Do antidepressants work against severe depression?

No, it is an illusion that comes from two mathematical artefacts

Psychiatrists sometimes admit that depression drugs are rather ineffective in mild or moderate depression, but most psychiatrists believe that the drugs are effective in severe depression, which is reflected in guidelines all over the world.

They also believe that psychotherapy doesn’t work for severe depression. Both beliefs are wrong,¹ and the misconceptions are dangerous for the patients because antidepressants double the risk of suicide,² with no age limits, whereas psychotherapy is so effective that it halves the risk of a new suicide attempt in people admitted to hospital after a suicide attempt.³ This is a dramatic effect in patients at high risk of suicide, many of whom must have had very severe depression.

A textbook of psychiatry illustrates these issues.⁴ It advises that SSRIs or tricyclics could be used instead of psychotherapy for moderate depression or in combination with it. For severe depression, psychotherapy was not advised, but hospital admission, tricyclics, tricyclics plus psychosis pills, and electroshock were.

This is a sad but very familiar theme in psychiatry. The worse the disease, the more the patients will be harmed by treatments that don’t help them.^1,5,6 It is the exact opposite of evidence-based medicine.

New Zealand has the highest suicide rate in the world among teenagers between 15 and 19, double that of Sweden and four times higher than Denmark.⁷ When Robert Whitaker, founder of the Mad in America website, and I visited John Crawshaw, Director of Mental Health and Chief Advisor to the Minister of Health in New Zealand, in February 2018, I asked him to make it illegal to use antidepressants in children to prevent some of the many suicides.⁸ He replied that some children were so severely depressed that antidepressants should be tried. When I asked what the argument was for driving some of the most depressed children to suicide with pills that didn’t work for their depression,^5,6 Crawshaw became uncomfortable, and the meeting ended soon after.

Mathematical artefacts explain the illusion

The misconception that the drug effect is related to the severity of the depression is due to two mathematical artefacts. I explained one of them in a letter to the editor in 2010,⁹ in reply to a meta-analysis of trials based on individual patient data. The authors concluded that:¹⁰

“The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.”

The authors made the error of regressing change in symptoms on initial symptom severity. Thus, they looked at (x − y) = ax + b, where x is the initial value and y the final value. Since x appears on both sides of the equation, 50% of the variation is already explained. This means that even when two factors are unrelated, the analysis will show a relation, which, however, is spurious.

The other mathematical artefact is caused by bias in assessment of the treatment effect. Due to the conspicuous side effects of the drugs, the placebo-controlled trials have not been adequately blinded.⁵ This introduces a bias that can be quite large, e.g. 68% on average when the observers had not been blinded compared to blinded observers in the same trials in a review that included all diseases.¹¹

The bias need not be large to explain the results in meta-analyses that have reported that the effect of depression drugs is larger if the patients are severely depressed.^12-14 Since the baseline scores for severe depression are higher than for mild depression, a bias will influence the measured result more in patients with severe depression than in those with mild depression.

I have given an example of this.³ If we assume that the unblinding bias is 10% when estimating the effect in the drug group, and that for the simplicity of the example there is no bias in the placebo group and nothing happens between baseline and the final visit, then a Hamilton baseline score of 25 would still be 25 after treatment in the placebo group, but because of the bias, there would be a 2.5-point difference between drug and placebo. If the baseline is 15, the difference would only be 1.5.

These results are close to those reported in a large meta-analysis¹⁴ that found that the effect was 2.7 for patients with a baseline Hamilton score above 23, which is considered very severe depression,¹⁰ and 1.3 for milder degrees of depression.

Even if we assume that the reported results are unbiased (which is clearly not correct^5,15), the measured effect in patients with very severe depression, 2.7, is considerably lower than the smallest effect that can be perceived on this scale, which is a Hamilton score difference of 5-6.¹⁶

We may therefore conclude that depression drugs are ineffective for all degrees of depression and that it is misleading to call them antidepressants.

The misconception about psychotherapy

The misconception about psychotherapy is also profound. Preventing suicide is paramount in treating depression, and it is bizarre that when a psychiatric textbook noted that the suicide risk is increased at the start of treatment with depression pills, it falsely claimed the same is true for psychotherapy.¹⁷ It looks like an excuse for using harmful pills to postulate that therapy also increases the suicide risk. There was no reference to this statement, but psychotherapy clearly decreases the risk of suicide.³

Conclusions

I have explained in a freely available book how I came to the conclusion that psychiatry is a crime against humanity.¹ These strong words are fully justified. Psychiatry is the only specialty that survives on lies,¹⁸ and the lies are deadly.¹⁹ Psychiatrists recommend the opposite of what they should recommend for treatment of severe depression and, most bizarrely, so-called suicide experts always recommend depression drugs to prevent suicide.²⁰

It is therefore not surprising that suicides among US adults have increase by 76% from 2001 to 2022.²¹ The suicide rate in the United States has risen steadily since the creation of a national strategy to prevent it,²² and in other countries, improved access to psychiatric services and psychiatric drugs have also been associated with an increase in national suicide rates.²³

Depression is only one of many examples of how harmful the lies are. Another, very deadly lie is that antipsychotics are good for patients with psychosis. They do not have relevant clinical effects; they kill many patients; and they cause serious and permanent neurological harms in many more.⁵ Psychiatric drugs are so harmful and so much overused that they are the third leading cause of death, after heart disease and cancer.¹⁹

I have argued, based on commonly used definitions of madness, that psychiatrists are more mad than their patients.²⁴ Both the World Health Organisation and the United Nations have realised that the existing approaches that focus on drugs are not working. In the UK, mental health disability has almost trebled in recent decades, and the gap in life expectancy between people with severe mental health issues and the general population has doubled.²⁵ The WHO and the UN have therefore called for systematic mental health reform emphasising psychosocial interventions.²⁵

When will we see this happening? Haven’t we and the patients waited long enough and seen enough? Only two weeks ago, two professors, one from Harvard and one from the University of Sydney argued that antidepressants protect against suicide. They disinformed their readers to such an extent that their dishonesty was total.²⁶

This article is a slightly revised version of Gøtzsche PC. The illusion that antidepressants are more effective when the depression is severe is due to mathematical artefacts. Institute for Scientific Freedom 2025;April 2.

References

1 Gøtzsche PC. Is psychiatry a crime against humanity? Copenhagen: Institute for Scientific Freedom; 2024 (freely available); Gøtzsche PC. Critical psychiatry textbook. Copenhagen: Institute for Scientific Freedom; 2022 (freely available).

2 Hengartner MP, Plöderl M. Newer-generation antidepressants and suicide risk in randomized controlled trials: a re-analysis of the FDA database. Psychother Psychosom 2019;88:247-8; Hengartner MP, Plöderl M. Reply to the Letter to the Editor: “Newer-Generation Antidepressants and Suicide Risk: Thoughts on Hengartner and Plöderl’s Re-Analysis.” Psychother Psychosom 2019;88:373-4; Gøtzsche PC. Observational studies confirm trial results that antidepressants double suicides. Mad in America 2025;Feb 8; Gøtzsche PC. Suicides increase after national suicide prevention introduced. Mad in America 2025;Feb 20.

3 Gøtzsche PC, Gøtzsche PK. Cognitive behavioural therapy halves the risk of repeated suicide attempts: systematic review. J R Soc Med 2017;110:404-10.

4 Mors O, Nordentoft M, Hageman I (eds.). Klinisk psykiatri. København: Munksgaard; 2016.

5 Gøtzsche PC. Deadly psychiatry and organised denial. Copenhagen: People’s Press; 2015.

6 Gøtzsche PC, Healy D. Restoring the two pivotal fluoxetine trials in children and adolescents with depression. Int J Risk Saf Med 2022;33:385-408.

7 UNICEF Office of Research. Building the future: children and the sustainable development goals in rich countries. Innocenti ReportCard 14; 2017.

8 Gøtzsche PC. Whistleblower in healthcare (autobiography). Copenhagen: Institute for Scientific Freedom; 2025 (freely available).

9 Gøtzsche P. Depression severity and effect of antidepressant medications. JAMA 2010;303:1597.

10 Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010;303:47-53.

11 Hróbjartsson A, Thomsen AS, Emanuelsson F, et al. Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. CMAJ 2013;185:E201-11.

12 Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008;5:e45.

13 Cipriani A, Zhou X, Del Giovane C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet 2016;388:881-90.

14 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. (In the clinical study reports of depression pills I obtained from the European Medicines Agency, the median standard deviation on the Hamilton scale after treatment was 7.5. Thus, an effect size of 0.25 corresponds to 2 on the Hamilton scale).

15 Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression. Cochrane Database Syst Rev 2004;1:CD003012.

16 Leucht S, Fennema H, Engel R, et al. What does the HAMD mean? J Affect Disord 2013;148:243-8.

17 Videbech P, Kjølbye M, Sørensen T, et al. (red.). Psykiatri. En lærebog om voksnes psykiske sygdomme. København: FADL’s Forlag; 2018.

18 Gøtzsche PC. The Only Medical Specialty That Survives on Lies. Brownstone Journal 2025;Sept 8.

19 Gøtzsche PC. Prescription drugs are the leading cause of death. And psychiatric drugs are the third leading cause of death. Brownstone Journal 2024;April 16.

20 Gøtzsche PC. So-called suicide experts recommend antidepressants, which increase suicides. Mad in America 2024;Oct 24.

21 2024 National Veteran Suicide Prevention Annual report. U.S. Department of Veterans Affairs, Office of Suicide Prevention 2024;Dec.

22 Whitaker R. Suicide in the age of Prozac. Mad in America 2018;Aug 6.

23 Whitaker R, Blumke D. Screening + drug treatment = increase in veteran suicides. Mad in America 2019;Nov 10.

24 Gøtzsche PC. Are psychiatrists more mad than their patients? Mad in America 2025;May 6.

25 Shifting the balance towards social interventions: a call for an overhaul of the mental health system. Beyond Pills All-Party Parliamentary Group 2024;May.

26 Gøtzsche PC. Two professors lied about suicide risk of antidepressants and vilified Kennedy. Substack 2026;Jan 19.