Mood disorders: Exploring the placebo effect, improving treatment and the promise of pharmacogenetics

Antidepressant drugs which alleviate symptoms of depression have received much attention in the news recently, showing that the UK is the 7th highest country in the West to prescribe the drugs. The astounding rise in NHS spending on these pharmacological agents is suggested to be due to “medicalization” of normal sadness. Selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants are commonly used to treat moderate to severe depression with new evidence showing one of these drugs, citalopram could slow down the onset of Alzheimer’s disease. However, on the other hand another recent study cautions the use of SSRIs during pregnancy as they are found to be linked to a higher incidence of autism spectrum disorder (ASD) and developmental delays (DD) in males.

Interestingly, there has been a long standing debate on the placebo effect in pharmacotherapy of depression especially in patients with mild to moderate forms of the illness. A network meta-analysis by Bruno Falissard and colleagues published in BMC Medicine compared sucrose-based placebos and showed their uncertain effect in clinical trials with antidepressants fluxoteine (a SSRI) and venlafaxine (a serotonin-norepinephrine reuptake inhibitor, SNRI). The authors argue that these clinical implications are more important compared with the differences in efficacy between antidepressants. Andrea Ciprani and John Geddes comment on this meta-analysis and in their view think this latter aspect is more clinically meaningful. However, they indicate that patients and clinicians should be aware that some antidepressants are less effective than others whilst some do not differ from placebo in treating depression. Florian Naudet and Bruno Falissard responded by admitting that while the data analysis in their paper is rhetorical they emphasize care does play a key role in the therapy of patients with depression.

Andrea Ciprani and John Geddes:

“ While avoiding the least effective antidepressants already available, clinicians should also combine active medication with a specific context and level of therapeutic contact, to enhance non-specific effects of treatment and gain greater treatment response.”

Improving treatment

istockBrain scan (Flickr, Patrick Denker)The topic of psychopharmacology was covered extensively at the recent International Congress of the Royal College of Psychiatrists. Delayed diagnosis and treatment of bipolar disorder was presented by Daniel Smith that included evidence from a large cross sectional study in Scotland showing the under-treatment of cardiovascular diseases in patients with the disorder. This highlighted the need to address the high physical healthcare requirements of people with the condition. The Collaborative Oxford Network for Bipolar Research to Improve Outcomes (CONBRIO) was addressed in a key symposium on “big data” by John Geddes. This programme has four integrative themes that aims to investigate mood stability in terms of assessment and factors which affect it, determination of its genetic, molecular and neural basis and lastly development of new treatments. Other integrative animal and human studies in major depressive disorder carried out by Leonard Schalkwyk and colleagues demonstrate reactive depression due to early and late stressors in mice show large gene expression differences. These changes overlap with those found in an endogenous depression rat model and in post-mortem brain tissue of depressed patients. The data suggests a common pathway could be targeted for therapies. One of these genes include vesicle associated membrane protein (VAMP-2) which is known to be associated with major depression, bipolar disorder and antidepressant response. Thus understanding the etiological pathways underlying depression will help to determine heterogeneity and predict treatment response.

Pharmacogenetics shows promise

istockIt is widely known that variability of treatment responses is related to differences in pathophysiology and drug metabolism, both of which are influenced by an individual’s genetic makeup. John Kelsoe and colleagues discuss the drug-genotype interactions in bipolar disorder, and propose a panel of genetic markers that could be implemented in clinical trials to test the use of pharmacogenetics in psychiatry. This will be a valuable approach once validated that could be introduced cost-effectively in the clinic. Kelsoe et al say:

“Although this is a very early stage in the discovery of pharmacogenetic guided treatment (PGT) markers in bipolar disorder BD, this set of genes is expected to be refined and enlarged over time, and we argue that there are already enough potentially informative results to warrant implementation studies to determine their clinical utility.”

In summary there is need for more effective drug treatments in mood disorders. It is anticipated that the substantial investment in large collaborative and integrative research programmers will help generate beneficial outcomes.

BMC Medicine has published several articles on mood disorders that focus on treatment, pharmacogenetics, diagnosis and prevention. These can be viewed at

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