Submitted 3/14/2025

We appreciate the opportunity to respond to the comments regarding our publication.

While we acknowledge the critique provided by Prof. Gøtzsche, we believe that some aspects of his argumentation deviate from the central issue of our research. Contrary to the widely held belief in the field, our position challenges the assumption that clozapine is unequivocally superior in efficacy. We continue to assert that a well-designed, industry-independent randomized controlled trial (RCT) comparing clozapine with other second-generation antipsychotics is necessary (as detailed in our original article). Furthermore, a plasma-level controlled, dose-finding study for clozapine remains a crucial unmet need. Contrary to the assertion made in the critique by Prof Gøtzsche, there is robust evidence for a dose-response relationship in antipsychotic medications,[1-5] within but not outside [6] the licensed dose ranges for newer drugs. However, as clozapine is an old drug, proper dose-finding studies have never been conducted, which represents a significant gap in the literature.

We firmly believe in the Popperian philosophy of scientific inquiry, where hypotheses are continuously tested and refined through rigorous debate. In this context, we acknowledge the value of differing perspectives and appreciate the contributions of Prof. Gøtzsche.[7] However, we frequently observe that studies of lower methodological quality that support certain viewpoints are given disproportionate weight, whereas higher-quality studies that present conflicting findings are often dismissed. This discrepancy in interpretation, observed in the letter by Prof. Gøtzsche, creates a significant barrier to objective scientific discourse. The risk of misinformation is substantial when discussions are framed exclusively in terms of criticisms without a balanced presentation of supporting and opposing evidence. Evidence-based medicine necessitates a fair assessment of both supporting and contradictory data.

For instance, in the commentary, the limitation we acknowledged—our inability to access individual patient data (IPD) from some studies demonstrating clozapine’s superiority—is dismissed with the assertion that data were withheld due to potential undisclosed biases. While data transparency is a valid concern, an alternative and more plausible explanation exists: many of these trials are over two decades old, and drug ownership has changed multiple times, as was the case in a study where the company made substantial efforts to provide the requested data.[8]

In the comment, the nationwide observational studies from Finland and Sweden, which consistently indicate clozapine’s superior efficacy, are disregarded. These studies show that the highest mortality rates are among patients who do not receive antipsychotic treatment.[9] While we acknowledge that observational studies have inherent limitations, their findings cannot be dismissed outright. The effects observed may not be purely causal, as untreated individuals may receive less overall medical care. However, ignoring a priori large-scale, population-based studies is to our view not good scientific practice.

The burden of psychiatric disorders is profound. While systemic issues in psychiatry exist, dismissing the efficacy of antipsychotic medications entirely is not evidence-based and promotes an untenable nihilistic perspective. Psychotherapy monotherapy is not an effective treatment for psychosis, despite promising initial data in select populations.[10] Psychiatric professionals universally attempt to reason with patients experiencing hallucinations and delusions, yet such efforts prove ineffective. We support the expansion of Soteria-style wards, insufficient financial resources are a reason for psychiatry being too drug-centered. The effect sizes of antipsychotics have been often characterised variably, from “small” to “moderate” by researchers and clinicians. However, it is only those who need the medication that can infer about whether the efficiacy of the pharmacological interventions is worthwhile, given their side effects. A recent survey suggested that one in three people who show signs of depressions, find the small effect of antidepressants worth the side effects.[11] I (SL) was very sceptical about antidepressants due to their low effect sizes. However, I have suffered from generalized anxiety disorder since puberty. While psychotherapy was helpful, it never addressed the root of the problem. A few years ago, I started taking antidepressants, and they were a game changer for me—the anxiety simply vanished. After 30 years of suffering, this is certainly not a placebo effect.[12] We collaborate closely with patient organisations (https://www.bastagegenstigma.de/; https://psychose-seminar-muenchen.de/) some tell us that clozapine was the only drug that helped them.

Until similar studies are undertaken that will give a voice to the people with lived experience of psychosis, researchers and clinicians should refrain from making definitive statements about the clinical value of antipsychotics.

We strongly advocate for an evidence-based, balanced discussion regarding psychiatric treatment. Dismissing the efficacy of psychotropic medications without considering the totality of available evidence and views of the patients is neither scientifically rigorous nor beneficial to those who needs these treatments.

Sincerely,

Stefan Leucht, Johannes Schneider-Thoma, Konstantina Chalkou, Tasmin Hamza, Spyridon Siafis, Georgia Salanti

Competing interests: In the last three years SL has received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Apsen, Boehringer Ingelheim, Janssen, Karuna, Kynexis, Lundbeck, Medscape, Otsuka, Neurotorium, NovoNordisk, Orionpharma, Otsuka, Roche, Rovi, TEVA. The other authors declare no conflict of interest.

References

1. Leucht S, Crippa A, Siafis S, Patel MX, Orsini N, Davis JM (2020) Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 177:342-353

2. Leucht S, Bauer S, Siafis S, Hamza T, Wu H, Schneider-Thoma J, Salanti G, Davis JM (2021) Examination of dosing of antipsychotic drugs for relapse prevention in patients with stable schizophrenia: A meta-analysis. JAMA psychiatry 78:1238-1248

3. Wu H, Siafis S, Wang D, Burschinski A, Schneider-Thoma J, Priller J, Davis JM, Leucht S (2023) Antipsychotic-induced akathisia in adults with acute schizophrenia: A systematic review and dose-response meta-analysis. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 72:40-49

4. Siafis S, Wu H, Wang D, Burschinski A, Nomura N, Takeuchi H, Schneider-Thoma J, Davis JM, Leucht S (2023) Antipsychotic dose, dopamine d2 receptor occupancy and extrapyramidal side-effects: A systematic review and dose-response meta-analysis. Mol Psychiatry 28:3267-3277

5. Wu H, Siafis S, Hamza T, Schneider-Thoma J, Davis JM, Salanti G, Leucht S (2022) Antipsychotic-induced weight gain: Dose-response meta-analysis of randomized controlled trials. Schizophr Bull 48:643-654

6. Samara MT, Klupp E, Helfer B, Rothe PH, Schneider-Thoma J, Leucht S (2018) Increasing antipsychotic dose for non response in schizophrenia. Cochrane Database Syst Rev 5:CD011883

7. Gøtzsche PC (2015) Deadly psychiatry and organised denial. ArtPeople

8. Azorin JM, Spiegel R, Remington G, Vanelle JM, Pere JJ, Giguere M, Bourdeix I (2001) A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. AmJPsychiatry 158:1305-1313

9. Taipale H, Tanskanen A, Mehtala J, Vattulainen P, Correll CU, Tiihonen J (2020) 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (fin20). World psychiatry : official journal of the World Psychiatric Association 19:61-68

10. Bighelli I, Ciray O, Salahuddin NH, Leucht S (2024) Cognitive behavioural therapy without medication for schizophrenia. Cochrane Database Syst Rev 2:CD015332

11. Sahker E, Furukawa TA, Luo Y, Ferreira ML, Okazaki K, Chevance A, Markham S, Ede R, Leucht S, Cipriani A, Salanti G (2024) Estimating the smallest worthwhile difference of antidepressants: A cross-sectional survey. BMJ Ment Health 27

12. Venkatesan P (2021) Stefan leucht: A (meta)analysis of his life. The lancet Psychiatry 8:186

The authors fail to address my substantial criticisms and talk about something else

Submitted 3/19/2025

Leucht et al. avoid addressing my criticisms and instead talk about something else. To my remark, with reference to a recent Cochrane review,[1] that “it won’t help increasing the dose, as adding drugs or increasing the dose do not result in better outcomes,” they claim that “there is robust evidence for a dose-response relationship in antipsychotic medications” and give five references.

None of their references are convincing. Three of them [2-4] are irrelevant because they do not address an increase in a better outcome but an increase in harms with increasing doses, which was not what I talked about.

The fourth reference is about relapse prevention,[5] which is also irrelevant because what people call relapse is most often also a harm, namely withdrawal effects after stopping with the drug.

That leaves one reference, which is a meta-analysis of 68 studies that I do not find convincing. The Cochrane review published only two years earlier had only included 10 studies, and the Cochrane authors were far more critical than Leucht et al. They noted that in most studies, the methods of randomisation, allocation and blinding were poorly reported, and the sample sizes were often small, limiting the overall quality of the evidence.

Moreover, I have issues with the statistical methods Leucht et al. used - models using regression splines, which represent a family of smooth functions that can describe a wide range of curves that consist of piecewise polynomials - and the confidence intervals were wide.

To suddenly talk of something else, as though it had a bearing on the matter, is a classic diversion, according to philosopher Arthur Schopenhauer’s book, The art of always being right.[7] Leucht et al’s focus on dose-response relationships have nothing to do with my main criticisms of their paper, which still stand.

Disclosures, Funding & Conflicts of Interest

None in relation to this paper.

Affiliations:

Peter C Gøtzsche, Professor emeritus, Institute for Scientific Freedom, Copenhagen, DK

Correspondence:

[email protected]

References

1. Samara MT, Klupp E, Helfer B, et al. Increasing antipsychotic dose for non response in schizophrenia. Cochrane Database Syst Rev 2018;5:CD011883.

2. Wu H, Siafis S, Wang D, et al. Antipsychotic-induced akathisia in adults with acute schizophrenia: A systematic review and dose-response meta-analysis. Eur Neuropsychopharmacol 2023;72:40-9.

3. Siafis S, Wu H, Wang D, et al. Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis. Mol Psychiatry 2023;28:3267-77.

4. Wu H, Siafis S, Hamza T, et al. Antipsychotic-induced weight gain: dose-response meta-analysis of randomized controlled trials. Schizophr Bull 2022;48:643-54.

5. Leucht S, Bauer S, Siafis S, et al. Examination of dosing of antipsychotic drugs for relapse prevention in patients with stable schizophrenia: a meta-analysis. JAMA Psychiatry 2021;78:1238-48.

6. Leucht S, Crippa A, Siafis S, et al. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2020;177:342-53.

7. Schopenhauer A. The art of always being right. London: Gibson Square; 2009.