As we delved into Carl Jung's archetype of the wounded healer last Monday, it reminded us of something we learned about the serotonin transporter gene. Has modern genetics discovered a pathway to the archetype? You be the judge in this throwback to a 2021 episode. 

Publication Date: 05/20/2024

Duration: 22 minutes, 31 seconds

KELLIE NEWSOME: The serotonin transporter gene is one of the most popular genes on a pharmacogenetic panel. Supposedly, it predicts whether someone will respond to an SSRI, but there's a whole other side of this gene that doesn't get told.

CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report.

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. Why do some people get depressed under stress, but not others? Many people have taken a stab at this question, but in 2003 psychologist Avshalom Caspi came upon a particularly eloquent answer. He and a team of researchers had been following a cohort of babies born in Dunedin, New Zealand around 1972. You may know it as the Dunedin Multidisciplinary Health and Development Study – the 1037 children that took part in it have given us around 300 papers on everything from heart disease to ADHD. But mainly the study has focused on how the environment shapes a child’s physical and mental health for years to come, and by the time of 2003 the human genome had just been mapped, and Dr. Caspi was able to test how a certain gene interacted with the environment to shape the development of depression.That gene was the serotonin transporter gene, also known as 5-HTT, SLC6A4, or the SERT gene. We’ll call it SERT in this podcast. The gene codes for the serotonin transporter which – as the name implies – helps transport serotonin back into the neuron in the brain. The gene comes in two major alleles, or forms – the short arm or S/S allele and the long arm or L/L allele. Technically there is a third, as some people have one of each allele – one S and one L. After Dr. Caspi’s study, this SERT gene would go on to be known as the gene for depression, but that’s not exactly what he found. Dr. Caspi began by making a simple graph with all the data he had gathered from the New Zealanders. On the bottom, X-axis, was the number of major life stressors they had been through between age 21 and 26, and on the top Y-axis was the number of depressive symptoms they endorsed when they were last interviewed, at age 26. As expected, as the number of life stressors went up, so did the number of depressed symptoms. And the chance of a depressed episode, and the chance of a suicide attempt. Nothing surprising there.But then he split the sample in two – those with the short arm S/S SERT allele, and those with the long arm. The result was striking. For people who experienced no major stressors in their early 20’s – 1 in 3 turned out to be so lucky – the two groups had the same level of depression. But as the number of stressors went up, the level of depression rose too, but only in the short-arm S group. The long-arms were unmoving – their level of depression did not rise even after 4 stressors – and we’re not talking about everyday stressors like losing your wallet. These were big ones like getting fired from a job, death of a parent, becoming homeless. 

CHRIS AIKEN: So the short-arm SERT gene conferred a risk for depression, but only in the presence of major stress. This was one of the first studies to prove the stress-diathesis model on a genetic level – that mental illness is shaped not by genes, and not by the environment – I mean, these long-arms were going through really rough times and not getting even a blip of depression about it – instead, it appeared that mental illness was due to an interaction between the genes and the environment. Dr. Caspi repeated the analysis, this time looking at abuse and neglect in early childhood instead of adult stress, and found the same results. Long-arm people did not get more depressed even after severe maltreatment, but short-arm people did. Others expanded his work, showing this interaction between stress and the short-arm influenced other mental illnesses as well, like PTSD and alcoholism. There’s a lot more that came out of the Dunedin study by the way. We covered one of their findings about adult-onset ADHD symptoms in our December 2019 issue, and Dr. Caspi has a new book that summarizes all he learned from this remarkable group of New Zealanders called The Origins of You: How Childhood Shapes Later Life.And we’ve also learned a lot more about the SERT gene in the past 20 years. And most of those studies suggest this gene is an undesirable one – that’s king of a bias in medicine as we tend to look for pathology. But the SERT gene only causes problems when people are under stress, which got us wondering – what is it doing when people aren’t stressed? It must have some survival advantage. Today we’ll talk with Vladimir Maletic about the bright side of the short arm. But first let’s get into the practical clinical application of the SERT gene, because it’s one of the most popular genes on pharmacogenetic testing and if you haven’t seen a patient walk in with that test in hand you will soon. The idea behind these test results is that patients with the short-arm gene do not respond as well to SSRIs. It kind of makes sense – the SSRIs work on the serotonin transporter, and if your genes are producing a short arm then they have less to work on. And the initial studies looked promising – people with the short arm not only didn’t recover as well on SSRIs as the long-arms, but they also had more SSRI side effects, including hypomania and suicidality. But life is complicated, and there’s a lot of diversity in the human species, as well as under the umbrella of major depressive disorder. Over time this finding didn’t hold up so well, but that didn’t stop it from widespread use in pharmacogenetic testing. Dr. Maletic follows this research closely and covered it in a recent book, but even he doesn’t really recommend relying on it in practice. Thank you for joining us Dr. Maletic. There’s been a few meta-analyses of the SERT gene’s influence on antidepressant therapy. What do they tell us?

[Vladimir Maletic]

Why do the meta-analyses differ so much?

[Vladimir Maletic]

It sounds like you could find studies to prove or disprove any hypothesis about this serotonin gene.

[Vladimir Maletic]

So the results are opposite in Caucasians vs. Asians. What about in African Americans?

[Vladimir Maletic]

So the SERT gene is limited in its ability to predict response to SSRIs. What about other classes of antidepressants?

[Vladimir Maletic]

And in particular the gene predicts opposite results in Caucasian men compared to Asians. Does the frequency of this gene also vary by population?

[Vladimir Maletic]

When it comes to lithium, the SERT gene also goes in opposite directions. There is one study suggesting the S/S gene predicts a worse response to long term lithium prophylaxis in bipolar disorder, but in unipolar we see the opposite – there is one study showing the S/S gene predicts a favorable response to lithium augmentation of antidepressants.Why do you think the S/S genotype is more common in Asian populations?

[Vladimir Maletic]

You said the S/S gene may confer greater abilities to live collectively, and that it also aids innate immunity.  What is innate immunity?

[Vladimir Maletic]

And you said there was a third advantage to the S/S – what is that?

[Vladimir Maletic]

Psychologists have found some positive traits like that in patients with dysthymic disorder – they call it depressive realism. Is it too speculative to think that may be linked to the S/S traits?

[Vladimir Maletic]

Another area where the same trait may confer advantages or disadvantages is rumination, which is a repetitive, negative style of thinking. On the one hand a ruminative mind can lead to great problem solving skills – particularly when it’s paired with creativity – on the other hand it’s a big risk factor for depression. Does the S/S gene tell us anything about this?

[Vladimir Maletic]

Do we see any differences with the S/S genotype in early childhood?

[Vladimir Maletic]

I’ve heard the S/S gene can make people more reactive to emotional expressions – is that true?You’ve shed some light on the positive aspects of the S/S gene, but on the other hand it can also lead to what I would loosely call neurotic traits. Is that true?

[Vladimir Maletic]

What are the advantages of the L/L phenotype?

[Vladimir Maletic]

What do you think explains how the same gene can act in different ways – does the environment change the way it’s expressed, or does it depend on how it interacts with other genes?

[Vladimir Maletic]

When a patient comes with an S/S gene on their genetic panel, how would you explain what the S/S means?

[Vladimir Maletic]

We’ve talked about psychiatric associations of the SERT gene. What about medical implications?

[Vladimir Maletic]

Back to practical implications of genetic testing. You’ve made it pretty clear that the SERT gene is not very helpful, but I can also see how it might influence the placebo and nocebo effect – kind of a self-fulfilling prophecy. And we see that in the research you know – in open label trials genetic testing was very helpful, but when the patients were randomized and blinded to the use of the test it no longer made a difference.

KELLIE NEWSOME: Vladimir Maletic is a Clinical Professor of Psychiatry at the University of South Carolina School of Medicine in Greenville and the program chair for the U.S. Psychiatric and Mental Health Congress. He is the author with Charles Raison of The New Mind-Body Science of Depression.

CHRIS AIKEN: And now for the word of the day…. Tachyphylaxis

KELLIE NEWSOME: Tachyphylaxis is the loss of antidepressant efficacy over time. It’s what patients call “antidepressant poop-out.” Like tachycardia, the word comes from the Greek root for rapid, but there’s nothing rapid about tachyphylaxis. In fact, it is quite slow and insidious, as Giovani Fava points out “Tachyphylaxis is the wrong term. It has a rapid connotation.  It is not rapid at all. We have data. There is, for instance, a meta-analysis that suggests the longer the duration of treatment the more likely the patient is to develop loss of clinical effect.” 

Now, for a 2024 update on PTSD and the serotonin transporter, the CERT gene got off to a running start 20 years ago with a clear and simple story.The short arm conferred a risk of depression, but only in the face of major stress. It's an intriguing story, and Dr. Maletic brings even more. intriguing details about empathy, as did a meta -analysis.

CHRIS AIKEN: When it comes to CERT and PTSD, the studies line up more on the positive side. although there are fewer of them. It makes sense that CERT might play a role in the vulnerability to PTSD. The CERT gene modulates the cortisol stress reactivity, and the short arm allele is associated with more intense reactions to fearful and angry faces in the amygdala. But how does the CERT gene influence response to treatment? in PTSD? We get a hint of that from a new study by Adam Lee and colleagues at the University of Minnesota. But how does the CERT gene influence response to treatment? in PTSD? We get a hint of that from a new study by Adam Lee and colleagues at the University of Minnesota. It's just a hint, as this is a novel finding, and it's going to need some heavy-duty replication. The researchers looked at 72 veterans who underwent mindfulness and meditation-based therapy for PTSD. Now, these were veterans with combat trauma, but some of them also had childhood trauma. And it's back in childhood that we expect stressful events to have an outsize effect in shaping genetic expression. So the researchers divided the sample into those who had experienced childhood trauma and those who did not. Here's the bottom line. The patients with the long-arm gene the LL, were more than twice as likely to respond to psychotherapy than were those with the short arm, the SS. But this association only held up in those who had undergone childhood trauma.The results follow with the dominant narrative of greater resilience with the LL gene, as in greater response. to psychotherapy. Remember that the short arm SS gene makes people more likely to develop PTSD after a childhood trauma. And this study suggests that the short arm gene also makes them less likely to respond to psychotherapy. Whether these particulars will hold up in future inquiry is unknown, but the pattern is one that we see again and again. Genes for psychiatric disorders and psychological traits are highly adaptable. The way they are expressed varies widely depending on which genes they are paired with and which life events they are exposed to. We see the same kind of story in our second search study from 2024 where Brazilian researchers showed that a high -fat diet. altered the expression of the "cert gene" in the rat brain, changes that were likely mediated by the gut microbiome. Both a high -fat diet and an unhealthy microbiome are implicated in depression.

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