A target trial emulation comparing the antidepressant effectiveness of selective serotonin reuptake inhibitors (SSRIs) highlighting the importance of patent-related confounding by indication.

BACKGROUND: The comparative effectiveness of selective serotonin reuptake inhibitors (SSRIs) has been subjected to relatively little research. However, a recent study based on target trial emulation suggested that sertraline may be more effective than escitalopram. AIMS: To investigate whether sertraline, citalopram, and escitalopram differ in their effectiveness-assessed via the risk of psychiatric hospital admission and suicide following treatment initiation. The choice to focus on sertraline, citalopram, and escitalopram was made to limit confounding by indication, as the Danish depression treatment guideline from 2007 specifically listed these three SSRIs as first choice. METHOD: We conducted a target trial emulation based on data from Danish registers. We identified all individuals that initiated treatment for depression with sertraline, citalopram, or escitalopram in the period from January 1, 2007, to March 1, 2019. These individuals were followed until psychiatric hospital admission or suicide (separate analyses), death, 1 year after treatment initiation or end of data. Cox proportional hazards regression adjusted for relevant baseline covariates was performed to emulate randomized treatment allocation, comparing the rate of psychiatric hospital admission and suicide for individuals treated with sertraline (used as reference), citalopram or escitalopram, respectively. For escitalopram, we conducted a sensitivity analysis excluding data from the period during which the drug was sold under patent, as the price of the drug during that time likely entailed a different prescription pattern, increasing the risk of ("patent-related") confounding by indication. RESULTS: We identified 56,865, 118,145, and 31,083 individuals initiating treatment with sertraline, citalopram, and escitalopram, respectively. Using sertraline as reference, the adjusted hazard rate ratio (aHRR) for psychiatric admission was 0.98 (95% CI = 0.91-1.05) for citalopram and 1.21 (95% CI = 1.10-1.32) for escitalopram. Notably, in the sensitivity analysis only including patients initiating treatment after the escitalopram patent had expired, the increased risk of psychiatric hospital admission associated with escitalopram treatment was no longer present (aHRR = 0.98, 95% CI = 0.82-1.18). The results of the analyses of suicide were inconclusive, due to few outcome events. CONCLUSIONS: Sertraline, citalopram, and escitalopram do not seem to have differential effectiveness in the treatment of depression. Taking potential patent-related, time varying, confounding by indication (via severity) into account is critical for pharmacoepidemiological studies, including those employing target trial emulation.

[Psychedelic psychiatry]. / Psykedelisk psykiatri ­ det finns anledning att vara optimistisk.

In the last 20 years there has been an increased interest in research on psychedelic compounds for treatment of psychiatric conditions such as depression, anxiety and substance use disorders. Despite existing treatments being efficacious for many patients, this is not the case for up to a third of the patients with depression. Additionally, treatments are often long and associated with side effects. This review focuses on the psychedelic compound psilocybin, a serotonin-2A-receptor agonist that has been seen to reduce depression and anxiety in patients after administration of only a single dose, with effects lasting several weeks. Recent findings from phase II studies suggest that psilocybin treatment for depression is safe and efficacious. A phase III study is currently recruiting. Whether psychedelics will become a part of standard healthcare remains to be seen, but findings do give rise to cautious optimism.

Initial severity of the Positive and Negative Syndrome Scale (PANSS)-30, its main subscales plus the PANSS-6, and the relationship to subsequent improvement and trial dropout: a pooled participant-level analysis of 18 placebo-controlled risperidone and paliperidone trials.

Greater initial severity on the 30-item Positive and Negative Syndrome Scale (PANSS-30) correlates positively with antipsychotic-placebo separation and trial dropout, but it is unknown whether these associations are present also on PANSS-derived subscales. We assessed the relationship between initial severity and antipsychotic-placebo separation as measured by PANSS-30 and four PANSS symptom subscales: the positive (PANSS-POS), negative (PANSS-NEG), general (PANSS-GEN) and 6-item (PANSS-6) subscales, using patient-level data from 18 placebo-controlled risperidone and paliperidone trials. Analysis of covariance in the intention-to-treat population (last-observation-carried-forward) was used to assess antipsychotic-placebo separation and trial dropout. Across 6685 participants (90% schizophrenia, 10% schizoaffective disorder), the initial severity-by-treatment interaction was statistically significant for PANSS-30 (beta: -0.155; p < 0.001) and all PANSS subscales (beta range: -0.097 to -0.135; p-value range: < 0.001 to 0.002). In all cases, antipsychotic-placebo differences increased with initial severity. Judging by the distribution of relative outcomes (percent remaining symptoms), the interaction was partly explained by an increased chance of responding, but also by larger numerical responses in those who did respond, as initial severity increased. Except for PANSS-NEG, high initial severity on all PANSS scales predicted increased trial dropout, although not statistically significantly so for PANSS-6. In summary, we thus replicate previous findings showing greater initial severity to predict larger antipsychotic-placebo separation and extend these results to four PANSS subscales. For PANSS-POS and PANSS-GEN, but not for PANSS-NEG and PANSS-6, we also replicate the association between initial severity and trial dropout. Patients with low initial negative symptom severity were identified as a group of particular interest for further study since their results diverged most from the average both with regard to antipsychotic-placebo separation (low separation measured by PANSS-NEG) and trial dropout (high level).

The complex clinical response to selective serotonin reuptake inhibitors in depression: a network perspective.

The clinical response to selective serotonin reuptake inhibitors (SSRIs) in depression takes weeks to be fully developed and is still not entirely understood. This study aimed to determine the direct and indirect effects of SSRIs relative to a placebo control condition on clinical symptoms of depression. We included data of 8262 adult patients with major depression participating in 28 industry-sponsored US Food and Drug Administration (FDA) registered trials on the efficacy of SSRIs. Clinical symptoms of depression were assessed by the 17 separate items of the Hamilton Depression Rating Scale (HDRS) after 1, 2, 3, 4 and 6 weeks of treatment. Network estimation techniques showed that SSRIs had quick and strong direct effects on the two affective symptoms, i.e., depressed mood and psychic anxiety; direct effects on other symptoms were weak or absent. Substantial indirect effects were found for all four cognitive symptoms, which showed larger reductions in the SSRI condition but mainly in patients reporting larger reductions in depressed mood. Smaller indirect effects were found for two arousal/somatic symptoms via the direct effect on psychic anxiety. Both direct and indirect effects on sleep problems and most arousal/somatic symptoms were weak or absent. In conclusion, our study revealed that SSRIs primarily caused reductions in affective symptoms, which were related to reductions in mainly cognitive symptoms and some specific arousal/somatic symptoms. The results can contribute to disclosing the mechanisms of action of SSRIs, and has the potential to facilitate early detection of responders and non-responders in clinical practice.

Performance of 3 Sets of Criteria for Potentially Inappropriate Prescribing in Older People to Identify Inadequate Drug Treatment.

Importance: Potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) are used in research to reflect the quality of drug treatment in older people and have been suggested for inclusion in core outcome sets for evaluation of interventions for improved prescribing. Their validation so far, however, is primarily restricted to expert opinion-based processes. Objective: To evaluate the performance of 3 explicit PIM/PPO criteria sets as diagnostic tools to identify inadequate drug treatment in older patients. Design, Setting, and Participants: This diagnostic study analyzed patients aged 65 years or older consecutively included from 2 primary health care centers from October to November 2017. Data were analyzed from February to August 2022. Exposures: The PIMs/PPOs were concordantly identified by 2 specialist physicians (2018-2019) retrospectively after a planned physician visit, using 3 European PIM/PPO criteria sets and without knowledge of this diagnostic study. Main Outcomes and Measures: Area under the receiver operating characteristic (ROC) curve, reflecting the ability of PIM/PPO criteria sets to identify the reference standard of inadequate drug treatment, determined by 2 specialist physicians in consensus. Inadequate drug treatment implied that additional action related to the medication could be medically justified before the next regular visit. Results: A total of 302 patients were analyzed (median age, 74 [IQR, 69-81] years; 178 women [59%]; median number of drugs in the medication list, 6 [IQR, 3-9]); 98 patients (32%) had inadequate drug treatment. A total of 0 to 8 PIMs/PPOs per patient were identified using the Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) criteria, 0 to 6 with the European EU(7)-PIM list, and 0 to 12 with the Swedish set of indicators of prescribing quality. The areas under the ROC curve for the 3 sets to identify the reference standard for inadequate drug treatment were 0.60 (95% CI, 0.53-0.66) for the STOPP/START criteria, 0.69 (95% CI, 0.63-0.75) for the EU(7)-PIM list, and 0.73 (95% CI, 0.67-0.80) for the Swedish set. For comparison, the area under the ROC curve was 0.71 (95% CI, 0.65-0.78) using the number of drugs in the medication list. Conclusions and Relevance: In this diagnostic study, the evaluated PIM/PPO sets had poor to fair performance as diagnostic tools to identify inadequate drug treatment, comparable with a simple count of the number of drugs in the medication list. These findings suggest that use of PIMs/PPOs as indicators of drug treatment quality in core outcome sets for the evaluation of interventions for improved prescribing may need reconsideration.

The efficacy of transcranial magnetic stimulation (TMS) for negative symptoms in schizophrenia: a systematic review and meta-analysis.

Several trials have shown preliminary evidence for the efficacy of transcranial magnetic stimulation (TMS) as a treatment for negative symptoms in schizophrenia. Here, we synthesize this literature in a systematic review and quantitative meta-analysis of double-blind randomized controlled trials of TMS in patients with schizophrenia. Specifically, MEDLINE, EMBASE, Web of Science, and PsycINFO were searched for sham-controlled, randomized trials of TMS among patients with schizophrenia. The effect of TMS vs. sham on negative symptoms in each study was quantified by the standardized mean difference (SMD, Cohen's d) with 95% confidence intervals (95%CI) and pooled across studies using an inverse variance random effects model. We identified 57 studies with a total of 2633 participants that were included in the meta-analysis. The pooled analysis showed statistically significant superiority of TMS (SMD = 0.41, 95%CI: 0.26; 0.56, p-value < 0.001), corresponding to a number needed to treat of 5. Furthermore, stratified analyses suggested that TMS targeting the left dorsolateral prefrontal cortex and using a stimulation frequency >1 Hz was most efficacious. There was, however, substantial heterogeneity and high risk of bias among the included studies. In conclusion, TMS appears to be an efficacious treatment option for patients with schizophrenia suffering from negative symptoms, but the optimal TMS parameters are yet to be established.

Impact of chosen cutoff on response rate differences between selective serotonin reuptake inhibitors and placebo.

Response defined as a 50% reduction in the sum score of the Hamilton Depression Rating Scale (HDRS-17-sum) is often used to assess the efficacy of antidepressants. Critics have, however, argued that dichotomising ratings with a cutoff close to the median may lead to scores clustering on either side, the result being inflation of miniscule drug-placebo differences. Using pooled patient-level data sets from trials of three selective serotonin reuptake inhibitors (SSRIs) (citalopram, paroxetine and sertraline) (n = 7909), and from similar trials of duloxetine (n = 3478), we thus assessed the impact of different cutoffs on response rates. Response criteria were based on (i) HDRS-17-sum, (ii) the sum score of the HDRS-6 subscale (HDRS-6-sum) and (iii) the depressed mood item. The separation between SSRI and placebo with respect to response rates increased when HDRS-17-sum was replaced by HDRS-6-sum or depressed mood as effect parameter and was markedly dependent on SSRI dose. With the exception of extreme cutoff values, differences in response rates were largely similar regardless of where the cutoff was placed, and also not markedly changed by the exclusion of subjects close to the selected cutoff (e.g., ±10%). The observation of similar response rate differences between active drugs and placebo for different cutoffs was corroborated by the analysis of duloxetine data. In conclusion, the suggestion that using a cutoff close to the median when defining response has markedly overestimated the separation between antidepressants and placebo may be discarded.

Antipsychotic-placebo separation on the PANSS-6 subscale as compared to the PANSS-30: a pooled participant-level analysis.

In order for measurement-based care to be implemented, there is a need for brief rating instruments that can be administered in a short amount of time, but that are still sufficiently informative. Here, we assessed the drug-placebo sensitivity of the six-item subscale (PANSS-6) of the 30-item Positive and Negative Syndrome Scale (PANSS-30) using a large collection of patient-level data (n = 6685) from randomized controlled trials of risperidone and paliperidone. When analyzing the data by study, we found no material difference in mean effect sizes (ES) between the two measures (PANSS-30 ES = 0.45, PANSS-6 ES = 0.44; p = 0.642). Stratifying the pooled population according to several putative effect moderators (e.g., age, formulation, dose, or diagnosis) generally yielded no meaningful ES differences between the two measures. Similarly, early improvement (≥20% improvement at week 1) on the PANSS-6 predicted subsequent response (≥40% improvement at endpoint) as well as the analog prediction using PANSS-30. Finally, cross-sectional symptom remission assessed via the PANSS-6 showed very good agreement (sensitivity = 100%, specificity = 98%) with cross-sectional symptom remission defined by the Remission in Schizophrenia Working Group.

Determining maximal achievable effect sizes of antidepressant therapies in placebo-controlled trials.

OBJECTIVE: Antidepressants outperform placebo with an effect size of around 0.30. It has been suggested that effect sizes as high as 0.875 are necessary for a minimal clinically important difference. Whether such effect sizes are achievable in placebo-controlled trials is unknown. Therefore, we aimed to assess what effect sizes are theoretically achievable in placebo-controlled trials of antidepressants. METHODS: Patient-level analyses comparing Hamilton Depression Rating Scale (HDRS-17) outcomes for simulated antidepressant therapies to placebo-treated participants (n = 2201) from clinical trials of selective serotonin reuptake inhibitors. RESULTS: An optimally effective antidepressant, where all treated participants achieve HDRS-17 scores comparable to those displayed by healthy volunteers (remission-type model), had a maximum effect size of 1.75, with a mean difference of 11.6 points on the HDRS-17. In simulations where patients received an additional 50% symptom reduction over that obtained with placebo (improvement-type model), the maximum effect size was 1.08 with a mean HDRS-17 difference of 7.2. When adjusting for normal rates of treatment discontinuation, maximum effect sizes were 1.10 (remission-type model) and 0.76 (improvement-type model) with HDRS-17 mean differences of 8.8 and 5.6, respectively. CONCLUSIONS: Three methodological issues (i) a large and variable placebo response, (ii) a high rate of dropout and (iii) HDRS-17-ratings significantly larger than zero in healthy volunteers, reduce the degree of treatment-placebo separation achievable in depression trials. Assuming that those who discontinue treatment have only partial response, even a highly effective antidepressant would have difficulties surpassing such effect size cut-offs as have been suggested to signify a minimal clinically important difference.

Do side effects of antidepressants impact efficacy estimates based on the Hamilton Depression Rating Scale? A pooled patient-level analysis.

The Hamilton Depression Rating Scale (HDRS-17) measures symptoms that may overlap with common antidepressant side effects (e.g., sexual dysfunction), thus making it possible that side effects of antidepressant treatment are erroneously rated as symptoms of depression, and vice versa. This study uses patient-level data from previously conducted antidepressant treatment trials to assess whether side effect ratings co-vary with HDRS-17 ratings. Data from all HDRS-17-rated, industry-sponsored pre- and post-marketing trials (n = 4647) comparing the serotonin and noradrenaline reuptake inhibitor, duloxetine, to placebo and/or to a selective serotonin reuptake inhibitor were pooled; three studies, which utilised sub-therapeutic doses, did not have symptom-level ratings available and could not be included. Severity was assessed for side effects related to sleep, somatic anxiety, gastrointestinal function, and sexual dysfunction. Analysis of covariance was used to assess the relation between these side effects and ratings of relevant HDRS-17-derived outcome parameters. Side effects related to sleep, somatic anxiety and sexual dysfunction significantly and exclusively associated with higher scores on HDRS-17 items measuring the corresponding domains. Side effects related to gastrointestinal function associated with higher HDRS-17 item scores on all assessed domains. Treatment outcome was significantly related to side effect severity when assessed using HDRS-17-sum (beta 0.32 (0.074), p < 0.001), but not when the HDRS-6-sum-score (beta 0.035 (0.043), p = 0.415) or the depressed mood item (beta 0.007 (0.012), p = .527) were used as effect parameters. That some HDRS-17 items co-vary with common antidepressant side effects suggests some of these adverse events are counted twice, potentially leading to an underestimation of antidepressant efficacy.

Low SSRI dosing in clinical practice-a register-based longitudinal study.

OBJECTIVE: Since several recent meta-analyses report a dose-response relationship for the antidepressant effect of the selective serotonin reuptake inhibitors (SSRIs), we investigated how these drugs are dosed in clinical practice. METHODS: Through linkage of nation- or region-wide registers, we describe SSRI doses in 50,365 individuals residing in Region Västra Götaland, Sweden, with an incident diagnosis of depression and initiating SSRI treatment between 2007 and 2016. The primary question was to elucidate to what extent these individuals had been prescribed a daily dose that according to recent meta-analyses is required to elicit the maximum antidepressant effect, that is >20 mg citalopram, >10 mg escitalopram, >10 mg fluoxetine, >10 mg paroxetine or >50 mg sertraline. RESULTS: In all, 21,049 (54%) out of 38,868 individuals <65 years of age, and 9,131 (79%) out of 11,497 individuals ≥65 years of age, never received an SSRI dose reported to exert maximum antidepressant effect. These prescribing practices were seen for citalopram, escitalopram and sertraline, but not for fluoxetine and paroxetine, and were frequent in both primary and secondary/tertiary care. Suggesting that doses here defined as maximum efficacy doses, when prescribed, are usually not intolerable, between 59% and 68% of individuals <65 years of age received such a dose also for the subsequent prescription, that is as frequently as in those prescribed a sub-maximum efficacy dose (52-69%). CONCLUSION: Most patients being prescribed an SSRI to treat their depression never receive the dose that according to recent meta-analyses is most likely to effectively combat their condition. The lack of consensus regarding effective dosing of SSRIs may have contributed to this state of affairs.

The efficacy of repetitive transcranial magnetic stimulation (rTMS) for bipolar depression: A systematic review and meta-analysis.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has established efficacy in the treatment of unipolar depression and a growing evidence base in the treatment of bipolar depression. The objective of this study was to provide an estimate of the efficacy of rTMS in bipolar depression as an up to date synthesis of this literature is lacking. METHODS: We conducted a systematic review of the sham-controlled randomized controlled trial (RCT) literature examining rTMS in bipolar depression. Studies were included if they included participants with bipolar depression in both sham- and active arms. The primary outcome parameter was rate of clinical response, defined as a 50% reduction as compared to baseline, on an established depression rating scale. Quantitative synthesis was performed using the Maentel-Haenszel random-effects model. RESULTS: Data from a total of 274 patients from 14 studies were retained in the quantitative synthesis. The response rates were higher in rTMS compared to sham treatment (odds ratio (OR) = 2.72. 95%CI: 1.44-5.14). When stimulation protocols were analysed separately, statistically significant clinical response was only observed for high-frequency rTMS over the left dorsolateral prefrontal cortex (OR = 2.57, 95%CI: 1.17-5.66). LIMITATIONS: Most data was extracted from trials including very few participants with bipolar depression (predominantly unipolar depression samples). Large confirmatory RCTs of rTMS specifically for bipolar depression are lacking. CONCLUSION: rTMS seems effective in the treatment of bipolar depression, but dedicated and adequately powered RCTs are needed in order to firmly conclude that rTMS should be offered routinely for the treatment of bipolar depression.

Pre-diagnostic and post-diagnostic psychopharmacological treatment of 16 288 patients with bipolar disorder.

OBJECTIVES: The aim was to describe the pre-diagnostic and post-diagnostic psychopharmacological treatment of bipolar disorder over the past two decades. METHODS: We identified all 16 288 individuals aged ≥ 18 years, who received their first diagnosis of bipolar disorder at a psychiatric hospital in Denmark between 1997 and 2014. For each calendar year, we calculated the proportion of patients (with index date in the respective calendar years) who were prescribed psychopharmacological treatment in the 2 years preceding and the 2 years following the date of the first diagnosis of bipolar disorder. For patients diagnosed with bipolar disorder from 2007 to 2010 (n = 3949), we described the psychopharmacological treatment from 1995 to 2016, that is, from up to 16 years prior to and up to 10 years after the diagnosis. RESULTS: Concomitant use of ≥ 2 antidepressants in the 2 years preceding the bipolar disorder diagnosis increased over the study period. In the 2 years following the diagnosis, the use of lithium decreased, while use of atypical antipsychotics (particularly quetiapine), valproate, and lamotrigine increased over the study period. During the 10 years following the diagnosis, 53%-90% of the patients received any psychotropic drug while 12%-26% received treatment with an antidepressant without overlapping treatment with a mood-stabilizing drug. CONCLUSION: The increased use of two or more antidepressants suggests more focus on bipolar disorder as a differential diagnosis to treatment-resistant unipolar depression. The decreased use of lithium (consistent with international trends) and the prevalent use of antidepressants without overlapping treatment with a drug with mood-stabilizing properties are concerning.

One (effect) size does not fit at all: Interpreting clinical significance and effect sizes in depression treatment trials.

The efficacy of antidepressants in major depressive disorder has been continually questioned, mainly on the basis of studies using the sum-score of the Hamilton Depression Rating Scale as a primary outcome parameter. On this measure antidepressants show a standardised mean difference of around 0.3, which some authors suggested is below the cut-off for clinical significance. Prompted by a recent review that, using this argument, concluded antidepressants should not be used for adults with major depressive disorder, we (a) review the evidence in support of the cut-off for clinical significance espoused in that article (a Hamilton Depression Rating Scale standardised mean difference of 0.875); (b) discuss the limitations of average Hamilton Depression Rating Scale sum-score differences between groups as measure of clinical significance; (c) explore alternative measures of clinical importance; and (d) suggest future directions to help overcome disagreements on how to define clinical significance. We conclude that (a) the proposed Hamilton Depression Rating Scale cut-off of 0.875 has no scientific basis and is likely misleading; (b) there is no agreed upon way of delineating clinically significant from clinically insignificant; (c) evidence suggests the Hamilton Depression Rating Scale sum-score underestimates antidepressant efficacy; and (d) future clinical trials should consider including measures directly reflective of functioning and wellbeing, in addition to measures focused on depression psychopathology.