It’s Unlikely That ‘Antidepressants’ Have a True Effect on Depression

Peter Gøtzsche, MD
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Almost all placebo-controlled drug trials in psychiatry are flawed due to their cold turkey design.1 Patients who are already in treatment first go through a “wash-out” period, when everyone is removed from the drug they had been on, and then randomized to placebo or drug. The wash-out period is too short to avoid abstinence symptoms in the placebo group.2

These abstinence symptoms can be the same as those that define the disorder, e.g. depression in depression trials, and the withdrawal effects can be very pronounced. One third of patients in long-term treatment with sertraline or paroxetine had an increase in their Hamilton score of at least 8 during a 5-8 day period where the drug was substituted with a placebo.3

We currently do systematic reviews of psychiatric drug trials at the Nordic Cochrane Centre where we only include trials in drug-naïve patients. The only such trial we found of neuroleptics in patients with psychosis was fraudulent (submitted manuscript).

In depression, trials exist in drug-naïve patients who have a chronic disease and developed depression in addition to this. An exemplary trial of this type was published in November 2017 in JAMA.4 It studied 201 patients with chronic kidney disease and depression for 12 weeks. Sertraline had no effect. The QIDS-C16 score changed by −4.1 in the sertraline group and by −4.2 in the placebo group; between-group difference, 0.1 (95% confidence interval −1.1 to 1.3; P = 0.82). The authors reported that a difference of 2 points on the QIDS-C16 is equivalent to a difference of 3 points on the Hamilton Rating Scale. The least clinically relevant effect on the Hamilton scale is 5-6.5

The authors hypothesized that the lack of effect of antidepressants — also in other trials in patients with chronic diseases — could be due to too low dose or to the presence of comorbidity.

I find both explanations unlikely. Receptor studies have shown that also when low doses are being used, the patients are dosed sufficiently because the dose-response curve has already flattened out.6DASB positron emission tomography study. Am J Psychiatry 2004;161:826-35.] In agreement with this, independently performed systematic reviews of dose-response studies of the effect in patients have been negative.7 The other argument is equally implausible. If depression pills work for depression, they should also work for depression in people with comorbidities.

A much more likely explanation is that the patients with chronic comorbidity in these trials were not already in treatment with depression pills before they were randomised.

Even helped by the withdrawal bias and bias caused by insufficient blinding, traditional trials of antidepressants have only found an effect of around 2 on the Hamilton scale.8

I have come to the conclusion that depression pills have no true effect on depression. What is being measured in most trials is likely bias. It is often claimed that they work for very severe depression but that isn’t correct either. The seemingly “better” effect (which is still clinically irrelevant) in very severe depression could simply be a mathematical artefact: the greater the score at baseline, the greater the bias will be when the “effect” is being assessed.9

I submitted a short letter to the editor of JAMA pointing out the likely explanation for the lack of effect of sertraline. I dutifully called depression pills antidepressants, although I prefer to avoid this term, as it is so misleading. Antibiotics can cure infections; depression pills cannot cure anything. JAMA rejected my letter, which “did not receive a high enough priority rating for publication in JAMA.” I have experienced this many times when I have submitted letters. Explaining why psychiatric drugs don’t work is not a priority for medical journals, it seems.

Show 9 footnotes

  1.  Gøtzsche PC. Deadly psychiatry and organised denial. Copenhagen: People’s Press; 2015. ↩
  2.  Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom 2015;84:72-81. ↩
  3. Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomised clinical trial. Biol Psychiatry 1998;44:77-87. ↩
  4.  Hedayati SS, Gregg LP, Carmody T, et al. Effect of sertraline on depressive symptoms in patients with chronic kidney disease without dialysis dependence: the CAST randomized clinical trial. JAMA 2017;318:1876-1890. ↩
  5.  Leucht S, Fennema H, Engel R, et al. What does the HAMD mean? J Affect Disord 2013;148:243-8. ↩
  6.  Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, et al. Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C ↩
  7. Adli M, Baethge C, Heinz A, Langlitz N, Bauer M. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005;255:387-400. ↩
  8. Jakobsen JC, Katakam KK, Schou A, et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC Psychiatry 2017;17:58. ↩
  9. Gøtzsche PC, Gøtzsche PK. Cognitive behavioural therapy halves the risk of repeated suicide attempts: systematic review. J R Soc Med 2017;110:404-10. ↩

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36 COMMENTS

  1. The antidepressants are not “safe smoking cessation meds” either, but lots and lots of doctors believe the common symptoms of antidepressant discontinuation syndrome (ADS), and the adverse effects of the antidepressants, is “bipolar.” This, of course, is untrue however.

    And trying to “cure” ADS or the adverse effects of the antidepressants with an antipsychotic will make a person “psychotic,” via anticholinergic toxidrome. But the psychiatrists and psychologists and mainstream doctors claim to not know this, despite learning about this in med school, because they worship from a scientifically invalid DSM billing code “bible,” which doesn’t include this known antidepressant/antipsychotic induced illness. The DSM even encourages such toxic drug cocktails for those mislabeled as “bipolar.”

    It’s a shame today’s DSM based psychiatric system is a multibillion dollar iatrogenic illness creation system, but it is. One does have to wonder how long it will take for those who create “mental illnesses” in innocent people for profit to realize that is the opposite of “appropriate health care,” and such appalling maltreatment of other human beings makes those doctors complete hypocrites.

  2. Sertraline inhibits quite a lot of CYP450. If a person can’t sleep and takes something like nytol which contains Valerian (blocks CYP450) they are at risk of significant akathisia. If they kill themselves it’s recorded as the depressive illness, if they kill someone else they go to jail. Sertraline is without doubt a killer.

  5. That was so concisely written. Thank you.
    The withdrawal depressive symptoms from these medications can be painful and lengthy; I can’t imagine how people would consider it appropriate to do placebo crossovers like they are doing. It appears to be both cruel and unscientific.

  7. Peter Gøtzsche does good work. I’ve read his book Deadly Medicines and Organised Crime. It is a good book. There’s just one problem here. These pills DO HAVE AN EFFECT on depression. They CAUSE depression. It’s a good thing that we have people who try to figure out the so-called science behind all the drugging. But all the theorizing in the world, and all the experiments in the world, will never explain the very real suffering of those who have actually been subjected to the drugging. If MIA writers want to know the truth about psychiatry, try taking some so-called “antidepressants” or a concoction of “antipsychotics” or any other psychotropic drugs for an extended period of time. Then try to withdraw from them. Then, if you survive, you will know the truth about psychiatry.

  9. They gave me anti-depressants as a “prophylactic” for nearly daily migraines. I did end up with depression in addition to the migraines, but it took me a long time to figure out their “chemical imbalance” was nonsense and that the depression was due to the excruciating chronic pain – and that is a pretty normal reaction. The anti-depressants did not help the migraines or the depression one bit.

    • Look up: nociception of the trigeminal nerve, bruxism and migraine. The role of facial and neck muscles in particular the muscles above the eyebrows in irritating the trigeminal nerve, the role of calcitonin gene related peptide, Peter Goadsby, NTI-tss mouth guard and this one.. GrindReliefN. Eventually magnesium will block the pain, but you have to take it for a long time before it kicks in, (many months into years) best in powdered form dissolved on the tongue or in carbonated water. Think about all the activities that make you use the muscles above your eyebrows, such as when you wash your face or take a shower to keep water out of the eyes, direct low level sunlight, yawning… anything that makes you use those muscles, avoid and/or train yourself to keep them relaxed. Remember the magnesium will work, it just takes time. I have very many years experience to know this, stay off the triptans and do not go near the tramadol.

      and btw Professor Gøtzsche, we support you big time !

    • A good friend of mine was prescribed Zoloft for migraines. She had never been suicidal in her life, but suddenly had these odd thoughts when struggling with a problem: “I could kill myself.” She was stunned and disturbed! It took her over a year to get off of it due to withdrawal reactions, had to cut the pills down into tiny fragments to wean off. So yes, this does happen, and it’s a horrible idea!

  10. Dr. Gotzsche:
    I don’t have the formal education in either statistics, or analyzing clinical studies, to accurately and thoroughly assess all the relevant details of what you’re saying here. But my language comprehension skills are more than sufficient to ask you a pertinent question. In the first sentence of your letter, above, you clearly state that “Almost all placebo-controlled trials”…etc., So, you ARE saying that at LEAST SOME trials are NOT flawed. Is that really the case? Are there in fact non-flawed drug trials?….
    My personal experience with both Zoloft and Wellbutrin is that they basically did NOTHING for me.
    But c’mon, Peter, are there ANY un-flawed studies?

  13. The disturbing thing is that they are still prescribed all the time, and for things they were never approved for (off-label use). I was recently offered trazadone for insomnia which is wasn’t approved for. It was prescribed by the same doctor for broken toes I had. Seems to have a lot more to do with my history than any actual benefit. Now insurance companies are pushing it as an alternative (cheaper for them, more politically accepted?). Makes me so mad.

  16. Interesting comments. One asks if there are any unbiased trials of depression pills? I am still looking, hoping to find one some day.

    Another says we should try how it is like to come of psychiatric drugs. I have often thought that I should try a depression and a psychosis pill, but I don’t dare to try! Some people become violent or suicidal, so why run this risk when you are healthy? I cannot even recommend sick people to run the risk, as none of these drugs have clinically relevant effects.

    • If you get a akathisia reaction, it can be horrific in the absolute extreme and yes you can become suicidal and violent very quickly indeed. It is way way more serious than anyone who has not had this experience can know. You do not ever, ever want to experience that. Those of us who have gone through it, know with great clarity that a terrible human rights crime is being committed with impunity. So we urge you to keep up the good work, no matter what labels are given to us, we know you are correct.

    • At least you’re honest (about why you wouldnt experiment with prescribed medication) Dr Gøtzsche,

      In my opinion it’s wishful thinking to believe a pill can be taken that will stop anxiety or stop depression without ending in a higher price being paid.

      I think the ‘easy way out’ is not to take the pills, and find some other healthy way of overcoming “depression” and “anxiety”; and there are lots of different healthy ways to do this.

  17. ‘When you’re manic you don’t sleep and get very paranoid. So I’m dealing with it with medication.’

    So I guess she was on mood stablisers/anti-psychotic/antidepressant, let me guess… Abilify, let me also guess… prolonged QT interval which will be seen as not suspicious and death due to natural cause –

    the ‘guardian’ say not suspicious:

    https://www.theguardian.com/music/2018/jan/16/dolores-oriordan-cranberries-death-not-suspicious-say-police