Table 1 Selected Characteristics of Studies Comparing Treatment with Antidepressant Medication to Combined Treatment with Psychotherapy and Medication Study Disorder Psychotherapy Medication Ncom Nmed Quality Country Azhar (28) PAN CBT SSRI 17 17 Other Barlow et al (29) PAN CBT TCA 65 83 USA Bellack et al (30) Mood Other TCA 17 18 USA Bellino et al (31) MDD IPT SSRI 16 16 Europe Berger et al (32) PAN Other SSRI 35 38 Europe Blackburn et al (33) MDD CBT TCA 22 20 USA Blanco et al (34) SAD CBT 32 35 USA Blom et al (35) MDD IPT SNRI 33 30 Europe Blomhoff et al (36) SAD BT SSRI 98 95 Europe Browne et al (37) DYS IPT SSRI 122 117 Canada Burnand et al (38) MDD DYN TCA 33 38 Europe Crits Christoph et al (39) GAD CBT SNRI 17 24 USA Davidson et al (40) SAD CBT SSRI 42 39 USA De Jonghe et al (41) MDD DYN Prot Other 83 84 Europe De Mello et al (42) DYS IPT 11 13 Other Dozois et al (43) MDD CBT Prot Other 21 Finkenzeller et al (44) MDD IPT SSRI 23 22 21 Canada 24 Europe Foa et al (45) OCD BT TCA 19 27 USA Hautzinger et al (46) Mood CBT TCA Hellerstein et al (47) DYS Other SSRI Hollon et al (48) MDD CBT TCA Hsiao et al (49) MDD Other Prot Other Keller et al (50) MDD Other SNRI King et al (51) PAN CBT Prot Other Koszycki et al (52) PAN CBT SSRI Lesperance et al (53) MDD IPT SSRI Loerch et al (54) PAN CBT Lynch et al (55) MDD Other Prot Other Macaskill Macaskill (56) MDD CBT TCA Maina et al (57) MDD, OCD DYN SSRI Markowitz et al (58) DYS IPT SSRI Misri et al (59) Mood CBT SSRI Mitchell et al (60) Mood Other Prot Other Murphy et al (61) MDD CBT TCA 2222222675022242 32 24 Europe 18 17 USA 57 USA 26 Other 220 USA 25 Other 59 62 Canada 75 Canada 14 16 Europe 15 16 USA 9 9 Europe 29 24 25 Europe USA 16 Canada Mynors Wallis et al (62) MDD PST SSRI 35 Naeem et al (63) MDD CBT SSRI 17 3237 53 24 USA USA 36 17 Europe Other Otto et al (64) PTSD CBT SSRI 5 5 USA Prasko et al (65) SAD CBT 22 Ravindran et al (66) DYS CBT SSRI 24 Reynolds et al (67) MDD IPT TCA 16 25 Rothbaum et al (68) PTSD BT SSRI 34 31 Shamsaei et al (69) MDD CBT SSRI 40 Shareh et al (70) OCD CBT SSRI 6 Sharp et al (71) PAN CBT SSRI 29 Sirey et al (72) MDD Other Prot Other 21 222222 20 Europe Canada USA USA 40 Other 6 Other 29 Europe 24 USA (Continued) 350 Summer 2014, Vol XII, No 3 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY CUIJPERS ET AL Table 5 Long Term Effects of Combined Therapy for Anxiety and Depressive Disorders Compared with Antidepressive Medication Only Relative Risk of Having a Positive Outcome Ncomp RR 95 CI 12 95 CI NNT 3 5 months after end of treatment 6 8 months after end of treatment 6 1 60 1 03 2 48 75 43 89 3 41 7 1 40 1 13 1 73 0 0 71 6 90 9 12 months after end of treatment 13 24 months after end of treatment 10 1 51 1 25 1 84 13 0 56 4 52 4 1 49 1 12 1 98 0 0 85 4 35 All long term outcomes pooled 19 1 48 1 23 1 78 55 25 73 4 29 Ncomp number of comparisons, NNT Number needed to treat, RR relative risk disorder, and OCD A trend indicated possible su perior effects in SAD We did not find sufficient evidence for a significant difference in dysthymia, PTSD and GAD, but this could be due to the small number of studies and associated lack of statistical power for these disorders The superior effects of combined treatment remained significant at one to two year follow up We found that the superior effects of combined treatment may have been overestimated by publi cation bias, which is in line with earlier research on pharmacotherapy (81) as well as psychotherapy (82), showing evidence of publication bias in both fields However, even after adjusting for publication bias, the superiority of combined treatment was still sta tistically significant We also found some indications that the difference between pharmacotherapy and combined treatment was especially high in clinical samples compared with samples that were (in part) recruited from the com munity Although this difference was only marginally significant (p 0 1), it does suggest that patients ac tively seeking treatment may benefit more from combined treatment than people who are recruited from the community Research up to now has not been able to answer the question of how large the effects of combined treatment are compared with pill placebo only We found indications that the effects of combined treatment compared with placebo only were about twice as large as those of pharmacotherapy compared with placebo only Until now it has not been established well whether the effects of pharmacotherapy and those of psy chotherapy are complementary to each other, whether they have effects independent from each other, or whether combined treatments lead to higher effects than the sum of the two treatments alone (83,84) The present study indicates that the effects of psy chotherapy and pharmacotherapy may be largely independent from each other and additive, not in terfering with each other, and both contribute about equally to the effects of combined treatment From a clinical point of view, this paper suggests that combined treatment should be used in more patients than is currently done in clinical practice Most patients receive either pharmacotherapy or psychotherapy (16,17), and only a minority receives combined ther apy Combined treatment is especially given to more severe and chronic cases Our data suggest that the superior effects of combined treatment are not associ ated with baseline severity, at least in depression Be cause the effects of the two treatments seem to be largely independent from each other, combined treat ment may also be beneficial in less severe cases This study has some limitations First, it is not possible to blind comparisons of pharmacotherapy to combined treatment and this may have introduced a bias in the outcomes Second, because patients refusing antidepressants may not have been willing to be enrolled in trials, there may have been a sampling bias that could limit the generalizability of these findings Third, we found considerable levels of het erogeneity among the studies, which could not fully be explained by moderator analyses Another limitation was the relatively small number of included studies for some disorders A final limitation is that we considered psychotherapy and pharmacotherapy as monolithic treatments, while in fact several different treatments were used in the included studies In sum, the present study found superior effects of combined treatment over pharmacotherapy alone, which are significant and relevant up to two years after treatment These results thus support the use of combined treatment for common mental disorders rather than monotherapy with psychotropic medi cation without psychotherapy REFERENCES 1 Kessler RC, Berglund P, Demler O, et al National Comorbidity Survey Replication The epidemiology of major depressive disorder results from 356 Summer 2014, Vol XII, No 3 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY Table 4 Long term Follow up Effects in Included Studies Definitions of Positive Outcome and Relative Risk Associated With Each Outcome Study Outcome Follow up (months) RR 95 CI Barlow et al (29) CGI response 6 8 1 52 1 07 2 16 Barlow et al (29) CGI response 9 12 1 39 0 75 2 58 Barlow et al (29) PDSS response 6 8 1 52 1 07 2 16 Barlow et al (29) PDSS response 9 12 1 31 0 69 2 45 Bellack et al (30) 10 on BDI HAMD 6 8 1 30 0 53 3 16 Blanco et al (34) remission 3 5 2 07 1 08 3 96 Blanco et al (34) response 3 5 1 61 1 09 2 37 Hautzinger et al (46) response 9 12 1 91 1 07 3 39 Hellerstein et al (47) remission 3 5 0 62 0 23 1 66 Hellerstein et al (47) response 3 5 1 53 0 74 3 14 Hollon et al (48) no relapse 9 12 1 87 0 99 3 52 Hollon et al (48) no relapse 13 24 1 73 0 90 3 32 Keller et al (50) no relapse 3 5 1 01 0 95 1 08 Loerch et al (54) FQ 10 6 8 1 17 0 79 1 74 Loerch et al (54) FQ 50 improvement 6 8 1 17 0 79 1 74 Lynch et al (55) BDI 9 6 8 1 29 0 43 3 88 Lynch et al (55) HAMD 7 6 8 2 35 1 07 5 16 Maina et al (57) CGI success 6 8 1 55 0 62 3 86 Maina et al (57) HAMD response 6 8 1 16 0 47 2 86 Maina et al (57) YBOCS response 6 8 0 77 0 38 1 58 Mitchell et al (60) HAMD 9 3 5 2 08 1 13 3 82 Mitchell et al (60) HAMD 9 9 12 1 76 1 01 3 08 Mitchell et al (60) HAMD 9 13 24 1 42 0 91 2 23 Murphy et al (61) no relapse 9 12 1 71 0 61 4 80 Mynors Wallis et al (62) recovered 9 12 1 18 0 81 1 73 Prasko et al (65) no relapse 3 5 1 62 0 89 2 95 Prasko et al (65) no relapse 9 12 2 16 0 81 5 77 Prasko et al (65) no relapse 13 24 1 94 0 71 5 31 Reynolds et al (67) no relapse 3 5 9 58 2 09 43 94 Sharp et al (71) FQ AG clinically significant change 6 8 1 60 0 88 2 91 Sharp et al (71) HAMA clinically significant change 6 8 1 64 0 95 2 82 SRT clinically significant change remission remission no DSM relapse remission Sharp et al (71) van Apeldoorn et al (76) van Apeldoorn et al (76) Wiborg Dahl (78) Wiborg Dahl (78) BDI Beck Depression Inventory, CGI Clinical Global Impression, FQ Fear Questionnaire, FQ AG Fear Questionnaire, Agoraphobia Subscale, HAMA Hamilton Anxiety Rating Scale, HAMD Hamilton Depression Rating Scale, PDSS Postpartum Depression Screening Scale, RR relative risk, SRT Kellner and Sheffield Symptom Rating Scale, YBOCS Yale Brown Obsessive Compulsive Scale 6 8 2 50 0 88 7 07 6 8 1 48 0 63 3 47 9 12 1 93 0 87 4 27 9 12 3 20 1 45 7 05 9 12 3 20 1 45 7 05 INFLUENTIAL PUBLICATIONS The RR of having a positive outcome for all follow up periods together was 1 48 (95 CI 1 23 1 78 NNT 4 29), and ranged from RR 1 40 to 1 51 (NNTs 3 41 to 6 90) for the four follow up periods we distinguished In each of the four follow up periods, combined treatment was significantly more effective than pharmacotherapy alone (Table 5) DISCUSSION In this meta analysis, we found clear evidence that combined treatment with psychotherapy and anti depressant medication is more effective than treat ment with antidepressant medication alone This difference was significant for major depression, panic focus psychiatryonline org CUIJPERS ET AL FOCUS Summer 2014, Vol XII, No 3 355 Figure 2 Effects of Pharmacotherapy Compared to Combined Treatment With Pharmacotherapy and Psychotherapy (Hedges' g) Study g 95 CI Azhar (28) 4 06 2 89 5 22 Barlow et al (29) 0 22 0 10 0 55 Bellack et al (30) Bellino et al (31) Berger et al (32) Blackburn et al (33) Blanco et al (34) Blom et al (35) Blomhoff et al (36) 0 04 0 81 0 89 0 90 0 19 1 61 0 31 1 05 0 43 0 71 0 05 1 46 0 74 0 25 1 23 0 26 0 23 0 75 0 12 0 16 0 40 0 07 0 32 0 18 0 11 0 35 0 57 g (95 CI) Browne et al (37) Burnand et al (38) Crits Christoph et al (39) 0 51 1 14 0 12 Davidson et al (40) 0 09 0 52 0 35 De Jonghe et al (41) 0 55 0 24 0 86 De Mello et al (42) 0 48 0 31 1 27 Dozois et al (43) 0 35 0 25 0 95 Finkenzeller et al (44) 0 12 0 68 0 45 Foa et al (45) 0 93 0 33 1 54 Hautzinger et al (46) 0 33 0 20 0 86 Hellerstein et al (47) 0 52 0 41 1 45 Hollon et al (48) 0 38 0 09 0 86 Hsiao et al (49) 0 34 0 21 0 89 Keller et al (50) 0 50 0 31 0 68 King et al (51) 0 59 0 03 1 15 Koszycki et al (52) 0 61 0 08 1 14 Lesperance et al (53) 0 13 0 20 0 46 Loerch et al (54) 0 95 0 21 1 69 Lynch et al (55) 0 25 0 51 1 00 Macaskill Macaskill (56) 1 30 0 32 2 29 Maina et al (57) 0 21 0 32 0 74 Markowitz et al (58) 0 04 0 54 0 62 Misri et al (59) 0 03 0 71 0 66 Mitchell et al (60) 1 16 0 74 1 59 Murphy et al (61) 0 30 Mynors Wallis et al (62) 0 03 0 27 0 87 0 43 0 49 Naeem et al (63) 1 36 0 63 2 09 Otto et al (64) 0 62 0 54 1 77 Prasko et al (65) 0 65 0 04 1 26 Ravindran et al (66) 0 38 0 28 1 04 Reynolds et al (67) 0 30 0 42 1 01 Rothbaum et al (68) 0 19 Shamsaei et al (69) 0 83 Shareh et al (70) 2 17 0 29 0 67 0 38 1 28 0 80 3 55 Sharp et al (71) 0 26 0 45 0 97 Sirey et al (72) 0 68 0 00 1 35 Spinhoven et al (73) 0 13 0 75 0 48 Tenneij et al (74) 0 44 0 01 0 89 Thompson et al (75) 0 41 0 07 0 88 van Apeldoorn et al (76) 0 35 0 11 0 80 Weissman et al (77) 0 94 0 01 1 87 Wiborg Dahl (78) Wiles et al (79) Overall 0 78 0 15 1 42 1 82 0 21 3 43 0 43 0 31 0 56 1 00 0 00 1 00 2 00 moderate to high (I 64 95 CI 52 73) After exclusion of three possible outliers with extremely large effect sizes (g 1 5 Table 2), the effect size was somewhat smaller (g 0 37 95 CI 0 27 0 47 NNT 4 85), but heterogeneity was reduced to a moderate level (I 48) The results of these analyses are reported in Table 2 A forest plot of the studies and their effect sizes is given in Figure 2 For specific disorders, we found evidence that combined treatment was more effective than phar macotherapy alone in major depression (g 0 43 95 CI 0 29 0 57 NNT 4 20), panic disorder (g 0 54 95 CI 0 25 0 82 NNT 3 36), and OCD (g 0 70 95 CI 0 14 1 25 NNT 2 63) We also found some indication that combined treatment may be more effective than pharmaco therapy in SAD (g 0 32 95 CI 0 01 0 71 NNT 5 56), although this was not significant (p 0 1) Insufficient evidence was found for dys thymia, PTSD, and GAD Inspection of the funnel plot and Duval and Tweedie's trim and fill procedure pointed at some risk of publication bias After adjustment for pos sible publication bias, the overall mean effect size focus psychiatryonline org CUIJPERS ET AL PUBLICATIONS INFLUENTIAL FOCUS Summer 2014, Vol XII, No 3 353 1 of 12 PUBLICATIONS INFLUENTIAL Pim Cuijpers Marit Sijbrandij Sander L Koole Gerhard Andersson Aartjan T Beekman Charles F Reynolds III Adding Psychotherapy to Antidepressant Medication in Depression and Anxiety Disorders a Meta Analysis Abstract We conducted a meta analysis of randomized trials in which the effects of treatment with antidepressant medication were compared to the effects of combined pharmacotherapy and psychotherapy in adults with a diagnosed depressive or anxiety disorder A total of 52 studies (with 3,623 patients) met inclusion criteria, 32 on depressive disorders and 21 on anxiety disorders (one on both depressive and anxiety disorders) The overall difference between pharmacotherapy and combined treatment was Hedges' g 0 43 (95 CI 0 31 0 56), indicating a moderately large effect and clinically meaningful difference in favor of combined treatment, which corresponds to a number needed to treat (NNT) of 4 20 There was sufficient evidence that combined treatment is superior for major depression, panic disorder, and obsessive compulsive disorder (OCD) The effects of combined treatment compared with placebo only were about twice as large as those of pharmacotherapy compared with placebo only, underscoring the clinical advantage of combined treatment The results also suggest that the effects of pharmacotherapy and those of psychotherapy are largely independent from each other, with both contributing about equally to the effects of combined treatment We conclude that combined treatment appears to be more effective than treatment with antidepressant medication alone in major depression, panic disorder, and OCD These effects remain strong and significant up to two years after treatment Monotherapy with psychotropic medication may not constitute optimal care for common mental disorders Anxiety and depressive disorders are highly prevalent (1,2) and are associated with a substantial loss of quality of life for patients and their relatives (3,4), high levels of service use, substantial economic costs (5 7), and a considerable disease burden for public health (8) Effective treatments are available for these disorders, including several types of psy chotherapy and antidepressant medication (9 11) Although psychotherapy and antidepressants are about equally effective for most anxiety and de pressive disorders (12), there is some evidence that combined treatments may be more effective than each of these treatment alone (13 15) At the same time, however, an increasing proportion of patients (Reprinted with permission from the World Psychiatry 2014 13 56 67) with mental disorders in the past decade have received psychotropic medication without psy chotherapy (16,17) It is important, therefore, to ex amine whether this has negative effects on the quality of care We conducted a meta analysis of studies com paring pharmacotherapy alone with combined psy chotherapy and pharmacotherapy Although some earlier meta analyses have examined this question, these were all aimed at one disorder, especially depression (13 15) and panic (18, 19) For some other disorders e g , social anxiety disorder (SAD) and obsessive compulsive disorder (OCD) several primary studies have been conducted, but these focus psychiatryonline org CUIJPERS ET AL FOCUS Summer 2014, Vol XII, No 3 347 Table 3 Direct Comparisons Between Psychotherapy, Pharmaco therapy, Combined Psychotherapy and Pharmacotherapy, and Placebo in Anxiety and Depressive Disorders (Hedges' g) Ncomp g 95 CI 95 CI NNT Combined vs placebo 11 0 74 0 48 1 01 65 33 82 2 50 Pharmacotherapy vs combined 11 0 37 0 12 0 63 43 0 72 4 85 Pharmacotherapy vs placebo 11 0 35 0 21 0 49 0 0 60 5 10 Psychotherapy vs combined 11 0 38 0 16 0 59 53 8 76 4 72 Psychotherapy vs Placebo 11 0 37 0 11 0 64 68 41 83 4 85 Ncomp number of comparisons, NNT number needed to treat was reduced from g 0 43 (NNT 4 20) to g 0 29 (95 CI 0 15 0 43 NNT 6 17 number of imputed studies 10) Egger's test of the intercept also indicated significant publication bias (intercept 1 33 95 CI 0 24 2 42 p 0 01) We found no indication that combined treatment resulted in lower dropout from treatment than pharmacotherapy alone The RR of dropping out of treatment, in the 35 studies in which dropout was reported, was RR 0 99 (95 CI 0 95 1 03 I 24 95 CI 0 50) Subgroup analyses indicated no significant dif ferences between the effects sizes of depressive and anxiety disorders, between the different depressive disorders (while excluding anxiety disorders), and between the different anxiety disorders (while ex cluding depressive disorders) (Table 2) We also found no indication that the effect sizes differed according to the type of medication (SSRI TCA other or protocolized), target group (adults in gen eral or more specific target group), psychotherapy treatment format (individual or group), type of therapy (CBT IPT other), number of treatment sessions (5 9 10 12 13 18 19) and quality of the studies (meeting 3 or 4 criteria versus less than 3 criteria) We did find a trend (p 0 1) indicating that the effect size may be higher in clinical samples (g 0 49) compared with samples that included patients recruited from the community (g 0 27) We examined whether baseline severity was as sociated with outcome in the 20 studies examin ing depressive disorders Mean baseline severity according to the Hamilton Depression Rating Scale (HAM D) was moderate in 16 of the 20 studies (score 18 24), severe in three studies (score 24), and mild in one study (score 18) (80) In a meta regression analysis, we did not find any indication that the effect size of difference between pharma cotherapy and combined treatment was associated with baseline severity of depression (slope 0 007 95 CI 0 022 0 038 p 0 63) COMBINED TREATMENT VERSUS PLACEBO In 11 of the 53 studies, the combined treatment could be compared to a pill placebo control group All of these studies also included a psychotherapy only condition (with or without a pill placebo), as well as a pharmacotherapy only condition This allowed us to calculate the effect sizes indicating the difference between pharmacotherapy and placebo, psycho therapy (with or without a pill placebo) and placebo, as well as between combined treatment and placebo With these effect sizes we could estimate the con tribution of pharmacotherapy and psychotherapy to the effects of combined treatment The results of the analyses are presented in Table 3 The effects of combined treatment compared with placebo are large (g 0 74 95 CI 0 48 1 01 NNT 2 50), with moderate to high heterogeneity (I2 65 95 CI 33 82) In these 11 studies, the effect size of pharmacotherapy compared with pla cebo was g 0 35 (95 CI 0 21 0 49) and that of psychotherapy compared with placebo was g 0 37 (95 CI 0 11 0 64) This suggests that the effects of psychotherapy and those of pharmacotherapy are largely independent of each other, and each add about 50 to the overall effects of combined treat ment The independence of the effects of the two kinds of treatments is further supported by the effect sizes of pharmacotherapy versus combined treatment (g 0 37 in this sample), and those of psychotherapy versus combined treatment (g 0 38) LONG TERM DIFFERENCES BETWEEN PHARMACOTHERAPY AND COMBINED TREATMENT Long term differences between pharmacotherapy and combined treatment were reported in 19 studies, with follow up periods varying from 3 to 24 months Because the way positive outcomes were defined differed from study to study, we have reported the definition of a positive outcome at each of the follow up points in Table 4 354 Summer 2014, Vol XII, No 3 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY CUIJPERS ET AL CUIJPERS ET AL have not yet been integrated into meta analyses The main goal of this paper, therefore, is to pro vide an overall meta analysis of studies comparing antidepressant medication with combined treat ment for anxiety and depressive disorders We also examined whether differences between combined treatment and placebo only were larger than those between combined treatment and pharmacother apy, in order to determine the relative contribution of psychotherapy and pharmacotherapy to the ef fects of combined treatments METHODS IDENTIFICATION AND SELECTION OF STUDIES We used several strategies to identify relevant studies We searched four major bibliographical databases (PubMed, PsycInfo, Embase and the Cochrane database of randomized trials) We first developed a search string for psychotherapy with text and key words indicating the different types of psychotherapy and psychological treatments This search string was combined with search strings in dicating each of the disorders we included major depression dysthymia generalized anxiety disorder (GAD) SAD panic disorder OCD post traumatic stress disorder (PTSD) We limited our search to randomized controlled trials We also checked the references of 116 earlier meta analyses of psycho logical treatments of the disorders (Figure 1) We included randomized trials in which the effects of treatment with antidepressant medication were compared to the effects of a combined antidepressant medication and psychological treatment in adults with a depressive disorder, panic with or without agoraphobia, GAD, SAD, OCD or PTSD Only studies in which subjects met diagnostic criteria for the disorder according to a diagnostic interview such as the Structured Clinical Interview for DSM IV Axis I Disorders (SCID I), the Composite Inter national Diagnostic Interview (CIDI), or the Mini International Neuropsychiatric Interview (MINI) were included Studies on inpatients, adolescents and children (below 18 years of age) were excluded We also excluded maintenance studies, aimed at people who had already recovered or partly re covered after an earlier treatment Studies in English, German, Spanish, and Dutch were considered for inclusion QUALITY ASSESSMENT AND DATA EXTRACTION We assessed the validity of included studies using the Risk of bias assessment tool, developed by the Cochrane Collaboration (20) This tool assesses possible sources of bias in randomized trials, including the adequate generation of allocation sequence the concealment of allocation to conditions the pre vention of knowledge of the allocated intervention (masking of assessors) and dealing with incomplete outcome data (this was assessed as positive when intention to treat analyses were conducted, mean ing that all randomized patients were included in the analyses) Assessment of the validity of included studies was conducted by two independent re searchers, and disagreements were solved through discussion We also coded participant characteristics (dis order recruitment method target group) type of antidepressant that was used (selective serotonin reuptake inhibitor, SSRI tricyclic antidepressant, TCA serotonin norepinephrine reuptake inhibitor, SNRI monoamine oxidase inhibitor, MAOI other or manualized treatment including several antide pressants) and characteristics of the psychotherapies (format number of sessions and type of psycho therapy) The types of psychotherapy we distin guished were cognitive behavior therapy (CBT), interpersonal psychotherapy (IPT), and others Because most CBT therapies used a mix of different techniques, we clustered them together in one large family of CBT treatments We rated a therapy as CBT when it included cognitive restructuring or abehavioral approach (such as exposure and response prevention) When a therapy used a mix of CBT and IPT, we rated it as other , along with other ther apeutic approaches (such as psychodynamic therapies) META ANALYSES For each comparison between a pharmacotherapy and the combined treatment group, the effect size indicating the difference between the two groups at post test was calculated (Hedges' g) Effect sizes were calculated by subtracting (at post test) the average score of the pharmacotherapy group from the av erage score of the combined treatment group, and dividing the result by the pooled standard deviation Because some studies had relatively small sample sizes, we corrected the effect size for small sample bias (21) In the calculations of effect sizes in studies aimed at patients with depressive disorders, we used only those instruments that explicitly measured symp toms of depression In studies examining anxiety disorders, we used only instruments that explicitly measured symptoms of anxiety If more than one measure was used, the mean of the effect sizes was calculated, so that each study provided only one effect size If means and standard deviations were not 348 Summer 2014, Vol XII, No 3 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY Figure 1 Selection and Inclusion of Studies GAD Generalized Anxiety Disorder, OCD Obsessive Compulsive Disorder, PTSD Post Traumatic Stress Disorder, SAD Social Anxiety Disorder Depression GAD SAD Panic OCD PTSD Total 21,729 references identified by literature search Pubmed 3320 547 296 849 91 5103 Cochrane 2988 1309 752 1436 128 6613 PsycInfo 2710 337 246 424 32 3749 Embase 4389 372 661 764 78 6264 Total 13407 2565 1955 3473 329 21729 After removal of duplicates 9860 1562 1228 2032 221 14903 Earlier meta analyses checked for references 42 7 14 26 27 116 Full text papers retrieved 1344 136 247 493 58 68 2278 Reasons for exclusion No correct comparison 243 49 86 Duplicate study 306 32 24 52 No diagnosis 165 32 52 No control group 167 7 39 33 No psychotherapy 151 7 1 76 g 170 112 2523 577 419 363 249 3 238 Other reason 280 8 41 40 Total 1312 135 243 483 52 120 10 379 2226 32 1 4 10 Included in meta analysis OCD 4 PTSD 2 52 59 reported, we used the procedures of the Compre hensive Meta Analysis software (version 2 2 021) to calculate the effect size using dichotomous out comes and if these were not available either, we used other statistics (such a t value or p value) To cal culate pooled mean effect sizes, we used the above mentioned software Because we expected considerable heterogeneity among the studies, we employed a ran dom effects pooling model Because the standardized mean difference (Hedges' g) is not easy to interpret from a clinical perspective, we transformed these values into the number needed to treat (NNT), using the formulae provided by Kraemer and Kupfer (22) The NNT indicates the number of patients that have to be treated in order to generate one additional positive outcome (23) We also calculated the relative risk (RR) of dropping out from treatment in pharmacotherapy com pared with combined treatment To compare the long term effects of the two treatments, we cal culated the RR of having a positive outcome at follow up focus psychiatryonline org PUBLICATIONS INFLUENTIAL FOCUS Summer 2014, Vol XII, No 3 349 Table 2 Effects of Combined Therapy for Adult Depressive and Anxiety Disorders Compared with Antidepressant Medication Only Ncomp g 95 CI 1 95 CI NNT Depressive and anxiety disorders 52 0 43 Possible outliers excluded (g 1 5) 49 0 37 0 31 0 56 64 0 27 0 47 48 28 63 52 73 0 81 4 20 4 85 Depressive disorders 32 0 41 0 28 0 54 50 25 67 0 17 4 39 Major depression 23 0 43 0 29 0 57 30 0 58 4 20 Dysthymia 5 0 20 0 21 0 60 0 0 79 8 93 Mixed depressive disorders 5 0 56 0 12 0 99 73 32 89 3 25 Anxiety disorders 21 0 47 0 23 0 71 75 61 84 0 66 3 85 Panic disorder 10 0 54 0 25 0 82 82 68 90 3 36 OCD 4 0 70 0 14 1 25 67 5 89 2 63 SAD 4 0 32 0 01 0 71 65 0 88 5 56 PTSD GAD 21 0 31 0 51 0 39 1 00 0 1 42 0 40 5 75 (3 55) Subgroup analyses Medication SSRI TCA 13 Other protocol 17 Recruitment Clinical samples Community 16 Target group Adult in general 43 237263 0 34 0 46 0 51 0 49 0 28 0 44 Specific group 9 0 41 0 12 0 71 64 0 15 0 53 76 63 84 0 22 0 71 9 0 31 0 72 41 0 34 0 64 63 46 75 0 08 0 47 45 2 70 0 30 0 57 65 51 74 27 83 0 45 5 26 0 47 0 67 3 91 3 55 0 09 3 68 6 41 0 89 4 10 4 39 Type of therapy CBT 33 0 51 0 35 0 66 70 58 79 0 20 3 55 IPT 9 0 24 0 05 0 53 32 0 69 7 46 Other 10 0 37 0 09 0 64 10 0 50 4 85 Number of sessions 5 9 11 0 67 0 40 0 93 86 76 91 0 10 2 75 10 12 16 0 24 0 03 0 46 48 8 71 7 46 13 18 18 0 47 0 26 0 67 4 0 52 3 85 19 7 0 41 0 06 0 76 33 0 72 4 39 Treatment format Individual 42 0 46 Group 9 0 29 0 02 0 60 40 0 32 0 59 68 55 76 0 73 0 35 3 91 6 17 Quality score 3 32 0 49 3 or 4 20 0 35 0 16 0 54 0 33 0 66 62 67 44 74 0 23 3 68 47 79 5 10 CBT cognitive behavior therapy, GAD generalized anxiety disorder, IPT interpersonal psychotherapy, Ncomp number of comparisons, NNT number needed to treat, OCD obsessive compulsive disorder, PTSD post traumatic stress disorder, SAD social anxiety disorder, SNRI serotonin norepinephrine reuptake inhibitor, SSRI selective serotonin reuptake inhibitor, TCA tricyclic antidepressant QUALITY ASSESSMENT The quality of the studies varied (Table 1) Twenty one studies reported an adequate sequence generation, while the other 31 did not Nineteen studies reported allocation to conditions by an in dependent (third) party Thirty nine studies re ported blinding of outcome assessors or used only self report outcomes, whereas 13 did not report blinding Thirty one studies conducted intention to treat analyses (a post treatment score was ana lyzed for every patient even if the last observation prior to attrition had to be carried forward or that score was estimated from earlier response trajecto ries) Thirteen studies met all four quality criteria, another six studies met 3 criteria, while the re maining 33 studies met two criteria or less EFFECTS OF COMBINED TREATMENT VERSUS ANTIDEPRESSANTS ONLY The overall mean effect size indicating the differ ence between pharmacotherapy only and combined treatment of pharmacotherapy and psychotherapy at post test for all 52 studies was 0 43 (95 CI 0 31 0 56) in favor of the combined treatment This cor responds to a NNT of 4 20 Heterogeneity was 352 Summer 2014, Vol XII, No 3 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY CUIJPERS ET AL Disorder PAN OCD Table 1 Continued Study Spinhoven et al (73) Tenneij et al (74) Thompson et al (75) van Apeldoorn et al (76) Weissman et al (77) MDD TE PAN MDD Wiborg Dahl (78) PAN Wiles et al (79) Mood Psychotherapy Medication Ncom Nmed Quality Country CBT SSRI 20 19 Europe BT Prot Other 34 46 Europe CBT TCA 36 33 USA CBT Prot Other 36 37 Europe IPT TCA 23 20 USA DYN TCA 20 20 Europe CBT Prot Other 14 11 Europe A positive or negative sign is given for four quality criteria allocation sequence, concealment of allocation to conditions, blinding of assessors, and intention to treat analysis BT behavior therapy, CBT cognitive behavior therapy, DYN psychodynamic therapy, DYS dysthymic disorder, GAD generalized anxiety disorder, IPT interpersonal psychotherapy, MAOI monoamine oxidase inhibitor, MDD major depressive disorder, Mood mixed mood disorder, Ncom number of patients in the combined treatment condition, Nmed number of patients in the pharmacotherapy condition, OCD obsessive compulsive disorder, PAN panic disorder with or without agoraphobia, Prot Other other antidepressant or protocolized treatment with antidepressants, PST problem solving therapy, PTSD post traumatic stress disorder, SAD social anxiety disorder, SNRI serotonin norepinephrine reuptake inhibitor, SSRI selective serotonin reuptake inhibitor, TCA tricyclic antidepressant As a test of homogeneity of effect sizes, we calculated the I statistic, which is an indicator of heterogeneity in percentages A value of 0 indicates no observed heterogeneity, and larger values indicate increasing heterogeneity, with 25 as low, 50 as moderate, and 75 as high heterogeneity (24) We calculated 95 confidence intervals around 12 (25), using the non central chi squared based approach within the Heterogi module for Stata (26) We conducted subgroup analyses according to the mixed effects model, in which studies within sub groups are pooled with the random effects model, while tests for significant differences between sub groups are conducted with the fixed effects model For continuous variables, we used meta regression ana lyses to test whether there was a significant rela tionship between the continuous variable and the effect size, as indicated by a Z value and an associated p value We tested publication bias by inspecting the funnel plot on primary outcome measures and by Duval and Tweedie's trim and fill procedure (27), which yields an estimate of the effect size after the publication bias has been taken into account We also conducted Egger's test of the intercept to quantify the bias captured by the funnel plot and test whether it was significant RESULTS SELECTION AND INCLUSION OF STUDIES After examining a total of 21,729 abstracts (14,903 after removal of duplicates), we retrieved 2,278 full text papers for further consideration We excluded 2,226 of the retrieved papers The flow chart describing the inclusion process, including the reasons for exclusion, is presented in Figure 1 A total of 52 studies met inclusion criteria for this meta analysis (28 79) Selected characteristics of the in cluded studies are reported in Table 1 CHARACTERISTICS OF INCLUDED STUDIES In the 52 studies, 3,623 patients participated (1,767 in the combined treatment conditions and 1,856 in the pharmacotherapy only conditions) Thirty two studies were aimed at depressive dis orders (22 on major depression, including one that was aimed at patients with both major depression and OCD 5 on dysthymia and 5 on mixed mood dis orders) and 21 at anxiety disorders (10 on panic disorder with or without agoraphobia 4 on OCD 4 on SAD 2 on PTSD, and one on GAD) Most studies (n 32) recruited patients exclusively from clinical samples, and were aimed at adults in general instead of a more specific population (such as older adults or patients with a comorbid somatic disorder) Most psychotherapies belonged to the family of cognitive and behavioral therapies, while nine studies examined IPT, and the remaining 10 examined other therapies (including psychodynamic therapies) The number of treatment sessions ranged from 5 to 56, with most therapies (n 36) having between 10 and 20 sessions The antidepressants that were examined in the studies included SSRIs (n 22), TCAs (n 13), SNRIs (n 3), MAOIS (n 4), and treatment protocols with different types of antidepressant med ication (n 10) Most studies were conducted in the US (n 20), or Europe (n 19) Two papers were published in German, the rest in English focus psychiatryonline org CUIJPERS ET AL INFLUENTIAL PUBLICATIONS FOCUS Summer 2014, Vol XII, No 3 351

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Table 1. Selected Characteristics of Studies Comparing Treatment with Antidepressant Medication to Combined Treatment with Psychotherapy and Medication Study Disorder Psychotherapy Medication Ncom Nmed

Table 1. Selected Characteristics of Studies Comparing Treatment with Antidepressant Medication to Combined Treatment with Psychotherapy and Medication Study Disorder Psychotherapy Medication Ncom Nmed Quality* Country Azhar (28) PAN CBT SSRI 17 17 Other Barlow et al (29) PAN CBT TCA 65 83 ++ USA Bellack et al (30) Mood Other TCA 17 18 USA Bellino et al (31) MDD IPT SSRI 16 16 Europe Berger et al (32) PAN Other SSRI 35 38 Europe Blackburn et al (33) MDD CBT TCA 22 20 USA Blanco et al (34) SAD CBT 32 35 ++++ USA Blom et al (35) MDD IPT SNRI 33 30 --++ Europe Blomhoff et al (36) SAD BT SSRI 98 95 ++++ Europe Browne et al (37) DYS IPT SSRI 122 117 +++ - Canada Burnand et al (38) MDD DYN TCA 33 38 --+- Europe Crits-Christoph et al (39) GAD CBT SNRI 17 24 --+- USA Davidson et al (40) SAD CBT SSRI 42 39 ++++ USA De Jonghe et al (41) MDD DYN Prot/Other 83 84 Europe De Mello et al (42) DYS IPT 11 13 --+- Other Dozois et al (43) MDD CBT Prot/Other 21 Finkenzeller et al (44) MDD IPT SSRI 23 22 21 -+-- Canada 24 +-+ + Europe Foa et al (45) OCD BT TCA 19 27 + USA Hautzinger et al (46) Mood CBT TCA Hellerstein et al (47) DYS Other SSRI Hollon et al (48) MDD CBT TCA Hsiao et al (49) MDD Other Prot/Other Keller et al (50) MDD Other SNRI King et al (51) PAN CBT Prot/Other Koszycki et al (52) PAN CBT SSRI Lesperance et al (53) MDD IPT SSRI Loerch et al (54) PAN CBT Lynch et al (55) MDD Other Prot/Other Macaskill & Macaskill (56) MDD CBT TCA Maina et al (57) MDD, OCD DYN SSRI Markowitz et al (58) DYS IPT SSRI Misri et al (59) Mood CBT SSRI Mitchell et al (60) Mood Other Prot/Other Murphy et al (61) MDD CBT TCA 2222222675022242 32 24 ++ Europe 18 17 USA 57 --++ USA 26 +-+ + Other 220 ++++ USA 25 -+ +- Other 59 62 ++++ Canada 75 ++++ Canada 14 16 ++ Europe 15 16 USA 9 9 Europe 29 24 25 ++++ Europe ++++ USA 16 +-+ + Canada Mynors-Wallis et al (62) MDD PST SSRI 35 Naeem et al (63) MDD CBT SSRI 17 3237 53 24 ++++ ++-+ USA USA 36 17 ++++ Europe ++++ Other Otto et al (64) PTSD CBT SSRI 5 5 USA Prasko et al (65) SAD CBT 22 Ravindran et al (66) DYS CBT SSRI 24 Reynolds et al (67) MDD IPT TCA 16 25 Rothbaum et al (68) PTSD BT SSRI 34 31 Shamsaei et al (69) MDD CBT SSRI 40 Shareh et al (70) OCD CBT SSRI 6 Sharp et al (71) PAN CBT SSRI 29 Sirey et al (72) MDD Other Prot/Other 21 222222 20 Europe +++- Canada --++ USA --++ USA 40 + + Other 6 Other 29 Europe 24 ++ USA (Continued) 350 Summer 2014, Vol. XII, No. 3 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY CUIJPERS ET AL. Table 5. Long-Term Effects of Combined Therapy for Anxiety and Depressive Disorders Compared with Antidepressive Medication Only: Relative Risk of Having a Positive Outcome Ncomp RR 95% CI 12 95% CI NNT 3-5 months after end of treatment 6-8 months after end of treatment 6 1.60 1.03-2.48 75 43-89 3.41 7 1.40 1.13-1.73 0 0-71 6.90 9-12 months after end of treatment 13-24 months after end of treatment 10 1.51 1.25-1.84 13 0-56 4.52 4 1.49 1.12-1.98 0 0-85 4.35 All long-term outcomes pooled 19 1.48 1.23-1.78 55 25-73 4.29 Ncomp number of comparisons, NNT - Number needed to treat, RR - relative risk disorder, and OCD. A trend indicated possible su- perior effects in SAD. We did not find sufficient evidence for a significant difference in dysthymia, PTSD and GAD, but this could be due to the small number of studies and associated lack of statistical power for these disorders. The superior effects of combined treatment remained significant at one to two-year follow-up. We found that the superior effects of combined treatment may have been overestimated by publi- cation bias, which is in line with earlier research on pharmacotherapy (81) as well as psychotherapy (82), showing evidence of publication bias in both fields. However, even after adjusting for publication bias, the superiority of combined treatment was still sta- tistically significant. We also found some indications that the difference between pharmacotherapy and combined treatment was especially high in clinical samples compared with samples that were (in part) recruited from the com- munity. Although this difference was only marginally significant (p

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