Adverse events of active and placebo groups in SARS-CoV-2 vaccine randomized trials: A systematic review.

BACKGROUND: For safety assessment in clinical trials, adverse events (AEs) are reported for the drug under evaluation and compared with AEs in the placebo group. Little is known about the nature of the AEs associated with clinical trials of SARS-CoV-2 vaccines and the extent to which these can be traced to nocebo effects, where negative treatment-related expectations favor their occurrence. METHODS: In our systematic review, we compared the rates of solicited AEs in the active and placebo groups of SARS-CoV-2 vaccines approved by the Western pharmaceutical regulatory agencies.We implemented a search strategy to identify trial-III studies of SARS-CoV-2 vaccines through the PubMed database. We adopted the PRISMA Statement to perform the study selection and the data collection and identified three trial: two mRNA-based (38403 participants) and one adenovirus type (6736 participants). FINDINGS: Relative risks showed that the occurrence of AEs reported in the vaccine groups was higher compared with the placebo groups. The most frequently AEs in both groups were fatigue, headache, local pain, as injection site reactions, and myalgia. In particular, for first doses in placebo recipients, fatigue was reported in 29% and 27% in BNT162b2 and mRNA-1273 groups, respectively, and in 21% of Ad26.COV2.S participants. Headache was reported in 27% in both mRNA groups and in 24% of Ad26.COV2.S recipients. Myalgia was reported in 10% and 14% in mRNA groups (BNT162b2 and mRNA-1273, respectively) and in 13% of Ad26.COV2.S participants. Local pain was reported in 12% and 17% in mRNA groups (BNT162b2 and mRNA-1273, respectively), and in 17% of Ad26.COV2.S recipients. These AEs are more common in the younger population and in the first dose of placebo recipients of the mRNA vaccines. INTERPRETATION: Our results are in agreement with the expectancy theory of nocebo effects and suggest that the AEs associated with COVID-19 vaccines may be related to the nocebo effect. FUNDING: Fondazione CRT - Cassa di Risparmio di Torino, IT (grant number 66346, "GAIA-MENTE" 2019).

Consistently Modest Antidepressant Effects in Clinical Trials: the Role of Regulatory Requirements.

Despite being widely heralded following their discovery, the effectiveness and clinical utility of antidepressants has been questioned, in part due to the release of several decades of regulatory trial data. Upon investigation, contemporary regulatory trials of antidepressants have demonstrated a nearly identical effect size (0.3) for the past 40 years, regardless of placebo response or attempts to improve trial design. In this review, we examine the historical methods of antidepressant trials and re-evaluate regulatory trial data over time and according to drug class (SSRIs, SNRIs, and atypicals) with the addition of two classes of antidepressants not previously analyzed: tricyclics used as active comparators and the recently-approved NMDA receptor antagonist, esketamine. We show that among these five classes of antidepressants there were no significant differences between effect sizes or percent symptom reduction. We suggest that within the context of a regulatory trial of antidepressants, effect sizes will remain modest (~0.3) regardless of class or novel drug mechanism, possibly due to regulatory changes to trial design and conduct following the Kefauver-Harris Act of 1962. We comment that the regulatory double-blind, parallel, placebo-controlled trial model is an artificial creation for a narrow purpose-designed to demonstrate simple superiority over placebo and to determine basic safety. We should be cautious of stretching trial results beyond their limited capacity to inform clinical practice as trials are not representative of real-world patients or medication management practices. There is a substantial need to develop more realistic models to evaluate the clinical utility of antidepressants.

How a Psychopharmacology Clinical Trial Site in the Seattle Area Managed Clinical Trials and Patient Care During the COVID-19 Pandemic.

OBJECTIVES: As the COVID-19 pandemic developed in March 2020 in greater Seattle, our clinical trial site faced several ethical and clinical dilemmas. We remained open to research patients including high-risk elderly patients and adapted to changing health recommendations. METHODS: Beginning March 14, 2020 we developed an in-person evaluation for potential risk of COVID-19. Included are the first 3 weeks of screening by our physicians for potential exposure to COVID-19, common symptoms, temperature, blood oxygen saturation, and heart rate. Individuals with higher risk (n = 23) were identified and managed. RESULTS: The 825 evaluations included 37 staff, 167 patients, and 152 visitors. No one needed isolation or transfer to acute care facility, staff attendance was 95%, all 33 geriatric patients continued in phase II trials, and others decreased by 5%. CONCLUSION: We share how we incorporated COVID-19 Center for Disease Control health recommendations to a clinical trial center and addition of pulse oximetry.

Mortality during US FDA clinical trials in patients with diabetes, hypertension, depression and schizophrenia.

Objectives: To evaluate the relationship between the mortality rates associated with psychiatric conditions like depression and schizophrenia compared with chronic medical conditions like hypertension and diabetes.Methods: Examined clinical trial safety data from New Drug Approval programmes reviewed by the US Food and Drug Administration and calculated all-cause and suicide/non-suicide mortality rates per 100,000 patient-exposure-years (PEY) for seven diabetes, 12 hypertension, 11 depression, and nine schizophrenia programmes (126,151 patients, 63,106.3 PEY).Results: Depression (894.8 ± 201.2) and schizophrenia (935.3 ± 214.6) had significantly higher all-cause mortality rates than diabetes (462.8 ± 70.8) and hypertension (448.4 ± 123.1). Psychiatric conditions had 1.9-2.1× the medical conditions' mortality (p < 0.001). Non-suicide mortality rates for depression (506.2 ± 151.3), schizophrenia (550.9 ± 164.7), diabetes (457.2 ± 70.4) and hypertension (430.8 ± 120.6) were comparable. Only antidiabetics showed a signal for all-cause mortality (reduction of 37%, p = 0.008).Conclusions: Depression and schizophrenia trial patients had comparable (if not higher) all-cause mortality rates as older populations in diabetes and hypertension trials, even when excluding suicides. While generalizability of the rates themselves is limited, this study can adequately estimate the relational mortality among these conditions because of the high internal consistency of clinical trials. Potential signals for mortality reduction with active treatment should be considered for all investigational medications for chronic conditions with increased mortality, including psychotropics.

The conundrum of depression clinical trials: one size does not fit all.

In this paper we review the history of antidepressant (AD) development, since the discovery of imipramine in 1957 to the present day. Through this exploration we will show that the increasing placebo response is likely a red herring and that a higher magnitude of placebo response is not an adequate explanation for AD trials' high failure rates. As a better explanation for their lack of success, we will examine some of the fundamental flaws of AD clinical trials and their origins in historical forces. We focus on underpowering, which occurs as a consequence of unrealistic expectations for AD performance. In addition, we describe the lack of precision in the depression outcome measurements for the past 40 years and show how these measures contrast with those used in clinical trials of other chronic diseases, which use simpler outcome measures. Finally, we describe the role of regulatory agencies in influencing clinical trial design and how the assumption that 'one size fits all' for the past 60 years has led to flawed design of AD clinical trials.

Does the rising placebo response impact antihypertensive clinical trial outcomes? An analysis of data from the Food and Drug Administration 1990-2016.

BACKGROUND: Recent studies show that placebo response has grown significantly over time in clinical trials for antidepressants, ADHD medications, antiepileptics, and antidiabetics. Contrary to expectations, trial outcome measures and success rates have not been impacted. This study aimed to see if this trend of increasing placebo response and stable efficacy outcome measures is unique to the conditions previously studied or if it occurs in trials for conditions with physiologically-measured symptoms, such as hypertension. METHOD: For this reason, we evaluated the efficacy data reported in the US Food and Drug Administration Medical and Statistical reviews for 23 antihypertensive programs (32,022 patients, 63 trials, 142 treatment arms). Placebo and medication response, effect sizes, and drug-placebo differences were calculated for each treatment arm and examined over time using meta-regression. We also explored the relationship of sample size, trial duration, baseline blood pressure, and number of treatment arms to placebo/drug response and efficacy outcome measures. RESULTS: Like trials of other conditions, placebo response has risen significantly over time (R2 = 0.093, p = 0.018) and effect size (R2 = 0.013, p = 0.187) drug-placebo difference (R2 = 0.013, p = 0.182) and success rate (134/142, 94.4%) have remained unaffected, likely due to a significant compensatory increase in antihypertensive response (R2 = 0.086, p<0.001). Treatment arms are likely overpowered with sample sizes increasing over time (R2 = 0.387, p<0.0001) and stable, large effect sizes (0.78 ±0.37). The exploratory analysis of sample size, trial duration, baseline blood pressure, and number of treatment arms yielded mixed results unlikely to explain the pattern of placebo response and efficacy outcomes over time. The magnitude of placebo response had no relationship to effect size (p = 0.877), antihypertensive-placebo differences (p = 0.752), or p-values (p = 0.963) but was correlated with antihypertensive response (R2 = 0.347, p<0.0001). CONCLUSIONS: As hypothesized, this study shows that placebo response is increasing in clinical trials for hypertension without any evidence of this increase impacting trial outcomes. Attempting to control placebo response in clinical trials for hypertension may not be necessary for successful efficacy outcomes. In exploratory analysis, we noted that despite finding significant relationships, none of the trial or patient characteristics we examined offered a clear explanation of the rise in placebo and stability in outcome measures over time. Collectively, these data suggest that the phenomenon of increasing placebo response and stable efficacy outcomes may be a general trend, occurring across trials for various psychiatric and medical conditions with physiological and non-physiological endpoints.

Decreased suicide rates in recent antidepressant clinical trials.

RATIONALE: The last systematic analysis of suicidality in antidepressant clinical trials submitted for approval by the US Food and Drug Administration was in 2000. Given the attention to suicide and antidepressants in the early 2000s, the authors aimed to evaluate if there have been any changes in suicide rates in antidepressant clinical trials following 2000. OBJECTIVE AND METHODS: The Integrated Safety Summary data from approval packets for 14 investigational antidepressant programs (1991-2013, 40,857 patients, 10,890.5 exposure years) were used to calculate suicides and suicide attempts per 100,000 patient exposure years (standardized rates) for antidepressant and placebo treatment groups separately. Suicides/suicide attempt rates, mean age, and percent female were compared between 1991 and 1998 (pre-2000) and 2002-2013 (post-2000). Drug-placebo differences in suicide/suicide attempt rates were explored. RESULTS: Among antidepressant-treated patients, the standardized suicide rate decreased significantly from pre- to post-2000 (643.6 to 25.8, p < 0.0001) as did the standardized suicide attempt rate (3975.7 to 645.4, p < 0.0001). For placebo-treated patients, the decrease was not significant for suicide rate (471.1 to 174.2, p = 0.66) but was significant for suicide attempt rate (from 3538.3 to 522.6, p < 0.001). Regression analysis showed a similar pattern with suicide/suicide attempt rates decreasing over time. None of the drug-placebo comparisons in suicide or suicide attempt rates were statistically significant. There was no change in percent female or mean age of patients in trials pre- and post-2000. CONCLUSIONS: Deaths by suicide and suicide attempts have decreased significantly in antidepressant clinical trials following 2000 compared to the decade before 2000. Basic demographic features of the patients have remained consistent and medication treatment effects on suicidality were not apparent. These findings may reflect enhanced screening procedures and effective exclusion of suicidal patients in clinical trials for depression.

Magnitude and Pattern of Placebo Response in Clinical Trials of Oral Antihyperglycemic Agents: Data From the U.S. Food and Drug Administration, 1999-2015.

OBJECTIVE: To evaluate the magnitude of placebo response and treatment response patterns in clinical trials of investigational oral antihyperglycemics over time. RESEARCH DESIGN AND METHODS: We examined the U.S. Food and Drug Administration medical and statistical reviews for 19 oral antihyperglycemic agents (23,438 patients, 50 trials, and 96 treatment arms) approved between 1999 and 2015. Placebo and medication treatment response (HbA1c reduction) and effect sizes were examined over time (year of approval). Exclusively placebo-controlled and augmented/adjunctive placebo-controlled trials were analyzed separately, and differences were compared. Potential effects of trial and patient characteristics were explored. RESULTS: In more recent trials, augmented placebo-controlled arms reduced HbA1c by 0.2% on average and more frequently lowered HbA1c from baseline compared with exclusively placebo-controlled arms (63 vs. 18%; χ2 = 9.93; P = 0.002). In exclusively placebo-controlled trials, placebo response increased significantly over time (ß = 0.035; R2 = 0.31; P = 0.0013), reaching ∼0% average change in HbA1c, whereas drug response also increased significantly (ß = 0.017; R2 = 0.076; P = 0.0498). In augmented placebo-controlled trials, placebo response (ß = 0.33; R2 = 0.407; P < 0.001) showed the same pattern, whereas the growth in drug response was not significant (R2 = 0.031; P = 0.207). Placebo response in both groups increased by 0.5% HbA1c reduction over time, whereas effect sizes remained stable with high success rates (100%; 96 out of 96). Drug response and effect size were not significantly predicted by patient or trial characteristics, but follow-up analysis suggested an inverse relationship of placebo baseline HbA1c with placebo response. CONCLUSIONS: Remarkably, placebo-treated patients with diabetes commonly experienced reduction in HbA1c, more markedly in augmented compared with exclusively placebo-controlled treatment arms. Placebo response increased significantly over time without impacting efficacy outcomes. Nonpharmacologic effects measured in the placebo response appear stronger when used with active medication than when implemented in isolation and may be related to the level of HbA1c at baseline.

Magnitude and pattern of placebo response in clinical trials of antiepileptic medications: Data from the Food and Drug Administration 1996-2016.

This study aimed to replicate and extend the findings of previous investigations looking at treatment responses in antiepileptic clinical trials over time and to examine the effects of subject age and duration of treatment. To address the potential biases of published literature, we examined the reported data from 14 investigational antiepileptic drugs (AEDs) (34 trials, 59 treatment arms, 10,783 patients) reviewed and approved by the US FDA (1996-2016). For each treatment arm, we recorded drug and placebo response (percent reduction in seizure frequency), calculated effect sizes, and examined these measures over time. Regression analysis showed that placebo response has increased significantly over time (R2=0.292, p=0.001) from 5% to 20% reduction in seizure frequency in 20years. Response to drug treatment appears to have increased in parallel but the trend was not statistically significant (p=0.143). Effect sizes have remained stable over time (p=0.084). Treatment duration was not related to treatment response or outcomes. Including younger patients in trials appeared to predict lower drug response (ß=1.44, p=0.012) and effect size (ß=0.014, p=0.047) but not placebo response (p=0.141). These FDA-reviewed and source-verified data support and extend prior findings from published literature that response to placebo treatment is noticeably increasing over time, nearly quadrupling in magnitude, while AED efficacy remains the same due to a parallel increase in drug response. The rise in placebo response appears to be an ongoing phenomenon rather than a mere historical artifact. Future design and interpretation of data from clinical trials of investigational antiepileptic drugs can be informed by these observations.

Does the increasing placebo response impact outcomes of adult and pediatric ADHD clinical trials? Data from the US Food and Drug Administration 2000-2009.

In a study of recent antidepressant clinical trial data, it was found placebo response had grown significantly over time and that contrary to expectations, trial outcome measures and success rate were not impacted. The aim of this paper was to evaluate if this trend of increasing placebo response and stable outcome measures could be seen in clinical trial data for Attention-Deficit Hyperactivity Disorder, a different psychiatric condition with susceptibility to placebo response. For this reason, we evaluated efficacy data reported in the FDA Medical and Statistical reviews for 10 ADHD medication programs (4917 patients, 17 trials, 29 treatment arms). Placebo and medication response were measured as percent symptom reduction and effect sizes and drug-placebo differences were calculated for each treatment arm and analyzed in relation to year of approval. We also investigated the potential role of age and medication class on trends and outcomes. Results showed a similar pattern to antidepressants wherein the placebo response is rising significantly over time (r = 0.636, p = 0.006) and effect size (r < 0.0001, p = 1.0), drug-placebo difference (r = -0.238, p = 0.214), and success rate (28/29 97%) have remained unaffected, likely due to a parallel, although not statistically significant increase in medication response (r = 0.326, p = 0.085). Age and medication class did not alter these observed time trends but pediatric trials and stimulants were found to have more robust treatment effects than adult trials and non-stimulants. The results of this study suggest that like antidepressants, the relationship between placebo response and the outcomes of ADHD clinical trials is weak at best.

Has the rising placebo response impacted antidepressant clinical trial outcome? Data from the US Food and Drug Administration 1987-2013.

More than fifteen years ago, it was noted that the failure rate of antidepressant clinical trials was high, and such negative outcomes were thought to be related to the increasing magnitude of placebo response. However, there is considerable debate regarding this phenomenon and its relationship to outcomes in more recent antidepressant clinical trials. To investigate this, we accessed the US Food and Drug Administration (FDA) reviews for sixteen antidepressants (85 trials, 115 trial arms, 23,109 patients) approved between 1987 and 2013. We calculated the magnitude of placebo and antidepressant responses, antidepressant-placebo differences, as well as the effect sizes and success rates, and compared these measures over time. Exploratory analysis investigated potential changes in trial design and conduct over time. As expected, the magnitude of placebo response has steadily grown in the past 30 years, increasing since 2000 by 6.4% (r=0.46, p<0.001). Contrary to expectations, a similar increase has occurred in the magnitude of antidepressant response (6.0%, r=0.37, p<0.001). Thus, the effect sizes (0.30 vs. 0.29, p=0.42) and the magnitude of antidepressant-placebo differences (10.5% vs. 10.3%, p=0.37) have remained statistically equivalent. Furthermore, the frequency of positive trial arms has gone up in the past 15 years (from 47.8% to 63.8%), but this difference in frequency has not reached statistical significance. Trial design features that were previously associated with a possible lower magnitude of placebo response were not implemented, and their relationship to the magnitude of placebo response could not be replicated. Of the 34 recent trials, two implemented enhanced interview techniques, but both of them were unsuccessful. The results of this study suggest that the relationship between the magnitude of placebo response and the outcome of antidepressant clinical trials is weak at best. These data further indicate that antidepressant-placebo differences are about the same for all of the sixteen antidepressants approved by the FDA in the past thirty years.

The placebo effect in psychiatric practice.

This well-known effect can be harnessed to improve treatment.

Antidepressants versus placebo in major depression: an overview.

Although the early antidepressant trials which included severely ill and hospitalized patients showed substantial drug-placebo differences, these robust differences have not held up in the trials of the past couple of decades, whether sponsored by pharmaceutical companies or non-profit agencies. This narrowing of the drug-placebo difference has been attributed to a number of changes in the conduct of clinical trials. First, the advent of DSM-III and the broadening of the definition of major depression have led to the inclusion of mildly to moderately ill patients into antidepressant trials. These patients may experience a smaller magnitude of antidepressant-placebo differences. Second, drug development regulators, such as the U.S. Food and Drug Administration and the European Medicines Agency, have had a significant, albeit underappreciated, role in determining how modern antidepressant clinical trials are designed and conducted. Their concerns about possible false positive results have led to trial designs that are poor, difficult to conduct, and complicated to analyze. Attempts at better design and patient selection for antidepressant trials have not yielded the expected results. As of now, antidepressant clinical trials have an effect size of 0.30, which, although similar to the effects of treatments for many other chronic illnesses, such as hypertension, asthma and diabetes, is less than impressive.

The clinical discovery of imipramine.

The major classes of psychotropic drugs were introduced in an extraordinary decade of discovery between the late 1940s and late 1950s. In the present climate of pessimism about the absence of new drug development, it may be instructive to look back at the research methods used during that era. The study that identified the first antidepressant is a case in point. It was conducted by Roland Kuhn, a Swiss psychiatrist working in a remote psychiatric hospital. Kuhn, like the other pioneering researchers of his day, was given access to new drug entities, and the method he used to discover their clinical effects was open-minded, exploratory, comprehensive, clinical observation. The paper that reported the results of his study has not been available in English, but because of its historical significance and because Kuhn's achievement stands in such contrast to the present impasse in drug development, the authors thought that it might be informative to read about his discovery in his own words. Accordingly, one of the authors (M.R.) translated the paper into English, and they now present excerpts of that translation with the intent of encouraging reevaluation of contemporary approaches to drug discovery. By today's clinical research standards, Kuhn's method of unfettered, exploratory, clinical observation was substandard, haphazard, even messy. Yet it produced a major breakthrough-the discovery that a drug can alleviate depression-that has had a lasting impact on the treatment of depression and on the development of antidepressant drugs. Kuhn's experience might usefully inform our strategies of drug development.

Expectation, the placebo effect and the response to treatment.

What we believe we will experience from a treatment--our expectation--has a substantial impact on what we actually experience. Expectation has been established as a key process behind the placebo effect. Studies in both laboratory and clinical settings consistently show that when people ingest a pharmacologically inert substance (placebo) but believe that it is an active substance, they experience both the subjective sensations and physiologic effects expected from that active substance. Expectation has an important place in the response to "real" treatment as well. This paper provides an overview of the data which point to the role of expectation in both the placebo effect and the response to treatment. These data suggest that clinicians might enhance the benefit of all treatments by promoting patients' positive expectations.

How expectation works: psychologic and physiologic pathways.

Although expectation has been the most widely studied of the mechanisms that drive the placebo effect, we still don't know how it works. We don't know how the thought that one will respond to a substance in a certain way is converted to symptom relief, intoxication, or airway resistance; the pathway between expectation of a response and the response itself remains uncharted. Nonetheless, in the last decade, brain-imaging studies have begun to uncover this pathway. This paper reviews both long-standing psychologic concepts about the underpinnings of expectation and some of the contemporary brain imaging research, which shows that when expectation alleviates depression, produces pain relief or improves parkinsonian symptoms, these effects come with relevant changes in brain activity and chemistry. These findings oblige us to reevaluate some of the traditional common sense notions of how expectation brings about its effects and how placebos work.