SPECIAL SESSION: Challenges in managing depression

The focus of this year’s special session was addressing different challenges faced by psychiatry in managing depression.

First out was Prof Elias Eriksson with his talk titled ‘Challenging the perception that antidepressants don’t work’. He started by providing a brief background regarding certain studies and views that question the efficacy of SSRIs. These opinions have recently gained widespread coverage in media in which SSRIs are claimed to be ineffective or even harmful. To this end, Prof Eriksson presented several studies in which they re-analysed previous trials to examine some of the main arguments that have been put forward against SSRI efficacy:

Argument 1: SSRIs are no better than placebo. This argument stems from the observation that about half of all company-sponsored trials have failed to show a significant difference between SSRIs and placebo. A big problem with these studies is the outcome measure used to assess efficacy, Prof Eriksson explained. When the data was reanalysed with a more sensitive measure, they found that over 90% of trials showed that SSRIs were better than placebo compared with the original ~40%. This suggests that the effect of SSRIs is more consistent than previously thought, showing significant effectiveness in improving depressive symptoms over placebo.

Argument 2: There is no dose-dependency for the antidepressant effect. To examine this, Prof Eriksson and colleagues performed a mega-analysis of fixed-dose trials from company-sponsored studies. In contrast to the argument against a dose-response relationship, they showed that low doses were less effective than higher ones. They also suggested that including suboptimal doses in previous meta-analyses led to underestimation of the efficacy of SSRIs, promoting the view that SSRIs are no better than placebo.

Argument 3: If there is an effect, it is too small to be clinically meaningful. Here, Prof Eriksson provided results demonstrating that SSRIs are significantly better than placebo when comparing adequate doses to placebo rather than looking at low doses. Importantly, this effect had an effect size of about 0.5-0.6, which is conventionally considered to be moderate and clinically meaningful.

Argument 4: If there is an effect of SSRIs, it only works on severe depression. Prof Eriksson explained that the jury is still out regarding this issue. However, he provided some preliminary data from one of their on-going studies indicating that there is a clinically meaningful effect of SSRIs even in moderate depression.

Argument 5: If there is an effect, it is due to side effects causing a placebo response. Prof Eriksson explained that if this was the case, then the antidepressants that were available before SSRIs (first generation antidepressants) should have been just as effective as any subsequent antidepressants. Further, he explained, we wouldn’t be able to assess a significant difference between two drugs without a placebo arm. Additionally, the placebo explanation cannot account for the observation that some antidepressants have shown to not have an effect. Finally, he presented data showing that side effects of antidepressants are not necessary for a treatment response.

Overall, Prof Eriksson provided evidence against the main arguments that antidepressants are ineffective and emphasised that media should be more careful in their coverage of this issue as it could deter patients from seeking antidepressant treatments, which could be detrimental to people’s wellbeing and increase suffering.

The second speaker, Dr Andrea Cipriani, asked the question: ‘Are there pharmacological options to reduce suicide risk?’ He explained that there is currently a debate on whether antidepressants have an effect or not on suicide risk. A meta-analysis from 2009 suggested that suicidal ideation and behaviours increased with antidepressant use in younger adults but protected against suicidal behaviours in older adults. This study could not however make any claims about the association between antidepressants and completed suicides due to the low number of such incidences.

Dr Cipriani highlighted that the effect of antidepressants on suicidal behaviours should not be covered with broad-brush strokes though. It has been shown that fluoxetine and sertraline has protective effects on suicidal behaviours while paroxetine has been associated with an increased risk, suggesting that not all antidepressants have the same effect on suicidal behaviours. In line with this, lithium has been shown to possess preventative effects for suicide in mood disorders. In a meta-analysis of 48 randomised controlled trials, Dr Cipriani demonstrated that compared with placebo, lithium reduced the risk of death and suicide by about 60%, suggesting that lithium is a very effective anti-suicidal treatment.

Dr Cipriani rounded off his talk by briefly exploring if other treatments have potential anti-suicidal effects. One of these is ketamine. Dr Cipriani however noted that more studies are required before we can make any definite conclusions regarding the anti-suicidal effects of ketamine. Similarly, low doses of buprenorphine have recently shown to reduce suicidal ideation. Finally, Dr Cipriani noted that electroconvulsive therapy also appears to reduce the frequency of suicide attempts but that the data is not as robust as it is for lithium.

In conclusion, Dr Cipriani highlighted the nuances of the antidepressant suicidal debate but provided compelling evidence that there are in fact pharmacological options to reduce suicide risk.

Prof Carmine Pariante continued the session by exploring if inflammation is a viable treatment target in depression. He started by explaining that this work emerged due to the lack of new antidepressants in the past decades but that there is a pressing need for new treatments with new mechanisms of action.

Prof Pariante and colleagues were among the first to demonstrate that inflammation and cortisol levels are higher in patients with depression compared with controls. This has now been demonstrated in a number of subsequent studies from other groups as well. In fact, a meta-analysis showed that increased inflammatory levels predict future incidence of depression.

Confirming a link between high inflammatory levels and depressive symptoms, Prof Pariante continued by exploring if those patients associated with increased inflammatory levels are characterised by any specific clinical features. From a study conducted by his group, they showed that high inflammatory levels were associated with treatment resistant patients. This finding has now been replicated in two independent samples as well. Considering that about a third of patients do not respond to antidepressants, these studies may carry important clinical implications for the future understanding and treatment of these patients, Prof Pariante noted. For example, a simple blood test could be used to measure inflammatory levels which could then be used to personalise treatment. This would be a huge improvement on the current trial-and-error practices.

Prof Pariante continued by presenting data on increased inflammatory levels in other psychiatric disorders. It seems that increased baseline inflammatory levels is associated with treatment resistance in psychosis as well, suggesting that perhaps there is something about high inflammation that disrupts treatment response.

The talk was rounded up by looking at what can currently be done for patients while we wait for studies developing anti-inflammatory treatments of depression. Prof Pariante mentioned that nutritional interventions to target inflammatory levels might be a current method to improve patient. In a recent randomised controlled trial they showed that fish oil (omega-3 fatty acids) is effective in the prevention of depression in patients receiving IFN-a therapy, which is frequently associated with depression.

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