Do anti-depressants work?

antidepressants safe and effective?

Anti-depressant drugs are common. Very very common. According to the Centers for Disease Control in the United States, 13% of adults reported taking an anti-depressant when surveyed a few years ago. Among women over the age of 60, almost one in four was taking an anti-depressant!

When I work in the hospital, I frequently see elderly people who are on five, ten, fifteen, or even twenty drugs simultaneously. Invariably, one or more of these drugs is an anti-depressant. This absurd overuse of medications, an issue known as polypharmacy, is one of the biggest health problems facing elderly people today. Anti-depressants are one of the main drug classes contributing to polypharmacy.

With so many people taking anti-depressants, you would think that they must at the very least be effective. And safe. Why else would so many millions of people be taking them on a daily basis? Why else would doctors prescribe them so freely?

The most commonly prescribed type of anti-depressant is the selective serotonin reuptake inhibitor (SSRI). Examples of this type of drug include sertraline (a.k.a. zoloft), escitalopram (a.k.a. cipralex), and fluoxetine (a.k.a. prozac). SSRI’s increase serotonin signalling in the brain, which is hypothetically a good thing for people who are depressed. They are generally considered to have the best balance of efficacy and safety of any anti-depressant drug, which is why they are the first line therapy.

So, how effective are SSRI’s at treating depression?

A systematic review and meta-analysis was published in BMC Psychiatry in 2017 that sought to answer this question. The review was funded by the Danish government. It identified 131 randomized placebo-controlled trials investigating SSRI’s as a treatment for depression in adults, with a total of 27,422 participants, and meta-analyzed them (i.e. added all their results together to create one big “meta” trial – this gives a more reliable result than the individual trials can provide).

Before we get in to the results, we need to quickly discuss the Hamilton Rating Scale for Depression (HDRS). The HDRS is the scale most commonly used to assess severity of depression in studies, and also to assess how the severity changes over time. It is a 52 point scale, so a score of 52 is as bad as it can get. A score below eight is considered normal (i.e. not depressed). 8 to 13 is considered to be “mild” depression. 14-18 is considered to be “moderate” depression. 19-22 is considered to be “severe” depression, and anything from 23 and up is considered to be “very severe” depression.

The authors of the review decided, before analyzing the data, that anything less than an average reduction of three points on the scale would be considered a negative result. Personally I think that this is a bit generous. I find it hard to believe that anyone would be able to notice a three point reduction on a 52 point scale. I would have set the threshold higher, at more like six points at the very least. One article published back in 2015 came to the conclusion that people are unable to detect anything less than a 7 point difference on the 52 point Hamilton scale. But as we shall soon see, setting the threshold higher wouldn’t have made a difference anyway. So, let’s get to the results.

Overall, SSRI’s resulted in a 1.94 point greater reduction on the 52 point HDRS scale than placebo. Even when only trials of people with very severe depression (a score of 23 or higher) were included, the improvement over placebo was still only 2.69 points.

So, SSRI’s were not able to get over even the generously low bar set by the reviewers. And let’s remember that most of the studies included in the analysis were industry funded, and industry funded studies usually show a bigger benefit than is seen in reality, so it is likely that the real effect is even smaller than was found in the systematic review.

In other words, SSRI’s are not effective as anti-depressants. Considering that they are currently the first line drug therapy for depression, that would seem to be quite a big problem. And before you suggest that we should use non-SSRI anti-depressants instead, like for example tricyclics, I would note that these have not been shown to be markedly more effective than SSRI’s in head-to-head comparisons. Otherwise we’d be using them as the first line therapy, not SSRI’s.

What about safety? Did SSRI’s cause any serious adverse events?

2.7% of participants in the SSRI arm developed a serious adverse event, as compared with 2.1% in the placebo arm. That is a 0.6% absolute difference, which would mean that roughly one in 170 people treated with an SSRI will suffer a serious adverse event as a result of the treatment. Note that the definition of a serious adverse event is an event that causes death, significant risk of death, disability, and/or hospitalization. In other words, “serious” is serious. So even a small increase in serious adverse events is something that needs to be taken quite, well, seriously.

Medical treatments should ideally result in a decrease in serious adverse events. They certainly should not cause an increase. A truly effective anti-depressant would not just make people feel better, it would also make them less likely to try to commit suicide, which would result in an overall reduction in serious adverse events. No such signal was seen here. Even if you look just at suicide attempts, rather than at adverse events overall, there was no signal that SSRI’s decrease their frequency.

Note that the trials in the review were generally of healthy people under 65 years of age. Frail elderly people treated with SSRI’s will likely experience serious adverse events at a much higher rate than that found here.

Speaking of frail elderly people, in particular those living in nursing homes, I want to take the opportunity to point out that they are frequently the heaviest users of anti-depressants. So you would think that there would be a lot of research showing that anti-depressants are useful to give to the frail elderly… Well, having seen that the evidence doesn’t support using anti-depressants in younger people, you might be a bit skeptical by now. A systematic review was published in the Journal of the American Medical Directors Association in 2012, that sought to determine how beneficial anti-depressants are when used as a treatment for depression in people over the age of 65 who are living in nursing homes. The review was funded by the US government.

Two(!) randomized controlled trials were identified that compared anti-depressants with placebo in nursing home residents, with a total of 55(!) participants. It’s pretty shocking that the evidence base is so small, when you consider that nursing home residents are such heavy user of anti-depressants. Basically, when we (doctors) use these drugs on elderly nursing home residents, we have pretty much zero idea what we’re doing, because there is so little evidence.

Neither of the two trials found any benefit to treating nursing home residents with anti-depressants (although to be fair, they were so small that I wouldn’t have expected them to find anything – they were statistically underpowered). The number of participants was far too small to gain any kind of estimate of the prevalence of serious adverse events, although I think it’s fair to assume, as mentioned above, that it would be much higher in this group than in the younger healthier group included in the studies in the previous review.

I’m mainly bringing this tiny systematic review up to illustrate how atrociously small the knowledge base often is when it comes to the effects of drugs on the frail elderly.

What conclusions can we draw these systematic reviews?

Anti-depressant drugs are ineffective against depression. The harms of these drugs clearly outweigh the practically non-existent benefits. That is true for everyone, but especially so for the frail elderly who are at much higher risk of side effects than the general population. In light of this information, which has now been in the public domain for at least a few years, you would expect large campaigns to get doctors to stop prescribing these drugs. Funnily enough, that hasn’t happened yet.

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65 thoughts on “Do anti-depressants work?”

  1. From personal experience the first time I was prescribed Citalopram it probably had no noticeable effect – I was stressed by work, family dynamics and terminal diagnosis in the family. That being said I think the pills prevented me from breaking down and crying when things built to a head at work – I got angry instead of breaking down into tears and walked out. Stopped taking them three months later at Christmas 2018 after suffering from a very bad viral infection (coughing etc etc – probably a coronavirus!). I was so ill I thought if there were any side effects from stopping taking them I wouldn’t notice!

    However I started taking them again at the end of March as I was crying everyday with the ongoing lockdown – I could find no joy in even good news. Had some pills left over and started taking them and contacted the doctor to ask for more – since then I have not cried – maybe a placebo effect but I find I am not stressing about the future anymore and have rediscovered pleasure in every day. My mum says I look much better too! So for me at the moment they are working and if they get me through to the other side of this whatever shape/ form it takes they will have done their job.

    1. So true for me too. I would cry very very easily and have no control over it. I was prescribed lexapro and can co trip the fears now and don’t feel nearly as low or ready as prior.
      They’ve been a real godsend for me personally.

    2. The article doesn’t address the effects or effectiveness of bupropion(Wellbutrin). Bupropion is a mild stimulant that appears to work well with male patients who find the “side-effects” of the SSRI’s intolerable (ED, etc.)

      1. Yes absolutely correct. Buproprion (Wellbutrin) is one of the good guys and not mentioned here.You actually lose weight or keep weight off on it, it has minor side effects, and is also used for cessation of smoking. It’s probably one of the safest out there, is effective , and minor or no side effects if you are on the proper dosage appropriate for your body. Also works somewhat for ADHD.

      2. Completely disagree. Personally know two people who had a terrible time with Wellbutrin, increased rage in one, and suicidal thoughts in the other. I personally would never take it.

  2. Dear author, please investigate how to use the effect size, not just p-value, when evaluating the quality and importance of the published study results. I discuss it here – I feel you have not good enough understanding of that important stuff.

    Regarding antidepressants, as far as I understand, the placebo effect greatly helps the patients. If patients do not think they are taking a potent pill, there will be no placebo effect and not depression relief. Therefore, simply stopping the medication is not a good option. Of course, cognitive therapy is better, however, most patients are too lazy and stupid to use it.

    1. Not sure what you mean, the 1.94 difference is the difference on the Hamilton scale. The difference with placebo is statistically significant, but not clinically significant.

      In medicine, it is generally considered unethical to prescribe treatments that don’t perform noticeably better than placebo.

      1. I have been looking back through some of your excellent output & realised you haven’t posted for a long time.

        Have you been taken out for not pushing the ludicrous narratives?

        I realy hope not.

        Best regards,

  3. Can you check the effects of benzodiazepines on depression? In my case prozac plus clonazepam was very helpful for suicidal thoughts. May be mostly placebo for prozac as the evidence seemingly shows but in my case the effect was quite fast and clear. Like 90 percent reduction after 2 weeks.

    1. My extensive experience taking benzodiazepines is that they are great sleeping pills in very low dosage, and if you take them while awake they may decrease your anxiety, but even in low dosage will also make you somewhat groggy – so you shouldn’t drive, use tools, etc. So they really aren’t very practical for anything other than sleeping. And even then, like I wrote, you need to start out with a VERY low dosage (e.g. like 1/4 mg with lorazepam), or you are likely to have “sleep inertia” and not be able to get out of bed for 12 hours. One more thing, they are meant to be taken only temporarily. If you take them long-term, one of the side effects is that they can be “ototoxic,” that is damage your high frequency hearing. As well as cause ringing in the ears.

  4. I have been on an emitional rollercoaster but I steer clear of drugs. I did extensive research and decided to try pregnenolone and progesterone in a carrier oil (sublingual).

    What a difference! At 56 yrs I was struggling through menopause and with Hashimotos (taking 120mg dessicated thyroid) so it was difficult. I started using an over the counter progesterone cream last year and found my energy levels increased. So, after 16 years approx on thyroid, I weaned myself off over several months.

    About a month ago I found a bio identical progesterone in coconut derived vit E carrier oil for sublingual delivery. After first day of using I felt the difference. On day two of using I did a thyroid function test.
    TSH 32.30 (Hypo)
    FT4 9.9 (“)
    FT3 3.4 (Normal low)

    One week later I did another Thyroid Function test
    TSH 18.70 (Hypo but improving)
    FT4 10.1 (Hypo but improving)
    FT3 3.5 (Normal low but improving)

    This is black and white evidence of the astounding effect that progesterone has on the body and other hormones. My physical and mental state has improved markedly. I am happier and have so much more eneryy joint pains reducing, flashes and sweats reducing.

    God knows where Id be if I was taking anti depressants! I doubt Id feel like my life was worth living again.

  5. I hear you. But I know at least three people who say the pills have helped them. And I saw positive change in one of them may selves (purely anecdotal). So how is that? And there are witnesses on the internet saying this medicine has worked wonders for them. (A doctor prescribed the medicine to me many years ago, upon hearing that I have a hard time keeping rooms tidy. I felt a lot of new anxiety, and quit after two weeks.)

    There is a lot of research on treating depression with psychedelics (such as LSD, psilocybin, DMT, ketamine, MDMA). Probably, most researchers in this field have a quite positive bias, in many cases no doubt due to personal experience. So maybe “high”- held hopes and results in studies will need some extra scrutiny.

  6. Is the variance of result important as well?
    If it helps a lot 20% of people by 10 points and 0 everybody else, and we dont have other good interventions, it might be worth trying it for a few weeks and see if it helps?

    1. I guess what I mean is ‘does the review show a significant increase in the percentage of people having a 6 points or more reduction?’ because it could make the treatment useful even if average response is low.

      1. The problem if you choose to do that calculation is that you also have to look at how many people get worse on the drug, compared to placebo. Otherwise it is an unfair comparison. Say 10% get better and 10% get worse. Then the drug is not a good bet overall. Unfortunately, drug companies only look at how many get better, never at how many get worse, so the data to be able to determine this doesn’t exist.

  7. Dr Rushworth

    With so many studies with different sizes and results it should be possible to plot a graph to check for publication bias.

  8. Have a look at their effect on the young! There’s a black box warning about suicidal ideation in the under-25s in the UK. I nearly lost a very close relative who attempted suicide once she was on them, and each time they changed the dose. Luckily she was in a psychiatric unit and was found each time, although once it was during a visit home and she ended up in A&E. There are countless anecdotes of parents whose children died after taking them 🙁

  9. Certainly in the UK, it feels like anti-depressants are the grown up equivalent of putting a plaster on a scraped knee that a child has. It is of little use but provides some kind of comfort and treatment.

    I took anti-depressants after a traumatic series of incidents in my 30s. What I really needed was some counselling but that is expensive and the waiting list for 6 x 30 minute sessions here in the UK is very long, so the GP gave me Citalopram instead. I’m not convinced it made any difference and it was difficult to wean myself off it.

    15 years on, I paid for my own counselling – a great deal more than 6 x 30 minute sessions and it was infinitely better and has had a profound and very positive impact on my life.

    However, I have some degree of sympathy for GPs and their over-prescription of ADs here in the UK. There is very little social support here, as the NHS has been decimated by cuts for years. Social services, health workers are so thinly spread that they only have time for the most acute people and often they don’t even have time for that, so GPs become the only available outlet for people with social issues, rather than medical issues to seek help. A GP can’t address the emotional or social issues that most adults have in a 5 minute appointment and there are few people they can refer them to unless the issue is acute or severe, so a sticking plaster is applied with ADs.

    As for care of the elderly in the UK – it is dreadful. We outsource care of our old people, partly because so many of them live so long now and partly because everyone either has to or wants to work, so there is little chance to offer care within families anymore. Who wouldn’t feel depressed knowing they are going to end their days in a care home, surrounded by strangers also waiting for death and lowly paid staff, with occasional visits from their family? And in the year gone by, they haven’t even been able to see family! In hat situation I’d want every drug they could give me.

    I appreciate my points are slightly at a tangent as to whether or not ADs are actually efficacious or not. However, even with evidence that they aren’t, I can’t envisage a decrease in prescription in the UK anytime soon!

    1. Excellent points ,Nigella. As an evidence based doctor, I totally agree with Sebastian’s assessment, but you have neatly outlined the reasons GPs still prescribe these drugs so much.

  10. Hello Dr. Rushworth!
    I have taken a drug called Effexor (venlafaxine) for the last 25 years. I couldn’t tell you if it works for me or not, as I have not been off of the medication for any length of time. I DO know, however, that when I run out of it for a few days I have a strange feeling as I am detoxing from it.
    Would you recommend I try to go off of it for a 30 day trial?? I would value your advice.

    Thank you!

    1. I can’t give individual patient advice on this forum. If I were you, I would discuss testing going without the drug for a period with the physician who is prescribing the venlafaxine. Withdrawal is common with SSRI’s, so patients are usually recommended to taper them over a few weeks.

      1. Thank you SO much for your excellent wisdom, and straight-forward approach!

      2. Where have you gone?

        “Places to go, people to see, things to do” would be fine, but please don’t tell me the evil ones have taken you out!

  11. Thank you so much for writing this. I prescribe them a lot, but, honestly, don’t believe in them. I’m a psychiatric PA who is transitioning into my own integrative practice. For the time being, it’s expected by my collaborating physician that I offer these medications despite their lack of proven efficacy. I truly believe some people *do* benefit from them…maybe 20% of people if I’m being generous. However, I’ve seen people respond beautifully to early morning sunlight, exercise, stress-reduction, mind-body techniques and increasing an emphasis on pleasure in their lives. I’ve seen people change from levothyroxine to dessicated thyroid (or supplement minerals necessary for conversion of T4 to T3) and their biological underpinnings of depression resolve. I’ve seen people with food intolerances have substantial mood improvements with removal of one or two foods that were difficult for the body to break down. Working with chronic illness, I’ve seen it all, yet there are no studies, just my own anecdotes.

    Biological forces aside, I see depression as a disconnection from one’s truest, deepest self. As a human species, we are living in boxes with artificial light, minimal movement, stress levels through the roof, toxic food, staring at screens, and disconnection/distraction. We are removed from nature and community.

    The biggest problem is that the neurotransmitter hypothesis of depression has never been proven. So, then, why would we think these drugs even work? Also, when you start taking these drugs, the body will compensate by changing your brain chemistry and after you come off of them, you often feel worse than before.

    In any event, thank you again for your review on this topic. I find your work easy to read and very helpful.

  12. Sebastian, thanks for this information. Is this review and metastudy applicable to bi-polar depression, as well?

  13. From personal experience I have to say that the placebo effect was what actually made get better. I felt confident to seek out counseling which actually helped. But counseling or therapy is hard work on the part of the patient and it takes time. A lot of time in some cases. And our human propensity for quick and easy solutions makes us take pills who promise to lighten our mood.

    Imagine those pills do work well. What good are they when people do not face the issues which led them to be depressive in the first place. Do we take pills for the rest of our lives. One doctor compared anti-depressants with having diabetes…you just have to take insulin all your life. Sure some people are genetically more prone to depression than others but ultimately it is a cognitive issue that has to be dealt with the hard way. We do not even have a good understanding how our brains work, how in the world are going to know how these pill really work and what else they might change.

    Back to my experience. Using SSRIs I felt like not being my whole self. Stopping them gave me back my own personality. Now 15 years later I am suffering from lockdown induced depression (can we call this long covid from now on?) but whatever I have learned from counseling and therapy in the years before gives me the strength to overcome this now. And these resources come only from working on oneself and not from a pill. Even anti-depressants work well and had little side effects (which they have quite a lot of) they could only ever be a support for the real healing.

  14. At various times over the last 30 years, my husband, his sister and my daughter were all diagnosed with depression. All three: had professional cognitive therapy first; reluctantly began taking a drug to halt the continuing downward spiral; saw a vast improvement on the drug; went off the drug when they felt they had reached ‘normal’ again; slowly started to go downhill again, though they consciously kept up with the lifestyle changes and mental health practices that were supposed to be the non-drug solution; went back on the drug. They are again their normal, happy, stable selves.
    All this is, of course, anecdotal. I’d have to say the same thing is true for the study you have referred to, which also records how the patients say they feel.

  15. My experience of increasing the seretonin available to the brain is that it made me ‘irresponsible’!
    Which sounds a bit odd. Let me explain. I’m very short and have a ‘lazy’ left eye. Together that makes me normally ‘hesitant’ in my driving, particularly at junctions and overtaking.
    After a while on an SSRI, then something else which made a more direct increase in seretonin available to my brain, I felt I had become reckless. I did not LIKE it so came off them gradually as recommended.
    So I guess that means for me modern anti depressants are more harmful than beneficial.
    On the other hand, way back I was prescribed ‘valium’, which I understand is a potentially addictive sedative. That helped me because that wise G.P. had correctly diagnosed panic attacks. I did NOT become addicted in any sense. When life changes removed the stresses I came off them no problem.
    I self diagnose, that I am again inclined to panic attacks At 76yrs with bronchitis and very little support from friends or community, this is hardly surprising.
    Most evenings now I am taking 2 or sometimes 3, valerian based ‘Sleepeasy’ tablets.
    May be I am addicted to them now but I think switching off and sleeping is helpful for me.

  16. One would need to discuss how much antidepressants and, indeed, ANY medical treatment has a PLACEBO effect as its ACTUAL effect.

    Prof Dr Ian Harris wrote the book “Surgery, the ultimate placebo”. Surgery!

    The point is, in order for a placebo to be effective, the patient needs to feel pain to indicate effectiveness. The greater the fear, the greater the pain necessary to have an effect.

    This is a very striking phenomenon here in Germany with Covid. People have great fear so they accept great risks to be “vaccinated”. A friend knows a man who is unsure about effect his AZ vaccination because he did not feel anything… There are reports of people who were happy to receive their AZ doses BECAUSE it was reported it might be withdrawn due to its many problems.

    Very thoughtful material on placebology in German can be found on Helmut Jäger’s “Medical Coaching”.

  17. Thank you Sebastian for your important work, and this post is really excellent.
    I organised a talk by Prof Peter Gotzsche when he was still head of the Nordic Cochrane Collaboration and he gave me a copy of his excellent work on this subject, ” Deadly Psychiatry and Organised Denial “.
    I’m surprised you didn’t mention it?
    Best wishes

  18. Just a personal observation here. I spent ten years on Lexapro and my wife spent 5 years on Cymbalta due to high pressure jobs . The drugs helped us somewhat making it through the workday at first, but the drugs seemed to lose their effectiveness as the years went by requiring an (unfortunate) upping of the dosage for both of us . We both put on significant weight while on these drugs, and I could not perform sexually. I often felt sedated instead of happier. I also developed non alcoholic fatty liver disease and my doctor pretty much admitted that the drug I was on could cause it!!. We finally stopped listening to the doctor (no longer our doctor)and weaned ourselves off these horrible drugs. It was very tough to do and the withdrawal symptoms were significant for both of us. Once we stopped we had to work at it but we finally got that weight off through intense exercise . My erectile dysfunction disappeared as did my fatty liver. Today we take a natural supplement S-adenosyl-L-methionine (SAMe) for support which works great with no side effects . Our BMI is now in the normal range . Perhaps , anti-depressants work on some level for some people but the side effects are not worth it. Exercise, sunshine, a healthy diet( everything in moderation) and natural supplements have restored our health. Polypharmacy BTW is definitely a huge problem in the U.S. and I thought doctors took an oath to do no harm. Thank-you Dr. Rushworth for addressing this issue in your writings.

  19. I’m on metoprolol for a cardiac arrhythmia. One of the off-label uses is to help with performance anxiety. I’ve had much less depression with it than when I was on Celexa.

  20. En större översikt i ämnet ges av Peter Gøtzsche i boken ”Dödlig psykiatri och organiserad förnekelse”. Väl värd att läsas.

  21. Thank you for your work Dr Rushworth
    I agree with you on the inability of antidepressants to help with depression. CBT therapy,EFT Therapy, Mindfulness, Qi Gong, Yoga
    Heart/ Math Institute (heart coherence, love and compassion) are all steps members of my family took
    in order to improve their state of mind.
    Michael Williams is doing wonders in schools in America, watch on YouTube , He ‘s written a book’ Stay Woke,’ very helpful for children, it is teaching compassion and self love.
    Being your own best friend is a very important life skill.

  22. Sebastian Rushworth writes ( ) ;

    // you also have to look at how many people get worse on the drug, compared to placebo //

    Indeed. I wonder, though, whether in looking only at what’s clinically significant in all patients, one may not risk overlooking important sub-groups. For instance, it seems that SSRIs have all but indisputably been godsends for a not insignificant number of people.

    I suggest that a larger problem here may be not so much the medicines themselves as their widespread misprescription.

  23. Sebastian, this is nice clickbait but this territory has been mined multiple times. The BMS Psychiatry meta-analysis in fact indicates a robust and statistically significant efficacy of antidepressants, especially in the more severely ill population. A mean reduction of 2 to 3 HDRS points sounds trivial but it includes patients who have a 10 point reduction along with patients who have a 7 point increase in depression scores! And it’s unfair to compare the 3-point benchmark between placebo and active treatment cases to the 52-point maximum HDRS score when, as you note, the majority of scores for moderately to severely ill patients are in the the high teens to the low to mid twenties to start with.
    Further, when one looks at the much more relevant Number Needed to Treat (NNT) metric, measuring how many patents need to receive a treatment for one patient to obtain clinically (not just statistically) significant improvement, antidepressant NNTs range from 6 to about 13, which compares quite favorably to treatments for many medical conditions which have never been subjected to this level of scrutiny and skepticism. As one example, the statin drugs, the most widely prescribed medicines on earth, have an NNT of approximately 100!
    So your Point One, “SSRIs are not effective as antidepressants”, is simply not true.
    As to safety, the serious adverse event rate of 2.7% again looks impressive until you compare it to our friends the statins, which have similar rates of adverse events with a much worse NNT. Also note that the meta-analysis is limited to relatively brief studies and therefore you would not see any meaningful signal with respect to the primary mortality and morbidity marker of depression, suicidal behavior. Long term suicide rates in depressive illness are in the 10 % to 15 % range. So you are wrong on Point Two as to the cost-benefit ratio as well.
    Thirdly, when it comes to geriatric polypharmacy, the great majority of the medications prescribed to nursing home residents are non-psychiatric. The side effect load of the SSRIs is trivial by comparison. You also note, accurately, that the low number of cases in the JAMA review limits any generalization (especially by comparison to the size of the BMC study).
    Based on the above, your concluding statements that “Anti-depressant drugs are ineffective against depression” and “The harms of these drugs clearly outweigh the practically non-existent benefits” are both false and inflammatory.

    Alex Vuckovic, MD
    Medical Director
    The Pavilion at McLean Hospital

    1. The subject may have been mined by others, but most are still unaware of the findings, including most doctors. Statistical significance is not the same thing as clinical significance. I totally disagree that NNT is more relevant than average benefit, both NNT and average benefit are equally important to consider.

      Only doctors who have been brainwashed to think that an NNT of 10 is good, can think that it is actually good. The comparison with statins is unfair, because statins are used for prophylaxis, while anti-depressants are used for treatment of symptoms. An NNT of 10 isn’t good, it’s awful. I would never personally take an anti-depressant if the doctor told me the odds of noticeable benefit are one in ten, especially when the drug has so many side effects that I would be far more likely to experience.

      A proper NNT is actually impossible to determine, since the only data provided in the studies is on the proportion who show a certain percentage improvement compared with placebo. When no data is provided on the proportion who show the same percentage worsening compared with placebo, it’s impossible to calculate whether the drug on balance is more likely to help than harm. That’s why the average difference is the number that is closer to the truth with the data available from most trials, because it includes both people who get better and people who get worse as a result of the treatment, while the NNT as currently calculated only includes people who get better, which makes it a biased metric.

      The reason the review is limited to brief trials is because the trials that have been conducted on SSRI’s are brief. That’s not the fault of the reviewers. It’s the fault of those conducting the trials (i.e. the companies that make the drugs). You say I’m wrong about SSRI’s not decreasing suicide rates, but you don’t present any evidence to the contrary. If you have that evidence, provide it.

      And as to geriatric polypharmacy – we know that frail elderly people experience all side effects at a much higher rate than the general population. No-one knows what the risk of a serious adverse event is in this group, because those studies haven’t been conducted. However, if the risk for a healthy young person is one in 170, it could easily be one in 17 in a frail elderly person in a nursing home. SSRI’s are known to increase susceptibility to infections, increase the risk of electrolyte imbalances, and also increase the frequency of nycturia, all of which are no problem for healthy young people but which can result in fatal complications to the frail elderly.

      The one thing I do agree with you on is that statins are not very good drugs. I’ve actually written multiple articles about them previously. Your passioned defence makes me wonder if you have any conflicts of interest you want to declare relating to SSRI’s?

      1. Cheap shot, Sebastian. I have absolutely no pharma industry connections and have spent my career as an academically based clinical doc. In fact, I’m developing a natural antidepressant which avoids many of the SSRI complications you cite (and which may slay the SSRI dragon!). However, your take on these drugs is ridiculously one-sided–just look at the comments section!
        To your specific points: you either think NNT matters or not. I agree that it does, of course while also looking at group differences. I assure you I’m not brainwashed but if any physician limits his prescribing to drugs with NNTs of, what?–less than 3?–his prescription pad will get pretty dusty. Also, in my field, the placebo response is robust enough that it inflates NNTs anyway. And since I see a pretty treatment resistant population, the dramatic responses are all the more gratifying.
        Sounds like we agree on statins, though I take one!
        You are of course correct about the absence of longtitudinal trials, reflecting the fact that more than half of patients who take SSRIs stop them within 2 months. The cause of these discontinuations has nothing to do with serious adverse events and everything to do with sexual dysfunction and emotional numbing (see what a shill I am for Pharma?). The fact that a robust minority of patients stays on them speaks to how awful it is to suffer from clinical depression.
        Suicide rates are a big issue and an indictment of our present state of technology . Short term SSRI studies do show improvement in suicidal ideation (in adults–aware of emergent suicidality in kids) but, again, the definitive answer would be found in a longtitudinal naturalistic format. Unfortunately, the only drugs which show robust long term suicide reduction are lithium and clozapine, both of which have major league toxicity issues.
        Your generic comments on SSRIs in the elderly are fine, but I can turn it around also–show me data from more than 55 patients.
        So maybe we’re not that far apart once we get past your hyperbole–I don’t know why you Brits hate SSRIs so much!
        All my best
        Alex V

      2. Maybe a cheap shot, but I couldn’t resist it.

        I’m Swedish actually (well, technically half-British, maybe that’s enough to make me genetically anti-antidepressants!).

        My prescription pad is probably quite a bit dustier than most physicians. I spend more time trying to make my patients medicine lists shorter than I do making them longer.

        I am interested to hear more about your natural antidepressant. What are the components? (If you can say)

      3. re: natural antidepressant components.
        Proprietary for now, will be rolling it out later this year. Happy to save a free sample for you!

      4. Drs. Rushworth and Vuckovic,

        I think I can provide a patient’s perspective on the effectiveness of antidepressants. I have taken nearly every class of antidepressant over the past 10 years with the exception of the tricyclics (multiple trials of various SSRIs, SNRIs, atypicals, MAOIs, including augmentation of those suitable with low-dose antipsychotics). The depression was brought on dealing with a long, difficult, stressful family situation (illness and death). I am now in remission, mostly due to the end of that situation, but on very low-dose maintenance medication – as psychitrists generally recommend (may be a placebo at this point). I am an engineer, and followed my psychiatrist’s and psych. nurse’s instructions carefully, and am rational in my analysis of what works and what doesn’t. We went through a long, logical process.

        To make a long story short, the only antidepressants that I found significantly effective in treating this serious depression were the Monoamine Oxidase Inhibitors (MAOIs), such as Parnate (tranylcypromine), Nardil (phenelzine), and selegiline (others such as Marplan (isocarboxazid) available in other countries). The other ADs had only a slight effect on mood, even at the highest recommended dosage – an came with annoying side effects, such as blood pressure increases (some significant).

        As you know, the MAOIs are the one class of antidepressant that strongly affects all the neurotransmitters, and thus significantly lifts the mood and produces motivation. My psychiatrist called them the “nuclear weapons” against depression – that is, very effective, but also can be dangerous. Also as you know, oral administration requires dietary restrictions and medication interaction restrictions (including even dental pain meds) to avoid dangerous increases in blood pressure. There is controversy about whether patients should self-administer nifedipine in hypertensive events if far away from an emergency clinic (I carried it). Wearing a medical ID bracelet or pendant is required in case the patient were to be injured and require emergency medical attention (interaction with certain anesthetics).

        Nadil can cause more weight gain than Parnate. Selegiline is available in a very expensive patch version (Emsam) to avoid dietary restrictions, but still requires medication restrictions. Strangely, the MAOIs can cause decreases in blood pressure as well as the dietary-related dangerous spikes. And like the benzodiazepines, they are ototoxic, taken long-term at the recommended dosage (high frequency hearing loss) – something that is not commonly known, and true with some other ADs.

        My impression is that many psychiatrists KNOW that MAOIs are the most effective ADs, acting strongly on all three neurotransmitters, but don’t use them because most patients won’t follow the necessary restrictions (including alcohol I believe) and precautions. That is why Emsam was developed, but it is expensive, and last I checked, not covered by many insurance plans. Even with it however, you have to wear a medical alert and carry a wallet card, due to the possible serious interactions with anesthetics in an emergency injury situation.

        What the pharmaceutical companys should do is find a way to make a similar antidepressant medication that doesn’t have the interactions. One that strongly acts on all the neurotransmitters (and is not addictive, of course). A tall order, I know.

        And by the way, I found that forcing myself to do exercise (as I had done before the depression) seemed to do as much good as any of the other classes of ADs. Hard to do when you are depressed though. It would be interesting for studies to compare various ADs simply with an exercise program. I think I recall such a study may have been done.

  24. Hello,
    I am on The verge of popping any psychoactive molecule available after listening to the recent podcast episode of The dark horse with Dr Geert Vanden Bossche. It is a lesson in innate versus acquired immunity and the big mistake we could be doing right now. I would appreciate your opinion on his hypothesis.

  25. All American doctors seem to know these days is how to write prescriptions and they defend this practice vehemently based on “studies” despite the horrendous side effects many drugs bestow on the unsuspecting with questionable efficacy.But is it any wonder this massive brainwashing exists when Big Pharma pretty much funds medical schools and use ghost writers employed by drug manufacturers to write up biased studies in a favorable manner?For young people and even the elderly who are struggling with depression, it might be a good idea to try some natural ways to cope. Exercise can release feel-good endorphins, and being outdoors is also a mood lifter, so why not combine these and play sports outside or sit in the sun? Other people are getting relief from meditation, yoga, art therapy, and aromatherapy. Natural supplements like SAMe are effective too.With the risks of antidepressants being so great and their efficacy in serious doubt, it’s disappointing that they continue to be prescribed in such high numbers to people. Americans in particular have a growing obesity problem and these natural approaches could go along way towards helping people cope without the drugs. Still everybody I know has a medicine cabinet bursting full of pills .

  26. Dear Sebastian,

    thanks for your work. It is not only sience based but also fun to read.

    Sentence like the following are a good example!

    “In other words, “serious” is serious. ”

    Keep going!



  27. (well, technically half-British, maybe that’s enough to make me genetically anti-antidepressants!).

    Hey you racist!


    That was a good one!

  28. My experience with Escitalopram is good. I suffer from anxiety and it helps me keep it under control. It also helped my mother against depression.

  29. Sebastian,

    I was very interested in this post by you, and not altogether surprised by what you discovered.

    So I have a general question: If a person is on any kind of a drug over a certain period of time does the efficacy of the drug fall off with time?

    Similarly, are there inevitable side effects from the drug? Are there inevitable long term effects?

    I am under the general impression that pharmaceuticals are synthetic and thus perhaps displacing natural molecules/ proteins, etc. and the body struggles to “recognize” and work with the introduced agent. I’m no doc or scientist so perhaps my take on all of this is too simplistic.

    Thanks, Ed

    1. As to the first question, it varies. For some drugs, the efficacy falls off, and you need a higher and higher dose to get the same effect. Morfine and nicotine are good examples. For many drugs that isn’t the case. It really depends on how the body reacts to the drug, whether it attempts to compensate and recreate the original equilibrium or not, which depends on which particular system the drug is targeting.

      As to side-effects – a good general principle is that if a drug doesn’t have any side-effects, then it probably doesn’t have any effects at all. Anything that affects the body’s functioning in any major way will have unintended additional consequences. So all real drugs have side effects.

      Long term effects aren’t inevitable. Some drugs have effects that continue to linger long after the drug has disappeared from the body. Most don’t.

      Whether a drug is “synthetic” or “natural” doesn’t really matter in itself. What matters is the biochemical properties of the particular drug molecule.

  30. According to what I’ve heard from psychiatrists, some antidepressants work fine for some patients and are useless for others. If that is the case, maybe the average is not a good measure for a study. Maybe the problem has not to do with RCTs but with a lack of personalized treatments.

    1. So I guess if it actually stops arthritic pain and you feel better in general than I guess you can claim this drug is an antidepressant by default even if it doesn’t work on depression directly. Interesting.

  31. Not just the old, but the very young. I was prescribed a SSRI when I was 12 and have been on one ever since. 25 years later, I am very proud of myself for withdrawing slooowly off of it. Prescribing these meds to such young people, during puberty, when brain chemistry is rapidly changing…inexcusable.

  32. My parents managed to marry a family history of depression/alcoholism/suicide to atypical migraine. My first antidepressant was a quatracyclic for chronic daily headache aged about 40. I now realize my first depressive episode was when I was 17. In the past 30 years i have since had just about all of them, including lithium. They made a high pressure academic career in neuroscience + 3 kids possible, but all had unpleasant side effects.

    Six years ago I insisted on being prescribed moclobemide with low dose quetiapine at bedtime. I have been completely stable since and I am able to titrate dose requirement accurately on the basis of mood (eg, up 50 mg when on a CYP 2C19 inducer).

    Most trials of antidepressants recruit from the “mild to moderate” category. My suspicion is that the majority are temporarily disordered by the normal stresses and strains of life. This group is probably mostly helped by placebo effects and discontinues the drugs fairly soon. This is not true endogenous depression, which may be worsened by stress, but is not tightly related to it. These are the people, like some of the comentators above, who are greatly helped by antidepressants.

  33. Dave Macleod, a noted Scottish rock climber, inadvertently cured his depression by following a ketogenic diet. He had been having difficulty keeping his weight down and went keto to achieve this. I had been watching his videos for years and had no idea he suffered from depression, he had turned down pharmaceuticals because he believed that the side effects would blunt his climbing ability. He says that climbing, outdoor pursuits were his therapy. Basically he has no axe to grind here. It could of course have been a coincidence that his depression lifted when he changed his diet, something he acknowledges, however his experience strongly suggests that our modern diet plays a major role in depression, and also that depression is a real medical condition, something I myself have been skeptical about.

  34. I am interested in this comment as I am looking into the possibility of keto as a therapy for epilepsy for a family member. Apparently this was the prescription for epilepsy 100 years ago. It was displaced when anti convulsants came in in the late 30’s. It was revived at Johns Hopkins in the 90’s

    I admit to a certain bias here as I have been on a Weston Price (nutrient dense, high fat, low carb) diet for the past decade, and I believe my good health (knock wood) is the direct result of this dietary regimen. The Weston Price diet is a modified form of the ketogenic diet. It emphasizes eating more traditional foods, i.e. those eaten by our ancestors prior to widespread industrialization – which included how food was/is produced.

    I think the modern diet, composed of overly processed and modified foods, is a contributor to all sorts of chronic diseases, and it would stand to reason that depression would be included in the mix. I would be interested to know what Sebastian thinks about this.

  35. I started experiencing anxiety and depression in December which affected my sleep which led to more anxiety. Since it had been a pretty gray, dismal winter, I looked for solutions to Seasonal affective disorder.
    After some reading, I started taking SAM-e which is considered a supplement here in the US. I have to say, I slept well the first night I took it and continues to help me.
    I’d be interested in your opinion of supplements in lieu of prescription drugs.

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