eTable 3. Criteria-based summary of the clinical evidence supporting digital health applications (DiGA).
| DiGA | Publication (first author) | Type | Inclusion criteria | n (intervention/ control) | Intervention | Control | Primary endpoint | Blinding | % female | % retention | Effect size of the primary endpoin | Comment |
| Deprexis | Twomey (2020) (1)*1 | MA | RCTs on Deprexis | 2 901; 12 RCTs | 8–12 w G or U | WL | Various | NA | – | 72.1 | g = 0.51 [0.40; 0.62] | Expansion by Twomey (2017) (2) by 4 RCTs |
| Twomey (2017) (11)*1 | MA | RCTs on Deprexis | 2 402; 8 RCTs | 8–12 w G or U | WL | Various | NA | – | 73.5 | g = 0.54 [0.39; 0.69] | ||
| Meyer (2009) (12)*1*2*3 | RCT | General population | 396 (320/76) | 9 w U; 6 mo FU | WL | BDI-I | – | 76 | 55 | d = 0.30 [0.05; 0.55]*5 | ||
| Berger (2011) (13)*1*2*3 | RCT | BDI-II > 13 | 76 (25/25/26) | 10 w G/U, 6 mo FU | WL | BDI-II | – | 69.7 | 90.1 | U: d = 0.66 (-/-)G: d = 1.14 (-/-) | ||
| Moritz (2012) (14)*2*3 | RCT | Depressive disorder | 210 (105/105) | 8 w U | WL | BDI-I | – | 78.6 | 78.1 | d = 0.36 (-/-) | ||
| Schröder (2014) (15)*2*3 | RCT | Epilepsy + depressive symptoms | 78 (38/40) | 9 w U | WL | BDI-I | Yes | 75.6 | 63 | d = 0.29 (-/-) | Diagnosis Epilepsy | |
| Meyer (2015) (16)*1*2*3 | RCT | Moderate or severe depressive symptoms (PHQ-9 > 14) | 163 (78/85) | 12 w U; 6 mo FU | WL | PHQ-9 | – | 74.8 | 78 | d = 0.57 [0.22; 0.92) 6 mo: d = 0.3 [−0.03; 0.69] |
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| Fischer (2015) (17)*2*3 | RCT | Multiple sclerosis+ depressive symptoms | 90 (45/45) | 9 w U; 6 mo FU | WL | BDI-II | Yes | 78 | 78 | d = 0.53(-/-) | Diagnosis Multiple sclerosis | |
| Klein (2016) (18)*2*3 | RCT | Mild to moderate depressive symptoms (PHQ-9 = 5–14) | 1 013 (509/504) | 12 w U (G if PHQ-9 >10); 6 mo FU | WL | PHQ-9 | Yes | – | 78.4 | d = 0.39 [0.13; 0.64] 6 mo: d = 0.32 [0.06; 0.69] |
Limited information available on population | |
| Beevers (2017) (19)*1*2*3 | RCT | Moderate depressive symptoms (QIDS-SR ≥ 10) | 376 (285/91) | 8 w U | WL | QIDS-SR | – | 74.4 | 79.6 | d = 0.8 [0.65; 1.04] | ||
| Zwerenz (2017) (20)*3 | RCT | Depressive disorder + BDI-II > 13 | 229 (115/114) | 12 w U + SB | SB | BDI-II | No | 60.7 | 88 | d = 0.44 (-/-) | Population: inpatients | |
| Berger (2018) (21)*1*2*3 | RCT | Unipolar depression | 98 (51/47) | 12 w U + PT 6 mo FU | PT | BDI-II | Yes | 66.3 | 70.4 | d = 0.51 [0.11; 0.91] | ||
| Bücker (2018) (22)*3 | RCT | Problem gambling + subjective sadness/despair | 140 (71/69) | 8 w U | WL | PHQ-9 | No | 24 | 44.3 | PP: d = 0.34 (-/-); ηp2 = 0.125; p = 0.03 |
Population: slot machine gamblers; no ITT analysis | |
| Fuhr (2018) (23)*1*2 | RCT | Subjective depressive symptoms | 27(14/13) | 10 w U | WL | PHQ-9 | No | 68 | – | I d = 0.22 (-/-)*5 K d = 0.37 (-/-)*5 |
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| Richter (2022) (24) | RCT | IP with depression | 69 (36/33) | 12 w G + SB | SB | BDI-II | n | 46.9 | 62.5 | d = −0.73 [1.4; 0.06] | Population: inpatients | |
| Zwerenz (2019) (25) | RCT | Diagnosed depressive disorder + BDI-II > 13 | 229 (115/114) | 12 w U + IP; 6 mo FU | IP | BDI-II | – | 60.7 | 87.8 | d = 0.58 (-/-) | Population: inpatients | |
| Klein (2017) (26)*1 | RCT | Mild to moderate depressive symptoms (PHQ-9 = 5–14) | 1 013 (509/504) | 12 w U (G if PHQ-9 > 10); 12 mo FU | WL | PHQ-9 | Yes | 86.7 | 77.6 | d = 0.13 [−0.18; 0.45] | Follow-up/Klein (2016) (9) | |
| Schuster (2020) (27)*1 | RCT | Mild to moderate depressive symptoms (PHQ-9 = 5–14) | 340 (166/174) | 12 w U (G if PHQ-9 > 10) + PT; 6 mo FU | PT | PHQ-9 | Yes | 71.1 | 88.8 | d = –0.32 [−0.11; 0.53] 6 mo: d = –0.31 [−0.09; 0.52] |
Follow-up/subgroup analysis from Klein (2016) (9) | |
| Mullarkey (2020) (28) | RCT | At least moderate depressive symptoms (QIDS-SR ≥ 10) | 295 (219/76) | 8 w U | WL | QIDS-SR | – | 75.2 | 100 | CC: sadness d = 0.81 [0.54; 1.08]; indecision d = 0.72 [0.45; 0.99]; etc | Symptom level analysis Beevers (2017) (10); no ITT analysis | |
| Klein (2020) (29)*1 | SAT | Depression or dysthymia | 104 | 12 w U or G + OP | NA | MADRS, PHQ-9 | NA | 60.6 | 79.8 | MADRS d = 1.42 [0.08; 2.76]*5 PHQ-9 d = 1.29 [0.60; 1.97]*5 | ||
| Gräfe (2020) (6) | RCT | At least mild depressive symptoms (PHQ-9 > 4) | 3 805 (1 904/ 1 901) | 12 w U 3 mo and 9 mo FU | WL | PHQ-9 | – | 79 | 72.6 | d = 0.37 [0.29; 0.44] 3 mo: d = 0.23 [0.15; 0.31] 9 mo: d = 0.5 [0.07; 0.23] |
Also evidence of reduced healthcare costs | |
| Selfapy’s Online course Depr. | Krämer (2022) (30)*1 | RCT | Mild to severe depression | 401 (151/150/ 100) | 12 w G/U 6 mo FU | WL | BDI-II | Yes | 83 | 75.1 | G: d = 1.63 [1.37; 1.93]; U: d = 1.47 [1.22; 1.73]; 6 mo G: d = 1.58 [1.29; 1.95]*5; 6 mo U: d = 1.88 [1.59; 2.24]*5 |
Effect sizes in DiGA Directory differ from publication*7 |
| Novego: coping with depression | Beiwinkel (2017) (31) | RCT | Mild to moderate depression, dysthymia | 180 (100/80) | 12 w G 6 mo FU | WL | PHQ-9, BDI-II | No | 68.3 | 48.8 | PHQ-9: d = 0.55 [0.25; 0.85] BDI-II: d = 0.41 [0.11; 0.70] |
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| Moritz (2016) (2) | RCT | Schizophrenia + subjective depressive symptoms | 58 (31/27) | 12 w U | WL | CES-D | Yes | 55.4 | 84 | p = 0.001, ηp2 = 0.179 CC: p = 0.003,. ηp2 = 0.176 |
Diagnosis Schizophrenia | |
| Miegel (2019) (32) | RCT | Subjective depressive and pain symptoms | 142 (71/71) | 12 w U | WL | BDI-II | No | 77.5 | 67.7 | p = 0.014, ηp2 = 0.043 | Diagnosis pain; study only in German language | |
| elona therapy Depression | Unpublished (e23) | RCT | Unipolar depression | 80(-/-) | 12 w + PT | PT | PHQ-9, BDI-II, GAD-7 | – | – | 77.5 | PHQ-9: d = 0.27(-/-); BDI-II: d = 0.22(-/-); GAD-7: d = 0.50(-/-) |
No information on population |
| Edupression.com*6 | Unpublished (e24) | RCT | Mild to moderate depressive symptoms | 62(-/-) | 12 w | WL | PHQ-9 | – | – | 67.2 | MD = –1.74 [−3.74; 0.26]; p = 0.09; PP: DOM = –3.67 [−6.35; 1.00]; p = 0.008 |
No information on population |
| Invirto - The Therapy for Anxiety | Unpublished (e25) | RCT | Agoraphobia +/- panic disorder, panic disorder, social phobia | 297 (197/100) | 6 mo | WL | BAI | – | 62 | 82 | Agoraphobia: DOM = 6.64 [2.33; 10.95]; p = 0.0029; Panic: DOM = 6.55 [1.38; 11.71]; p = 0.0137; Social phobia: DOM = 3.42 [0.01; 6.85]; p = 0.0499 |
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| Mindable: Panic disorder, Agoraphobia *6 | Unpublished (e26) | RCT | Panic disorder/ agoraphobia | 107 (57/50) | 8 w | WL | PAS | – | – | 84.1 | d = 0.64 (-/-) | |
| Selfapy’s online course for gen. anxiety disorder | Unpublished (e27) | RCT | Generalized anxiety disorder | 156 (78/78) | 12 w | WL | GAD-7, WHO-5 | – | 82 | 76.9 | GAD-7: d = –0.85 [−1.19; 0.51] WHO-5 d = 0.60 [0.29; 0.91] |
No information about statistical analysis |
| Velibra *6 | Berger (2017) (33)*1 | RCT | Social anxiety disorder, panic disorder +/- agoraphobia, generalized anxiety disorder | 139 (70/69) | 9 w U 6 mo FU | WL | DASS-21, BAI, BDI-II, SF-12 MH | No | 70.5 | 81 | DASS-21: d = 0.47 [0.13; 0.81] BAI d = 0.41 [0.07; 0.74] BDI-II d = 0.61 [0.27; 0.95] SF-12 MH d = 0.49 [0.15; 0.83] |
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| HelloBetter Panic | Ebenfeld (2021) (34) | RCT | Mild to moderate symptoms of anxiety (PAS 9–28) | 92 (45/47) | 8 w G 3 mo + 6 mo FU | WL | PAS | Yes | 55.4 | 91 | d = 0.66 [0.24; 1.08] 3 mo: d = 0.89 [0.46; 1.31] 6 mo: d = 0.81 [0.38; 1.24] |
Exclusion of PTSD, dissociative disorders; effect size in DiGA D < in publication |
| Nichtraucher Helden app | Unpublished (e28) | SAT | Nicotine dependence | 50 | 4 mo | NA | Nicotine abstinence | NA | – | – | Smoking abstinence (7-day prevalence) in 30% (n = 15)*5 | No information about statistical analysis and population |
| Vorvida*6 | Zill (2019) (35)*1 | RCT | Harmful use of alcohol (> 12/24 g/d in m/f or AUDIT-C > 3) | 608 (306/302) | 6 mo U | WL | QFI (intake in last 30 days), TFB (intake in last 7 days | No | 52.5 | 68 | 3 mo QFI: d = 0.38 (-/-) 3 mo TFB: d = 0.42 (-/-) 6 mo QFI: d = 0.33 (-/-) 6 mo TFB: d = 0.54 (-/-) |
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| Somnio | Lorenz (2019) (36)*1 | RCT | ISI > 8 | 56 (29/27) | 6 w U; 12 mo FU | WL | ISI | Yes | 67.2 | 86.2 | d = 1.79(-/-) 12 mo: d = 1.98 [1.31; 2.66] |
Exclusion of shift work, OSAS, RLS, parasomnia |
| HelloBetter Sleep | Unpublished (e29) | IPD-MA | NA | 433 (216/217) | 8 w | WL | ISI | NA | – | – | d = 1.06 [0.85; 1.26] | Inhomogeneous study population |
| Thiart (2015) (37)*1*4 | RCT | ISI ≥ 15 | 128 (64/64) | 6 w G; 6 mo FU | WL | ISI | No | 74.2 | 92.2 | d = 1.45 [1.06; 1.84] 6 mo: d = 1.43 [1.04; 1.82] |
Population: teachers | |
| Eber (2015) (38)*1*4 | RCT | ISI ≥ 15 | 128 (64/64) | 6 w U; 6mo FU | WL | ISI | No | 74.2 | 59.4 | d = 1.37 [0.99; 1.77] 6 mo: no control available |
Population:teachers | |
| Behrendt (2020) (39)*1*4 | RCT | Interest in iCBT-I | 177 (88/89) | 6 w U; 6 mo FU | WL | ISI | No | 65.5 | 40 | d = 0.97 [0.66; 1.28] 6 mo: d = 0.86 [0.55; 1.17] |
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| HelloBetter Stress/Burnout | Heber (2016) (40)*1 | RCT | PSS-10 ≥ 22, healthy employees | 264 (132/132) | 7 w G; 6 mo FU | WL | PSS-10 | No | 73.1 | 69.7 | d = 0.83 [0.58; 1.08] 6 mo: d = 1.02 [0.76; 1.27] |
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| HelloBetter Vaginismus Plus | Zarski (2017) (3)*1 | RCT | Vaginismus + no vaginal intercourse since >6 mo | 77(40/37) | 10 w G; 6 mo FU | WL | PEQ item 7 | No | 100 | 90 | CC: d = 0.16 [−0.32; 0.64] 6 mo: d = 0.37 [−0.17; 0.92] |
No ITT analysis |
| Zarski (2021) (4)*1 | RCT | Nonorganic vaginismus/dyspareunia (PEQ item 7 ≥ 1) | 200 (100/100) | 12 w G; 6 mo FU | WL | PEQ item 7 | No | 100 | 79 | Ability of coital vaginal penetration: 12 w: χ2(1) = 9.44; p < 0.01; 6 mo: χ2(1) = 2.19; p = 0.19 |
Effect size in DiGA D >in publication | |
| HelloBetter ratiopharm Chronic Pain | Lin (2017) (5)*1 | RCT | Pain >3 mo + one of the diagnoses: M79.7, M54, F45.40, F45.41, R52.1, R52.2 | 302 (100/101/ 101) | 9 w G/U; 6 mo FU | WL | WHYMPI, (pain interference subscale) | – | 84.1 | 76 | G: d = 0.58 [0.30; 0.86] 6 mo guided d = 0.58 [0.30; 0.86] U: no significant effect |
Effect sizes of the unguided intervention not shown |
| Unpublished (e30) | RCT | Pain >3 mo + one of the diagnoses: M79.7, M54, F45.40, F45.41, R52.1, R52.2 | 201 (100/101) | 9 w G | WL | WHYMPI, (pain interference subscale) | – | – | – | β = −0.756; p<0.001; θ = −0.66 |
No information about statistical analysis and population |
*1 Trial carried out with participation of the manufacturer. *2 Study was included in Twomey (2017). *3 Study was included in Twomey(2020). *4 Study was included in an IPD-MA. *5 Gray font color: highlights pre-post analysis-based statistics. *6 Studies also show improvements in structure and processes (not shown here). *7 According to the manufacturer, various ITT processes were used. –, not stated.% female, proportion of women in the sample (%);% Retention, retention of subjects at the end of intervention; OP, outpatient psychiatric/psychotherapeutic/medical treatment; AUDIT-C, Alcohol Use Disorders Identification Test; short version; BAI, Beck Anxiety Inventory; BDI-I, Beck‘s Depression Inventory, version 1; BDI-I, Beck’s Depression Inventory, version 2; CC, complete case analysis; CES-D, Center for Epidemiologic Studies Depression Scale; d, Cohen’s d (measure of effect size); DASS-21, Depression Anxiety Stress Scale (21 items); FU, Follow-up; G, guided (personal assistance from trained staff); g, Hedges’ g (measure of effect size); GAD-7, Generalized Anxiety Disorder Scale (7 items); ICBT-I, Internet-Based Cognitive Behavioral Therapy for Insomnia; IPD-MA, individual patient data meta-analysis; ISI, Insomnia Severity Index; ITT, intention-to-treat analysis; C, control; MA, meta-analysis; mo, months; DOM, baseline-adjusted difference of means; NA, not applicable; OSAS, obstructive sleep apnea syndrome; p, p-value (significance level); PAS, Parkinson Anxiety Scale; PEQ, Primary Endpoint Questionnaire; PHQ-9, 9-question Patient Health Questionnaire; PP, per-protocol analysis; PSS-10; Perceived Stress Scale (10 items); PT, psychotherapy; PTSD, posttraumatic stress disorder; QFI, Quantity Frequency Index; QIDS-SR, Quick Inventory of Depressive Symptomatology – Self-Report; RCT, randomized controlled trial; RLS, Restless Legs Syndrome; SAT, single-arm trial; IP, in-patient psychiatric/psychosomatic treatment; SF-12 MH, Short Form 12 Health Survey – Mental Health (12 items); SvMADRS, Montgomery-Åsberg Depression Rating Scale, short version; TFB, Timeline-followback method; U, unguided (independent use); w, weeks; WHO-5, World Health Organisation Five Well-Being Index; WHYMPI, West Haven Yale Multidimensional Pain Inventory; WL, waiting list; ηp2, partial eta-squared; χ2, chi-square test. If available, 95% confidence intervals were shown in square brackets after the effect size measure. Example: d = 0.23 [0.15; 0.31]. Missing 95% confidence intervals are shown as (-/-).