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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.

Totura, C.M.W., Fields, S.A., & Kraver, M.S. (2018). The role of the therapeutic relationship in psychopharmacological treatment outcomes: A meta-analytic review. Psychiatric Services, 69, 41-47.

There is evidence to suggest that pharmacological treatments are effective for a wide range of disorders. However, a high level of adherence to taking psychotropic medications is necessary in order for them to have a chance of working. Medical interventions in general do not work well when patients are non-adherent to the regimen, and non-adherence is a significant problem in medicine. Treatment adherence is particularly problematic in those with a mental health condition. Low adherence may have to do with problems with the medications themselves, like unpleasant side effects. And low adherence also may be due to issues related to mental health impairment, like low motivation and problems with reasoning. A particular issue in mental health treatment is the manner in which patients receive the medication. Unlike some medical interventions, psychotropic medications are often taken by patients on their own and away from the clinic or hospital. In psychotherapy, we know that a good therapeutic alliance improves outcomes partly because a good alliance provides a context within which psychological interventions can work (i.e., clients may be more adherent to the treatment recommendations) and partly because the alliance itself may be therapeutic. In this meta analysis, Totura and colleagues examine if there is an association between the therapeutic alliance and mental health outcomes for patients who receive pharmacological interventions for their mental illness symptoms. Eight studies of 59 samples representing over 1,000 patients were included. Four studies were of pharmacological treatment for affective disorders, two for schizophrenia, and two for mixed diagnoses. The results indicated a statistically significant and moderate effect: z = .30 (CI=.20, .39, SE=.048, z=6.192, p=.05), such that greater therapeutic alliance predicted better mental health outcomes among patients receiving pharmacotherapy.

Practice Implications

Higher quality of the physician-patient relationship was related to better mental health treatment outcomes for patients taking pharmacotherapy. The therapeutic alliance appears to be just as import in pharmacological treatment as it is in psychotherapy. It is possible that a good alliance with the provider may increase patient adherence, which may lead to better outcomes. It is also possible, however, that the alliance itself is therapeutic. That is, negotiating an alliance and repairing alliance tensions may lead to positive changes in patients’ ability to cope with emotions and to make the most of their social supports. The results also suggest the importance of training physicians in communication skills to improve therapeutic relationships.

Swift, J.K., Greenberg, R.P., Tompkins, K.A., & Parkin, S.R. (2017). Treatment refusal and premature termination in psychotherapy, pharmacotherapy, and their combination: A meta-analysis of head-to-head comparisons. Psychotherapy, 54, 47-57.

Treatment refusal occurs when a patient is offered an intervention but then fails to begin it. In treatment studies, this may occur when a patient initially agrees to participate in a trial but then discontinues immediately after finding out what intervention they will receive. In a clinic setting, a patient might call a mental health professional to schedule an initial appointment but not show up. This causes problems for the patient who is not receiving treatment, and for the professional who has an unfilled therapy hour. Premature termination, on the other hand occurs when a patient begins treatment but ends unilaterally against the provider’s recommendations and prior to recovery. Again, these patients typically do not improve and they do not receive an adequate dose of the treatment. Barriers to accepting or completing psychotherapy might include the cost, and the time and effort involved to engage in the therapeutic process. Barriers to accepting or completing pharmacotherapy might also include cost, unpleasant side effects, and fewer contacts with a non-judgemental listening professional. The aim of Swift and colleagues’ meta-analysis was to compare rates of treatment refusal and premature termination between psychotherapy and pharmacotherapy. The meta-analysis included 186 studies, 57 of which (with 6,693 participants) reported data on treatment refusal. A significant number of patients (8.2%; 95% CI: 7.0, 9.6%) failed to start treatment after they were told what treatment they would receive. Participants were 1.76 times more likely (95% CI: 1.27, 2.45) to refuse treatment if they were offered pharmacotherapy compared to psychotherapy. The average premature termination rate from treatment was 21.9% (95% CI: 20.6%, 23.3%). Patients assigned to pharmacotherapy were 1.2 times more likely (95% CI: 1.03, 1.41) than those who were assigned to psychotherapy to discontinue treatment prematurely.

Practice Implications

Participants were almost 2 times more likely to refuse treatment if they were offered pharmacotherapy compared to psychotherapy, especially for social anxiety disorder, depression, and panic disorder. Similarly, premature termination was higher for pharmacotherapy compared to psychotherapy, especially for eating disorders and depressive disorders. Previous research indicated that patients are 3 times more likely to prefer psychotherapy over medications for mental disorders. Research indicates that mental health professionals should work to incorporate patient preferences, values, and beliefs when making treatment decisions in order to reduce premature termination and treatment refusal.

Gueorguieva, R., Chekroud, A.M., & Krystal, J.H. (2017). Trajectories of relapse in randomised, placebo-controlled trials of treatment discontinuation in major depressive disorder: An individual patient-level data meta-analysis. Lancet Psychiatry.

Individuals with a history of depression who get better have a 30% to 50% chance of relapse in the first year. That is, major depression tends to take a recurrent course, so that about a third to half of patients who initially improve will then experience a re-emergence of symptoms. In this meta-analysis, Gueorguieva and colleagues looked at whether they could identify classes of patients who respond differently to antidepressant medications depending on whether they discontinued or continued with the medications after symptoms improved. The meta-analysis included over 1,400 patients from four studies of duloxetine or fluoxetine (i.e., Cymbalta or Prozac) who participated in a discontinuation trial. A discontinuation trial design involves randomly assigning patients who respond positively to the medication either (1) to stay on the effective medication or (2) to discontinue the treatment and receive a placebo. Such a design gives us an estimate of the advantage of maintenance versus discontinuation of medications to reduce relapse of depression in the longer term. Gueorguieva and colleagues found that 33% of those in the medication continuation condition relapsed (i.e., 33% those who responded well to the initial trial of medications and who then continued with medications had a recurrence of depressive symptoms). By contrast, 46% of those in the placebo/medication discontinuation condition relapsed (i.e., 46% of those who responded well to the initial trial of medications and who then received a placebo had a recurrence of depressive symptoms). In other words, continuation of antidepressant medications resulted in a small 13% reduction in relapse rates compared to continuation with a placebo.

Practice Implications

This meta analysis indicates that continuing with antidepressant medications after depressive symptoms remit provides only a modest level of protection against a relapse of depression. Thus continuation with antidepressants after symptoms improve may not be worth it for patients who struggle with medication side effects and complications, or who cannot afford continuation of the medications. There is growing evidence that psychotherapy is effective for preventing relapse, likely because psychotherapy teaches patients ways of coping and interacting with others that allows them to manage life stresses more effectively after the treatment is over.

Kuyken, W., Warren, F.C., Taylor, R.S., Whalley, B., Crane, C….Dalgliesh, T. (2016). Efficacy of mindfulness-based cognitive therapy in prevention of depressive relapse An individual patient data meta-analysis from randomized trials. JAMA Psychiatry, 73, 565-574.

Depression results in a high level of disability and its social and economic costs appear to be rising. Although many effective treatments for depression do exist, relapse of depressive symptoms is a significant problem for many who successfully complete treatment. One of the interventions used to prevent relapse is mindfulness-based cognitive therapy (MBCT). MBCT teaches psychological skills that target cognitive factors that may cause relapse among those who have a history of depression by combining mindfulness training with cognitive interventions. Previous reviews have indicated the efficacy of MBCT for relapse prevention. In this meta-analysis, Kuyken and colleagues update the previous reviews and look at specific sub groups of patients who may respond differently to MBCT. From a comprehensive search of the literature, they identified 9 published randomized controlled trials comparing MBCT to another condition such as usual care, antidepressant medications, or another active treatment. These 9 studies included 1258 patients. MBCT resulted in a reduced risk of relapse in depressive symptoms compared to those who did not received MBCT within a 60 week follow up period (hazard ratio (HR), 0.79; 95%CI, 0.64-0.97). Four studies specifically compared MBCT to antidepressant medication and showed that those who received MBCT had a reduced risk of relapse compared to antidepressants (HR, 0.77; 95%CI, 0.60 – 0.98; I², 0%). The authors also found that the preventive effect of MBCT on depression relapse declined over time. No demographic variables were associated with the effects of MBCT, but higher levels of depression at baseline were associated with a larger effect of MBCT.

Practice Implications

The findings of this meta analysis show that MBCT helps to prevent depression relapse in those who have recovered from depressive symptoms. Its effects appear to be superior to usual care and to antidepressant medications. Unlike anti depressants, those who were treated with MBCT learned skills that helped them to cope with stressors that may precipitate another depressive episode. The effects of MBCT appear to be particularly useful for those with greater depressive symptoms at the outset, but those with lower depressive symptoms may not benefit as much from MBCT.