Anxiety, Depression and Quality of Life—A Systematic Review of Evidence from Longitudinal Observational Studies

This review aimed to systematically review observational studies investigating the longitudinal association between anxiety, depression and quality of life (QoL). A systematic search of five electronic databases (PubMed, PsycINFO, PSYNDEX, NHS EED and EconLit) as well as forward/backward reference searches were conducted to identify observational studies on the longitudinal association between anxiety, depression and QoL. Studies were synthesized narratively. Additionally, a random-effects meta-analysis was performed using studies applying the mental and physical summary scores (MCS, PCS) of the Short Form Health Survey. The review was prospectively registered with PROSPERO and a study protocol was published. n = 47 studies on heterogeneous research questions were included, with sample sizes ranging from n = 28 to 43,093. Narrative synthesis indicated that QoL was reduced before disorder onset, dropped further during the disorder and improved with remission. Before onset and after remission, QoL was lower in comparison to healthy comparisons. n = 8 studies were included in random-effects meta-analyses. The pooled estimates of QoL at follow-up (FU) were of small to large effect sizes and showed that QoL at FU differed by disorder status at baseline as well as by disorder course over time. Disorder course groups differed in their MCS scores at baseline. Effect sizes were generally larger for MCS relative to PCS. The results highlight the relevance of preventive measures and treatment. Future research should consider individual QoL domains, individual anxiety/depressive disorders as well as the course of both over time to allow more differentiated statements in a meta-analysis.

Looking at longitudinal rather than cross-sectional data from observational studies has several advantages. It allows for the identification of trajectories over time within the same individuals rather than focusing on group differences at one point in time only [26]. Moreover, when appropriate methods are applied to longitudinal data, intraindividual heterogeneity can be taken into account, resulting in more consistent estimates [27]. This has previously been demonstrated in QoL research [28]. A need to analyze longitudinal changes in QoL domains in QoL research in people with mental disorders has also been previously identified [29]. Beyond individual longitudinal studies suggesting a link between anxiety or depression and QoL, several systematic reviews have synthesized longitudinal evidence on these associations and mostly reported negative associations between the variables. These reviews have tended to focus on specific age groups, such as older adults [30], samples with specific diseases [31,32], or have investigated the effect of specific treatments on QoL in patients with anxiety [33]. Investigating these associations in samples without these limitations could reduce the effect of specific conditions and treatments on the association and strengthen the conclusions that can be drawn.
In light of the previous findings, this study aims to add to the present literature by systematically synthesizing evidence from observational studies on the longitudinal association between anxiety, depression and QoL across all age groups in samples who do not have other specific illnesses and do not receive specific treatments.

Materials and Methods
This review was registered with PROSPERO (CRD42018108008) and a study protocol was published [34].

Search Strategy
Five electronic databases from several fields of research (PubMed, PsycINFO, PSYN-DEX, NHS EED and EconLit) were examined until December 2020. Where possible, search terms were entered as Medical Subject Headings (MeSH) or as keywords in the title/abstract. The PubMed search strategy was: (anxi*[Title/Abstract] or depress*[Title/Abstract] or anxiety disorder [MeSH] or depressive disorder [MeSH]) and quality of life [MeSH] and longitudinal study [MeSH]. Please note that "*" is a truncation symbol. Time or location were not restricted. In addition, we applied backward and forward reference searches of included studies to identify additional references. The forward reference search was conducted until January 2021 using Web of Science to identify cited papers.

Study Selection Process
The study selection process is displayed in Figure 1. Most identified studies were screened in a two-step process (title/abstract; full-text screening) independently by two reviewers (J.K.H., E.Q.) against defined criteria (see Table 1). The last updated literature screening before submission was conducted by one reviewer (J.K.H.) and encompassed 9% of the studies included for title/abstract screening. Before the final criteria were applied, they were pretested and refined. Disagreements during the selection process were resolved through discussion or by the inclusion of a third party (A.H.) if a consensus could not be reached.

Inclusion criteria
Studies were eligible for inclusion if they: (i) Were observational studies analyzing the longitudinal association between anxiety or depression (disorders as well as symptom severity) and QoL, (ii) Analyzed samples without a specific disease or disorder other than anxiety and depression, (iii) Applied appropriate, validated measures for the main variables (e.g., for anxiety/depression: psychiatric diagnosis according to criteria of the International Classification of Diseases (ICD), the Diagnostic and Statistical Manual of Mental Disorders (DSM), or using a valid self-report screening tool), and (iv) Were published in English or German in a peer-reviewed journal.

Exclusion criteria
Studies were excluded if they: (i) Analyzed samples where participants were suffering or recovering from conditions other than anxiety/depression, (ii) Analyzed samples receiving or recovering from a specific intervention or treatment, (iii) Had no observational study design, (iv) Used a measure for the main variables other than those defined, or (v) Had publication characteristics that were different than those defined (e.g., were published in a language other than German or English, as well as not published in a scientific, peer-reviewed journal).

Refinements after pre-tresting and reason for refinement
After pre-testing, the following refinements were made to the screening criteria (ii) and (iii): (ii) Regarding the samples of interest, we decided to exclude studies analyzing dyads such as caregivers or partners to ill family members, due to possible spillover-effects on the individual's QoL, which has been demonstrated in previous studies [35,36]. Additionally, samples consisting exclusively of people with anxiety or depressive disorders may receive some unspecific type of care for their mental health problems. We eliminated studies evaluating the effects of treatments using pre-post-treatment comparisons. Only studies where some naturalistic treatment that is usual for mental health problems that began prior to study baseline (BL) were included. Studies indicating that treatment was initiated at or after study BL (e.g., before or at admission to a psychiatric clinic) were excluded. (iii) Lastly, we specified the QoL assessments. In health and medicine research, numerous QoL instruments are used [37]. Guided by previous literature reviews [38][39][40]), we compiled a list of ten validated QoL assessments that have been used in children, adolescents or adults from the general population and/or samples with mental health problems, and that are frequently used in QoL research. Versions of the following instruments were included: Short Form Health Survey (e.g., SF-36, SF-12), EuroQol (e.g., EQ-5D, EQ-5D-Y), WHOQOL (e.g., WHOQOL-100, WHOQOL-BREF), Quality of Well-Being Scale, Quality of Life Scale, Pediatric Quality of Life Inventory, KIDSCREEN, KINDL, Quality of Life in Depression Scale, and the Quality of Life Enjoyment and Satisfaction Questionnaire.

Data Extraction and Synthesis
We extracted information regarding the study design, operationalization of the variables, sample characteristics, statistical methods and results regarding the research question of interest. If several analyses were presented for the same research question, we extracted the final covariate-adjusted model for narrative synthesis. Data were extracted by one reviewer (J.K.H.) and cross-checked by a second reviewer (E.Q.). If needed, extracted data were standardized (e.g., by calculating the weighted average means when combining groups) to present comparable information. If clarification was needed, the corresponding authors were contacted.
For the narrative synthesis, all studies were first grouped by research question, e.g., whether disorders or the degree of symptoms were analyzed, which comparison groups were used, which QoL domains were considered, and at which waves the variables of interest were considered in the analyses. Because research questions and analyses were heterogeneous, a concise narrative synthesis of the main results of all studies was not feasible. Therefore, we provide an overview of all identified studies in the tables and a detailed narrative synthesis of those studies, analyzing trajectories of disorders or changes in symptoms in association with changes in QoL over time.
Additionally, we examined whether data were appropriate for meta-analysis. The specific research questions, the operationalization of main variables and statistical methods were heterogeneous across studies and not all the statistical estimates needed could be obtained from covariate-adjusted analyses. Therefore, to enhance the comparability of the underlying data and the interpretation of the pooled estimates, we used descriptive information. Because most papers applied variations of the Short Form Health Survey and analyzed mental and physical component scores (MCS, PCS), we considered these studies as eligible for meta-analysis. The necessary information could be obtained for 8 publications. Random-effects meta-analysis was used for pooling. Heterogeneity was assessed by means of I 2 , with higher values representing a larger degree of heterogeneity in terms of variability in effect size estimates between studies [41]. Pooled estimates are reported as Hedge's g standardized mean difference (SMD), representing the difference in mean outcomes between groups relative to outcome measure variability [42]. According to Cohen (as cited in [43]), SMDs can be grouped into small ≤0.20, medium = 0.50 and large effects ≥0.80. Stata 16 was used for meta-analyses.

Quality/Risk of Bias Assessment
Two reviewers (J.K.H., E.Q.) independently assessed the quality and risk of bias of the included studies using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, which was developed by the National Heart, Lung, and Blood Institute [44].

Selection Process
The literature search yielded 4027 unique references. After title/abstract screening, 215 studies were included for full-text screening. Finally, 47 publications were included in the final synthesis. During full-text screening, most studies were excluded because they exclusively analyzed data on a cross-sectional level (56.5%). For further details, see the PRISMA flow chart (Figure 1).

Overview of Included Studies
Descriptive characteristics and quality/risk of bias assessment of the included studies are provided in Table S1 (Supplementary Material). In short, sample size ranged from 28 to 43,093. Most studies focused on adults; only four analyzed children/adolescents. Regarding the settings, 17 of the analyzed samples were exclusively recruited in a health care setting, 12 of the studies analyzed general population samples, 14 recruited in another or in several settings, and all studies on children/adolescents recruited in schools (n = 4). Twenty studies (42.6%) applied data from the same seven underlying datasets. Most studies reported on depression (n = 36), less reported on anxiety (n = 20) and some reported on the comorbidity between depression and anxiety (n = 7). To assess mental disorders, half (48.9%) used structured interviews. Regarding QoL, most studies applied variations of the Short Form Health Survey (SF, n = 27) or the WHOQOL (n = 12). A total of 38.3% of the studies were rated as "good", 55.3% as "fair" and 6.4% as "poor" in the quality assessment.

Overview of Studies on the Association between Anxiety/Depression as Independent Variables and QoL Outcomes
Detailed results on all studies investigating the association between anxiety/depression as independent variables and QoL outcomes are reported in Table 2. As described in the methods section, the following paragraphs give an overview of those studies focusing on disorder trajectories/changes in symptoms over time and changes in QoL outcomes over time, because they allow for more differentiated interpretations. Comparing pre-and post-morbid levels, QoL did not differ or was higher after MDE in some domains (significantly higher for psychological health and psychological role). Moreover, before MD onset, QoL was significantly lower compared to healthy controls in all domains. After remission from MDE, QoL scores in nearly all domains (not significant for psychological role) were significantly lower compared to healthy controls. (b) About 40% of the MDE group had worse QoL after recovery from MDE compared to pre-morbid levels. The severity of depression was associated with worse QoL only for the psychological health domain, but no other domains. The number of depressive episodes was not significantly associated with worsening QoL in any domain. (c) In the MDE cohort, comorbid anxiety was associated with a significant reduction in QoL (significant for physical role and psychological health).
Cabello (2014) [47] Chronic MD (AUDADIS interview; summary score of the number of symptoms to identify severity); SF-12, "disability" (i.e., domain-specific reduced QoL, defined as score ≤ 25th percentile in the subscale; physical functioning, physical role, bodily pain, general health, vitality, social functioning, emotional role and mental health) (a) Whether chronic MD is associated with the incidence/persistence of "disability" (i.e., reduced QoL) in a general population sample. (b) Whether the severity of depressive symptoms is associated with the incidence/persistence of "disability" (i.e., reduced QoL) in the MD subgroup of the sample.
Both (a) and (b) Generalized Estimating Equations and logistic regressions (a) In the general population, chronic MD was a significant risk factor for the persistence of disability (i.e., reduced QoL) in all domains and of the incidence of disability (i.e., reduced QoL) in all domains except for the physical role. (b) In the chronic MD subgroup, the severity of depressive symptoms was associated with the persistence of disability (i.e., reduced QoL) (significant for general health, social functioning, emotional role and mental health) and not significantly associated with the incidence of reduced QoL in any domain. Whether the pooled number of (a) depressive episodes over time, (b) panic and anxiety episodes over time are are associated with the pooled QoL over time.   . Every other quartile of change in depressive symptoms was significantly associated with changes in QoL in most scales/domains (significant for: QLDS, all domains of WHOQOL-Bref and SF-12 MCS), meaning a higher reduction in depressive symptoms was associated with a higher increase in QoL, and more severe depressive symptoms were associated with a reduction in QoL.
(b) Remission of depression at FU was associated with improvement in all QoL measures and domains (SF-12, QLDS and WHOQOL-Bref). There was no significant change in QoL in those with persistent clinical depression at FU.
Hajek (2015) [21] Depressive symptoms (GDS); EQ-VAS Whether an initial change in depressive symptoms is associated with a subsequent change in QoL in the whole sample and by sex.

Vector autoregressive models
No significant association between an initial change in depression score and a subsequent change in QoL was found for the whole sample or stratified by sex. (a) t-tests (b) Linear mixed effects regression models (a) At 6-and 12-month FU, those with and without depression at BL differed significantly in QoL scores, with the depression group reporting lower QoL at FUs (significant for MCS and PCS).
(b) While depression at BL was significantly related to improvements in MCS (but not PCS) scores over time, those with depression still reported lower QoL compared to those without.
Heo (2008) [53] Depression (BDI ≥ 10); SF-36 (decrease in total score over time) Whether FU depression is associated with a reduction in QoL over time.

Binary logistic regression
Depression at FU was associated with a significant reduction in QoL total score over time.
Ho (2014) [54] Depression (according to GDS ≥ 5); SF-12 (PCS, MCS) Whether depression at BL is associated with QoL at FU. Random/fixed effects model There was no significant interaction between time and diagnostic group (no depression/PTSD, PTSD, depression and comorbid depression/PTSD) on QoL. Comparing the adjusted means for all three times among the disorder groups showed significant differences between the groups in most domains. In comparison, those with depression at BL reported reduced QoL over time in several domains compared to the PTSD group and the group without PTSD/depression. In comparison, those with PTSD only showed higher QoL compared to those with depression or comorbid depression/PTSD in several domains.  Ormel (1999) [63] Depression at BL (according to CIDI); "disability" (i.e., reduced QoL according MOS SF 6-item physical functioning scale ≥ 2) Whether depression at BL is associated with the onset of disability (i.e., reduced QoL) during FU.

Logistic regression models
Compared to the non-depressed group, people with depression at BL showed higher odds for the onset of disability (i.e., reduced QoL) during FU (significant for 12-month FU, but not 3-month FU).

Linear mixed-effects models
Higher depressive symptoms were associated with lower QoL in MDD patients (significant for overall score, physical, psychological, social and environmental).

Multivariate regression models
Higher depressive symptoms at BL were associated with a decline in QoL over time (significant for physical and psychological).
Pakpour (2018) [66] Dental anxiety at BL (MDAS); PedsQL 4.0 general hrqol and oral hrqol scale at FU Whether dental anxiety at BL predicted oral-and general-health-related QoL at FU.

Structural equation modeling
Dental anxiety at BL was no significant direct predictor of generic QoL at FU and was significantly associated with worse oral-health-related QoL at FU. There was no significant interaction term between group status and time, indicating that changes in QoL did not differ between the groups. At both points in time, QoL differed significantly among all groups, except between the incident depression and continuous depression group.
Remmerswaal (2020) [68] OCD course (SCID), Y-BOCS, BDI, BAI over time; EQ-5D over time there was no significant difference compared to the general population. When comparing the OCD course groups, the chronic OCD group had a significantly lower QoL over time compared to the other groups. The remitting group had moderately improved until FU1 and a small QoL improvement between FU1 and FU2 relative to the chronic group. (c) In those with a remitting OCD, only more severe symptoms of comorbid anxiety and depressive symptoms, but not OCD symptom severity over time, were significantly associated with a lower QoL over time.

Rhebergen (2010) [69]
MD-/dysthymia-/DD diagnosis at BL and subsequent recovery at FU (according to CIDI); comorbid anxiety at BL (CIDI); SF-36 (physical health summary score) Whether QoL trajectories over time differ between: (a) different depression status groups who achieved remission (MDD, dysthymia and double depression) and a comparison group without mental health disorders. (b) The different depression status groups.
(c) Whether comorbid anxiety at BL in a sample recovering from depression is associated with changes in QoL.
(a)-(c) Linear mixed models (a) There was a significant interaction between group status and time. More specifically, compared to changes in QoL over time in people without a mental health diagnosis, QoL improved over time in those with MDD and DD, but not dysthymia. All depression diagnosis groups showed a significantly lower QoL compared to the no diagnosis group at all waves. (b) Considering the depression groups, only the interaction term between dysthymia and time until FU1 was significant. Those with dysthymia had a significantly lower QoL compared to those with MDD at FU1. This difference was not significant at FU2. (c) Comorbid anxiety disorder at BL in people who recovered from depression over time was not associated with a significant change in QoL over time.  in QoL compared to non-remitted cases. (e) Remission of PD, SAD, specific phobia and GAD was associated with significantly lower QoL at FU compared to people without history of a specific diagnosis. (f) Remission of "pure" PD, SAD, specific phobias and GAD was associated with significantly lower QoL at FU compared to people without any lifetime psychiatric diagnosis.

Multinomial logistic regression
There was no significant association between depressive symptom severity and QoL change score profiles at FU. ANOVA (a) QoL at FU was significantly reduced in depressed samples compared to the non-depressed group, and lower in the persistently depressed compared to the recovered group (significant for: role emotional and social). Among the depressed subgroups, there was no significant difference between a persistent or a relapsing course regarding QoL at FU.
(b) In the persistently depressed group, comorbid anxiety was significantly associated with reduced QoL at FU (significant for role emotional and social). (c) In those who recovered from depression, comorbid anxiety was significantly associated with reduced QoL (significant for role emotional).

Random coefficient analysis
While change in QoL over time did not differ between course groups, QoL at BL (MCS) was lower in those with a chronic course compared to those who remitted from BL. (a)-(c) Random coefficient model (a) While changes in QoL over time did not differ significantly between those with MDD at BL and those without any psychiatric diagnosis, QoL at BL was lower in those with depression. (b) While changes in QoL over time did not differ significantly between those with anxiety syndrome at BL and those without any psychiatric diagnosis, QoL at BL was lower in those with anxiety compared to those without any psychiatric diagnosis. (c) While changes in QoL over time did not differ significantly between those with comorbid anxiety and MDD at BL and those without any psychiatric diagnosis, QoL at BL was lower in those with comorbid anxiety and MDD compared to those without any psychiatric diagnosis.
Stevens (2020) [77] Posttraumatic stress symptoms (VETR-PTSD); SF-36 (    Depression as independent variable and QoL as outcome. One study investigated QoL at several time points during the entire course of an episode of MD. Buist-Bouwman, Ormel, de Graaf and Vollebergh [46] analyzed an MD group from a general population setting (NEMESIS) with data on SF-36 domains in the onset, acute and recovery phase of the depressive episode. The onset of MD was associated with a significant drop in several QoL domains and recovery with a significant increase. Pre-and post-morbid QoL levels were not significantly different for most domains, and post-morbid QoL was even higher for the psychological role functioning and psychological health domains. In comparison to a group without MD, pre-and post-morbid QoL levels in the MD group were significantly lower, except for the psychological role functioning domain, where no significant differences were found. Additionally, it should be noted that 40% of the sample had lower post-morbid QoL compared to pre-morbid levels.
Two studies investigated changes in QoL for people experiencing an onset of depression relative to different comparison groups over two points in time.
One study investigated incident MD in a general population sample (NESARC; Rubio, Olfson, Perez-Fuentes, Garcia-Toro, Wang and Blanco [14]). Here, incident MD (compared to those without a history of MD as well as to a group without any mental disorder) was associated with a significant drop in QoL (SF-12 MCS). Additionally, analyzing two waves, Pyne, Patterson, Kaplan, Ho, Gillin, Golshan and Grant [67] compared the QoL (Quality of Well-Being scale) between MD patients and community controls. The patient group was further divided into those continuously not receiving an MD diagnosis, those who continuously received the diagnosis and those who only received the diagnosis at FU (onset). The authors found that changes in QoL did not differ between the groups. At both points in time, QoL scores differed significantly between the groups, except for the incident and the continuous depression group [67].
Six studies investigated different courses of depression over time in people with depression at BL with or without a healthy comparison group as reference.
Two primary care studies analyzed groups with clinical depression at BL with different FU depression statuses (remission, no remission). One study [51] analyzed changes in generic QoL measures (SF-12, WHOQOL-Bref) and the disease-specific Quality of Life in Depression Scale. In this study, remission was associated with an improvement in all QoL domains, whereas QoL did not change significantly over time for the non-remitted group. Another study [60] investigated SF-12 MCS and PCS scores and reported a significant increase in MCS over time in the remitting group. MCS scores in the continuously depressed group and PCS scores in both groups improved, albeit not significantly.
Another study [47] investigated whether chronic MD in a general population sample (NESARC) was associated with domain-specific reduced QoL (SF-12). They found that chronic MD was a significant risk factor for persistently reduced QoL in all domains and for the onset of reduced QoL at FU in all domains except for physical role.
Two population-based studies further differentiated between the depressive disorders. Analyzing MCS scores (NESARC), Rubio, Olfson, Villegas, Perez-Fuentes, Wang and Blanco [15] reported a significant increase in QoL for those who remitted from MD and from dysthymia relative to those who had a persistent disorder. Rhebergen, Beekman, de Graaf, Nolen, Spijker, Hoogendijk and Penninx [69] differentiated between people with MD, double depression or dysthymia at BL who remitted until FU relative to a group without a mental health diagnosis (NEMESIS). Physical health (SF-36) was lowest at BL for double depression, dysthymia and then the MD group. Over time, the MD and double depression groups improved significantly in their physical health, while the dysthymia group did not improve significantly. QoL was significantly lower relative to healthy comparisons for all depression groups at all waves. There were no significant differences regarding physical health trajectories over time among the depressive disorder groups.
Stegenga, Kamphuis, King, Nazareth and Geerlings [75] investigated more than two MD course groups over time (remitted, intermittent and chronic MD) in association with SF-12 MCS and PCS over time in a primary care-recruited sample with BL MD (Predict study). MCS increased over time in all groups, while changes in PCS were small. Compared to those who remitted, MCS at BL was significantly lower for the chronic course group. While the intermittent group also displayed a lower mean MCS at BL, the coefficient was not significant.
Three studies investigated changes in depressive symptom levels as the independent variable and changes in QoL as outcomes in adults.
One study found no significant association between an initial change in depressive symptoms and subsequent change in QoL (EQ-VAS) in older adults recruited in primary care [21]. The two other studies analyzed changes in depressive symptoms in samples with MD at BL [50,51]. Chung, Tso, Yeung and Li [50] found that changes in depressive symptom levels was associated with changes in several QoL domains (SF-36: general health, vitality, social functioning, mental health and MCS). Diehr, Derleth, McKenna, Martin, Bushnell, Simon and Patrick [51] investigated whether quartiles of change in depressive symptoms were associated with changes in QoL (SF-12, QLDS and WHOQOL-Bref). Those without any change in depressive symptoms generally showed no change in QoL. For all QoL domains and scores except for SF-12 PCS, improvement in depressive symptoms over time was associated with a significant increase in QoL, while a reduction in depressive symptoms was associated with a significant reduction in QoL. Those who had the largest reduction in depressive symptoms also had the largest improvement in QoL measures.
Anxiety as an independent variable and QoL as an outcome. Two publications used a general population sample (NESARC) to investigate incident anxiety disorders [14] and the remission of anxiety disorders [15] in association with SF-12 MCS. Both studies separated generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD) and social phobia (SP). All incident disorders were associated with a significant reduction in QoL compared to people without a history of the specific disorders. When the analysis was restricted to incident cases without comorbidities, QoL levels were not significantly different compared to people without a history of any psychiatric disorder [14]. Those who remitted from SAD showed a significant increase in QoL compared to persistent cases. While QoL improved for all remitting anxiety disorders, change scores for PD and SP were not significant [15].
Another study investigated different courses (intermittent, chronic or remitting) of obsessive compulsive disorder (OCD) and course in QoL (EQ-5D) as well as a comparison group from the general population [68]. They found that the OCD groups mostly reported a lower QoL compared to the general population. Moreover, the course groups differed regarding their QoL over time, with remitters reporting small to moderate improvements compared to the chronic group.
One study investigated changes in anxiety symptoms in association with changes in all SF-36 domains and both summary scores over time in a sample with MD at BL [50]. Changes in anxiety symptoms were significantly associated with changes in bodily pain, general health and the mental health domain.

Overview of Studies on the Association between QoL as Independent Variable and Anxiety/Depression as Outcomes
Additionally, we identified publications operationalizing QoL as the independent variable and anxiety/depression as outcomes with details on all studies reported in Table 3. Only one study reported on change in QoL over time and change/trajectories in mental health outcomes over time. This study operationalized change in QoL as a predictor of future change in depressive symptoms over time and reported that an initial improvement in EQ-VAS was associated with a future reduction in depressive symptoms in older adults [21]. Table 3. Studies on depression/anxiety as independent variables and QoL outcomes.

Multiple regression
Lower QoL at BL was associated with higher depressive symptoms at FU. Whether QoL at BL is associated with course of depression (complete remission vs. non-complete remission) in a depressed sample.

De Almeida
Stepwise multiple logistic regression Disease-specific QoL measure at BL significantly predicted the remission of depression at FU (significant for QLDS).
Hajek (2015) [21] Depressive symptoms (GDS); EQ-VAS Whether an initial change in QoL is associated with subsequent changes in depressive symptoms.

Vector autoregressive model
Initial changes in QoL were associated with a subsequent reduction in depression score (significant for total sample and women).

Structural equation model
Lower QoL at BL was a predictor of risk of persistence (PCS and MCS) and recurrence of MDE over time.

Structural equation model
QoL did not significantly predict PTSD symptoms at FU.
Kuehner (2009) [20] Depressive symptoms (MADRS); WHOQOL (overall, physical, psychological, social and environmental) Whether the lag of levels of QoL predicts future levels of depressive symptoms and whether the association differs by group (formerly depressed inpatients vs. community controls)

Time-lagged linear models
Lower levels of QoL were associated with higher future depressive symptoms (significant for physical, psychological, environmental and overall). The association was not moderated by group status. (a) Whether "dysfunction" (i.e., reduced QoL) at BL (mildly reduced, moderately reduced or severely reduced; compared to no reduced QoL) predicts MDD onset over time.
(b) Whether "dysfunction" (i.e., reduced QoL) at BL (mildly reduced, moderately reduced or severely reduced; compared to no reduced QoL) predicts anxiety syndrome onset over time.
(c) Whether "dysfunction" (i.e., reduced QoL) at BL (mildly reduced, moderately reduced or severely reduced; compared to no reduced QoL) predicts onset of comorbid anxiety and MDD over time.
(a)-(c) Multinomial logistic regressions (a) Dysfunction (i.e., reduced QoL) at BL was associated with higher odds of onset of MDD over time in the sample of people without a diagnosis at BL (significant for severely reduced QoL). (b) Dysfunction (i.e., reduced QoL) at BL was associated with higher odds of onset of anxiety syndrome over time in the sample of people without a diagnosis at BL (significant for moderately and severely reduced QoL). (c) Dysfunction (i.e., reduced QoL) at BL was associated with higher odds of onset of comorbid anxiety and depression over time in the sample of people without a diagnosis at BL (significant for mild, moderately and severely reduced QoL).
Wu (2016) [85] Elevated social anxiety symptoms (SASC cutoff 9); QOLS Whether QoL is associated with changes in elevated social anxiety symptoms over time.

Generalized Estimating Equation
Higher QoL was associated with a decreased risk for developing elevated social anxiety symptoms over time.

Multiple stepwise logistic regression
QoL at BL was not significantly related to depressive symptoms at FU.

Meta-Analyses on Anxiety, Depression and SF Summary Scores
In total, eight studies on adults were included in a supplementary meta-analyses of several research questions on SF PCS and MCS in association with anxiety and depressive disorders. Forest plots for the analyses are provided in the supplementary materials (Figures S1-S10).
BL differences in SF summary scores among adults with MD at BL with and without remitting courses over time. Based on a pooling of two studies [19,84] of samples with MD at BL, those with persistent MD at FU had significantly lower MCS at BL (SMD = −0.25, 95% CI: −0.41 to −0.10, p = 0.001, I 2 = 74.95) and PCS scores at BL (SMD = −0.24, 95% CI: −0.39 to −0.09, p = 0.002, I 2 = 73.14) compared to those who achieved remission until FU. Effect sizes were small for both summary scores.
FU differences in SF summary scores among adults with depressive and anxiety disorders at BL with and without remitting courses. Based on the pooling of two studies [71,81] of samples with MD and/or dysthymia, the group where the disorder had persisted/a co-morbid condition was present/had a suicide attempt until FU had significantly lower MCS scores at FU compared to the group where the disorder had remitted without treatment until FU, with a medium effect size for depressive disorders (

Main Results
This review adds to the present literature by providing an overview of longitudinal observational studies investigating the association between depression, anxiety and QoL in samples without other specific illnesses or specific treatments. Additional meta-analyses investigated group differences according to SF MCS and PCS.
While a concise synthesis of all the identified studies is challenging due to heterogeneity, the following picture emerges from studies investigating change-change associations: before the onset of disorders, QoL is already lower in disorder groups in comparison to healthy comparisons. The onset of the disorders further reduces the QoL. Remission is associated with an increase in QoL, mostly to pre-morbid levels. Additionally, some studies show that remission patterns are relevant for QoL outcomes as well. Moreover, a bi-directional effect was reported, whereby QoL is also predictive of mental health outcomes.
Evidence for a bi-directional association as well as studies showing lower QoL across the entire course of the disorders (before onset, during disorder, after disorder) relative to a healthy comparison group seem to suggest that impairments in QoL may result from a certain pre-disorder vulnerability in these groups. Longitudinal studies using general population data have investigated different hypotheses on (QoL) impairments after remission of anxiety disorders and MD [87,88]. One hypothesis suggests that impairments after the illness episode reflect a pre-disorder vulnerability (vulnerability or trait hypothesis), while the another states that impairments develop during the mental health episode and remain as a residual after recovery (scar hypothesis). Generally, both studies favored the vulnerability hypothesis [87,88]. For subgroups with recurrent anxiety disorders, scarring effects were also found for mental functioning [88]. Yet, it has to be noted that it was not the aim of our review to gather evidence for these hypotheses using QoL as an indicator, which represents an opportunity for future research.
To be able to investigate possible domain-specific differences across studies, we aimed to conduct a meta-analysis on all studies on the same research question which reported on QoL subdomains (e.g., using WHOQOL and SF). However, as described in the Methods section above, only eight studies reported comparable information on different research questions and could be included in meta-analyses. Due to the limited number of studies included in each meta-analysis, the focus on SF MCS and PCS scores, and most studies reporting on depression, the results of the meta-analyses should be viewed with caution. Keeping this in mind, our results indicate that both mental and physical QoL are significantly impacted by anxiety and depressive disorders and that the course of the disorder is also relevant for QoL outcomes. Not surprisingly, effect sizes for MCS were larger compared to PCS for most research questions. A pooling of two studies on different courses of anxiety and depressive disorders found that effect sizes for MCS at FU were of moderate size for depressive (SMD = −0.59) and of small size for anxiety disorders (SMD = −0.44), while SMDs for PCS at FU were negligible in size.
Overall, effect sizes from meta-analyses ranged from negligible to large, and heterogeneity varied considerably (I 2 between 0% and 95%). Because of the small number of studies, possible influential study-level factors (e.g., setting, operationalization of the variables, length of FU) could not be investigated in further detail by means of a metaregression, which remains a question for future research.

Implications for Future Research
Based on the results described and study heterogeneity discussed above, we provide recommendations for future research.
First recommendation: future research should differentiate between individual disorders and focus on anxiety disorders. The majority of the studies investigated depressive disorders or symptoms. On the level of individual disorders, most focused on MD, while two studies additionally reported on dysthymia [15,69]. One of these investigated double depression [69]. On the level of anxiety disorders, three publications differentiated between individual anxiety disorders within the same study [14,15,63]. While it was not possible to conduct a meta-analysis comparing different anxiety disorders in our case, individual studies suggest possible disorder-specific differences when analyzing changes in QoL over time: Rubio, Olfson, Villegas, Perez-Fuentes, Wang and Blanco [15] suggest that QoL significantly improved for those remitting from GAD and SAD (compared to non-remission). QoL improved for PD and SP as well, but differences in change scores were smaller and did not reach statistical significance. The incidences of all of these disorders were associated with a significant drop in QoL [14]. In summary, future longitudinal studies should focus on anxiety disorders and generally differentiate between individual disorders to investigate possible disorder-specific differences.
Second recommendation: future research should consider trajectories of disorders/change in symptoms and changes in QoL over time. We would have liked to include a meta-analysis of disorder trajectories and change scores in QoL over time. Because of the small, diverse number of studies on this association in general and the number of assumptions that would have had to have been made for a meta-analysis, we refrained from pooling effects for this research question. In total, 17 studies investigated changes in independent variables associated with changes in outcomes. This approach has several advantages. On the one hand, different disorder or symptom trajectories can be identified. Several studies reported that QoL outcomes differ according to disorder course and the degree of change in symptoms. The focus on the change in characteristics over time in future research could additionally reduce the problem of unobserved time-constant heterogeneity in observational studies when appropriate methods are applied [26].
Third recommendation: future research should investigate individual QoL domains. Several systematic reviews on cross-sectional studies found that effect sizes differed by QoL domains [32,89]. For example, Olatunji, Cisler and Tolin [89] reported that health and social functioning were most impaired for anxiety disorders (compared to non-clinical controls).
Comparing individuals with diabetes and depressive symptoms to those with diabetes only, Schram, Baan and Pouwer [32] reported that while SF pain scores were mild to moderately impaired, role and social functioning displayed moderate to severe impairments in those with comorbid depressive symptoms. The other scores were moderately impaired. As described above in detail, a meta-analysis using all subdomains was not feasible in this review. Further research differentiating between QoL domains would thus allow future meta-analyses to investigate whether the observed domain-specific differences reported in previous reviews of cross-sectional data can be observed in longitudinal studies as well.
Fourth recommendation: future research should consider bi-directional effects. While investigating QoL as the outcome measure and anxiety/depression as independent variables seems relatively straightforward, ten studies investigated QoL as the independent variable and anxiety/depression as outcomes. In light of possible bi-directional effects and pre-existing vulnerability suggested by individual studies, future research considering QoL as an independent variable could inform a deeper understanding of this complex association.

Strengths and Limitations
A strength of this work is the transparent methodological process: the review was prospectively registered with PROSPERO and a study protocol was published [34]. Two reviewers were included in screening, data extraction and quality assessment processes. There were no limitations regarding the time or location of the publications. Moreover, all versions of the ICD/DSM and validated questionnaires were considered eligible to identify anxiety or depression. Another strength is the thorough literature search that enabled us to identify all relevant studies. Additionally, we did not limit the age range and were therefore able to shed light on studies investigating children/adolescents. Moreover, some studies could be pooled using random-effects meta-analyses, which allows for stronger conclusions regarding effect sizes compared to individual studies. Besides the content analysis, this review emphasizes difficulties in meta-analysis from observational, longitudinal studies. We hope that our work can facilitate discussion on this topic.
The study has some limitations. We did not limit our search to specific research questions, which led to the inclusion of heterogeneous studies. Heterogeneity particularly stemmed from the operationalization of the variables of interest. Due to this, a concise narrative synthesis of all results was not feasible. The positive aspect of this broad focus is that it allowed us to provide an overview of studies and research questions analyzed and to formulate more nuanced recommendations for future research. We have to acknowledge that there is an abundance of QoL assessments used in medicine and health sciences [37]. The list applied in this work was derived with respect to previous relevant reviews on QoL research. It was not designed to be fully comprehensive or exhaustive. Rather, it provided us with a working definition for this review and helped to enhance the transparency of our selection processes. Additionally, because we included validated QoL measures frequently used in research, we assume that exclusion would particularly have been the case for novel or study-specific measures. Finally, the focus on peer-reviewed literature means that studies in other languages and gray literature were not considered. Nonetheless, this focus on literature published in peer-reviewed journals should ensure a certain scientific quality.

Conclusions and Relevance for Clinical Practice
Overall, the results indicate that QoL is lower before the onset of anxiety and depressive disorders, further reduces upon onset of the disorders and generally improves with remission to pre-morbid levels. Moreover, disorder course (e.g., remitted, intermittent, chronic) seems to play an important role; however, only a few studies analyzed this. Changes in anxiety and depressive symptoms were also associated with changes in QoL over time. Meta-analyses found that effect sizes were larger for MCS relative to PCS, highlighting the relevance of differentiation between QoL domains. While our review identified some gaps in the current literature and made recommendations for future research, the following should be noted for clinical practice. On the one hand, an improvement in mental health is associated with better QoL, which emphasizes the relevance of support during the disorders. This is also shown by meta-analyses, which show that cognitive behavioral therapy additionally improves QoL [90,91]. Moreover, the results indicate reduced QoL even before disorder onset, highlighting the relevance of early preventive measures in vulnerable groups. In line with this, studies on school-based prevention programs show a significant reduction in anxiety and depressive symptoms [92,93], and psychosocial prevention programs may additionally improve QoL [94].
During the COVID-19 pandemic, it is of high relevance to tackle the arising challenges associated with this pandemic. For example, it is important to face the high prevalence rates of both depression and anxiety with appropriate measures.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/ijerph182212022/s1, Table S1: detailed descriptive information for included studies (n = 47); Figure S1: forest plot for differences in SF MCS at FU among adults with and without depressive disorders at BL; Figure S2: forest plot for differences in SF PCS at FU among adults with and without depressive disorders at BL; Figure S3: forest plot for differences in SF MCS at FU among adults with and without depressive disorders at BL (sensitivity analysis); Figure S4: forest plot for differences in SF PCS at FU among adults with and without depressive disorders at BL (sensitivity analysis); Figure S5: forest plot for BL differences in SF MCS among adults with MD at BL with and without remitting courses over time; Figure S6: forest plot for BL differences in SF PCS among adults with MD at BL with and without remitting courses over time; Figure S7: forest plot for FU differences in SF MCS among adults with depressive disorders at BL with and without remitting courses; Figure  S8: forest plot for FU differences in SF PCS among adults with depressive disorders at BL with and without remitting courses; Figure S9: forest plot for FU differences in SF MCS among adults with anxiety disorders at BL with and without remitting courses; Figure S10: forest plot for FU differences in SF PCS among adults with anxiety disorders at BL with and without remitting courses. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Institutional Review Board Statement: Not applicable.
Data Availability Statement: Not applicable.