Markus Dold

Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses

BACKGROUND The efficacy of psychopharmacological treatments has been called into question. Psychiatrists are unfamiliar with the effectiveness of common medical drugs. AIMS To put the efficacy of psychiatric drugs into the perspective of that of major medical drugs. METHOD We searched Medline and the Cochrane Library for systematic reviews on the efficacy of drugs compared with placebo for common medical and psychiatric disorders, and systematically presented the effect sizes for primary efficacy outcomes. RESULTS We included 94 meta-analyses (48 drugs in 20 medical diseases, 16 drugs in 8 psychiatric disorders). There were some general medical drugs with clearly higher effect sizes than the psychotropic agents, but the psychiatric drugs were not generally less efficacious than other drugs. CONCLUSIONS Any comparison of different outcomes in different diseases can only serve the purpose of a qualitative perspective. The increment of improvement by drug over placebo must be viewed in the context of the diseases seriousness, suffering induced, natural course, duration, outcomes, adverse events and societal values.

Efficacy of Pharmacotherapy and Psychotherapy for Adult Psychiatric Disorders: A Systematic Overview of Meta-analyses

IMPORTANCE There is debate about the effectiveness of psychiatric treatments and whether pharmacotherapy or psychotherapy should be primarily used. OBJECTIVES To perform a systematic overview on the efficacy of pharmacotherapies and psychotherapies for major psychiatric disorders and to compare the quality of pharmacotherapy and psychotherapy trials. EVIDENCE REVIEW We searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Library (April 2012, with no time or language limit) for systematic reviews on pharmacotherapy or psychotherapy vs placebo, pharmacotherapy vs psychotherapy, and their combination vs either modality alone. Two reviewers independently selected the meta-analyses and extracted efficacy effect sizes. We assessed the quality of the individual trials included in the pharmacotherapy and psychotherapy meta-analyses with the Cochrane risk of bias tool. FINDINGS The search yielded 45,233 results. We included 61 meta-analyses on 21 psychiatric disorders, which contained 852 individual trials and 137,126 participants. The mean effect size of the meta-analyses was medium (mean, 0.50; 95% CI, 0.41-0.59). Effect sizes of psychotherapies vs placebo tended to be higher than those of medication, but direct comparisons, albeit usually based on few trials, did not reveal consistent differences. Individual pharmacotherapy trials were more likely to have large sample sizes, blinding, control groups, and intention-to-treat analyses. In contrast, psychotherapy trials had lower dropout rates and provided follow-up data. In psychotherapy studies, wait-list designs showed larger effects than did comparisons with placebo. CONCLUSIONS AND RELEVANCE Many pharmacotherapies and psychotherapies are effective, but there is a lot of room for improvement. Because of the multiple differences in the methods used in pharmacotherapy and psychotherapy trials, indirect comparisons of their effect sizes compared with placebo or no treatment are problematic. Well-designed direct comparisons, which are scarce, need public funding. Because patients often benefit from both forms of therapy, research should also focus on how both modalities can be best combined to maximize synergy rather than debate the use of one treatment over the other.

Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis

IMPORTANCE In treatment-resistant schizophrenia, clozapine is considered the standard treatment. However, clozapine use has restrictions owing to its many adverse effects. Moreover, an increasing number of randomized clinical trials (RCTs) of other antipsychotics have been published. OBJECTIVE To integrate all the randomized evidence from the available antipsychotics used for treatment-resistant schizophrenia by performing a network meta-analysis. DATA SOURCES MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov were searched up to June 30, 2014. STUDY SELECTION At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form of administration) with another antipsychotic or placebo. DATA EXTRACTION AND SYNTHESIS At least 2 independent reviewers extracted all data into standard forms and assessed the quality of all included trials with the Cochrane Collaborations risk-of-bias tool. Data were pooled using a random-effects model in a Bayesian setting. MAIN OUTCOMES AND MEASURES The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. Secondary outcomes included change in positive and negative symptoms of schizophrenia, categorical response to treatment, dropouts for any reason and for inefficacy of treatment, and important adverse events. RESULTS Forty blinded RCTs with 5172 unique participants (71.5% men; mean [SD] age, 38.8 [3.7] years) were included in the analysis. Few significant differences were found in all outcomes. In the primary outcome (reported as standardized mean difference; 95% credible interval), olanzapine was more effective than quetiapine (-0.29; -0.56 to -0.02), haloperidol (-0. 29; -0.44 to -0.13), and sertindole (-0.46; -0.80 to -0.06); clozapine was more effective than haloperidol (-0.22; -0.38 to -0.07) and sertindole (-0.40; -0.74 to -0.04); and risperidone was more effective than sertindole (-0.32; -0.63 to -0.01). A pattern of superiority for olanzapine, clozapine, and risperidone was seen in other efficacy outcomes, but results were not consistent and effect sizes were usually small. In addition, relatively few RCTs were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. The most surprising finding was that clozapine was not significantly better than most other drugs. CONCLUSIONS AND RELEVANCE Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia, and blinded RCTs-in contrast to unblinded, randomized effectiveness studies-provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics. Future clozapine studies with high doses and patients with extremely treatment-refractory schizophrenia might be most promising to change the current evidence.

Pharmacotherapy of treatment-resistant schizophrenia: a clinical perspective

A significant number of patients with schizophrenia do not respond adequately to an initial antipsychotic trial. As first step within a treatment algorithm for therapy-refractory schizophrenia ‘pseudoresistance’ should be ruled out (eg, re-evaluation of the diagnosis, comorbidities, compliance and adherence in terms of medication intake, adequate dose and treatment duration, and achievement of sufficient plasma levels). In case of treatment resistance, two strategies that are often used in clinical routine care contain dose increase of the current administered antipsychotic drug (dose escalation, high-dose treatment) and switch to another, new antipsychotic. Although the response rates for both options are generally rather low, we see from the evidence-based perspective a slight advantage of the switching strategy (preferably to an antipsychotic with a different receptor-binding profile) compared to a high-dose treatment. After treatment failures with at least two different antipsychotic drugs, a monotherapy with clozapine is considered to be the treatment option of first choice. At present, pharmacological combination and augmentation strategies cannot be regarded as a generally recommendable evidence-based treatment method. Antipsychotic monotherapy should be preferably sought. In case of combination treatment, it appears more appropriate to combine preferentially two antipsychotics with different receptor-binding profiles. Augmentation of antipsychotics with other agents should be used primarily to treat specific target symptoms.

Discontinuous Patterns of Brain Activation in the Psychotherapy Process of Obsessive-Compulsive Disorder: Converging Results from Repeated fMRI and Daily Self-Reports

This study investigates neuronal activation patterns during the psychotherapeutic process, assuming that change dynamics undergo critical instabilities and discontinuous transitions. An internet-based system was used to collect daily self-assessments during inpatient therapies. A dynamic complexity measure was applied to the resulting time series. Critical phases of the change process were indicated by the maxima of the varying complexity. Repeated functional magnetic resonance imaging (fMRI) measurements were conducted over the course of the therapy. The study was realized with 9 patients suffering from obsessive-compulsive disorder (subtype: washing/contamination fear) and 9 matched healthy controls. For symptom-provocative stimulation individualized pictures from patients’ personal environments were used. The neuronal responses to these disease-specific pictures were compared to the responses during standardized disgust-provoking and neutral pictures. Considerably larger neuronal changes in therapy-relevant brain areas (cingulate cortex/supplementary motor cortex, bilateral dorsolateral prefrontal cortex, bilateral insula, bilateral parietal cortex, cuneus) were observed during critical phases (order transitions), as compared to non-critical phases, and also compared to healthy controls. The data indicate that non-stationary changes play a crucial role in the psychotherapeutic process supporting self-organization and complexity models of therapeutic change.

Benzodiazepine augmentation of antipsychotic drugs in schizophrenia: A meta-analysis and cochrane review of randomized controlled trials

Applying various psychopharmacological combination and augmentation strategies in schizophrenia is common clinical practice. This meta-analysis evaluated the efficacy of benzodiazepines added to antipsychotics. The Cochrane Schizophrenia Group trial register (until February 2011) and PubMed/Medline (until July 2012) were searched for randomized controlled trials (RCTs) with a minimum duration of one week that compared benzodiazepine augmentation of antipsychotics with a control group receiving antipsychotic monotherapy in schizophrenia and schizophrenia-like psychoses. Study selection and data extraction were conducted independently by at least two authors. The primary outcome was response to treatment. Secondary outcomes were positive and negative schizophrenic symptoms, anxiety symptoms, and dropouts due to any reason, inefficacy of treatment, and adverse events. Pooled risk ratios (RRs) with the 95% confidence intervals (CIs) were calculated using a random-effects model, with number-needed-to-treat/harm (NNT/H) calculations where appropriate. Overall, 16 relevant RCTs with 1045 participants were identified. Benzodiazepine augmentation was not associated with statistically significantly more responders (N=6; n=511; RR 0.97, 95% CI 0.77-1.22). Adjunctive benzodiazepines were well accepted and tolerated according to dropout-rates and adverse effects apart from dizziness (N=3; n=190; RR 2.58, 95% CI 1.08-6.15) and somnolence (N=2; n=118; RR 3.30, 95% CI 1.04-10.40). There is no evidence for antipsychotic efficacy of additional benzodiazepine medication in schizophrenia. Therefore, benzodiazepines should be considered primarily for desired ultra short-term sedation of acutely agitated patients but not for augmentation of antipsychotics in the medium- and long-term pharmacotherapy of schizophrenia and related disorders.

Evidence-based pharmacotherapy of treatment-resistant unipolar depression

Abstract Treatment resistance to the antidepressive pharmacotherapy represents one of the most important clinical challenges in the pharmacological management of unipolar depression. In this review, we aimed to summarise the evidence for various pharmacological treatment options in therapy-resistant unipolar depression derived from clinical trials, systematic reviews, meta-analyses and treatment guidelines. The first measure in case of insufficient response to the initial antidepressant monotherapy contains the debarment of ‘pseudo-resistance’, potentially caused by inadequate dose and treatment duration of the antidepressant, insufficient plasma levels, non-compliance of the patient regarding medication intake or relevant psychiatric and/or somatic comorbidities. Applying a dose escalation of the current antidepressant cannot be generally recommended as evidence-based treatment option and the efficacy depends on the class of antidepressants. There is no compelling evidence for a switch to another, new antidepressant compound after insufficient response to a previous antidepressant. The combination of two antidepressants should be preferentially established with antidepressants characterised by different mechanisms of action (e.g. reuptake inhibitors together with presynaptic autoreceptor inhibitors). At present, the most convincing body of evidence exists for the augmentation of antidepressants with second-generation antipsychotic drugs and lithium. Hence, both strategies are consistently advised by treatment guidelines as pharmacological first-line strategy in treatment-resistant depression.

Pharmacological treatment strategies in unipolar depression in European tertiary psychiatric treatment centers – A pharmacoepidemiological cross-sectional multicenter study

This multicenter, cross-sectional study with retrospective assessment of treatment response evaluated the current prescription trends and pharmacological treatment strategies applied in European university/academic psychiatric centers in unipolar depression. Altogether, 1181 adult in- and outpatients with major depressive disorder (MDD) were enrolled in 9 academic sites in 8 European countries. Socio-demographic, clinical, and medication information were retrieved and the present symptom severity was assessed by the Montgomery and Åsberg Depression Rating Scale (MADRS). The symptom improvement during the current MDD episode was covered by retrospective MADRS measurements. Beyond descriptive statistics, analyses of variance (ANOVA) and Spearman correlation analyses were accomplished to determine the influence of symptom severity and treatment response on the prescription patterns. 53.4% of all MDD patients received a selective serotonin reuptake inhibitor (SSRI) and 23.6% a serotonin-norepinephrine reuptake inhibitor (SNRI) as first-line treatment. The majority of participants (59.4%) were treated with polypharmaceutical strategies (median: 2 psychiatric compounds per patient) and for the number of individual drugs we found a significant correlation with the current MADRS total score and the MADRS total score change during the present depressive episode. Benzodiazepines (33.2% of patients), antidepressants (29.0%), antipsychotics (24.2%), and mood stabilizers (10.1%) were the most frequently prescribed adjunctive agents. There were no significant differences between the different psychopharmacological classes used as augmentors in terms of symptom severity and treatment response. In summary, this international cross-sectional study revealed the widespread use of polypharmaceutical treatment strategies in European tertiary psychiatric treatment centers for the management of MDD.

Factors contributing to the increasing placebo response in antidepressant trials.

In their interesting paper, Khan and Brown (1) sought to summarize the factors contributing to the trend of continuously decreasing drug-placebo differences in antidepressant randomized controlled trials (RCTs) (2). This trend conveys the impression that the newer marketed antidepressants are less efficacious than the older ones, or even that the older and well-established antidepressants have lost efficacy over time. Thus, recognizing the methodological reasons for the decline in antidepressant-placebo separation within RCTs is highly relevant in order to appraise the clinical value of an antidepressant for psychiatric routine care. This is especially meaningful with regard to newly developed and newly introduced antidepressants. In our opinion, the constant increase in placebo response over the last decades is the main factor accounting for the mitigation of the drug-placebo differences in antidepressant RCTs. Due to the larger symptom improvement of study participants randomized to placebo, it is much more difficult for an antidepressant to outperform placebo at a statistically significant level. This could be the beginning of an ominous cascade. The diminishing drug-placebo contrast leads to a higher probability of so-called inconclusive or even negative trials. As a consequence, the risk for a newly developed compound to fail the market approval because of negative phase III studies increases. As such late failure is associated with enormous costs for the pharmaceutical industry, this could result in a slowdown of research efforts for new antidepressant agents. An often cited reason for the continuously increasing placebo response is the fact that placebo administration represents in itself a non-specific treatment (3). Study participants in the placebo groups of RCTs receive enormous clinical attention. Indeed, parallel to the raising placebo response in RCTs, the requirements concerning the accomplishment of RCTs have become more stringent, for instance through the need of an increasingly closer monitoring of participants (4). The intensive contact with the clinical staff can produce positive effects in terms of symptom improvement, particularly in not severely ill participants, who are nowadays increasingly included in RCTs, because the enrollment of more severely ill patients is often not possible due to ethical concerns (a phenomenon called “baseline inflation”). Another element contributing to the magnitude of placebo response in RCTs is the hope of participants in the placebo groups to receive an active, efficacious treatment (a phenomenon called “hope induction” or “expectation bias”). A number of systematic evaluations corroborate this assumption: the more study arms an RCT comprised (i.e., the lower the probability to receive placebo), the higher was the placebo response. On the other hand, the highest antidepressant response was found in direct drug comparisons (head-to-head trials), where participants were certain to receive active drug treatment (5). Furthermore, in many antidepressant RCTs, the enrolled subjects are not representative of clinical practice, in which a number of depressive patients suffer from severe comorbidities or suicidal ideation. Exactly those severely ill patients who are excluded from RCTs might particularly benefit from antidepressant pharmacotherapy. However, it must be noted that, in some analyses, a higher symptom severity at baseline was associated with a higher placebo response (6), a phenomenon which is not fully understood as yet. There is a large body of evidence suggesting that clinical studies carried out in the U.S. are characterized by a larger placebo response compared to non-U.S. trials. This phenomenon could be observed, to provide a recent example, in RCTs of vortioxetine (7). The inclusion of so-called professional research participants in U.S. studies may account for this finding. These subjects are mainly recruited by advertisements, and their motivation is often the prospect for free medication or other financial compensation. Therefore, they often aim to please the investigators in order to be invited again for participation in a clinical study. It appears meaningful to emphasize that the drug-placebo contrast in long-term, relapse-prevention studies is usually higher compared to acute-phase trials (8). Interestingly, in a double-blind, long-term citalopram RCT, responders to acute-phase treatment were randomized to either placebo or continuing citalopram, while placebo responders of the acute phase continued the placebo administration under double-blind conditions. Both placebo responders and citalopram responders receiving placebo in the long-term study exhibited a higher relapse rate compared to the participants in the citalopram continuation arm (9), suggesting that the underlying biological abnormality is not sensitive to placebo. In summary, the reasons contributing to the raising placebo response over time and the subsequent decreasing drug-placebo separation should be critically considered in the interpretation of antidepressant clinical trial results. Expectation bias and increased clinical attention are often called “unspecific effects” of placebo administration, and these effects are not present in routine clinical care (10). Therefore, it can be assumed that the effectiveness of an antidepressant in the routine care is higher than the antidepressant-placebo difference of RCTs indicates. The increase over time of placebo response should also be considered in meta-analyses (11), in which data are pooled from trials carried out in different periods.

Clinical characteristics and treatment outcomes of patients with major depressive disorder and comorbid anxiety disorders - results from a European multicenter study

This naturalistic European multicenter study aimed to elucidate the association between major depressive disorder (MDD) and comorbid anxiety disorders. Demographic and clinical information of 1346 MDD patients were compared between those with and without concurrent anxiety disorders. The association between explanatory variables and the presence of comorbid anxiety disorders was examined using binary logistic regression analyses. 286 (21.2%) of the participants exhibited comorbid anxiety disorders, 10.8% generalized anxiety disorder (GAD), 8.3% panic disorder, 8.1% agoraphobia, and 3.3% social phobia. MDD patients with comorbid anxiety disorders were characterized by younger age (social phobia), outpatient status (agoraphobia), suicide risk (any anxiety disorder, panic disorder, agoraphobia, social phobia), higher depressive symptom severity (GAD), polypsychopharmacy (panic disorder, agoraphobia), and a higher proportion receiving augmentation treatment with benzodiazepines (any anxiety disorder, GAD, panic disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder). The results in terms of treatment response were conflicting (better response for panic disorder and poorer for GAD). The logistic regression analyses revealed younger age (any anxiety disorder, social phobia), outpatient status (agoraphobia), suicide risk (agoraphobia), severe depressive symptoms (any anxiety disorder, GAD, social phobia), poorer treatment response (GAD), and increased administration of benzodiazepines (any anxiety disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder) to be associated with comorbid anxiety disorders. Our findings suggest that the various anxiety disorders subtypes display divergent clinical characteristics and are associated with different variables. Especially comorbid GAD appears to be characterized by high symptom severity and poor treatment response.