From the Editor

This week, hundreds of thousands of Canadians will not go to work because of mental health problems, depression being the most common.

But despite the long shadow cast by depression on our society, it’s difficult not to feel that we fall short in terms of our active management. Many people struggle with their symptoms; even when they can beat the “black dog” – to use Winston Churchill’s term – they are at high risk for relapse.

Can we do better with the black dog?

Here are two papers that look at bettering outcomes.

In the first, the authors ask if mindfulness can prevent the relapse of depression. The second paper considers the use of statins to improve the effects of antidepressants.


Depression and Relapse

“Efficacy of Mindfulness-Based Cognitive Therapy in Prevention of Depressive Relapse: An Individual Patient Data Meta-analysis From Randomized Trials”

Willem Kuyken et al., JAMA Psychiatry, Online First, 27 April 2016


Although progress has been made in the treatment of many psychiatric conditions, recurrent depression continues to cause significant disability and remains a high cost to society. Interventions that prevent depressive relapse among people at high risk of recurrent episodes have significant potential to reduce the disease’s burden. Mindfulness-based cognitive therapy (MBCT), one such intervention, teaches psychological skills that target cognitive mechanisms implicated in depressive relapse to people with a history of depression by combining systematic mindfulness training with elements from cognitive therapy. A systematic review and meta-analysis of 6 randomized clinical trials (N = 593 patients) suggested that MBCT was associated with a significant reduction in the rates of depressive relapse compared with usual care or placebo, corresponding to a 34% relative risk reduction (risk ratio [RR], 0.66; 95% CI, 0.53-0.82).

While we have a growing body of evidence pointing to the efficacy of MBCT in preventing depressive relapses, we do not know whether MBCT is differentially efficacious for subgroups of people known to be at greater or lesser risk for depressive relapse/recurrence.

Here, we present an analysis of individual patient data (IPD) compiled from 9 published randomized trials of MBCT identified through a systematic literature search.

Willem Kuyken

So opens a new paper by Willem Kuyken et al., just published in JAMA Psychiatry (Online First). Pause for a moment and contemplate the weight of that first paragraph (and, hey, enjoy the exceptional writing of the authors).

In this paper, they focus on a few questions: How does MBCT compare to the usual care in terms of relapse prevention? How about compared to other active treatments? And are the effects of MBCT moderated by certain demographic or depression variables?

Here’s what they did:

· The authors searched articles published up to November 2014 with several keywords and titles, using several databases, including Medline.

· The authors had specific criteria for inclusion, including that the therapy was meant to prevent depression, participants needed to be adults, the MBCT was done according to the treatment manual, and that comparisons were made with the usual care.

· After reviewing the original abstracts (2555 studies), 766 were evaluated with the full inclusion criteria. The authors then identified 4 studies, and combined them with 6 from a previous meta-analysis, though one study was then dropped (due to a lack of full patient data).

· As noted above, the authors looked at relapse prevention – they considered a specific time window: within 60 weeks. They also looked at demographics (sex, age, education, relationship status, race/ethnicity, socioeconomic status, and employment status).

· The analysis was done with individual patient data (IPD). “Unlike meta-analyses of aggregate data at the trial level, IPD analyses permit the investigation of patient-level characteristics that may be potential moderators of treatment effects.” (!)

· Heavy statistical analyses were performed, including two-step meta-analyses.

Here’s what they found:

· Across the nine studies, there was data on 1258 participants. Their demographics: the mean age was 47.1; they tended to be female (75.0%) and married or with a partner (58.6%). In terms of their illness experience, the onset was depression was at 26, with the majority having had 5 or more past episodes.

· “Of 596 participants who received MBCT, 229 (38%) had a depressive relapse within 60 weeks’ follow-up, whereas 327 of 662 participants (49%) who did not receive MBCT had a depressive relapse within 60 weeks.” (!) MBCT compared favourably to antidepressant management in 4 studies (for a hazard ratio of 0.77).

· The authors did heavy statistical analysis to consider demographic and depression-related variables. What was relevant? “[P]atients with a higher baseline depression z score received greater benefit from MBCT therapy compared with all non-MBCT treatments.” In other words, sicker patients benefited more.

· Pulling this together:

The authors report:

Replicating previous work, we found clear evidence that MBCT was associated with a significant reduction in the risk of depressive relapse/recurrence over 60 weeks compared with usual care. Extending previous work, we found that MBCT reduces the risk of depressive relapse/recurrence compared with the current mainstay approach, maintenance antidepressants. We further showed that there is no support for MBCT having differential effects for patients based on their sex, age, education, or relationship status, suggesting the intervention’s generalizability across these characteristics.

A few thoughts:

1. This paper is a good paper. It looks at a major problem – recurrence of depression – and provides important findings.

2. Kuyken does good work. You will recall that he was the first author of a 2015 Lancet paper considering mindfulness and depression. I consider that paper to be one of the best I read last year. Kuyken had many co-authors on this effort, and I proudly note the Canadian (and the Toronto) connection: Zindel Segal was a co-author.

3. Meta-analysis can be complex. The statistical work here was very complex. Not surprisingly, the paper closes with a call for more study in the area. In a press interview, Kuyken describes the results as “heartening.” “MBCT offers people a safe and empowering treatment choice alongside other mainstay approaches such as cognitive-behavioral therapy and maintenance antidepressants.”


Depression and Medications

“The Effect of Concomitant Treatment With SSRIs and Statins: A Population-Based Study”

Ole Köhler et al., The American Journal of Psychiatry, In Advance, 3 May 2016

Remission rates for patients with depression are modest despite treatment with antidepressants at adequate dosages for sufficient duration. Even after switching to other antidepressants, augmenting with additional antidepressants, or undergoing adjunctive psychotherapy, a large proportion of patients experience only partial response or no response at all. Therefore, alternative strategies to relieve depression have been investigated intensively in recent decades.

One such strategy, which has shown some promise, is treatment with anti-inflammatory agents. The “inflammatory hypothesis” for depression has been revived in recent years in the wake of large studies linking inflammatory processes with the emergence of depression. Also, a series of clinical trials indicated that anti-inflammatory drugs such as selective cyclooxygenase-2 (COX-2) inhibitors and aspirin may have antidepressant effects.

Despite being used primarily for their lipid-lowering properties, statins have direct anti-inflammatory effects that are not mediated by their hypocholesterolemic activity.

Ole Köhler

So opens a new paper Ole Köhler et al.published in The American Journal of Psychiatry (In Advance).

This paper is relatively straight-forward, and requires less of a summary.

Here’s what they did:

· The authors used national databases to consider people in Denmark who used SSRIs, with those who also used statins, between 1997 and 2012.

· The authors then looked at several outcomes: psychiatric hospital contacts, psychiatric hospital contacts due to depression, suicidal behavior, and mortality.

Here’s what they found:

· There were 872,216 SSRI users; 113,108 (or 13.0%) used a statin at the same time.

· In terms of outcomes, antidepressants combined with statins were found to have significantly lower risk for both psychiatric hospital contacts and psychiatric hospital contacts due to depression, but had not effect on suicides or mortality.

The authors conclude:

In conclusion, the results from this large naturalistic cohort study are in accordance with those from prior studies, including a small randomized controlled trial, and indicate that the antidepressant potential of the SSRI-statin combination should be subjected to further testing in larger randomized controlled trials. Since the most prevalent SSRI-statin combination in this study was citalopram-simvastatin, which therefore represents the main driving force behind the positive results, we believe that this specific combination would be a good candidate for a head-to-head test against a citalopram-placebo combination in a randomized controlled trial.

My final thought: wow – I’m not quite sure what to think. But, yes, a randomized controlled trial sounds appropriate.

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.