Lord, it's like reading a hysterically passionate defense of antacids.
I'm a peer worker, and I’m supposed to believe people’s lived experiences, but even I find this stretches belief beyond all credulity. You're talking about the weakest class of psychiatric medication, and your argument rests on reports from the masses of people who crowd doctors offices with common complaints.
Since your entire argument rests on elevating personal anecdotes to the level of detailed case histories, I’ll meet you on the same level:
I don’t know any doctors I respect who believe SSRIs are effective for serious depression. (Sorry Roland)
I don’t know anyone with a clear-cut depressive illness with vegetative features who has benefited from an SSRI.
If we look at the history of primary care, it’s not the birthplace of great ideas. Freud practiced his theories on the wealthy unwell, and family clinicians for centuries swore by bloodletting and purging. We know ECT works because people with melancholia rise like Lazarus. Your demoralized patient sitting a little nervously in the waiting room chair isn’t a proper equivalent to a catatonic person waking up in front of you after lorazepam.
And why, of all drugs, do people rush to defend SSRIs so passionately? (I assume we're not passionately defending imipramine, that would just be too much to ask) Where were all the voices when Moncrieff attacked lithium? Why does Prozac get these long-winded polemics when treatments like lithium, ECT, and benzodiazepines are left to rot? Yes, let’s focus on Prozac when less than half of people with bipolar are even trialed on lithium. I don’t think I go a week without hearing about Lazarus-like recoveries from one of those three treatments. ECT? Sure, heard it many times, another one just last week. Benzos? Absolutely, just don't go bananas. Lithium? People take too much when depressed, but I don’t hear horror stories and I see people get well and stay well. SSRIs? Sure, half of everyone I know takes them, from friends who are totally well to friends who are neurotic. The neurotics swear they work, but they swear everything works, and they swear they have every illness, so it’s impossible to keep up.
Who are these melancholics you’re rescuing with Prozac? Where are they? Name one expert on melancholia who praises SSRIs. I’ve never heard of a serious doctor in acute care using SSRIs for melancholia (except Roland apparently). No academic psychiatrist praises their use. Name one. I’d love to speak to them. I get your argument: they're in an ivory tower, unable to see the work-a-day doctors treating all these gravely ill people with Prozac. Those same work-a-day doctors who can't even tell in their five-minute appointments when Prozac is making a patient agitated, irritable, or impotent. Yes, those doctors primary care doctors, who spend hours taking detailed notes from patients, interviewing family members, and filling volumes of case histories that clearly show the dramatic efficacy of Prozac. Oh, please. You know, many years ago when I was a wee young lad I had a doctors appointment that lasted an entire quarter of an hour. The things he must have learnt in such a time as that, an entire fifteen minutes, well I'm sure they would fill all the medical textbooks of the world.
The reality is: you see the doctor for five minutes, say “I’ve been feeling anxious and depressed,” they give you Zoloft, you take it for two months, it makes it so your dick doesn’t move, you stop taking it, and your doctor has no idea. But they go on thinking they’re doing a wonderful job. Maybe it’s you who needs to come down from the ivory tower. It’s as absurd as not understanding the effects of alcohol. Take one, just take one, and tell me that’s not more or less the experience. I don’t buy the "your mileage may vary" stuff. I'm like you, I accept the reasonable evidence of peoples eyes. Some people are happy drunks, some people are sad drunks, but how much does the mileage really vary? Heroin users give pretty accurate accounts, and yet Prozac’s effects are a mystery? Here's what I think, most people take it, and it does pretty much what I just said, but they never bother telling their doctor. A fairly large number of nervous people take it and swear they feel better—same people who last week told me they have ADHD and Adderall makes them feel better, the same people who tell me about their joint pain, upset stomachs, and how they’re neurodivergent and no one believes them about their back pain. I’m not meant to be saying this, but I just don’t care anymore. I know too many people like this and they are so unhealthy from the medical system. It’s not an uncommon personality type. We all know people like this, and most of them are on some pill or another. Frankly, they’d probably feel better on anything. Multiply that out, and you get a pretty good theory about why these drugs have caught on.
I would suggest the reason SSRIs are so popular is because they don’t do a whole lot, which is absolutely perfect for people who don’t have much wrong to begin with.
The only reason you can give is that millions swear by them. Suddenly there are all these melancholics at death’s door, and Prozac 100% did the trick did it? And everyone was too stupid to notice all these gravely ill people for centuries? We only started noticing once we started giving Prozac to people? Jeez, how about that?
Here is my challenge: I don’t want to see any more RCTs. Just give me a case series—three or four full case histories. I want to see a detailed history of the course of illness, detailed psychopathology demonstrating the existence of a serious form of depression, regular detailed follow-ups, and extensive interviews with close family members, friends, and work colleagues. I want to see the long-term outcome. I want you to buy a cot and sleep in the corridor outside the patients’ bedrooms for, say, a month each. Maybe try having sex with them. If you can show me those things, I’ll relent—no RCTs required. I’m perfectly happy to accept careful, detailed empirical observations. I’m pretty sure the lions share of the observations you’re talking about are careless five-minute med checks.
Those are my anecdotal thoughts. Now, should we have antidepressants? Yeah, doctors need options. I don't know, some people have this kind of rumination thing that, they take an SSRI and they don't have as many thoughts, that's my anecdote. Useful. Sure. Sorry to be an arsehole about it, I just can't understand how recreational drug users can describe drug effect in the most vivid detail and psychiatrists can't even describe the most simple effects. I don't like Moncrieff much but when she describes the effects of SSRIs, it just jibes with reality and the straight forward descriptions I hear most people give. My only critique is that she conveniently forgets a whole bunch of other effects. Including some, which may be of some benefit.
Anyway, it's fun speculating and living in an evidentiary vacuum, we can all come up with the wildest opinions.
Excellent rebuttal of this garbage dump of an article. But I wouldn't praise ECT. Read enough online anecdotes and a more realistic picture emerges of most people getting harmed while the lucky few get all the publicity.
I do read online testimonials and I take them quite seriously but I try to ground my opinions on people I've met or that wife has met. I think it helps tremendously if a treatment is first of all markedly effective. It seems to me ECT works well if people are carefully selected and I don't think the phenotype for ECT response is aware near the mystery it's made out to be. That said, it's a serious treatment for a serious disease.
I'm honestly quite bullish about psychopharm and I'm a believer that acedotal evidence, gathered with care, that is of a high quality is very persuasive. I just cannot fathom the enthusiasm for SSRIs other than to put it down to the sheer amount prescribed. Make something ubiquitous enough and you'll have a legion of fans. But this ubiquity has reached a point where so many people are on these drugs, most of have seen enough to know what they do, in same way that the widespread use of alcohol makes it effects fairly well known. This situation makes the experts look rather foolish when they cannot describe such ubiquitous phenomenon. Thus my point about Moncrieff and her observations of SSRI effects, which to me are about as controversial as observing that alcohol makes people tipsy. Moncrieff conveniently omits other effects though and I dislike her cherry picking rhetoric. Its very Maudsley.
I just find SSRIs to be strangest hill to die on. There are some people, who have a particular type of apprehensive rumination, a tendency to worry about "what if this (terrible) happens", perhaps it's related to OCD or perhaps it's a form of nervous illness, but they are the people I notice who when they take an SSRI they stop caring about all these apprehensive thoughts, it makes them apathetic. I think that is more than just useful and is a really good effect in those cases. The problem is that it has virtually nothing to do with depression, psychomotor slowing, vegetative symptoms, delusions of guilt. And further more people with more bolt from the blue agitated anxiety seem to do worse on these drugs. There is one other effect that Moncrieff fails to mention, I have met people in whom certain antidepressants do seem to stifle panic attacks. Most recently a woman with very prototypical panic attacks that seemed to be blocked by bupropion.
I'm also inclined to the idea that serotonin isn't wholly unimportant in depression. I heard Nemeroff say something in video the other day along the lines of "I wouldn't say serotonin has nothing at all to do with it", or something to that effect. Its more that I just cannot fathom the urge that possesses people to wax lyrical about SSRIs. I don't think they should be removed from the armamentarium for the above reasons. But all these people defending them on the basis of experience, anecdotes, pattern recognition, where are their detailed case reports? Emphasis on "detailed". A few good case reports where I had confidence in the validity of the diagnosis and in which the improvement was marked would be more than enough to satisfy me. Instead the whole issue spins round and like some "trust me bro" vortex, like people debating who kidnapped Madeleine McCann. How about producing one of these acedotes in the form of a detailed vignette.
Wait a sec - anecdotes and historical analysis from a practicing physician are "garbage" but online anecdotes (ie and opportunistic sample) are helpful and informative? I'm confused...
Nitpicking statistics is a waste of time, especially when most pharmaceutical research (and science in general) is fraudulent. A doctor that won't take his own medicine is a shill. Actions speak louder than words and Wikipedia links.
Sometimes I find comfort in the idea that some of the supposedly over prescribed drugs don't work, because the other option would mean that many people really are mentally ill in a way that requires chemical intervention to fix and that's even worse imo
I find this comment really relatable—I've definitely thought this way in the past too. I think it's partly a symptom of how drugs are framed. As I mentioned, I think Moncrieff sometimes goes too far and can be a bit hyperbolic, but her framing offers a better perspective. When drugs are marketed as the perfect 'lock and key' solution, where the disease is the lock and the drug is the key, it can make it seem like people are born needing these drugs—as though nature somehow decreed it. I'm exaggerating here, but I think this narrative often drifts too far in that direction. This is the mainstream drug narrative we're all familiar with, and it starts to sound like these drugs are almost predestined to be necessary. If we think about it more like Moncrieff does—that drugs simply have 'effects' that may or may not be useful—we're probably closer to the objective reality. Though she pushes the point too hard at times, and some drugs do seem to have more direct effects on disease processes (lithium, for example), it’s by no means certain.
Another way to look at it is serendipity, which is how many early drug discoveries were understood. Moncrieff isn't the best historian, but she does a better job than most of her peers. For instance, she often quotes Jean Delay on antipsychotics without acknowledging that Delay had a reputation for avoiding direct clinical work—Deniker was the one who actually did the hands-on work. Quoting Delay on drugs is like quoting Freud—it’s not especially persuasive. But serendipity, that’s the key. People like Donald Klein talked about it: a lot of these breakthroughs are luck, and we get a disease, and by chance, a certain chemical happens to help. Once you realize that many drugs were discovered, at least in part, by luck—or trial and error—the 'lock and key' model starts to disappear. You can then view drugs as something other than perfect machines designed to do a specific task. David Healy calls this "magic bullet" thinking. I call it lock and key. Sometimes we get very luck and we do find a magic bullet, like antibiotic, or insulin, but the idea any psychiatric drug is "like insulin" a comparison which even Donald Klein made in the book Understanding Depression, is really rather silly and every bit as hyperbolic and sweeping as anything Moncrieff has ever said. Its useful for public consumption and sometimes a bit of oversimplification is needed, but here in 2025 far too many people picture a "magic bullet" when they picture a drug.
Of course, as drug research has progressed, so has the engineering of drugs. This is where someone like Alvid Carlsson comes in—he worked on SSRIs, which were designed with more specificity in mind. But still, some of the best drugs, like lithium and imipramine, were found by sheer luck. So, it's not that we're born needing drugs, but we can be born with a disease whose symptoms just happen to respond to a drug—or, in even luckier cases, part of the disease process might respond to a drug. I think it's fine to use internal medicine as a model here. Modern medicine can do incredible things, but a lot of it is down to serendipity. We shouldn’t assume that the universe has ordained that drugs should work or that we should need them. It’s a mix of bad luck that we get ill, and good luck that some drug might help. Once you understand that, you can approach drugs with the right skepticism, knowing that the odds are against them working and that the burden of proof is on demonstrating that they do.
I'm really not such an arse in person. And I really do tend to believe what people tell me, it's just people tell me things they don't tell their doctor.
And that is why medicine is becoming increasingly dysfunctional and discredited. As women take over institutions agreeableness becomes the order of the day and the dialectic process is abandoned. Next thing you know we are castrating children and it’s easier to get testosterone as a teenage girl than a middle aged man.
We have not met, but my friend and colleague, Dr. Mark Ruffalo, sent me the link to your posting. There is far too much to say on this topic for a brief space like this, but I did want to commend you for so many of the points you make. Most are very closely aligned with what I have been banging on about for nearly 40 years!
I particularly agree with your valuation and affirmation of the clinician's and the patient's felt experience with antidepressant medication. Thousands of us who have had the privilege of working with desperately ill and suffering depressed patients have seen, over many years, the benefits of these medications. (And yes--we are well aware of the important downsides, risks and potential side effects--nearly all of which can be mitigated and managed with expert care). Furthermore, in my view, there has been far too little emphasis on "quality of life" and too much focus on the Hamilton Depression Scale, in assessing the benefits of antidepressants. [1]
Much more could be said, but I simply wanted to register my agreement with the essence of your article. My own views are well-registered on the Psychiatric Times website, including my most recent posting, much of which resonates with yours.
1. Pies RW. Antidepressants, the Hamilton Depression Rating Scale Conundrum, and Quality of Life. J Clin Psychopharmacol. 2020 Jul/Aug;40(4):339-341. doi: 10.1097/JCP.0000000000001221. PMID: 32644322.
Thank you so much Ron for taking the time to read this, and for your thoughtful response. I appreciate your work, have been following since I was a resident! Doug Beech
The history of medicine becoming a science rather than pseudoscience is a history of the rejection of "felt experience" in favor of data. Apparently, it's very hard to embrace the scientific mindset, so hard that even those nominally educated in science often cannot do so. Sad.
Having read through nearly all of the comments on Dr. Beech’s posting, I’d like to suggest an alternative perspective to either of two extreme views of antidepressants—i.e., either they are little more than “expensive sugar pills,” or else they are tremendously effective agents in the treatment of depression. (I recognize that several of the comments avoid either of these extremes).
My view, as a mood disorder specialist (now retired from practice), is that antidepressants now in use are modestly-to-moderately effective agents for a substantial number of patients with acute, moderate-to-severe, unipolar major depression. Having written and taught about these agents for nearly 40 years, I am not so naïve as to imagine that what I have to say will persuade anybody at either of the “extremes” I mentioned. However, I am hoping that those open to a “middle ground” will reflect on the bullet points below and will also read the excellent (2022) review by my colleague, Dr. Awais Aftab, which can be found at this link:
• Healthy skepticism about antidepressants (AD s) is reasonable and justified, in view of the mixed results of published studies. Skepticism, however, need not devolve into cynicism.
• The evidence-base for the claim that AD s are at least modestly effective (as qualified above) consists of much more than personal “anecdotes”.
• Clinical experience based on careful, repeated examination of patients over months or years should not be dismissed as “anecdotal.”
• The effectiveness of these agents depends on many factors, including:
1. How efficacy is measured (e.g., the Hamilton Depression Scale (HDS) or a subset of HDS items). The effect size (how effective the AD is vs. placebo condition) increases substantially when measured with a subset of HDS items (the HAM-D-6. See P.Bech, below)
2. The severity of the depression. The less severe the depression, the less separation between the active treatment condition and the placebo condition (the latter involving many hours of supportive contact with the patient). Most studies find that AD s are most effective for the more severe forms of depression. Put another way, the more the clinical picture resembles “ordinary sadness,” the less effective and less appropriate is antidepressant medication.
3. The type of depression. Antidepressants are not usually helpful or effective for bipolar depression, and may make the patient worse. Melancholic depression (a very severe form) does not respond well to either placebo or psychotherapy, but does respond to antidepressant treatment.
4. The specific antidepressant used, according to some studies (see Cipriani et al, cited below). By the way, bupropion is a non-serotonergic antidepressant that avoids nearly all the “SSRI” side effects and is FDA approved.
5. Whether one is looking at single drug studies (i.e., only one AD is tested), or the “real world” of clinical practice, in which we routinely “treat until the patient is better” using two, three, or more antidepressants in sequence, often augmented with other agents, such as thyroid hormone.
• Clinical evaluation is not merely a matter of picking up good or bad “vibes” from the patient. Many psychiatrists—and virtually all mood disorder specialists—assess the patient’s response using, for example, the Beck Depression Inventory or other related scales. Use of the BDI was a regular part of my private practice as a psychopharmacology consultant, usually with repeated testing over weeks, months, or even years. These findings constitute data, not mere subjective impressions.
• Most meta-analyses and clinical studies involve use of the Hamilton Scale (HDS), which has several limitations and drawbacks. Most studies looking at the patient’s “quality of life” (QOL) are supportive of the beneficial effects of antidepressants, though there is a paucity of randomized, placebo-controlled studies of QOL. [See Andrade, below]
Finally, I view antidepressant medication as basically a “bridge” between feeling miserable and feeling better. The patient must still walk across that bridge, and that is where “talk therapy”, behavioral and cognitive change, and the therapeutic relationship come into play. For readers who want to delve into the research literature, I strongly recommend starting with Dr. Awais’s review. Other pertinent references are listed below.
Respectfully,
Ronald W. Pies, MD
For further reading:
1. Cipriani A et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet, Volume 391, Issue 10128, 1357 - 1366
2. Stone et al. Response to acute monotherapy for major depressive disorder in randomized, placebo-controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ 2022; 378 doi: https://doi.org/10.1136/bmj-2021-067606 [Note: this study has been widely misinterpreted. For a discussion, see:
3. Pies R. Are antidepressants effective in the acute and long-term treatment of depression? Sic et Non. Innov Clin Neurosci. 2012 May;9(5-6):31-40. PMID: 22808447; PMCID: PMC3398684.
4. Andrade C. Antidepressant drugs and health-related quality of life: a reader’s guide on how to examine a “viral” research paper with a critical eye. J Clin Psychiatry. 2022;83(3):22f14527.
Dr Pies, thank you for taking the time to elaborate on the topic of efficacy of antidepressants. Your notations and references show what a broad and complex topic it is, and how difficult it is to study these questions scientifically. I agree that Dr. Awais's piece is a great place to begin a deeper dive. The thesis of my original post was much more narrow, focused on the role of clinical experience(s) in contrast to published trials research. As the comments reveal there are many more facets to the discussion. I appreciate your thoughtful and measured contribution.
Former psychiatrist. Nicely put. My worry has always been that the costs and benefits - principally for me the human ones but, to be realistic, also the economic benefits - are ignored in the interests of an ideological drive to halt prescription of these life-saving medicines. The therapeutic fashions come and go, but the evidence is clear. I don’t see this going away, so thanks for weighing in.
The scientific evidence is absolutely clear: antidepressants work - far beyond clinical anecdotes. The author, unfortunately, goes backwards. Peter Kramer, OTOH, noticed results in his patients, reluctantly as a believer in talk therapy, and did the research, instead of vice versa or apologizing for the research. The research's flaws only show up in poorly designed studies. Antidepressants work as well as any other "ordinary" drug does, hence the title of his latest (nonfiction) book, "Ordinarily Well."
Thank you for taking time to read the article and for your comment. I agree that the whole of the scientific evidence is clear, and supports the efficacy of the medications. The thesis of the post is a narrow one: a comparison of the weight of unpublished evidence (clinical experience by the tens of millions of cases, observed over time) vs published studies. The post also focused narrowly on three particular criticisms common in the public discourse and social media forums, which tend to double down on the flaws in the industry-sponsored studies (and those left in the 'file drawer') and dismiss clinical experience and knowledge of the uniqueness of individual patients as anecdotal. Even the best-designed studies are still limited (true randomization isn't possible, and selection filters, flawed instruments of measurement), as is the evidence seen in clinical practice (expectancy, compliance, subjectivity of patients and practitioners, diagnostic variability and imprecise measures). This is true in so much of medical practice, however. I am generally in alignment with sentiments expressed by Dr. Kramer in his book. One excerpt from his book captures a slice of it here: "I treated patients. Like most doctors, I kept abreast of research results, but I read them in the context of what I saw in my daily work." I agree the published literature contains good evidence. I just don't think it's the best evidence. DB
Understood. I felt the piece was too apologetic of the published evidence, but perhaps my impassioned belief in antidepressants - while knowing they don't work for everyone, nor do they work as well for everyone as the kind of anecdotes in, say, "Listening to Prozac" - led to a defensiveness in my position. I will re-read. (Like many people, Peter's book/s have had a huge influence on my life, as lifelong sufferer of depression and anxiety. I read as much as I can, as a layperson who doesn't always but tries to understand all the scientific intricacies, and if antidepressants didn't work, I would accept that. They've worked ordinarily well for me, and save the lives of many I know. Anecdotes! Now, like many, I fear what's to come, as RFK Jr. has had his anti-SSRI position endorsed by Trump, and Musk, who seems from his own statements as well as behavior to suffer from bipolar disorder, self-medicates with ketamine - I understand it is a legitimate treatment under doctor's supervision, which is not how he takes it - and other drugs. That worry, too, surely informs my reading of the subject. Thank you.
Thanks very much, Dr. Beech (Doug, if I may...). Yes, the issues are complex and nuanced, and avoiding "absolutist" positions is, in my view, important. But nothing should detract from your original post and thesis; namely, that careful, long-term, clinical observation of patients and their responses to treatment is a valid and critical type of empirical evidence--and certainly not "anecdotal" information! Best wishes on your new blog, which--by the way--garnered a shout-out on Dr. Awais's substack for March 15. [1]
Thank you so much Ron! Appreciate your time and attention to this. Thanks for letting me know about the mention in the psychiatry margins Substack also.
As someone who is NOT a physician I very much appreciate your approach to this topic. I have seen the anecdotal evidence that you talk about in my loved ones who have very clearly benefited from antidepressants. It is so important, anytime we aim to create public policy, that we listen to the experts on the ground. In this case, the doctors who prescribe these medications and see their effects every day. Thank you for your thoughtful article! Looking forward to more.
In the current climate there is no way I'm hell that I am taking the anecdotal musings of a single physician over 2 decades of research. I took antidepressants for 5 years, to no effect. That's my experiencial analysis. They did nothing. Why not take your faith and priors and retrain as a homeopath, you might find peace.
The probability that clinical trials understate the benefit of anti-depressants is near-negligible, given the powerful incentives and the thumb on the scale.
If the most depressed people are excluded from clinical trials then no most depressed individual should be prescribed an antidepressant precisely because there is no evidence but anecdotal that antidepressants would help him or her.
Prescribing to such people, not patients, would be baseless from the lack of targeted at them clinical trials and it would be done by analogy. With no physiopathology to support their use in them, none at all.
You are not clear enough: if there are two positive trails for an antidepressant and more than two that come negative, a reasonable person would conclude there is evidence for its ineffectiveness more than for their utility. They are more useless than beneficial, absent side effects as severe as genital anesthesia, or orgasmic inability.
As for seeing improvement in the clinical office there is a dictum, an old one: patients improve despite treatment.
Practicing physicians do follow Guidelines because if they don´t and a patient has a bad outcome they get a law suit for not following a Guideline.
Practicing clinicians are not mavericks, they are more conservative than the MAGAs, just to avoid liability.
People confuse Belief with Opinion and Fact, Beliefs are impervious to facts, Believing in God does not respond to evidence of God´s inexistence or existence outside Reality and Science and its methods.
No one needs antidepressants, the mind is not real, nothing mental is real:
You lost me... "Found no evidence" is different from "there is no evidence?" Only if you have no confidence in your judgement, skills, capacity etc surely? If the person who looked for the evidence was a competent "looker" then surely "found no evidence" means "there is no evidence"? It doesn't mean we might not find some in the future, but it does mean that at this moment in time, there is no evidence... To say otherwise is to have no confidence in your ability to do research I would think. One confused med student here.
My standard line about drug company studies (or when people ask about psychogenomics) is my cats' response to catnip... One cat loves it, one hates it, the other is indifferent... This is a stable response over time. But if this was a study, the conclusion would be that that catnip does nothing, because one positive, one negative, and one indifferent all adds up to no effect. The fact that people have individual responses to drugs is not something captured adequately in studies.
Personally I'm not a fan of meds for anything other than severe/melancholic depression (for depression); most of the anxiety/depression I've seen in primary care and ED has social and personality "causes" and I think it's obscene to label social/personality issues a mental illness and respond with drugs... Colluding with neoliberalism and reconstructing social issues as psychiatric illnesses simply allows for the diversion of resources from social support services, housing etc to big pharma's pocket. Psychodynamic psychotherapy is my treatment of choice for the remaining personality factors and is rarely funded.
*"You lost me... "Found no evidence" is different from "there is no evidence?"*
These are indeed very different. The principle is more commonly expressed as "Absence of evidence is not evidence of absence". This applies to benefits and harms and every other conceivable relationship between two clinical factors.
Consider, for instance the hypothesis that smoking causes lung cancer. At one stage, there was an absence of evidence of a causal relation. This was not evidence of absence of that causal relation.
More generally, a negative study must be assessed for its statistical power, not summarised as "Scientists looked and found no effect." Drug companies are very quick to cite lack of a significant effect as sufficient reason not to worry about potential harms for which there is a weak, unconfirmed signal, and this conflation should be strenuously resisted.
Moreover, clinicians are often forced to make decisions for which the relevant study has not been done and won't be done, so they need to move beyond the strict guardrails of evidence-based medicine. If a small crappy study fails to resolve an important issue because it is underpowered, that does not put the matter to rest, and clinicians must fall back on judgement.
Whether antidepressants have adequate evidence of efficacy is a separate, more complicated matter.
I write this as a physician who has also worked for decades auditing drug company research.
Interesting and thought provoking article. But I am left a bit conflicted.
In the nutrition space, carnivore or keto doctors rely on the same type of arguments to 'extol the virtues' of their respective protocols and the 'show me the science' crowd rightly (I think) criticise them for over reliance on anecdotes and ignoring the broader research. How is it different in this case?
At what point do we decide that the 'anecdotes' have reached a level where they can override research?
Very good questions and I agree there are a lot of similarities between the two areas, in comparing published research with actual experience.
In my post, the narrow point I emphasize is what practitioners rely on in terms of decision-making in clinical contexts, and contrasting that with the chief sources of the skepticism about efficacy. Critics rightly point to the published research that calls into question efficacy, but practitioners have other evidence that they rely on in addition to this.
Very interesting that you bring up nutrition research and make this comparison because in my post I edited out a quote from fitness blogger Mark Sisson who advocates for some unconventional diet and nutrition approaches such as high fat. In a 2012 interview responding to critics who ask “where are your controlled studies? Where are your randomized controlled trials?” He responded that he has over 10,000 email testimonies several paragraphs long from people losing large amounts of weight, getting healthier, reversing hypertension and type 2 diabetes and getting off of medication. He was making a similar point.
It seems the root issue with the topic is the quality of the research. My narrow point was that practitioners look at the published research but don’t rely on it for their decisions nearly as much as what they see in their offices. It is of course limited because it’s anecdotal ,prone to lots of subjectivity and impressionistic opinions… But that’s true in a lot of of what practitioners do especially in general medicine.
From what I understand almost all published research in the nutrition world is epidemiological. And let’s face it the cost and time involved to systematically study and compare different nutritional approaches would be astronomical. There are some small (30 day) type studies that compare different diets where the participants are housed in a dormitory and it is known what they are eating. These are rare and only show the short term effects versus long-term impacts. Most of the studies involve people answering questions to surveys so it is difficult to rely on them and controlling for all the different variables.
I do highly recommend the Peter Kramer book on this particular topic diving into it in a deeper way. Some of the comments to the article extrapolated my narrow point into broader assertions that I wasn’t making about antidepressants and their place in the overall scheme of mental healthcare.
Thank you for your detailed response. All your points are well taken and I will definitely be reading Kramer's book to understand the topic on a deeper level.
As a layman, I don't really have the knowledge and skills to evaluate all the evidence and land strongly on any side of this. It's interesting to read how practising clinicians make these decisions and weigh them up against the published research.
Thats not what the Surgeon General said, he Tweeted this last century:
"General bloodletting is never necessary. It will calm a highly-maniacal patient, but so will a sufficiently severe blow on the head." - William Hammond
Companies have moved past SSRIs, they are legacy generic drugs. Now, patented antipsychotic drugs are heavily promoted for their ability to enhance the efficacy of SSRIs. The scientific basis for this has not been adequately explained.
A large analysis found the most effective antidepressants are two ancient tricyclic drugs. What they have in common? The most potent antihistamines ever discovered. They are highly sedating.
Not so much on the tricyclics but I think part of the appeal of SGAs in some cases is the sedative effects, particularily olanzapine and seroquel.
I was at a comedy night hosted by a local Hearing Voices charity. One of the running gags was knocking patients out with Seroquel. Every time the comedian playing the doctor brought out a giant, oversized bottle of it, the audience roared with laughter, friends, family members, peer workers—they all got the joke. It’s telling when a drug’s effects are so universally recognized that it can be used as a bit gag.
Why shouldn't sedation be useful. I'd probably feel better too if I was half zonked.
The opposition to antidepressants always seems to rest on this weird unstated intuition that it's somehow bad to be taking psychiatric meds unless there is some really strong case they treat a well-defined chemical imbalance (whatever the fuck that means). I mean if your only concern was to make people's quality of life better than even if SSRIs and SNRIs etc were mere placebos they have sufficiently mild side effects it seems clear they would make people's lives better. They aren't just placebos but that's kinda besides the point, the case for them was already sufficient.
But that isn't the only reason to worry about antidepressants. Sure, they are helpful but it also seems like we lack any clear mechanism and they are very hit or miss. For all we know we are just doing the human equivalent of waking the electronic device to make it work -- randomly perturbing the system since an extreme state is more likely to be moved towards the normal equilibrium. And that's all great, whatever works, but I fear the sense the public has that we have decent antidepressants discourages looking for something else that works for those who aren't fully treated by the usual antidepressants (both individually and at the research level). In other words, if you tell people prozac is an effective antidepressant they won't understand why you might need something else.
Maybe that's just me being paranoid but I've met lots of people with depression (inc myself at times) and while modern antidepressants certainly were helpful they often were still in a quite bad way and just stopped mentioning it to docs etc bc they were on an effective antidepressant so what else was there. To their credit I know many psychiatrists will try drugs like MAOIs, tricyclics etc when SSRIs, SNRIs etc fail but many people just see a GP and since they are told these are effective drugs they don't say anything when they are still pretty badly off (if these are effective and I still feel bad guess there is nothing to do)
I was thinking something similar recently about "perturbing" a system. Its a bit humbug but I'm reminded of something Alvid Carlsson said about paradoxical effects, I can't recall the quote but Shorter was asking him about akathisia and Carlsson sort of said something to the effect of if a system control certain effects we can't be surprised if we occasionally produce the opposite effect when interact with it. Go poking around in the part of the CNS that controls anxiety and we can't be too surprised if perturbing it produces agitation.
I wondered for a while now why doctors don’t lean more on the placebo aspect at the beginning of treatment by prescribing sub-therapeutic doses for a period long enough to assess whether positive expectation and care alone can resolve the problem.
Another point in response to patients misrepresenting their actual condition: Why not administer and track their state with Dr. Burns’s Brief Mood Survey so there’s a good quantitative snapshot each visit? Seems to me at least that this should be standard practice?
I think you could throw a rock in almost any direction and improve matters. Any digging into the history of bad pharmacy just about always reveals the same issues of neglect, ignorance and rushed care.
I'm not sure how the mood survey would help with patients who are deliberately and consciously trying to present as having a worse condition -- especially since most docs want to help their patients so they may not want to stand in the patient's way of getting into a trial.
Regarding the placebo effect, the issue is that doctor-patient trust is very important. If I don't believe what my doctor tells me or suspect he might be giving me placebos I might decide not to put in so much effort taking them or ignore her advice.
At least when it comes to anti-depressants doctors truly believe they work so even if the evidence for that claim turned out to be a hugely unlucky coincidence it still wouldn't be a reason to try and reduce usage. In other words, we don't want docs adopting a policy of patient deception (except maybe w/ some kind of general prior consent) but even if they happened to be wrong about these meds being effective (which they aren't) it wouldn't be harmful.
On the use of sub-therapeutic doses I agree that doctors should be transparent in their thinking as they are in open placebo trials.
Script: “Studies have shown that even placebo-level doses can help some people in your condition with the added benefit of fewer side effects. Do you want to try that first?”
Lord, it's like reading a hysterically passionate defense of antacids.
I'm a peer worker, and I’m supposed to believe people’s lived experiences, but even I find this stretches belief beyond all credulity. You're talking about the weakest class of psychiatric medication, and your argument rests on reports from the masses of people who crowd doctors offices with common complaints.
Since your entire argument rests on elevating personal anecdotes to the level of detailed case histories, I’ll meet you on the same level:
I don’t know any doctors I respect who believe SSRIs are effective for serious depression. (Sorry Roland)
I don’t know anyone with a clear-cut depressive illness with vegetative features who has benefited from an SSRI.
If we look at the history of primary care, it’s not the birthplace of great ideas. Freud practiced his theories on the wealthy unwell, and family clinicians for centuries swore by bloodletting and purging. We know ECT works because people with melancholia rise like Lazarus. Your demoralized patient sitting a little nervously in the waiting room chair isn’t a proper equivalent to a catatonic person waking up in front of you after lorazepam.
And why, of all drugs, do people rush to defend SSRIs so passionately? (I assume we're not passionately defending imipramine, that would just be too much to ask) Where were all the voices when Moncrieff attacked lithium? Why does Prozac get these long-winded polemics when treatments like lithium, ECT, and benzodiazepines are left to rot? Yes, let’s focus on Prozac when less than half of people with bipolar are even trialed on lithium. I don’t think I go a week without hearing about Lazarus-like recoveries from one of those three treatments. ECT? Sure, heard it many times, another one just last week. Benzos? Absolutely, just don't go bananas. Lithium? People take too much when depressed, but I don’t hear horror stories and I see people get well and stay well. SSRIs? Sure, half of everyone I know takes them, from friends who are totally well to friends who are neurotic. The neurotics swear they work, but they swear everything works, and they swear they have every illness, so it’s impossible to keep up.
Who are these melancholics you’re rescuing with Prozac? Where are they? Name one expert on melancholia who praises SSRIs. I’ve never heard of a serious doctor in acute care using SSRIs for melancholia (except Roland apparently). No academic psychiatrist praises their use. Name one. I’d love to speak to them. I get your argument: they're in an ivory tower, unable to see the work-a-day doctors treating all these gravely ill people with Prozac. Those same work-a-day doctors who can't even tell in their five-minute appointments when Prozac is making a patient agitated, irritable, or impotent. Yes, those doctors primary care doctors, who spend hours taking detailed notes from patients, interviewing family members, and filling volumes of case histories that clearly show the dramatic efficacy of Prozac. Oh, please. You know, many years ago when I was a wee young lad I had a doctors appointment that lasted an entire quarter of an hour. The things he must have learnt in such a time as that, an entire fifteen minutes, well I'm sure they would fill all the medical textbooks of the world.
The reality is: you see the doctor for five minutes, say “I’ve been feeling anxious and depressed,” they give you Zoloft, you take it for two months, it makes it so your dick doesn’t move, you stop taking it, and your doctor has no idea. But they go on thinking they’re doing a wonderful job. Maybe it’s you who needs to come down from the ivory tower. It’s as absurd as not understanding the effects of alcohol. Take one, just take one, and tell me that’s not more or less the experience. I don’t buy the "your mileage may vary" stuff. I'm like you, I accept the reasonable evidence of peoples eyes. Some people are happy drunks, some people are sad drunks, but how much does the mileage really vary? Heroin users give pretty accurate accounts, and yet Prozac’s effects are a mystery? Here's what I think, most people take it, and it does pretty much what I just said, but they never bother telling their doctor. A fairly large number of nervous people take it and swear they feel better—same people who last week told me they have ADHD and Adderall makes them feel better, the same people who tell me about their joint pain, upset stomachs, and how they’re neurodivergent and no one believes them about their back pain. I’m not meant to be saying this, but I just don’t care anymore. I know too many people like this and they are so unhealthy from the medical system. It’s not an uncommon personality type. We all know people like this, and most of them are on some pill or another. Frankly, they’d probably feel better on anything. Multiply that out, and you get a pretty good theory about why these drugs have caught on.
I would suggest the reason SSRIs are so popular is because they don’t do a whole lot, which is absolutely perfect for people who don’t have much wrong to begin with.
The only reason you can give is that millions swear by them. Suddenly there are all these melancholics at death’s door, and Prozac 100% did the trick did it? And everyone was too stupid to notice all these gravely ill people for centuries? We only started noticing once we started giving Prozac to people? Jeez, how about that?
Here is my challenge: I don’t want to see any more RCTs. Just give me a case series—three or four full case histories. I want to see a detailed history of the course of illness, detailed psychopathology demonstrating the existence of a serious form of depression, regular detailed follow-ups, and extensive interviews with close family members, friends, and work colleagues. I want to see the long-term outcome. I want you to buy a cot and sleep in the corridor outside the patients’ bedrooms for, say, a month each. Maybe try having sex with them. If you can show me those things, I’ll relent—no RCTs required. I’m perfectly happy to accept careful, detailed empirical observations. I’m pretty sure the lions share of the observations you’re talking about are careless five-minute med checks.
Those are my anecdotal thoughts. Now, should we have antidepressants? Yeah, doctors need options. I don't know, some people have this kind of rumination thing that, they take an SSRI and they don't have as many thoughts, that's my anecdote. Useful. Sure. Sorry to be an arsehole about it, I just can't understand how recreational drug users can describe drug effect in the most vivid detail and psychiatrists can't even describe the most simple effects. I don't like Moncrieff much but when she describes the effects of SSRIs, it just jibes with reality and the straight forward descriptions I hear most people give. My only critique is that she conveniently forgets a whole bunch of other effects. Including some, which may be of some benefit.
Anyway, it's fun speculating and living in an evidentiary vacuum, we can all come up with the wildest opinions.
Excellent rebuttal of this garbage dump of an article. But I wouldn't praise ECT. Read enough online anecdotes and a more realistic picture emerges of most people getting harmed while the lucky few get all the publicity.
I do read online testimonials and I take them quite seriously but I try to ground my opinions on people I've met or that wife has met. I think it helps tremendously if a treatment is first of all markedly effective. It seems to me ECT works well if people are carefully selected and I don't think the phenotype for ECT response is aware near the mystery it's made out to be. That said, it's a serious treatment for a serious disease.
I'm honestly quite bullish about psychopharm and I'm a believer that acedotal evidence, gathered with care, that is of a high quality is very persuasive. I just cannot fathom the enthusiasm for SSRIs other than to put it down to the sheer amount prescribed. Make something ubiquitous enough and you'll have a legion of fans. But this ubiquity has reached a point where so many people are on these drugs, most of have seen enough to know what they do, in same way that the widespread use of alcohol makes it effects fairly well known. This situation makes the experts look rather foolish when they cannot describe such ubiquitous phenomenon. Thus my point about Moncrieff and her observations of SSRI effects, which to me are about as controversial as observing that alcohol makes people tipsy. Moncrieff conveniently omits other effects though and I dislike her cherry picking rhetoric. Its very Maudsley.
I just find SSRIs to be strangest hill to die on. There are some people, who have a particular type of apprehensive rumination, a tendency to worry about "what if this (terrible) happens", perhaps it's related to OCD or perhaps it's a form of nervous illness, but they are the people I notice who when they take an SSRI they stop caring about all these apprehensive thoughts, it makes them apathetic. I think that is more than just useful and is a really good effect in those cases. The problem is that it has virtually nothing to do with depression, psychomotor slowing, vegetative symptoms, delusions of guilt. And further more people with more bolt from the blue agitated anxiety seem to do worse on these drugs. There is one other effect that Moncrieff fails to mention, I have met people in whom certain antidepressants do seem to stifle panic attacks. Most recently a woman with very prototypical panic attacks that seemed to be blocked by bupropion.
I'm also inclined to the idea that serotonin isn't wholly unimportant in depression. I heard Nemeroff say something in video the other day along the lines of "I wouldn't say serotonin has nothing at all to do with it", or something to that effect. Its more that I just cannot fathom the urge that possesses people to wax lyrical about SSRIs. I don't think they should be removed from the armamentarium for the above reasons. But all these people defending them on the basis of experience, anecdotes, pattern recognition, where are their detailed case reports? Emphasis on "detailed". A few good case reports where I had confidence in the validity of the diagnosis and in which the improvement was marked would be more than enough to satisfy me. Instead the whole issue spins round and like some "trust me bro" vortex, like people debating who kidnapped Madeleine McCann. How about producing one of these acedotes in the form of a detailed vignette.
Wait a sec - anecdotes and historical analysis from a practicing physician are "garbage" but online anecdotes (ie and opportunistic sample) are helpful and informative? I'm confused...
Physicians have a monetary incentive to lie (including to themselves), how is this confusing?
Whereas internet randos are reliable narrators that accurately represent the general population.
https://en.wikipedia.org/wiki/Convenience_sampling?wprov=sfla1
Nitpicking statistics is a waste of time, especially when most pharmaceutical research (and science in general) is fraudulent. A doctor that won't take his own medicine is a shill. Actions speak louder than words and Wikipedia links.
Sometimes I find comfort in the idea that some of the supposedly over prescribed drugs don't work, because the other option would mean that many people really are mentally ill in a way that requires chemical intervention to fix and that's even worse imo
I find this comment really relatable—I've definitely thought this way in the past too. I think it's partly a symptom of how drugs are framed. As I mentioned, I think Moncrieff sometimes goes too far and can be a bit hyperbolic, but her framing offers a better perspective. When drugs are marketed as the perfect 'lock and key' solution, where the disease is the lock and the drug is the key, it can make it seem like people are born needing these drugs—as though nature somehow decreed it. I'm exaggerating here, but I think this narrative often drifts too far in that direction. This is the mainstream drug narrative we're all familiar with, and it starts to sound like these drugs are almost predestined to be necessary. If we think about it more like Moncrieff does—that drugs simply have 'effects' that may or may not be useful—we're probably closer to the objective reality. Though she pushes the point too hard at times, and some drugs do seem to have more direct effects on disease processes (lithium, for example), it’s by no means certain.
Another way to look at it is serendipity, which is how many early drug discoveries were understood. Moncrieff isn't the best historian, but she does a better job than most of her peers. For instance, she often quotes Jean Delay on antipsychotics without acknowledging that Delay had a reputation for avoiding direct clinical work—Deniker was the one who actually did the hands-on work. Quoting Delay on drugs is like quoting Freud—it’s not especially persuasive. But serendipity, that’s the key. People like Donald Klein talked about it: a lot of these breakthroughs are luck, and we get a disease, and by chance, a certain chemical happens to help. Once you realize that many drugs were discovered, at least in part, by luck—or trial and error—the 'lock and key' model starts to disappear. You can then view drugs as something other than perfect machines designed to do a specific task. David Healy calls this "magic bullet" thinking. I call it lock and key. Sometimes we get very luck and we do find a magic bullet, like antibiotic, or insulin, but the idea any psychiatric drug is "like insulin" a comparison which even Donald Klein made in the book Understanding Depression, is really rather silly and every bit as hyperbolic and sweeping as anything Moncrieff has ever said. Its useful for public consumption and sometimes a bit of oversimplification is needed, but here in 2025 far too many people picture a "magic bullet" when they picture a drug.
Of course, as drug research has progressed, so has the engineering of drugs. This is where someone like Alvid Carlsson comes in—he worked on SSRIs, which were designed with more specificity in mind. But still, some of the best drugs, like lithium and imipramine, were found by sheer luck. So, it's not that we're born needing drugs, but we can be born with a disease whose symptoms just happen to respond to a drug—or, in even luckier cases, part of the disease process might respond to a drug. I think it's fine to use internal medicine as a model here. Modern medicine can do incredible things, but a lot of it is down to serendipity. We shouldn’t assume that the universe has ordained that drugs should work or that we should need them. It’s a mix of bad luck that we get ill, and good luck that some drug might help. Once you understand that, you can approach drugs with the right skepticism, knowing that the odds are against them working and that the burden of proof is on demonstrating that they do.
I’m glad I have never been assigned to work with you.
I'm really not such an arse in person. And I really do tend to believe what people tell me, it's just people tell me things they don't tell their doctor.
And that is why medicine is becoming increasingly dysfunctional and discredited. As women take over institutions agreeableness becomes the order of the day and the dialectic process is abandoned. Next thing you know we are castrating children and it’s easier to get testosterone as a teenage girl than a middle aged man.
Hi, Dr. Beech,
We have not met, but my friend and colleague, Dr. Mark Ruffalo, sent me the link to your posting. There is far too much to say on this topic for a brief space like this, but I did want to commend you for so many of the points you make. Most are very closely aligned with what I have been banging on about for nearly 40 years!
I particularly agree with your valuation and affirmation of the clinician's and the patient's felt experience with antidepressant medication. Thousands of us who have had the privilege of working with desperately ill and suffering depressed patients have seen, over many years, the benefits of these medications. (And yes--we are well aware of the important downsides, risks and potential side effects--nearly all of which can be mitigated and managed with expert care). Furthermore, in my view, there has been far too little emphasis on "quality of life" and too much focus on the Hamilton Depression Scale, in assessing the benefits of antidepressants. [1]
Much more could be said, but I simply wanted to register my agreement with the essence of your article. My own views are well-registered on the Psychiatric Times website, including my most recent posting, much of which resonates with yours.
https://www.psychiatrictimes.com/view/the-ongoing-movement-against-psychiatric-medications
Best regards,
Ron
Ronald W. Pies, MD
Professor Emeritus of Psychiatry
SUNY Upstate Medical University
1. Pies RW. Antidepressants, the Hamilton Depression Rating Scale Conundrum, and Quality of Life. J Clin Psychopharmacol. 2020 Jul/Aug;40(4):339-341. doi: 10.1097/JCP.0000000000001221. PMID: 32644322.
Thank you so much Ron for taking the time to read this, and for your thoughtful response. I appreciate your work, have been following since I was a resident! Doug Beech
I absolutely agree.
I am not a prescriber, but my patients (as well as my family members) report significant benefits from medication.
Many thanks, Doug! It is a comfort to hear from a kindred spirit.
Kind regards,
Ron
And my thanks, as well, to Dr. Hickox (Annie) for her stalwart efforts in behalf of our patients!
Best regards,
Ron
The history of medicine becoming a science rather than pseudoscience is a history of the rejection of "felt experience" in favor of data. Apparently, it's very hard to embrace the scientific mindset, so hard that even those nominally educated in science often cannot do so. Sad.
Having read through nearly all of the comments on Dr. Beech’s posting, I’d like to suggest an alternative perspective to either of two extreme views of antidepressants—i.e., either they are little more than “expensive sugar pills,” or else they are tremendously effective agents in the treatment of depression. (I recognize that several of the comments avoid either of these extremes).
My view, as a mood disorder specialist (now retired from practice), is that antidepressants now in use are modestly-to-moderately effective agents for a substantial number of patients with acute, moderate-to-severe, unipolar major depression. Having written and taught about these agents for nearly 40 years, I am not so naïve as to imagine that what I have to say will persuade anybody at either of the “extremes” I mentioned. However, I am hoping that those open to a “middle ground” will reflect on the bullet points below and will also read the excellent (2022) review by my colleague, Dr. Awais Aftab, which can be found at this link:
https://www.psychiatrymargins.com/p/the-case-for-antidepressants-in-2022
• Healthy skepticism about antidepressants (AD s) is reasonable and justified, in view of the mixed results of published studies. Skepticism, however, need not devolve into cynicism.
• The evidence-base for the claim that AD s are at least modestly effective (as qualified above) consists of much more than personal “anecdotes”.
• Clinical experience based on careful, repeated examination of patients over months or years should not be dismissed as “anecdotal.”
• The effectiveness of these agents depends on many factors, including:
1. How efficacy is measured (e.g., the Hamilton Depression Scale (HDS) or a subset of HDS items). The effect size (how effective the AD is vs. placebo condition) increases substantially when measured with a subset of HDS items (the HAM-D-6. See P.Bech, below)
2. The severity of the depression. The less severe the depression, the less separation between the active treatment condition and the placebo condition (the latter involving many hours of supportive contact with the patient). Most studies find that AD s are most effective for the more severe forms of depression. Put another way, the more the clinical picture resembles “ordinary sadness,” the less effective and less appropriate is antidepressant medication.
3. The type of depression. Antidepressants are not usually helpful or effective for bipolar depression, and may make the patient worse. Melancholic depression (a very severe form) does not respond well to either placebo or psychotherapy, but does respond to antidepressant treatment.
4. The specific antidepressant used, according to some studies (see Cipriani et al, cited below). By the way, bupropion is a non-serotonergic antidepressant that avoids nearly all the “SSRI” side effects and is FDA approved.
5. Whether one is looking at single drug studies (i.e., only one AD is tested), or the “real world” of clinical practice, in which we routinely “treat until the patient is better” using two, three, or more antidepressants in sequence, often augmented with other agents, such as thyroid hormone.
• Clinical evaluation is not merely a matter of picking up good or bad “vibes” from the patient. Many psychiatrists—and virtually all mood disorder specialists—assess the patient’s response using, for example, the Beck Depression Inventory or other related scales. Use of the BDI was a regular part of my private practice as a psychopharmacology consultant, usually with repeated testing over weeks, months, or even years. These findings constitute data, not mere subjective impressions.
• Most meta-analyses and clinical studies involve use of the Hamilton Scale (HDS), which has several limitations and drawbacks. Most studies looking at the patient’s “quality of life” (QOL) are supportive of the beneficial effects of antidepressants, though there is a paucity of randomized, placebo-controlled studies of QOL. [See Andrade, below]
Finally, I view antidepressant medication as basically a “bridge” between feeling miserable and feeling better. The patient must still walk across that bridge, and that is where “talk therapy”, behavioral and cognitive change, and the therapeutic relationship come into play. For readers who want to delve into the research literature, I strongly recommend starting with Dr. Awais’s review. Other pertinent references are listed below.
Respectfully,
Ronald W. Pies, MD
For further reading:
1. Cipriani A et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet, Volume 391, Issue 10128, 1357 - 1366
2. Stone et al. Response to acute monotherapy for major depressive disorder in randomized, placebo-controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ 2022; 378 doi: https://doi.org/10.1136/bmj-2021-067606 [Note: this study has been widely misinterpreted. For a discussion, see:
https://www.psychiatrictimes.com/view/antidepressants-placebos-and-lithium-some-parting-thoughts, and
https://www.psychiatrictimes.com/view/hooked-on-hype-a-critical-examination-of-recent-anti-antidepressant-reporting]
3. Pies R. Are antidepressants effective in the acute and long-term treatment of depression? Sic et Non. Innov Clin Neurosci. 2012 May;9(5-6):31-40. PMID: 22808447; PMCID: PMC3398684.
4. Andrade C. Antidepressant drugs and health-related quality of life: a reader’s guide on how to examine a “viral” research paper with a critical eye. J Clin Psychiatry. 2022;83(3):22f14527.
To share: https://doi.org/10.4088/JCP.22f14527
5. P. Bech. Is the antidepressive effect of second-generation antidepressants a myth?
Psychol. Med., 40 (2010), pp. 181-186
Dr Pies, thank you for taking the time to elaborate on the topic of efficacy of antidepressants. Your notations and references show what a broad and complex topic it is, and how difficult it is to study these questions scientifically. I agree that Dr. Awais's piece is a great place to begin a deeper dive. The thesis of my original post was much more narrow, focused on the role of clinical experience(s) in contrast to published trials research. As the comments reveal there are many more facets to the discussion. I appreciate your thoughtful and measured contribution.
Former psychiatrist. Nicely put. My worry has always been that the costs and benefits - principally for me the human ones but, to be realistic, also the economic benefits - are ignored in the interests of an ideological drive to halt prescription of these life-saving medicines. The therapeutic fashions come and go, but the evidence is clear. I don’t see this going away, so thanks for weighing in.
The scientific evidence is absolutely clear: antidepressants work - far beyond clinical anecdotes. The author, unfortunately, goes backwards. Peter Kramer, OTOH, noticed results in his patients, reluctantly as a believer in talk therapy, and did the research, instead of vice versa or apologizing for the research. The research's flaws only show up in poorly designed studies. Antidepressants work as well as any other "ordinary" drug does, hence the title of his latest (nonfiction) book, "Ordinarily Well."
Thank you for taking time to read the article and for your comment. I agree that the whole of the scientific evidence is clear, and supports the efficacy of the medications. The thesis of the post is a narrow one: a comparison of the weight of unpublished evidence (clinical experience by the tens of millions of cases, observed over time) vs published studies. The post also focused narrowly on three particular criticisms common in the public discourse and social media forums, which tend to double down on the flaws in the industry-sponsored studies (and those left in the 'file drawer') and dismiss clinical experience and knowledge of the uniqueness of individual patients as anecdotal. Even the best-designed studies are still limited (true randomization isn't possible, and selection filters, flawed instruments of measurement), as is the evidence seen in clinical practice (expectancy, compliance, subjectivity of patients and practitioners, diagnostic variability and imprecise measures). This is true in so much of medical practice, however. I am generally in alignment with sentiments expressed by Dr. Kramer in his book. One excerpt from his book captures a slice of it here: "I treated patients. Like most doctors, I kept abreast of research results, but I read them in the context of what I saw in my daily work." I agree the published literature contains good evidence. I just don't think it's the best evidence. DB
Understood. I felt the piece was too apologetic of the published evidence, but perhaps my impassioned belief in antidepressants - while knowing they don't work for everyone, nor do they work as well for everyone as the kind of anecdotes in, say, "Listening to Prozac" - led to a defensiveness in my position. I will re-read. (Like many people, Peter's book/s have had a huge influence on my life, as lifelong sufferer of depression and anxiety. I read as much as I can, as a layperson who doesn't always but tries to understand all the scientific intricacies, and if antidepressants didn't work, I would accept that. They've worked ordinarily well for me, and save the lives of many I know. Anecdotes! Now, like many, I fear what's to come, as RFK Jr. has had his anti-SSRI position endorsed by Trump, and Musk, who seems from his own statements as well as behavior to suffer from bipolar disorder, self-medicates with ketamine - I understand it is a legitimate treatment under doctor's supervision, which is not how he takes it - and other drugs. That worry, too, surely informs my reading of the subject. Thank you.
Thanks very much, Dr. Beech (Doug, if I may...). Yes, the issues are complex and nuanced, and avoiding "absolutist" positions is, in my view, important. But nothing should detract from your original post and thesis; namely, that careful, long-term, clinical observation of patients and their responses to treatment is a valid and critical type of empirical evidence--and certainly not "anecdotal" information! Best wishes on your new blog, which--by the way--garnered a shout-out on Dr. Awais's substack for March 15. [1]
Kind regards,
Ron
1. https://www.psychiatrymargins.com/p/notable-links-and-miscellanea-march-a15
Thank you so much Ron! Appreciate your time and attention to this. Thanks for letting me know about the mention in the psychiatry margins Substack also.
Best wishes,
Doug
As someone who is NOT a physician I very much appreciate your approach to this topic. I have seen the anecdotal evidence that you talk about in my loved ones who have very clearly benefited from antidepressants. It is so important, anytime we aim to create public policy, that we listen to the experts on the ground. In this case, the doctors who prescribe these medications and see their effects every day. Thank you for your thoughtful article! Looking forward to more.
In the current climate there is no way I'm hell that I am taking the anecdotal musings of a single physician over 2 decades of research. I took antidepressants for 5 years, to no effect. That's my experiencial analysis. They did nothing. Why not take your faith and priors and retrain as a homeopath, you might find peace.
Great piece, Dr Beech!
The probability that clinical trials understate the benefit of anti-depressants is near-negligible, given the powerful incentives and the thumb on the scale.
If the most depressed people are excluded from clinical trials then no most depressed individual should be prescribed an antidepressant precisely because there is no evidence but anecdotal that antidepressants would help him or her.
Prescribing to such people, not patients, would be baseless from the lack of targeted at them clinical trials and it would be done by analogy. With no physiopathology to support their use in them, none at all.
You are not clear enough: if there are two positive trails for an antidepressant and more than two that come negative, a reasonable person would conclude there is evidence for its ineffectiveness more than for their utility. They are more useless than beneficial, absent side effects as severe as genital anesthesia, or orgasmic inability.
As for seeing improvement in the clinical office there is a dictum, an old one: patients improve despite treatment.
Practicing physicians do follow Guidelines because if they don´t and a patient has a bad outcome they get a law suit for not following a Guideline.
Practicing clinicians are not mavericks, they are more conservative than the MAGAs, just to avoid liability.
People confuse Belief with Opinion and Fact, Beliefs are impervious to facts, Believing in God does not respond to evidence of God´s inexistence or existence outside Reality and Science and its methods.
No one needs antidepressants, the mind is not real, nothing mental is real:
https://federicosotodelalba.substack.com/p/beauty?r=4up0lp
And they do cause manic, hypomanic and akathisic behavior, yet, they can´t be stopped suddenly nor abruptly.
You lost me... "Found no evidence" is different from "there is no evidence?" Only if you have no confidence in your judgement, skills, capacity etc surely? If the person who looked for the evidence was a competent "looker" then surely "found no evidence" means "there is no evidence"? It doesn't mean we might not find some in the future, but it does mean that at this moment in time, there is no evidence... To say otherwise is to have no confidence in your ability to do research I would think. One confused med student here.
My standard line about drug company studies (or when people ask about psychogenomics) is my cats' response to catnip... One cat loves it, one hates it, the other is indifferent... This is a stable response over time. But if this was a study, the conclusion would be that that catnip does nothing, because one positive, one negative, and one indifferent all adds up to no effect. The fact that people have individual responses to drugs is not something captured adequately in studies.
Personally I'm not a fan of meds for anything other than severe/melancholic depression (for depression); most of the anxiety/depression I've seen in primary care and ED has social and personality "causes" and I think it's obscene to label social/personality issues a mental illness and respond with drugs... Colluding with neoliberalism and reconstructing social issues as psychiatric illnesses simply allows for the diversion of resources from social support services, housing etc to big pharma's pocket. Psychodynamic psychotherapy is my treatment of choice for the remaining personality factors and is rarely funded.
*"You lost me... "Found no evidence" is different from "there is no evidence?"*
These are indeed very different. The principle is more commonly expressed as "Absence of evidence is not evidence of absence". This applies to benefits and harms and every other conceivable relationship between two clinical factors.
Consider, for instance the hypothesis that smoking causes lung cancer. At one stage, there was an absence of evidence of a causal relation. This was not evidence of absence of that causal relation.
More generally, a negative study must be assessed for its statistical power, not summarised as "Scientists looked and found no effect." Drug companies are very quick to cite lack of a significant effect as sufficient reason not to worry about potential harms for which there is a weak, unconfirmed signal, and this conflation should be strenuously resisted.
Moreover, clinicians are often forced to make decisions for which the relevant study has not been done and won't be done, so they need to move beyond the strict guardrails of evidence-based medicine. If a small crappy study fails to resolve an important issue because it is underpowered, that does not put the matter to rest, and clinicians must fall back on judgement.
Whether antidepressants have adequate evidence of efficacy is a separate, more complicated matter.
I write this as a physician who has also worked for decades auditing drug company research.
Interesting and thought provoking article. But I am left a bit conflicted.
In the nutrition space, carnivore or keto doctors rely on the same type of arguments to 'extol the virtues' of their respective protocols and the 'show me the science' crowd rightly (I think) criticise them for over reliance on anecdotes and ignoring the broader research. How is it different in this case?
At what point do we decide that the 'anecdotes' have reached a level where they can override research?
Very good questions and I agree there are a lot of similarities between the two areas, in comparing published research with actual experience.
In my post, the narrow point I emphasize is what practitioners rely on in terms of decision-making in clinical contexts, and contrasting that with the chief sources of the skepticism about efficacy. Critics rightly point to the published research that calls into question efficacy, but practitioners have other evidence that they rely on in addition to this.
Very interesting that you bring up nutrition research and make this comparison because in my post I edited out a quote from fitness blogger Mark Sisson who advocates for some unconventional diet and nutrition approaches such as high fat. In a 2012 interview responding to critics who ask “where are your controlled studies? Where are your randomized controlled trials?” He responded that he has over 10,000 email testimonies several paragraphs long from people losing large amounts of weight, getting healthier, reversing hypertension and type 2 diabetes and getting off of medication. He was making a similar point.
It seems the root issue with the topic is the quality of the research. My narrow point was that practitioners look at the published research but don’t rely on it for their decisions nearly as much as what they see in their offices. It is of course limited because it’s anecdotal ,prone to lots of subjectivity and impressionistic opinions… But that’s true in a lot of of what practitioners do especially in general medicine.
From what I understand almost all published research in the nutrition world is epidemiological. And let’s face it the cost and time involved to systematically study and compare different nutritional approaches would be astronomical. There are some small (30 day) type studies that compare different diets where the participants are housed in a dormitory and it is known what they are eating. These are rare and only show the short term effects versus long-term impacts. Most of the studies involve people answering questions to surveys so it is difficult to rely on them and controlling for all the different variables.
I do highly recommend the Peter Kramer book on this particular topic diving into it in a deeper way. Some of the comments to the article extrapolated my narrow point into broader assertions that I wasn’t making about antidepressants and their place in the overall scheme of mental healthcare.
Thank you for your detailed response. All your points are well taken and I will definitely be reading Kramer's book to understand the topic on a deeper level.
As a layman, I don't really have the knowledge and skills to evaluate all the evidence and land strongly on any side of this. It's interesting to read how practising clinicians make these decisions and weigh them up against the published research.
Next up: bloodletting really works! My patients tell me so.
Thats not what the Surgeon General said, he Tweeted this last century:
"General bloodletting is never necessary. It will calm a highly-maniacal patient, but so will a sufficiently severe blow on the head." - William Hammond
Companies have moved past SSRIs, they are legacy generic drugs. Now, patented antipsychotic drugs are heavily promoted for their ability to enhance the efficacy of SSRIs. The scientific basis for this has not been adequately explained.
A large analysis found the most effective antidepressants are two ancient tricyclic drugs. What they have in common? The most potent antihistamines ever discovered. They are highly sedating.
Don't tell me you've noticed this too?
Not so much on the tricyclics but I think part of the appeal of SGAs in some cases is the sedative effects, particularily olanzapine and seroquel.
I was at a comedy night hosted by a local Hearing Voices charity. One of the running gags was knocking patients out with Seroquel. Every time the comedian playing the doctor brought out a giant, oversized bottle of it, the audience roared with laughter, friends, family members, peer workers—they all got the joke. It’s telling when a drug’s effects are so universally recognized that it can be used as a bit gag.
Why shouldn't sedation be useful. I'd probably feel better too if I was half zonked.
The opposition to antidepressants always seems to rest on this weird unstated intuition that it's somehow bad to be taking psychiatric meds unless there is some really strong case they treat a well-defined chemical imbalance (whatever the fuck that means). I mean if your only concern was to make people's quality of life better than even if SSRIs and SNRIs etc were mere placebos they have sufficiently mild side effects it seems clear they would make people's lives better. They aren't just placebos but that's kinda besides the point, the case for them was already sufficient.
But that isn't the only reason to worry about antidepressants. Sure, they are helpful but it also seems like we lack any clear mechanism and they are very hit or miss. For all we know we are just doing the human equivalent of waking the electronic device to make it work -- randomly perturbing the system since an extreme state is more likely to be moved towards the normal equilibrium. And that's all great, whatever works, but I fear the sense the public has that we have decent antidepressants discourages looking for something else that works for those who aren't fully treated by the usual antidepressants (both individually and at the research level). In other words, if you tell people prozac is an effective antidepressant they won't understand why you might need something else.
Maybe that's just me being paranoid but I've met lots of people with depression (inc myself at times) and while modern antidepressants certainly were helpful they often were still in a quite bad way and just stopped mentioning it to docs etc bc they were on an effective antidepressant so what else was there. To their credit I know many psychiatrists will try drugs like MAOIs, tricyclics etc when SSRIs, SNRIs etc fail but many people just see a GP and since they are told these are effective drugs they don't say anything when they are still pretty badly off (if these are effective and I still feel bad guess there is nothing to do)
I was thinking something similar recently about "perturbing" a system. Its a bit humbug but I'm reminded of something Alvid Carlsson said about paradoxical effects, I can't recall the quote but Shorter was asking him about akathisia and Carlsson sort of said something to the effect of if a system control certain effects we can't be surprised if we occasionally produce the opposite effect when interact with it. Go poking around in the part of the CNS that controls anxiety and we can't be too surprised if perturbing it produces agitation.
I wondered for a while now why doctors don’t lean more on the placebo aspect at the beginning of treatment by prescribing sub-therapeutic doses for a period long enough to assess whether positive expectation and care alone can resolve the problem.
Another point in response to patients misrepresenting their actual condition: Why not administer and track their state with Dr. Burns’s Brief Mood Survey so there’s a good quantitative snapshot each visit? Seems to me at least that this should be standard practice?
I think you could throw a rock in almost any direction and improve matters. Any digging into the history of bad pharmacy just about always reveals the same issues of neglect, ignorance and rushed care.
I'm not sure how the mood survey would help with patients who are deliberately and consciously trying to present as having a worse condition -- especially since most docs want to help their patients so they may not want to stand in the patient's way of getting into a trial.
Regarding the placebo effect, the issue is that doctor-patient trust is very important. If I don't believe what my doctor tells me or suspect he might be giving me placebos I might decide not to put in so much effort taking them or ignore her advice.
At least when it comes to anti-depressants doctors truly believe they work so even if the evidence for that claim turned out to be a hugely unlucky coincidence it still wouldn't be a reason to try and reduce usage. In other words, we don't want docs adopting a policy of patient deception (except maybe w/ some kind of general prior consent) but even if they happened to be wrong about these meds being effective (which they aren't) it wouldn't be harmful.
Fair point regarding the mood survey.
On the use of sub-therapeutic doses I agree that doctors should be transparent in their thinking as they are in open placebo trials.
Script: “Studies have shown that even placebo-level doses can help some people in your condition with the added benefit of fewer side effects. Do you want to try that first?”