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Guidi, J. & Fava, G.A. (2021). Sequential combination of pharmacotherapy and psychotherapy in major depressive disorder: A systematic review and meta-analysis. JAMA Psychiatry, 78, 261-269.

A sequential model of treatment suggests that one apply two treatments consecutively in order to reduce relapse of symptoms. This might include pharmacotherapy followed by psychotherapy, or vice versa. One reason to consider a second consecutive treatment for depression is that many individuals continue to have symptoms after a first treatment, and having residual symptoms is related to higher relapse rates. Another reason is that many with depressive disorders have comorbid symptoms of anxiety or other disorders, and so one course of treatment may not be enough for such complex situations. In this study, Guidi and Fava conducted a meta-analysis to examine if sequential combination of medications and psychotherapy reduced the risk of relapse for major depression. They reviewed 17 randomized controlled trials representing 2283 adult patients that examined the sequential use of psychotherapy following medications. The primary outcome was remission of depressive symptoms. The methodological quality of the studies was high. After adjusting for publication bias, the sequential approach was significant (RR = 0.885; 95% CI, 0.793-0.988), indicating that sequencing treatment resulted in a lower risk of relapse or recurrence. Continuing versus discontinuing medications during psychotherapy did not result in any advantage for patients. However, providing psychotherapy while continuing with antidepressant medications reduced rates of relapse and recurrence, RR = 0.821 (95% CI, 0.710-0.949).

Practice Implications

The chronic and recurrent nature of major depression is an important clinical challenge. The results of Guidi and Fava’s meta-analysis suggests that adding psychotherapy following pharmacotherapy, either alone or in combination with pharmacotherapy, will reduce the risk of relapse from major depression. Discontinuing medications is reasonable after adding psychotherapy in order to help patients with major depression to stay symptom free. The results support the notion that psychotherapy results in patients acquiring skills to regulate their emotions, and that this might result in reduced relapse of depressive symptoms. Such skill acquisition does not take place with pharmacotherapy alone.

Dreissen, E., Dekker, J.J.M., Peen, J., Van, H.L., Maiana, G…. Cuijpers, P. (2020). The efficacy of adding short-term psychodynamic psychotherapy to antidepressants in the treatment of depression: A systematic review and meta-analysis of individual participant data. Clinical Psychology Review, 80.

Depression is the single largest contributor to disability worldwide. There are a number of established treatments for depression including antidepressant medications and psychotherapies. One of the psychological treatments that is evidence-based is short-term psychodynamic psychotherapy (STPP). There is evidence in the general psychotherapy research literature that combining psychotherapy with antidepressant medications is more efficacious than providing medications alone. However, no meta-analysis has looked specifically at adding STPP to antidepressant medication. In this meta-analysis Driessen and colleagues analysed data from 7 studies that compare STPP plus medications versus antidepressant medications alone, or that compare STPP plus medications versus supportive therapy plus medications. Although the number of studies was small, the unique aspect of this meta-analysis is that Driessen and colleagues were able to get all of the individual level data from each study, so they were able to analyse data from 482 participants. Typical meta analyses only look at study level data (effects reported from the study as a whole) and not individual level data (effects for each individual who participant in each study). So, the results from Driessen and colleagues’ study provides a more precise and specific analysis of the findings. Combined treatment of STPP and antidepressant medications was significantly more efficacious than antidepressants with and without supportive therapy at post-treatment, but the effects were small (d = 0.26, SE = 0.01, p = .01). At follow up, combined treatment of STPP and antidepressant medications was again more efficacious than antidepressant medications and supportive therapy, but the effects were moderately large (d = 0.50, SE = 0.10). Other findings also suggested that STPP’s specific interventions provided significant added benefit over and above the non-specific effects of supportive therapy. The findings were consistent whether or not analyses were done on studies with complete versus incomplete data, controlling for baseline depression scores, and use or not of a treatment manual. Overall, the quality of the studies was good, and the findings were stable across studies.

Practice Implications

People with depression and their clinicians might expect better outcomes in terms of depressive symptoms if they combine STPP and antidepressant medications, rather than receiving medications alone. The benefits might be related to the specific interventions of STPP, which suggests that therapists may need specific training and supervision in order to make the most of STPP’s effectiveness.

Cuijpers, P., Noma, H., Karyotaki, E.,  Vinkers, C.H., Cipriani, A., & Furukawa, T.A. (2020). A network meta‐analysis of the effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression. World Psychiatry, 19, 92-107.

Mental disorders represent a significant health burden worldwide, with over 350 million people affected. Depression is the second leading cause of disease burden. There is ample evidence that psychotherapies and pharmacotherapies are effective in the treatment of depression. There is also evidence for the efficacy of different types of psychotherapy (CBT, IPT, PDT), and for different types of antidepressant medications. Some research suggests that combining psychotherapy and medications is better than either intervention alone, but the evidence is inconclusive. Existing meta analyses only compare two existing treatments directly to each other at a time: psychotherapy vs medications, psychotherapy vs combined treatments, medications vs combined treatments. In this meta-analysis, Cuijpers and colleagues use a method called “network meta-analysis” to study the relative impact of medications, psychotherapy, or their combination. Network meta-analysis is controversial because it relies on indirect comparisons to estimate effects. For example, let’s say one study compared medications (A) to psychotherapy (B), and another study compared medication (A) to combination treatment (C), then a network meta-analysis would estimate the effects of psychotherapy vs combination treatment by using the transitive principle (if A = B, and B = C, then A = C). This logic relies on everything being equivalent across studies. However, in treatment trials one cannot assume that the different studies comparing A, B, and C are equivalent in terms of quality and bias (in fact, we know they are not). In any case, Cuijpers and colleagues found that combined treatment was superior to ei­ther psychotherapy alone or pharmacotherapy alone in terms of standardized effect sizes (0.30, 95% CI: 0.14-0.45 and 0.33, 95% CI: 0.20-0.47). No significant difference was found between psychotherapy alone and pharmacotherapy alone (0.04, 95% CI: –0.09 to 0.16). Interestingly, acceptability (defined as lower patient drop-out rate and better patient adherence to the treatment) was significantly better for combined treatment compared with pharmacotherapy (RR=1.23, 95% CI:

1.05-1.45), as well as for psychotherapy compared with pharmacotherapy (RR=1.17, 95% CI: 1.02-1.32). In other words, pharmacotherapy alone was less acceptable to patients than another treatment approach that included psychotherapy.

Practice Implications

This network meta-analysis by a renowned researcher and in a prestigious journal adds to the controversy around the relative efficacy of psychotherapy vs medications vs their combination. What is clear is that patients find medication alone to be less acceptable as a treatment option, and previous research shows that patients are 4 times more likely to prefer psychotherapy over medications. Unfortunately, most people with depression receive medications without psychotherapy.

Merz, J., Schwarzer, G., & Gerger, H. (2019). Comparative efficacy and acceptability of pharmacological, psychotherapeutic, and combination treatments in adults with posttraumatic stress disorder: A network meta-analysis. JAMA Psychiatry, 76, 904-91.

Posttraumatic stress disorder (PTSD) is a highly debilitating disorder characterized by re-experiencing trauma, avoidance of situations related to the trauma, negative mood and cognitions, and hyperarousal. The lifetime prevalence of PTSD in the population is about 8%, and PTSD is associated with a great deal of medical problems, and social and economic burden. Difference between a variety of psychological treatment approaches for PTSD are small and not statistically significant. Some treatment guidelines tend to recommend both psychotherapy and pharmacotherapy to treat PTSD, but other guidelines indicate only psychotherapy as the first-line treatment. Merz and colleagues conducted a meta-analysis to examine comparative outcomes and acceptability of psychotherapy and pharmacotherapy and their combination in adults with PTSD. The authors focused on randomized controlled trials because these designs tend to produce the most reliable evidence. The authors identified 12 published studies with a total of 922 participants. Six of the studies included data on long term outcomes. The meta-analytic procedures that the authors used in this study included network meta-analyses (which some have argued may produce unreliable results) and direct comparison meta-analysis (which is more reliable, but resulted in fewer studies being included here). I report in this blog only results that were consistent between the network and direct comparison analyses. Pharmacological and psychotherapeutic treatments and their combinations were not significantly different in their effectiveness immediately post-treatment. However, at long-term follow-up psychotherapy was significantly more beneficial than pharmacotherapy (SMD, −0.63; 95% CI, −1.18 to −0.09). Combined psychotherapy plus pharmacotherapy was not significantly more effective that pharmacotherapy alone (SMD, −1.02; 95% CI, −2.77 to 0.72), and combined treatment was not more effective that psychotherapy alone (SMD, 0.06; 95% CI, −0.31 to 0.42). There were also no statistically significant differences between psychotherapy, pharmacotherapy, or their combination in the acceptability of treatments to participants as defined by differing rates of dropping out from the studies.

Practice Implications

This meta-analysis of a small number of studies suggests that psychotherapy produces better long-term outcomes than pharmacotherapy for PTSD. There is also a suggestion that combining psychotherapy and pharmacotherapy does not improve outcomes compared to either treatment alone. This research area seems to be new and not well developed, but so far, the results seem to favor psychotherapy for longer term outcomes. These findings are similar to those from a larger meta-analysis for depression. In that study, the authors suggested that the long-term benefit of psychotherapy was due to participants learning coping and interpersonal skills that were not gained from receiving pharmacological intervention alone.

Carl, E., Witcraft, S.M., Kauffman, B.Y., Gillespie, E.M., Becker, E.S…. Powers, M.B. (2019). Psychological and pharmacological treatments for generalized anxiety disorder (GAD): a meta-analysis of randomized controlled trials. Cognitive Behaviour Therapy, DOI:10.1080/16506073.2018.1560358

Generalized anxiety disorder (GAD) is characterized by excessive and difficult to control worry about events or activities. GAD is associated with a high level of impairment in social functioning, work productivity, and health-related quality of life. GAD is also associated with a high level of medical costs and health care utilization. About 4.3% of the general population have experienced GAD at one time in their life. In this updated meta-analysis, Carl and colleagues reviewed the empirical literature to compare the effects of psychotherapies and pharmacotherapy to control conditions. Seventy-nine studies with over 11,000 participants were included in the review. In 39 comparisons, evidence-based psychotherapies outperformed control conditions on measures of anxiety at posttreatment (g = 0.76, 95% CI: 0.61–0.91, p < 0.001), suggesting a medium to large effect. Only 12 studies evaluated follow-up data, and they found that psychotherapy resulted in a small but statistically significant average effect on anxiety symptoms (g = 0.27, 95% CI: 0.00–0.53, p = 0.05). Compared to older patients, younger patients tended to do better in psychotherapy. Forty-three studies found that pharmacotherapy consistently outperformed control conditions at post-treatment (g = 0.38, 95% CI: 0.30–0.47, p < 0.001) suggesting a small effect. There were no studies that assessed pharmacotherapy at a follow-up date. Patient age or treatment dose did not affect outcomes of pharmacotherapy. The authors were careful to point out that that the effect sizes of psychotherapy and pharmacotherapy were not comparable in this meta-analysis because psychotherapy trials tended to use no-treatment controls whereas pharmacotherapy trials tended to use placebo controls, and the latter tends to produce more conservative (smaller) estimates of effects.

Practice Implications

Both psychotherapy and pharmacotherapy appear to be effective by post-treatment for patients with GAD. The effects of psychotherapy at follow-up is diminished, and no studies evaluated whether patients receiving pharmacotherapy maintained any gains at follow-up. Research has suggested that compared to psychotherapy, pharmacotherapy outcomes for depression at follow up is poorer. Although this study does not allow one to compare psychotherapy to pharmacotherapy, evidence from another meta-analysis suggests that patients would strongly prefer psychotherapy if given the choice. And patients receiving their preferred treatment tend to experience significantly better outcomes.

Author email: emilycarl@utexas.edu

Razza, L. B., Moffa, A. H., Moreno, M. L., Carvalho, A. F., Padberg, F., Fregni, F., & Brunoni, A. R. (2018). A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 81, 105-113.

Transcranial magnetic stimulation (TMS) is a new treatment for depression thought to modulate brain activity through electromagnetic pulses delivered by a coil placed over the patient’s scalp. A meta analysis shows that TMS may be effective in treating depressive disorders when compared to a placebo control, although only 18.6% of those receiving TMS were no longer depressed at the end of treatment. The placebo control condition usually involves a sham version of TMS in which the coil is placed over the scalp but no magnetic stimulation is applied. In antidepressant trials, the placebo response is quite high such that approximately 40% of patients respond to the placebo condition (in antidepressant trials, the placebo condition includes an identical pill that is inert). In this meta analysis, Razza and colleagues assess the placebo response in TMS. They included only double blind randomized controlled trials (i.e., trials in which both the patient and physician were not aware if the treatment was real or a sham). The authors estimated the placebo response based on pre- to post-sham TMS scores of common measures of depression. The meta analysis included 61 studies of over 1300 patients. The main result showed that sham response was large (g = 0.80; 95%CI = 0.65–0.95). Trials including patients with only one episode of depression or who were not treatment resistant (g =0.67, 95%CI = 0.06–1.28, p= 0.03) had higher placebo responses than those trials in which patients previously had two or more failed antidepressant treatments (g = 0.5, 95%CI = 0.03–0.99, p = 0.048).

Practice Implications

The results of this meta analysis demonstrates a high placebo response in trials testing TMS. This is similar to the high level of placebo response commonly seen in patients in antidepressant medication trials. It appears that psychological factors like attention, instillation of hope, patient expectations of receiving benefit, and perhaps working alliance may account for an important portion of why pharmacological and other medical interventions appear to work for those with depressive disorders. This is particularly true for patients who are receiving treatment for the first time or for whom previous medical treatment was successful.