Why do some people get PTSD after a trauma and not others? What goes on in the brain during PTSD.

Publication Date: 08/26/2024

Duration: 17 minutes, 38 seconds

KELLIE NEWSOME: Why do some people get PTSD after a trauma, and others walk away unscathed? 

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.We’re back with more coverage of the American Journal of Psychiatry’s 2024 review of PTSD by Arieh Shalev and colleagues from NYU. In this episode, you’ll learn who is at risk for PTSD after a trauma, and what goes on in the brain during PTSD. Trauma is very common. Around 2 in 3 people have had a traumatic experience, especially accidents and assaults. But most survivors of trauma don’t develop PTSD. They may have brief symptoms after the trauma or anniversary reactions, but otherwise function well. And not everyone who develops significant symptoms after a trauma has PTSD. Trauma can be part of the cause of nearly every psychiatric disorder – depression, bipolar, addiction, even schizophrenia – but PTSD is the only disorder that calls out trauma in the criteria. That can lead to overdiagnosis, so think twice next time you see, say, a young man with a family history of bipolar disorder who develops severe insomnia after a traumatic event, followed by irritability, racing thoughts, impulsivity, and other manic symptoms. Around 1 in 14 people will meet criteria for PTSD in their lifetime, and gender plays a role here. Rates of PTSD are 2-3 times higher for women than men. Putting all these stats together, what we arrive at is this: 70% of people will have a trauma, but only 7% will have PTSD.

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CHRIS AIKEN: There aren’t many top ten songs that quote medical research, so hats off to Paul Hardcastle for his “19.” But we need to update his 1985 statistics – current estimates are little lower, around 30% of Vietnam veterans meet criteria for PTSD at some point in their life. Charles Marmar, one of the authors on this American Journal review, lead one of the main investigations of PTSD in Vietnam veterans. In full disclosure, Dr. Marmar is also the department chair at NYU where I teach. If we put the DSM diagnosis aside and just look at symptoms, this next study tells us how PTSD symptoms play out after a trauma. They tend to fall over the first 3 months and then wax and wane, if they continue at all. The study followed people after a sexual assault. 2 weeks after the assault, nearly all, 95%, had prominent PTSD symptoms, enough symptoms to meet DSM criteria if we ignore the duration criteria, which requires that the symptoms last at least a month. If it’s been less than a month, it’s called Acute Stress Disorder. And that is the next point of measurement. 1 month after the assault, the rate of PTSD dropped from 95 to 63% 3 months after the assault it started to plateau, from 63% to 46%, and then down a little more to 42% at 6 months. What that tells us is that DSM’s cut off of 1 month is a reasonable time to start treatment, and after 3 months we should worry about persistence if the symptoms haven’t gone away.

KELLIE NEWSOME: Careful listeners will notice that the rates of PTSD after a sexual assault were twice as high as the rates for PTSD after combat – 63% vs 30%. That is true. Sexual assault leads to higher rates of PTSD than most other traumas. So who is most likely to get PTSD after a trauma? Here are the risk factors: being a woman, poor social supports, lower education, having a history of childhood adversity, family history of mental illness. People are more at risk if they drink after a trauma, or have dissociation, racing heart, or other intense symptoms during the trauma. On the other hand, those who retain a sense of control – however unrealistic that sense may be – are at a lower risk for PTSD. Then there are genetic risks.

CHRIS AIKEN: A twin study of Vietnam veterans suggests that 30% of the variance in the risk for PTSD is genetic. That’s a lot less than the genetic variance we see with other psych disorders like OCD, ADHD, bipolar and schizophrenia, where twin studies suggest that genes explain 60-80% of the variance. There are a host of genes with obscure names that raise the PTSD risk, but there’s one you might recognize: the short arm of the serotonin transporter, also known as the s/s genotype and featured on a lot of genetic panels. People with S/S are at greater risk for depression after stress, and greater risk for PTSD after a trauma. Next, we’ll look at what happens in the brain during PTSD, and how trauma can change the way that genes are expressed, but first a preview of the CME quiz for this podcast. Start earning CME through the link in the show notes.

KELLIE NEWSOME: What is the name of the process where conditioned responses gradually go away with repeated exposure and lack of reinforcement?

A. Negative reinforcement

B. Classical conditioning

C. Extinction

D. Kindling

What causes PTSD? The guiding theory is that PTSD is a conditioned fear response, but that something has gone awry because the fear never gets deconditioned. The fear response is normal and essential for survival. It’s central organizer is the amygdala, the seat of emotional reactions in the brain. The amygdala sets off a cascade of sympathetic and parasympathetic reactions, like racing heart and faster breathing, freezing, heightened sensation and focused awareness, as well as activation of the HPA neuroendocrine system. So we learn to be afraid, not just of the trauma but of anything that resembles the trauma – a process called overgeneralization. What goes wrong in PTSD is that we don’t unlearn this response. In other words, the fear is not extinguished. But why is that? Doesn’t behavioral science teach us that conditioned responses will eventually get deconditioned – extinguished – if there is enough repeated exposure without an actual threat? In other words, shouldn’t a war veteran eventually learn that loud car noises are not the sound of guns?

CHRIS AIKEN: Maybe something is going on in the brain that bypasses the safety valves of extinction. We don’t know exactly why that is, but there are a few theories that explain the persistence of PTSD and the lack of extinction. One is the kindling hypothesis. Kindling was first observed in epilepsy, where it was used to explain how seizures get entrained. The more seizures you have the more you’re likely to have, and the more intense they get. Robert Post extended it to mood disorders to explain rapid cycling and a telling phenomenon in mood recurrence – the first 2-3 mood episodes tend to be stress induced, but after that they develop a life of their own, as if automatically entrained, or kindled. So maybe some kind of kindling is involved to train the fear response in the brain? Another explanation of persistent PTSD is the allostatic stress hypothesis, which basically means the brain is worn down by chronic stress and can’t engage its usual healing mechanisms. We see some evidence of this in imaging studies of the hippocampus and emotional control networks in the brains of people with PTSD. A third popular theory is the subsystem clash or truncated response view. The idea here is that the normal balance of conditioning and extinction breaks down because one part of the brain blocks another from performing its homeostatic tasks. Here’s a bit of evidence that supports that allostatic stress hypothesis. The amygdala is more likey to stay in an active state of fear if the person has ongoing stress in their life after a trauma. Imagine a military veteran who has returned home from Iraq, only to face financial problems and daily fights with her husband. She is no longer facing shrapnel, but is facing continued stress, and the PTSD triggers left over from the war are going to take longer to go away. After a trauma, the nervous system needs to calm down to unlearn the strong encoding of a traumatic event, to forget. So anything a person can do to self-soothe after a trauma is helpful. And that points us to the approach in psychotherapy. People need to engage with reminders of trauma, and learn that they are safe – that is, re-experience them in a new way, with greater sense of control and calm. But exposure is not going to solve the problem if it keeps flooding the nervous system with sympathetic overload. Let’s take a deeper look at what happens in the PTSD brain.

KELLIE NEWSOME: Brain areas involved in PTSD include the amygdala, which registers emotions and threat responses; the prefrontal cortex, which regulates emotions; the hippocampus, which encodes important memories; and the default mode network which is responsible for that circular style of negative self-talk called rumination. There is noradrenergic hyperactivity, which is why the alpha-1 adrenergic antagonist prazosin is often used in PTSD. And there is abnormal cortisol signaling. Keep that in mind for a future podcast where you’ll learn that giving a dose of hydrocortisone shortly after a trauma can prevent PTSD from setting in and enhances extinction learning. GABA receptors are involved in PTSD, which may be why allopregnanolone, a neurohormone that regulates GABA, is being studied for PTSD. Yes researchers are exploring the in the synthetic form of allopregnanolone, zuranolone in PTSD, that’s the neurosteroid that was recently FDA approved in postpartum depression.

CHRIS AIKEN: There are other brain changes in PTSD. Dopamine is downregulated, and the serotonin system off balance. Perhaps that is why SSRIs treat PTSD, but it may also explain a lesser known pharmacologic phenomenon involving a metabolite of trazodone: meta-chlorophenylpiperazine (mCPP). When mCPP rises too fast, it tiggers serotonin release, causing symptoms of PTSD including anxiety, panic, flashbacks, and dysphoria. (So what I am about to say is speculation not entirely proven, but something to watch out for.) Maybe that is why a large 2019 study of veterans found an association between trazodone use for insomnia and suicidality. That doesn’t mean you can’t use trazodone in PTSD – the association is rare and not confirmed – but I would raise the dose slowly, like every week, if using it for depression and be careful when adding it to antidepressants that inhibit CYP 2D6, as they block mCPP’s exit route, causing the aggravating metabolite to spike. Antidepressants that can do that include bupropion, duloxetine, tricyclics, and two SSRIs that are often used for PTSD: fluoxetine and paroxetine.

KELLIE NEWSOME: One of the most replicated brain findings in PTSD involves brain structure: Shrinkage of the brain’s memory center, the hippocampus, which was first noticed in a 1995 study of Vietnam veterans. There is some debate as to whether this is a result of trauma, or part of what sets people up for PTSD. Some studies suggest that people with a smaller hippocampus more vulnerable to PTSD. What to do about it? We don’t have a clear answer, but aerobic exercise is pretty good at building a stronger hippocampus. Exercise and yoga do help PTSD – that’s something we know from 23 randomized controlled trials – and some studies are testing exercise as an augmentation to psychotherapy, where the patient does 30 minutes of aerobic exercise before an exposure session.

CHRIS AIKEN: Moving beyond the brain, we see epigenetic changes with PTSD like DNA methylation, changes which can be passed down through the generations after stress or trauma – and indeed some interesting studies have traced that transmission through the DNA of people born during times of major historic stress like the Great Depression.

KELLIE NEWSOME: Which is the better choice for anxiety: Gabapentin or pregabalin? Find out the answer in our new Carlat Video Series hosted by Greg Maltzberg, yes the same Dr. Maltzberg who anchors Carlat News with us. He is now the editor in chief of multimedia productions at Carlat. Watch it free on the Carlat Psychiatry Report YouTube Channel. Next week on the podcast, learn about the psychotherapies that treat PTSD and what to do when your patient calls you right after a trauma.

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