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Objectives To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine. Design Double blind randomised placebo controlled trial. Setting 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. Participants 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality. Interventions Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo. Main outcome measures The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified. Results The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group. Conclusions Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.

The risks and benefits of standard antidepressants for patients with bipolar disorder are not well understood. In this randomized, placebo-controlled trial of patients with bipolar disorder, all of whom received a mood stabilizer, adjunctive treatment with an antidepressant did not reduce the symptoms of bipolar depression or increase the risk of mania. In patients with bipolar disorder, all of whom received a mood stabilizer, adjunctive treatment with an antidepressant did not reduce the symptoms of bipolar depression or increase the risk of mania. Bipolar disorder, the sixth-leading cause of disability worldwide, 1 is a chronic and recurrent psychiatric illness with a lifetime prevalence of just under 4% 2 and annual costs that exceed those of diabetes or recurrent (unipolar) major depressive disorder. 3 Although abnormal mood elevation is the cardinal diagnostic feature that distinguishes bipolar disorder from recurrent major depressive disorder, depression that alternates with manic episodes (bipolar depression) is the leading cause of impairment and death among patients with bipolar disorders. 4 – 6 Two main limitations related to standard antidepressant medications hamper their use in the treatment of bipolar depression. First, though these agents have proved . . .

It has been suggested that the superiority of antidepressants over placebo in controlled trials is merely a consequence of side effects enhancing the expectation of improvement by making the patient realize that he/she is not on placebo. We explored this hypothesis in a patient-level post hoc-analysis including all industry-sponsored, Food and Drug Administration-registered placebo-controlled trials of citalopram or paroxetine in adult major depression that used the Hamilton Depression Rating Scale (HDRS) and included a week 6 symptom assessment (n=15). The primary analyses, which compared completers on active treatment without early adverse events to completers on placebo (with or without adverse events) with respect to reduction in the HDRS depressed mood item showed larger symptom reduction in patients given active treatment, the effect sizes being 0.48 for citalopram and 0.33 for paroxetine. In actively treated subjects reporting early adverse events, who also outperformed those given placebo, the severity of the adverse events did not predict response. Several sensitivity analyses, for example, including (i) those using change of the sum of all HDRS-17 items as effect parameter, (ii) those excluding all subjects with adverse events (that is, also those on placebo) and (iii) those based on the intention-to-treat population, were all in line with the primary analyses. The finding that both paroxetine and citalopram are clearly superior to placebo also when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects.

Posttraumatic stress disorder (PTSD)-a chronic, debilitating condition, broadly characterized by emotion dysregulation-is prevalent among US military personnel who have returned from Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF). Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for PTSD, but treatment mechanisms are unknown and patient response varies. SSRIs may exert their effects by remediating emotion regulatory brain activity and individual differences in patient response might be explained, in part, by pre-treatment differences in neural systems supporting the downregulation of negative affect. Thirty-four OEF/OIF veterans, 17 with PTSD and 17 without PTSD underwent 2 functional magnetic resonance imaging scans 12 weeks apart. At each scan, they performed an emotion regulation task; in the interim, veterans with PTSD were treated with the SSRI, paroxetine. SSRI treatment increased activation in both the left dorsolateral prefrontal cortex (PFC) and supplementary motor area (SMA) during emotion regulation, although only change in the SMA over time occurred in veterans with PTSD and not those without PTSD. Less activation of the right ventrolateral PFC/inferior frontal gyrus during pre-treatment emotion regulation was associated with greater reduction in PTSD symptoms with SSRI treatment, irrespective of pre-treatment severity. Patients with the least recruitment of prefrontal emotion regulatory brain regions may benefit most from treatment with SSRIs, which appear to augment activity in these regions.

The identification of biomarkers of response might speed drug development and set the premises to assist clinical practice in psychiatry. In this work, we evaluated a panel of peripheral biomarkers (including IL-6, IL-10, TNF-α, TNFRII, BDNF, CRP, MMP9 and PAI1) in depressed patients receiving paroxetine, venlafaxine, or placebo. Samples were obtained from two randomised placebo-controlled studies evaluating the efficacy and tolerability of a novel drug candidate, using either paroxetine or venlafaxine as active comparators. In both studies, the biomarker candidates were analysed in plasma collected at randomization and after 10 weeks of treatment with either placebo or active comparator (for a total of 106 and 108 subjects in the paroxetine and venlafaxine study, respectively). Data were obtained by multiplexing sandwich-ELISA system. Data were subjected to statistical analysis to assess their correlation with baseline severity and with response outcome. Increases in biomarker levels were correlated with reduction in depression severity for TNF-α, IL-6 IL-10 and CRP. Response to paroxetine treatment correlated with baseline IL-10, IL-6 and TNF-α levels, with the strongest signal being observed in males. In the venlafaxine study, a correlation was observed only between CRP level at randomisation and response, suggesting differences between the two active treatments and the two studies. Our investigations suggest that a combination of pro- and anti-inflammatory cytokines may predict response outcome in patients treated with paroxetine. The potential for IL-10, IL-6 and TNF-α as response biomarkers for a wider range of antidepressants warrants further investigations in clinical trials with other monoamine reuptake inhibitors.

Despite advances in pharmacological interventions for rheumatoid arthritis (RA), a subset of patients continues to experience disease activity, highlighting the need for adjunctive therapeutic strategies. To assess the therapeutic efficacy of paroxetine when administered as adjuvant therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA). In this randomized, double-blind, clinical trial, one hundred patients were randomized in 1:1 ratio to receive either csDMARDs including methotrexate plus placebo (control group) or paroxetine (paroxetine group). The primary endpoint was the change in Disease Activity Score using 28 joint counts (DAS-28) [Tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP), visual analogue scale (VAS)] at three months. Secondary endpoints included multidimensional health assessment questionnaire [morning stiffness (MS), pain, fatigue, physical functioning (PF)]. After treatment, both groups demonstrated significant within-group improvements in TJC, SJC, VAS, and DAS-28, with superior improvements observed in the paroxetine group ( = 0.016, 0.0006, 0.03, and 0.005, respectively). CRP showed no significant change in the control group ( = 0.933). Paroxetine group showed significant reductions in MS, pain, and fatigue ( = 0.024, 0.03, and 0.006, respectively) compared with the control group, while PF were significant within groups but not between groups ( = 0.208). Adverse events were comparable, except for a higher incidence of decreased libido in the paroxetine group. Adjunctive paroxetine significantly improved clinical and patient-reported outcomes in mild and moderate RA patients and was generally well tolerated, supporting its potential as an effective adjunctive therapy. The relatively small single-center sample, the exclusion of severe RA patients, the short disease duration, the low seropositivity, absence of mental health assessment, the possibility of overlapping with secondary pain mechanisms (eg, central sensitization or early fibromyalgia features) may limit the generalizability of the findings to broader and more diverse patient populations. NCT06231745.

In this randomized, controlled trial of elderly patients with major depression who had had a response to initial treatment with paroxetine and psychotherapy, two years of maintenance paroxetine prevented recurrent depression, but maintenance psychotherapy did not. Major depression recurred in 35 percent of patients receiving paroxetine plus psychotherapy, 37 percent of those receiving paroxetine plus clinical-management sessions, 68 percent of those receiving placebo plus psychotherapy, and 58 percent of those receiving placebo plus clinical-management sessions. In elderly patients with major depression who had had a response to initial treatment with paroxetine and psychotherapy, two years of maintenance paroxetine prevented recurrent depression, but maintenance psychotherapy did not. Depression has a strong tendency to recur in elderly persons, with rates of recurrence of 50 to 90 percent over a period of two to three years 1 ; hence, the goal of treatment is not only recovery but also the prevention of recurrence. 2 Finding practical and affordable depression-management strategies that prevent recurrence is of great importance. 3 – 6 There are few data from controlled studies on the efficacy of maintenance antidepressant medication or depression-specific psychotherapy in patients 70 years of age or older. We have reported that maintenance nortriptyline, monthly interpersonal psychotherapy, and the two in combination 7 are superior to placebo . . .

Treatment effect in clinical trials for major depressive disorders (RCT) can be viewed as the resultant of treatment specific and non-specific effects. Baseline individual propensity to respond non-specifically to any treatment or intervention can be considered as a major non-specific confounding effect. The greater is the baseline propensity, the lower will be the chance to detect any treatment-specific effect. The statistical methodologies currently applied for analyzing RCTs doesn’t account for potential unbalance in the allocation of subjects to treatment arms due to heterogenous distributions of propensity. Hence, the groups to be compared may be imbalanced, and thus incomparable. Propensity weighting methodology was used to reduce baseline imbalances between arms. A randomized, double-blind, placebo controlled, three arms, parallel group, 8-week, fixed-dose study to evaluate efficacy of paroxetine CR 12.5 and 25 mg/day is presented as a cases study. An artificial intelligence model was developed to predict placebo response at week 8 in subjects assigned to placebo arm using changes from screening to baseline of individual Hamilton Depression Rating Scale items. This model was used to predict the probability to respond to placebo in each subject. The inverse of the probability was used as weight in the mixed-effects model applied to assess treatment effect. The analysis with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect-size about twice larger than the non-weighted analysis. Propensity weighting provides an unbiased strategy to account for heterogeneous and uncontrolled placebo effect making patients’ data comparable across treatment arms.

Background: The most efficacious treatments for social anxiety disorder (SAD) are the SSRIs and cognitive therapy (CT). Combined treatment is advocated for SAD but has not been evaluated in randomized trials using CT and SSRI. Our aim was to evaluate whether one treatment is more effective than the other and whether combined treatment is more effective than the single treatments. Methods: A total of 102 patients were randomly assigned to paroxetine, CT, the combination of CT and paroxetine, or pill placebo. The medication treatment lasted 26 weeks. Of the 102 patients, 54% fulfilled the criteria for an additional diagnosis of avoidant personality disorder. Outcomes were measured at posttreatment and 12-month follow-up assessments. Results: CT was superior to paroxetine alone and to pill placebo at the end of treatment, but it was not superior to the combination treatment. At the 12-month follow-up, the CT group maintained benefits and was significantly better than placebo and paroxetine alone, whereas there were no significant differences among combination treatment, paroxetine alone, and placebo. Recovery rates at 12 months were much higher in the CT group (68%) compared to 40% in the combination group, 24% in the paroxetine group, and 4% in the pill placebo group. Conclusions: CT was the most effective treatment for SAD at both posttreatment and follow-up compared to paroxetine and better than combined treatment at the 12-month follow-up on the Liebowitz Social Anxiety Scale. Combined treatment provided no advantage over single treatments; rather there was less effect of the combined treatment compared to CT alone.

Depression can adversely affect employment status. To examine whether there is a relative advantage of cognitive therapy or antidepressant medication in improving employment status following treatment, using data from a previously reported trial. Random assignment to cognitive therapy (n = 48) or the selective serotonin reuptake inhibitor paroxetine (n = 93) for 4 months; treatment responders were followed for up to 24 months. Differential effects of treatment on employment status were examined. At the end of 28 months, cognitive therapy led to higher rates of full-time employment (88.9%) than did antidepressant medication among treatment responders (70.8%), χ(2) 1 = 5.78, P = 0.02, odds ratio (OR) = 5.66, 95% CI 1.16-27.69. In the shorter-term, the main effect of treatment on employment status was not significant following acute treatment (χ(2) 1 = 1.74, P = 0.19, OR = 1.77, 95% CI 0.75-4.17); however, we observed a site×treatment interaction (χ(2) 1 = 6.87, P = 0.009) whereby cognitive therapy led to a higher rate of full-time employment at one site but not at the other. Cognitive therapy may produce greater improvements in employment v. medication, particularly over the longer term.