KELLIE NEWSOME: The placebo effect is everywhere, but some situations exaggerate it more, and knowing how to spot them can keep the treatment on the right path. Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003.  

CHRIS AIKEN: I’m Chris Aiken, the editor-in-chief of the Carlat Psychiatry Report.  

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. 

CHRIS AIKEN: I’ve been in practice for 25 years, and for most of that time, I’ve made it a habit to rate symptoms at every visit. That means years of ratings in thousands of patients, and today I’m going to share two patterns I’ve seen that can help you separate the real medication effects from the placebo effect a little better. 

KELLIE NEWSOME: The placebo effect is not evenly distributed. Some disorders are more responsive to it than others. Last year, Tom Bschor and colleagues from Germany ranked the placebo effect for each major psychiatric disorder. At the top are major depression and generalized anxiety, with an effect size of 1.2-1.4. That’s larger than the effect of Adderall in ADHD. By comparison, the effect size for antidepressants is small, around 0.3. That placebo effect is even higher for children and for mild depression, but it falls a bit lower in treatment-resistant depression. Next comes diagnoses in the middle, where the placebo effect is still large, around 0.7-0.9. Those are panic disorder, ADHD, PTSD, social anxiety, and mania. Yep, mania. Most mania trials are done in the hospital, where a structured environment and a few PRN lorazepams quickly stabilizes the symptoms. At the bottom are OCD and schizophrenia, but even for these, the placebo has a medium effect size around 0.6. 

CHRIS AIKEN: When this paper came out, some people said, “What am I going to do with this – I don’t prescribe placebo.” Ah, but you do. We all prescribe it. It is baked into every med we give and includes not just the patient's hopeful expectations but the natural course of the illness. The question isn’t “is my patient have a placebo effect” – which is impossible to answer – but “How much of a placebo effect are they having.” Dr. Bschor’s study helps us estimate thatby each disorder. Now let’s look at two other factors you’ll need to know about to assess treatment response. 

KELLIE NEWSOME: And that brings us to our first clinical pearl: The placebo effect is bigger at the first visit. 

CHRIS AIKEN: I don’t have proof of this one, but it’s something I saw in thousands of mood charts. Patients tended to report the biggest improvement after their first visit, regardless of which medication was started. Sometimes, they’d come off that first-visit medication and then restart it later, but their second response was not as impressive as the first. So, what’s going on here? While I don’t have proof, it is consistent with a lot of psychotherapy studies that show must improvements are made in the first few visits, and it’s consistent with what we know about placebo. Yes, patients bring a lot of hope and expectation to their first visit, especially if they put a lot of thought into choosing their provider. But that's not the only reason. There’s also regression toward the mean. 

KELLIE NEWSOME: Regression toward the mean. It sounds like a primitive defense mechanism, but it’s really a statistical concept discovered by the early geneticist Francis Galton. When Galton was studying the heritability of height, he noticed that parents who were really tall or really short tended to have children closer to the middle. They regressed toward the mean. In psychiatric practice, it means that we all go through highs and lows, triumphs and crises through life, but these peak experiences are – by definition – rare. You can’t reach an all-time low every day of your life, and random flux is a part of the slings and arrows of outrageous fortune, so translating this into practice. Patients are most likely to start treatment when they are at a historic low, and chances are they are likely to move closer to an average low by the next visit.  

CHRIS AIKEN: So, it's saying we all move toward the average, which is what the mean means. In his book The Mind Has Mountains, psychiatrist Paul McHugh talks about how he used regression toward the mean to counsel parents. McHugh was chair at Johns Hopkins, so he saw a different kind of patient than the rest of us, as his story will show. Highly accomplished parents would consult with him because their child was not as talented or intelligent as they were, and they wanted to know what was wrong. McHugh would counsel these parents on Galton’s law of regression toward the mean… that if your IQ is unusually high, chances are your child’s will be several degrees lower. I’m not sure if the parents were reassured by this. Maybe you’re scratching your head about it. I mean, wouldn’t you expect Einstein’s children to be highly intelligent? 

Regression to the mean only applies to random events, the kind that scatter among the bell curve is what we are talking about. This isn’t easy to wrap our minds around because our minds try to see the world as controllable and purposeful. Your child’s IQ – and your patient’s mood – are not entirely driven by chance, but we got to admit chance plays a bigger role than we give it. Bringing this back to practice, patients are likely to get better on their first visit by chance alone – regression to the mean – even if I don’t inspire a lot of placebo-laden hope; and even if I prescribe the wrong medication. 

KELLIE NEWSOME: Dr. Aiken you may not have proof of this first-visit idea, but you’re in good company with this idea. I found a nice article by Daniel Zigman and Pierre Blier called “A Framework to Avoid Irrational Polypharmacy in Psychiatry.” Love the title. Here’s what they say: “Clinicians should routinely consider tapering any extra medications that were added during times of crisis for additional symptomatic control. It is always possible that a patient improved due to placebo effects, regression to the mean or the natural history of their illness rather than the specific benefits of the medication.” Then it goes on to say cite studies where patients with stable, chronic schizophrenia were successfully tapered off antidepressants and mood stabilizers – stuff that – you know – isn’t really evidence-based for schizophrenia – and most were tapered off antipsychotic polypharmacy down to just one antipsychotic without any worsening. 

CHRIS AIKEN: Wow that’s from 2012? I didn’t know they had that evidence back then, but we did just review a pretty convincing study of antipsychotic polypharmacy in schizophrenia – these were patients in a long-term hospital unit, and they were randomized to either taper down to monotherapy or stay on the complex regimen. Not only was their no worsening, but their schizophrenia symptoms actually improved when they whittled it down to one antipsychotic.  

KELLIE NEWSOME: The bottom line. Watch for exaggerated placebo effects if you start a medication at the first visit or in a time of crisis. Those are times when patients are likely to improve on their own – either by the power of hope or regression toward the mean. Let’s pause for a preview of the CME quiz for this episode. Earn CME for each episode through the link in the show notes.  

1. What is the name of the phenomenon where an extreme random variable tends to be followed by a one that is closer to the mean of the sample? 

A. Sampling error 

B. Mean Inference 

C. Galton’s inference 

D. Regression toward the mean 

CHRIS AIKEN: We’ll conclude with another hidden placebo effect next week, but let’s end with a research update. Last month, two studies found alarming trends in recreational psilocybin and ketamine use. In the first one, Joseph Palamar at NYU found a 37% increase in recreational ketamine use between 2017 and 2024 after interviewing over 3,000 adults at New York City nightclubs over that time span. In 2024, nearly 1 in 4 nightclub attendees had used it. Ketamine use rose the most among women, adults over age 25, the college-educated, people who identify as lesbian/gay/bisexual or "other" sexuality, and people who use cocaine. Ketamine use peaked in the 1990s and then declined, so this may be a return to earlier trends. Other studies find that its approval in depression – which occurred in 2019 – has made people more willing to use it. 

Our next drug is not approved in depression, but it sure is acting like it is, with patients seeking out psilocybin therapy through underground networks or – in Oregon – perfectly legal ones. Using 5 national datasets from the US, Karilynn Rockhill and colleagues from the Federal SAMSA and Colorado’s Rocky Mountain Poison and Drug Safety program found that more people have used psilocybin in the past year than cocaine, LSD, methamphetamine, and illegal opioids. Before 2019, use of psilocybin was low and stable, but by 2023 the rate of past-year use nearly doubled, from around 1 in 100 to 1 in 50, with the largest increase among men, young adults, and people with depression, anxiety, or physical pain. Those numbers are for past year use; in 2023, 1 in 8 adults report at least one use of psilocybin in their lifetime. Some might argue that this is all self-medication, and everyone will be a little more content and creative on these drugs, but I’m not so sure. Ketamine causes thalamic hyperconnectivity, which is a robust marker for both schizophrenia and autism. It causes positive and negative symptoms of schizophrenia in healthy subjects and recreational users – that’s from multiple studies in people – and at least one study has used it to model autism in animals (Abram SV et al., Mol Psychiatry 2022;27(5):2448-2456; Cao H et al., Nat Commun 2018;9(1):3836; Beck K et al., JAMA Netw Open 2020;3(5):e204693; Cheng WJ et al., Schizophr Res 2018;199:313-318; Luo T et al., Front Psychiatry 2022;12:786622; Bove M et al., Prog Neuropsychopharmacol Biol Psychiatry 2022;117:110560).  As for psilocybin, Rockhill’s study is already finding problems. Between 2019 and 2023, there was a 201% rise in calls to poison center calls after psilocybin exposure. That was for adults; for children with potential psilocybin poisoning, the rise was even starker: 723%. 

KELLIE NEWSOME: Have you heard the news? The FDA has dismantled the clozapine REMS program. Find out what that means for practice in our June/July issue of the Carlat Psychiatry Report, where we also give a full review of the new antipsychotic Cobenfy, including new studies that look at its long-term risks and whether it can augment other antipsychotics. Get $30 off your first year’s subscription with the promo code PODCAST. The Carlat report operates 100% free of industry support.