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Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial

Olof R. Hjorth, Andreas Frick, Malin Gingnell

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Johanna M. Hoppe, Vanda Faria, Sara Hultberg, Iman Alaie, Kristoffer N. T. Månsson, Jörgen Rosén, Margareta Reis, Kurt Wahlstedt, My Jonasson, Mark Lubberink, Gunnar Antoni, Mats Fredrikson, Tomas Furmark

2021 · Translational Psychiatry

Biology & medicinePsychologyNeuroscience
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From the abstract

AbstractIt has been extensively debated whether selective serotonin reuptake inhibitors (SSRIs) are more efficacious than placebo in affective disorders, and it is not fully understood how SSRIs exert their beneficial effects. Along with serotonin transporter blockade, altered dopamine signaling and psychological factors may contribute. In this randomized clinical trial of participants with social anxiety disorder (SAD) we investigated how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment. Twenty-seven participants with SAD (17 men, 10 women), were randomized, to 9 weeks of overt or covert treatment with escitalopram 20 mg. The overt group received correct treatment information whereas the covert group was treated deceptively with escitalopram, described as an active placebo in a cover story. Before and after treatment, patients underwent positron emission tomography (PET) assessments with the [11C]DASB and [11C]PE2I radiotracers, probing brain serotonin (SERT) and dopamine (DAT) transporters. SAD symptoms were measured by the Liebowitz Social Anxiety Scale. Overt was superior to covert SSRI treatment, resulting in almost a fourfold higher rate of responders. PET results showed that SERT occupancy after treatment was unrelated to anxiety reduction and equally high in both groups. In contrast, DAT binding decreased in the right putamen, pallidum, and the left thalamus with overt SSRI treatment, and increased with covert treatment, resulting in significant group differences. DAT binding potential changes in these regions correlated negatively with symptom improvement. Findings support that the anxiolytic effects of SSRIs involve psychological factors contingent on dopaminergic neurotransmission while serotonin transporter blockade alone is insufficient for clinical response.

Metadata: Crossref. Abstracts retain their original authors’ rights.

In the conversation

Original HN comments, with labels from simple text rules. A label describes the whole comment and may miss context or irony. Read the discussion to make up your own mind. About the labels

4 selected excerpts · 4 total mentions

NickM
Neutral mention · rule
Unfortunately it's hardly possible to do proper case control studies with psilocybin, since the psychedelic effects cause unblinding. This is a problem with SSRIs as well; studies have found most people can correctly guess if they’re in the study group or control group. A true double blind study would require a drug that has similar side effects via an unrelated mechanism, but nobody has attempted that as far as I’m aware. There was this interesting one though where they deceived patients into believing they were taking an “active placebo” instead of an SSRI, and found that the benefits went away, which is very interesting and raises a lot of questions about the true efficacy of these medications: https://www.nature.com/articles/s41398-021-01682-3.pdf
Original comment Psilocybin bests SSRI for major depression in first long-term comparison
psychphysic
Neutral mention · rule
No one in recent history thought it was a chemical imbalance. But there was a recent paper on it yes. Here's a real mind bender. In social anxiety (at least), people on the same antidepressants will have detectable differences in neurochemicals based on if they were told the pills would work, or won't work. Mind bender. https://www.nature.com/articles/s41398-021-01682-3
Original comment Antidepressants are over-prescribed, but genuinely help some patients
fragcula
Neutral mention · rule
> Other clinicians say, however, that the notion of depression being because of a simple chemical imbalance is outmoded anyway, and that antidepressants remain a useful option for patients alongside other approaches including talking therapies. This is the key line in the summary. The concept of attacking an idea no one really believes is really a straw man. More importantly the modern practice of medicine is "evidence based medicine", not "mechanism based medicine". That means treatments are tested as to if they work, not how they work. Ideally in multiple well run double blinded randomised controlled trials with at least some against treatment as usual. Unlike the past…
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when we thought more about how they might work, theorising something is off about someone's humors and adjusting with leeches. Anyone looking for a truly mind bending result should look at Hjorth et al. 2021 [0], the study recruited people with social phobia and gave them all an SSRI (escitalopram). Half were told they were getting a sham active placebo and "should not expect to get better", half were told "you're getting the known effective treatment". Headline result being told you are being treated leads to 4x as much response with brain changes in the dopamin networks. In the meanwhile, rather than worry about how antidepressants work, why not take a look at electroconvulsive therapy which has proven time and again to be the most effective treatment for depression. Yet we have no idea how it works, other than knowing a decent seizure in those without epilepsy makes you less sad? What on earth. [0] https://www.nature.com/articles/s41398-021-01682-3
Original comment “No convincing evidence” that depression is caused by low serotonin levels
NickM
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The trouble is that the placebo effect has been repeatedly demonstrated to be extremely, profoundly strong for depression and anxiety treatments. Yes research has found improvements when you put people on SSRIs, but double blind placebo controlled studies generally find that about 80% of the benefits also occur in the placebo group, so the actual benefit over placebo is only about 2 points on the HAM-D scale. [1] On top of that, SSRIs have well-known side effects that are pretty noticeable for most people, so it’s hard to know how much of their benefit vs placebo is due to loss of blinding and/or the “active placebo” effect. It is, however, notable that one study found a…
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loss of effect when subjects were deceived and told that the SSRI they were given was an active placebo with similar side effects to an SSRI, and the differences were visible on brain scans, not just in their subjective reports.[2] [1] https://journals.plos.org/plosmedicine/article?id=10.1371/jo... [2] https://www.nature.com/articles/s41398-021-01682-3
Original comment Everyone Was Wrong About Antipsychotics

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