite a great deal of uncertainty around the evolution of long COVID, it is incumbent on researchers to build upon the trials currently under way and to rapidly generate rigorous evidence in this entirely new domain. We therefore call on researchers around the world to develop high-quality clinical trials testing a wide range of candidate interventions addressing mental health, cognition, and psychological wellbeing in diverse patient populations experiencing the symptoms of long COVID.
Financial support
This work is supported by Canadian Institutes of Health Research (Funding reference number WI1-179893).
Conflict of interest
David Castle has received grant monies for research from Servier, Boehringer Ingelheim; Travel Support and Honoraria for Talks and Consultancy from Servier, Seqirus, Lundbeck. He is a founder of the Optimal Health Program (OHP), and holds 50% of the IP for OHP; and is part owner of Clarity Healthcare. He does not knowingly have stocks or shares in any pharmaceutical company. Other authors have no conflict of interest to declare.
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