Editor’s Note: The following is an original research article by Peter C Gøtzsche at the Institute for Scientific Freedom, Copenhagen. We are presenting it in its native format as a scientific paper. In the paper, he reviews the problems with the usual double-blind, placebo-controlled trials on which drug approvals are based, and advocates for a stricter form of testing psychiatric drugs with patient-relevant outcomes, real comparators, long-term outcomes, and assessment of harms.
Since the 1950s, the paradigm for testing psychiatric drugs has been the double-blind, placebo-controlled trial. This looks appealing, but the tacit assumptions for using it are not met. The universal use of short-term trials with ineffective blinding, subjective outcomes assessed on rating scales with unclear clinical relevance, exposure of patients in the placebo group to drug withdrawal effects, and reporting results selectively has produced a literature with misleading results. This has resulted in harm for the patients.
I suggest a new paradigm for testing psychiatric drugs. Trials should: Only include treatment-naïve patients; have psychotherapy as comparator; have patient-relevant outcomes; focus on drug harms; have a follow-up over several years; be planned and conducted by people with no conflicts of interest; and provide easy access to anonymised raw data.
Since the 1950s, the paradigm for testing psychiatric drugs has been the double-blind, placebo-controlled trial, in which the investigator assesses the effect using rating scales. This paradigm looks appealing, but the tacit assumptions for using it are not met. This had led to a flawed research literature and to harm for the patients.1,2 I describe the major issues here and suggest a new paradigm.
Flawed drug-withdrawal design
In so-called placebo-controlled drug trials, the patients are virtually always treated with a similar drug before randomisation. The patients in the placebo group are therefore harmed by withdrawal effects.
Moreover, the measured benefits are exaggerated. In depression trials, for example, the withdrawal design often causes abstinence depression. In a study where patients who had been in remission for 4-24 months had their maintenance therapy changed to placebo for 5-8 days at a time unknown to the patients and clinicians, the three most common withdrawal symptoms were worsened mood, irritability, and agitation, and 25 of 122 patients on sertraline or paroxetine fulfilled the authors’ criteria for depression.3 I have estimated, based on published research,4 that not a single patient of 122 would become depressed during 5-8 random days after having received psychotherapy. This is a clear demonstration that abstinence depression is not a true depression but a drug harm.
For psychosis, I have only found two trials where none of the patients had received a neuroleptic before randomisation. One was from China5 and appeared to be fraudulent.6 The authors reported that olanzapine was effective although patients on placebo fared much better. In 2020, another such trial was published, in patients with a first-episode psychosis.7 The authors found that the differences were small and clinically trivial, and that placebo “was no less effective than conventional antipsychotic treatment.”
The drug-withdrawal design can be lethal. One in every 138 patients who entered the trials for newer neuroleptics died, but none of these deaths were mentioned in the scientific literature, and the FDA didn’t require them to be mentioned.8 Many patients killed themselves, and the suicide rate was two to five times the usual rate for patients with schizophrenia. A major reason was drug-withdrawal akathisia.8
Trials with washout periods before randomisation cannot avoid this problem as some drug-induced changes in the brain are irreversible, and other changes may take years to come back to normal.9,10
The so-called maintenance studies appear to provide evidence for longer-term use of the medications, but these studies are also seriously flawed by withdrawal effects in the “placebo” group. Even after two years, on average, they find the relapse rate to be twice as large on placebo than on a depression pill,4 which is totally unrealistic, given the drugs’ doubtful short-term effect (see below). A large meta-analysis of the placebo-controlled trials of neuroleptics showed that the apparent benefit of continued treatment on relapse prevention decreases over time and is close to zero after three years.11
There are two maintenance studies in psychosis with a very long follow-up. The first one randomised 128 remitted first-episode patients with schizophrenia to dose reduction or discontinuation, or to maintenance therapy, for two years, after which the clinicians were free to choose the treatments they felt the patients needed.12 Two years after randomisation, more patients had relapsed in the dose reduction/discontinuation group than in the maintenance group (43% vs 21%). However, after seven years, there was no difference (62% vs 69%), and more patients had recovered in the dose reduction/discontinuation group than in the maintenance group (40% versus 18%). Recovery was the study’s primary outcome.
In the other study, the researchers treated first-episode patients with quetiapine for two years; discontinued the treatment in half of them by introducing placebo; and reported the results at 10 years.13 They found that a poor clinical outcome occurred in 35 (39%) of 89 patients in the discontinuation group and in only 19 (21%) of 89 patients in the maintenance treatment group.
I immediately suspected that the investigators had tapered off the drug too quickly, as this result was the exact opposite of the first study. As there was nothing about the tapering scheme in the article, I looked up an earlier publication.14 The researchers didn’t taper at all; all patients randomised to placebo were exposed to a cold turkey withdrawal.
The 10-year report was revealing: “A post-hoc analysis suggested that the adverse consequences of early discontinuation were mediated in part through early relapse during the 1-year period following medication discontinuation.”13 The researchers defined a poor outcome as a composite of persistent psychotic symptoms, a requirement for clozapine treatment, or death by suicide. It is impossible to maintain the blind in a trial with cold turkey symptoms, and it is highly subjective whether there are any persistent psychotic symptoms and whether clozapine should be given. It is much more relevant if the patients return to a normal life. After 10 years, 69% of those who continued taking their drug were employed versus 71% in the cold turkey group, a remarkable result considering the iatrogenic harms inflicted on the latter group.
Please think about this: Why would drugs that have no clinically relevant effects when used for acute psychosis suddenly have dramatic effects on relapse when they are withdrawn after a considerable period of time? This makes no sense.
The bias caused by ineffective blinding can be substantial.2 Systematic reviews of trials in all diseases that had both a blinded and a non-blinded observer found that the bias was 36%, on average, measured as an odds ratio,15 and 68% when the outcome was assessed on a scale.16
The lack of blinding can even change the direction of the results. In a large, publicly funded, and often cited placebo-controlled trial in 1964, the investigators reported that phenothiazines make patients with schizophrenia less indifferent, reduce apathy, and improve motor movement.17 These drugs do the exact opposite, which psychiatrists had correctly reported a decade earlier.8
Fallacies of rating scales
Psychiatric rating scales do not measure specific drug effects. The Hamilton Depression Rating Scale, for example, contains three items on sleep, two on anxiety, and one on agitation, summing up to a maximum of 16 points on the 52-point scale.18 Any sedative—including alcohol, benzodiazepines, and neuroleptics—can be shown to have an effect on depression using this scale. Moreover, unwanted effects such as emotional numbing and caring less for oneself and others2,19-21 might cause patients to have fewer feelings of sadness and therefore a lower Hamilton score, although these effects are not desirable.
Despite the biases inherent in the drug-withdrawal trial design and in the composition of rating scales, the effect of psychiatric drugs is of doubtful clinical relevance.2 The effect of depression pills on the Hamilton scale is only about 2 points,22,23 which is less than the minimal clinically relevant effect of 5-6 points.24 It is a little higher in very severe depression, but only 2.7, and this is likely just a mathematical artefact, as the bias caused by insufficient blinding increases with baseline severity.25
The effect of the newer neuroleptics is also disappointing, only 6 points better than placebo on the Positive and Negative Syndrome Scale,26 even though scores easily improve when someone is subdued by a tranquillizer and expresses abnormal ideas less frequently.27 The smallest effect that can be perceived on this scale is 15 points.28
Psychiatrists routinely use a 50% reduction in a score as a success criterion, but this mathematical abstraction is clinically meaningless and misleading.22 They count the number of patients who cross a certain line for benefit and ignore those who get worse. Any useless treatment that increases the variance in responses compared to placebo will therefore seem effective.
Patients are far less positive towards psychiatric drugs than psychiatrists are. When evaluated by psychiatrists or their research assistants, the standardised mean difference for depression pills compared to placebo in children and adolescents was 0.28, but when evaluated by the patients in the same six trials, it was only 0.06.29 When we analysed the two pivotal trials of fluoxetine in minors, which led to approval of this indication, we found, based on the clinical study reports submitted to the drug regulators, that the drug was totally ineffective, as evaluated by the patients, but not as evaluated by the investigators.30 In adults, a similar discrepancy exists.31
However, patients are rarely asked what they think or how they function. By far, most of the reported data on rating scales are those generated by the investigators.22,32 Reports of drug trials usually conclude that the drug was effective,2 even when that is not supported by the data,33 with no discussion of whether the difference in scores is clinically relevant and no data on what the patients felt.34
Results on rating scales are not relevant for patients, whose concept of remission includes normal levels of functioning and coping, quality of relationships, quality of life, being satisfied with oneself, and enjoying a meaningful life.35-38
In DSM-5, major depression is present when the patient exhibits five or more of nine possible symptoms that “cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.”39 It is nonsensical that drug trials do not use these outcomes. The same argument can be used for trials of other psychoactive drugs. If we break a leg, we would not be satisfied with a treatment that reduces the pain so little that we cannot feel the difference, while the leg is still broken. But this is where we generally are with psychiatric drugs.
Quality of life is important as it combines the patients’ perception of the benefits and harms of drugs. Because of social desirability bias and the power imbalance in the psychiatrist-patient relationship, one would expect patients to be too positive when asked. Even so, it is clear that the drug companies did not like their results. We found extensive selective reporting of quality of life, not only in published trial reports but also within the 64,381 pages of clinical study reports of 70 depression pill trials that we studied,40 even though the companies are obliged to ensure that no important data have been left out in what they submit to drug regulators to obtain marketing approval.
Based on these reports, we also found that 12% more patients drop out of the trials when they are on a drug than when they are on placebo.41 This means that the patients think placebo is better than a depression pill, even though many of those on placebo had been harmed by drug withdrawal effects. This is remarkable.
The biasing impact of the power imbalance
The discussion of symptoms is an interpretative process where researchers and patients interact. The ineffective blinding may therefore bias not only the researchers’ ratings but also the patients’ self-reports.
People in distress are often unsure of what to make of their feelings.42 Depressed people have noted they have no vocabulary for it.43,44 They have often dealt with their distress for a while,44,45 felt helpless,46 been uncertain about their experiences and eager to find a meaning,47 and have been dependent on their doctors’ views. Qualitative studies have illustrated that this can impact the patient’s self-reports.35-37,48-50
The power of professional language, the power to label,51 and the psychiatrists’ authority may make certain answers more likely than others.48,52 There is a substantial risk that the researchers’ questions will be answered in accordance with what the patients think they would want to hear as a kind of social reinforcement.
Also in clinical psychiatric practice, patients may try to fine-tune their expression of symptoms in order to be heard53 and they may find it difficult to challenge what their doctors say.48 Depressed patients are concerned with how others evaluate them and with being normal.48,51,54 This could result in a kind of Hawthorne effect, in which people modify their behaviour or thoughts in response to their awareness of being observed.
Sexual dysfunction illustrates how financial incentives and social desirability effects may influence reporting. In the registration application for fluoxetine, only 1.9% of the patients were reported to have developed sexual dysfunction on the drug,55 but the true occurrence on depression pills is about 30 times higher. A Spanish study designed to look at this found that sexual disturbances developed in 59% of 1,022 patients who all had a normal sex life before they started on the drug, and about 40% of the patients considered their sexual dysfunction unacceptable.56 In another study, only 6% of patients on depression pills reported sexual dysfunction spontaneously whereas 41% had such problems when asked explicitly.57
The power imbalance can degenerate into arrogance, which can make results of psychiatric drug trials even more unreliable. In a survey of 493 patients with closed-ended questions, 82% agreed that as long as they were taking antidepressants, they did not really know if the drugs were actually necessary; 43% agreed that the treatment could alter their personality; and 42% that they had less control over their thoughts and feelings.58 The psychiatrists refused to believe what the patients had told them; they called them ignorant and negative and felt they needed “psychoeducation.” However, the patients’ responses reflect what the drugs do to them. Furthermore, their relatives shared their views about depression pills.
The social desirability bias would be expected to be particularly problematic when the power imbalance is extreme, e.g. when testing neuroleptics, because forced treatment is allowed.
Psychoactive substances may render the patients unaware that they can no longer think clearly or evaluate themselves. This lack of insight into their feelings, thoughts and behaviours is called intoxication anosognosia, or medication spellbinding.46,59 Medication spellbinding is usually ignored, both by patients and doctors, which is surprising as everybody knows that people under the influence of alcohol cannot judge their ability to drive. Patients taking psychiatric drugs may act violently in an out of character fashion and may only understand that this was due to the drugs after they have come off them.2,17,46,59-61 Children and adolescents receiving SSRIs may experience apathy accompanied by a lack of insight, which increases with increasing doses.62-64
Even patients with tardive dyskinesia caused by neuroleptics very often ignore this,46,65 and it is also frequently overlooked by their psychiatrists.2,46 In one study, the researchers found 10 patients with tardive dyskinesia, but the psychiatrists only made this diagnosis in one of them.66 In the same study, the researchers diagnosed akathisia in 27 patients, the clinicians only in seven.
The main effect of medication spellbinding is that the harms of psychiatric drugs are underestimated.
Drug-induced unknown territory
In other areas of healthcare, the researchers usually have a clear concept of what a healthy body is, and there are often objective signs and symptoms of the disease. A successful treatment means that the signs and symptoms have disappeared.
In mental health, this is not the case. There are many ways of being in good mental health, but the criteria in DSM-5 are so broad that most healthy people could get one or more diagnoses if tested according to just a few of this manual’s many disorders.2 I have experienced that one-third or more of normal people attending courses and lectures test positive for adult ADHD.
Another difference to somatic medicine is that psychiatric drugs—in contrast to antibiotics, for example—are not curative, but change brain functions and bring the patient to an unknown territory where the patient has not been before. This is problematic because you cannot go from a chemically induced new condition back to a more normal state unless you taper off the drugs, and even then, it will not always be possible, as you might have developed irreversible brain damage. In contrast, the aim of psychological treatments is to change a brain that is not functioning well back towards a more normal state.
Since suffering and the experience of the effects of psychoactive drugs is personal, the patients’ perspective should prevail. Moreover, they may remember what it is like for them to be in good mental health; they know what it is like to have a mental health problem; and they know what it is like to be under the influence of a psychoactive drug.
Even though the drug-induced artificial state is qualitatively different from being healthy and from having a mental health problem, it is assumed that if patients exhibit fewer symptoms on a rating scale, they have returned towards normal. This assumption is false. It is far too simplistic to focus on a rating scale result and call everything else that happens side effects that the patients will have to endure in order to obtain the assumed benefit defined by the psychiatrists.
Harms of the biomedical model
Since the predominating paradigm among psychiatrists is the biomedical model, it is not surprising that many patients have a medical understanding of their disorder, e.g. that it is being caused by a gene defect or a chemical imbalance in the brain, which a drug can fix.
Most psychiatrists have scientifically unsupported beliefs about causes.2,46 Only 0.4% of 2813 British psychiatrists believed that schizophrenia primarily has social causes; around half believed it primarily has biological causes while another half believed it to be a balance between biological and social causes.67 In contrast, those diagnosed with schizophrenia primarily listed psychosocial causes like pressure at work or school, parental style in childhood, personality factors, family conflicts and psychological trauma.68,69 This agrees with the evidence. Adverse childhood experiences are associated with a high risk of psychosis and display a marked dose-response relationship.70,71
No reliable research has shown that patients become ill because they have a chemical imbalance in the brain,72 and it is highly unlikely to be the case.2 However, psychiatrists routinely tell this myth to their patients, for all kinds of mental disorders.2,27,73 In 2019, 29 of 39 popular websites (74%) in 10 countries attributed depression to a chemical imbalance or claimed that depression pills could fix or correct such an imbalance.74 Patients believing in this myth will tend to believe they need a drug, perhaps even life-long, sometimes referring to the chemical imbalance in their brain as the reason for not stopping.75 In an experiment, when patients with a past or current depression received a bogus test showing that their depression was caused by a chemical imbalance, they experienced more prognostic pessimism, expected to be less able to regulate negative mood, and viewed pharmacotherapy as more likely to be effective than psychotherapy.76 Furthermore, taking a pill might elicit beliefs that are consistent with pill-taking behaviour in general to avoid cognitive dissonance.77 Women starting on SSRIs showed a pattern of phases, which entailed redefining themselves as people with a biochemical disease.52,78
It is likely that all psychoactive drugs can cause dependence and abstinence symptoms.2,46,60 This iatrogenic chemical imbalance causes great harm. Even though many patients have difficulty stopping their medication,2,46,60 this problem was denied for depression pills for about 50 years.2,79 A 2019 systematic review showed that half of the patients experience withdrawal symptoms; half of those with symptoms experience the most extreme severity rating on offer; and some people experience withdrawal for months or years.10 It is therefore not surprising that the use of psychiatric drugs is not evidence-based. Many patients take them for decades even though the randomised trials have only lasted for a few weeks or months.80,81
A new paradigm for testing psychiatric drugs
The prevailing paradigm has served the patients and society badly. If we treat people with bacterial infections with antibiotics, we will cure some of them, but in psychiatry, the opposite happens. The increase in usage of psychiatric drugs has been accompanied by an increase in number of people on disability pension because of mental health problems in all countries where this relationship has been examined.1
This disaster is mainly caused by seriously flawed drug trials, and the drug companies continue with this deplorable practice.82
The criticism I have raised can be raised against all psychoactive drugs.79 It is clear, for example, that the benefits of lithium and antiepileptics are doubtful,79,83 and that drugs against ADHD are harmful.79,84,85 In a large US trial of stimulants, those who consistently took their pills were 5 cm shorter after 16 years than those who took very little, and there were many other harms.85 We can only speculate which permanent effects these drugs might have on the children’s developing brains.
When a method does not work as intended, it should be discarded, and I have the following suggestions for a new paradigm for testing psychiatric drugs.
The drug industry and doctors with financial conflicts of interest should not be allowed to do clinical trials, as this leads to unreliable results and to harm for patients.2,82,86
To avoid withdrawal effects, only patients who have not received the drug or similar drugs before should be included.
Psychiatric drugs should not be compared with placebo but with interventions that have a documented effect, primarily psychotherapy and other psychosocial interventions.
To be reliable, the trials should have a follow-up over several years. Studies with long-term follow-up show that psychotherapy has an enduring effect that outperforms pharmacotherapy.87-93
Maintenance studies should not be performed. They are flawed by withdrawal effects in the placebo group. Moreover, when drugs do not have meaningful effects in short-term trials, there is no reason to expect that they could prevent relapse. In fact, depression pills become less effective over time.94
Rating scales should not be used. The outcomes should reflect to what degree patients are able to live normal lives, as this is the aim of all psychiatric treatments. The trials should focus on drug harms, as these are plenty and often serious. Only about half of deaths and suicides that occur in trials of psychoactive drugs are reported in medical journals,95 but recent analyses of trials in human volunteers, clinical study reports, and FDA data have shown that depression pills double the risk of suicide at all ages.96-99 It was also recently shown that SSRIs increase aggression in children and adolescents,100 which is an important finding considering the many school shootings where the killers were on SSRIs.
All results should be fully reported and there should be easy access to anonymised raw data allowing independent analyses.
I thank psychologist Marie Jensen for fruitful discussions and input on earlier drafts.
Conflicts of interest
- Whitaker R. Anatomy of an Epidemic: magic bullets, psychiatric drugs, and the astonishing rise of mental illness in America. New York: Broadway Books; 2015.
- Gøtzsche PC. Deadly psychiatry and organised denial. Copenhagen: People’s Press; 2015.
- Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomised clinical trial. Biol Psychiatry 1998;44:77-87.
- Sim K, Lau WK, Sim J, et al. Prevention of relapse and recurrence in adults with major depressive disorder: systematic review and meta-analyses of controlled trials. Int J Neuropsychopharmacol 2015;19:pyv0764.
- Wang CH, Li Y, Yang J, et al. A randomized controlled trial of olanzapine improving memory deficits in Han Chinese patients with first-episode schizophrenia. Schizophr Res 2013;144:129-35.
- Danborg PB, Gøtzsche PC. Benefits and harms of antipsychotic drugs in drug-naïve patients with psychosis: A systematic review. Int J Risk Saf Med 2019;30:193-201.
- Francey SM, O’Donoghue B, Nelson B, et al. Psychosocial intervention with or without antipsychotic medication for first episode psychosis: a randomized noninferiority clinical trial. Schizophr Bull Open 2020; Mar 20. https://doi.org/10.1093/schizbullopen/sgaa015.
- Whitaker R. Mad in America. Cambridge: Perseus Books Group; 2002.
- 9. Leucht S, Tardy M, Komossa K, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012;379:2063-71.
- 10. Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based? Addict Behav 2019;97:111-21.
- Leucht S, Tardy M, Komossa K, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012;379:2063-71.
- Wunderink L, Nieboer RM, Wiersma D, et al. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry 2013;70:913-20.
- Hui CLM, Honer WG, Lee EHM, et al. Long-term effects of discontinuation from antipsychotic maintenance following first-episode schizophrenia and related disorders: a 10 year follow-up of a randomised, double-blind trial. Lancet Psychiatry 2018;5:432-42.
- Chen EY, Hui CL, Lam MM, et al. Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial. BMJ 2010;341:c4024.
- Hróbjartsson A, Thomsen AS, Emanuelsson F, et al. Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors. BMJ 2012;344:e1119.
- Hróbjartsson A, Thomsen ASS, 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.
- Cole J. Phenothiazine treatment in acute schizophrenia; effectiveness: the National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group. Arch Gen Psychiatry 1964;10:246–61.
- Moncrieff J, Cohen D. Do antidepressants cure or create abnormal brain states? PLoS Med 2006;3:e240.
- Healy D. Let them eat Prozac. New York: New York University Press; 2004.
- Read J, Cartwright C, Gibson K. Adverse emotional and interpersonal effects reported by 1829 New Zealanders while taking antidepressants. Psychiatry Res 2014;216:67–73.
- Opbroek A, Delgado PL, Laukes C, et al. Emotional blunting associated with SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses? Int J Neuropsychopharmacol 2002;5:147–151.
- 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.
- 23. 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.
- Leucht S, Fennema H, Engel R, et al. What does the HAMD mean? J Affect Disord 2013;148:243-8.
- 25. Gøtzsche PC, Gøtzsche PK. Cognitive behavioural therapy halves the risk of repeated suicide attempts: systematic review. J R Soc Med 2017;110:404-10.
- Khin NA, Chen YF, Yang Y, et al. Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration. J Clin Psychiatry 2012;73:856–64.
- Moncrieff J. The bitterest pills: the troubling story of antipsychotic drugs. Basingstoke: Palgrave Macmillan; 2013.
- Leucht S, Kane JM, Etschel E, et al. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacology 2006;31:2318-25.
- Spielmans GI, Gerwig K. The efficacy of antidepressants on overall well-being and self-reported depression symptom severity in youth: a meta-analysis. Psychother Psychosom 2014;83:158–64.
- 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.
- Greenberg RP, Bornstein RF, Greenberg MD, Fisher S. A meta-analysis of antidepressant outcome under “blinder” conditions. J Consult Clin Psychol 1992;60:664–9.
- Thornley B, Adams C. Content and quality of 2000 controlled trials in schizophrenia over 50 years. BMJ 1998;317:1181–4.
- Le Noury J, Nardo JM, Healy D, et al. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015;351:h4320.
- Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 2001;40:762–72.
- Zimmerman M, Martinez JA, Attiullah N, et al. Why do some depressed outpatients who are in remission according to the Hamilton depression rating scale not consider themselves to be in remission? J Clin Psychiatry 2012;73:790–5.
- Demyttenaere K, Donneau A-F, Albert A, et al. What is important in being cured from depression? Discordance between physicians and patients (1). J Affect Disord 2015;174:390–6.
- 3 Zimmerman M, McGlinchey JB, Posternak MA, et al. How should remission from depression be defined? the depressed patient’s perspective. Am J Psychiatry 2006;163:148–50.
- Pasquini M, Tarsitani L, Piacentino D, et al. Patients’ expectations for antidepressant treatment outcome. Psychother Psychosom 2009;78:390–1.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington: American Psychiatric Publishing Group; 2013.
- Paludan-Müller AS, Sharma T, Rasmussen K, et al. Extensive selective reporting of quality of life in clinical study reports and publications of placebo-controlled trials of antidepressants. Int J Risk Saf Med 2021;32:87-99.
- Sharma T, Guski LS, Freund N, et al. Drop-out rates in placebo-controlled trials of antidepressant drugs: A systematic review and meta-analysis based on clinical study reports. Int J Risk Saf Med 2019;30:217-32.
- Karp DA. Illness ambiguity and the search for meaning: a case study of a self-help group for affective disorders. J Contemp Ethnogr 1992;21:139–70.
- Smale R. Peering through the darkness: the subjective experience of clinical depression. J Psychiatr Ment Health Nurs 2000;7:277.
- Karp DA. Living with depression: illness and identity turning points. Qual Health Res 1994;4:6–30.
- Anderson C, Kirkpatrick S, Ridge D, et al. Starting antidepressant use: a qualitative synthesis of UK and Australian data. BMJ Open 2015;5:e008636.
- Breggin PR. Brain-disabling treatments in psychiatry: drugs, electroshock, and the psychopharmaceutical complex. New York: Springer; 2008.
- Casey B, Long A. Meanings of madness: a literature review. J Psychiatr Ment Health Nurs 2003;10:89–99.
- Buus N. Adherence to anti-depressant medication: A medicine-taking career. Soc Sci Med 2014;123:105–13.
- Gibson K, Cartwright C, Read J. Conflict in men’s experiences with antidepressants. Am J Mens Health 2016;1-13.
- Leydon GM, Rodgers L, Kendrick T. A qualitative study of patient views on discontinuing long-term selective serotonin reuptake inhibitors. Fam Pract 2007;24:570–5.
- Hagen B, Nixon G. Spider in a jar: women who have recovered from psychosis and their experience of the mental health care system. Ethical Hum Psychol Psychiatry 2011;13:47–63.
- Knudsen P, Hansen EH, Traulsen JM, et al. Changes in self-concept while using SSRI antidepressants. Qual Health Res. 2002;12:932–44.
- Ringer A, Holen M. ‘Hell no, they’ll think you’re mad as a hatter’: Illness discourses and their implications for patients in mental health practice. Health 2016;20:161–75.
- Anderson C, Roy T. Patient experiences of taking antidepressants for depression: A secondary qualitative analysis. Res Soc Adm Pharm 2013;9:884–902.
- Medawar C. The antidepressant web – marketing depression and making medicines work. Int J Risk Saf Med 1997;10:75-126.
- Montejo A, Llorca G, Izquierdo J, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the study of psychotropic-related sexual dysfunction. J Clin Psychiatry 2001;62 (suppl 3):10–21.
- Landén M, Högberg P, Thase ME. Incidence of sexual side effects in refractory depression during treatment with citalopram or paroxetine. J Clin Psychiatry 2005;66:100–6.
- Kessing LV, Vibe Hansen H, Demyttenaere K, et al. Depressive and bipolar disorders: patients’ attitudes and beliefs towards depression and antidepressants. Psychol Med 2005;35:1205–13.
- Breggin PR. Intoxication anosognosia: the spellbinding effect of psychiatric drugs. Ethical Hum Psychol Psychiatry 2006;8:201–15.
- Breggin P. Psychiatric drug withdrawal: A guide for prescribers, therapists, patients and their families. New York: Springer; 2012.
- Lucire Y, Crotty C. Antidepressant-induced akathisia-related homicides associated with diminishing mutations in metabolizing genes of the CYP450 family. Pharmgenomics Pers Med 2011;4:65–81.
- Garland EJ, Baerg EA. Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents. J Child Adolesc Psychopharmacol 2001;11:181–6.
- Reinblatt SP, Riddle MA. Selective serotonin reuptake inhibitor-induced apathy: a pediatric case series. J Child Adolesc Psychopharmacol 2006;16:227–33.
- Barnhart WJ, Makela EH, Latocha MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatr Pract 2004;10:196–9.
- Myslobodsky MS. Anosognosia in tardive dyskinesia:‘ tardive dysmentia’ or‘ tardive dementia’? Schizophr Bull 1986;12:1-6.
- Weiden PJ, Mann JJ, Haas G, et al. Clinical nonrecognition of neuroleptic-induced movement disorders: a cautionary study. Am J Psychiatry 1987;144:1148-53.
- Kingdon D, Sharma T, Hart D, et al.. What attitudes do psychiatrists hold towards people with mental illness? Psychiatric Bulletin 2004;28:401-6.
- Holzinger A, Löffler W, Müller P, et al. Subjective illness theory and antipsychotic medication compliance by patients with schizophrenia. J Nerv Ment Dis 2002;190:597–603.
- Magliano L, Fiorillo A, Del Vecchio H, et al. What people with schizophrenia think about the causes of their disorder. Epidemiol Psichiatr Soc 2009;18:48–53.
- Shevlin M, Houston JE, Dorahy MJ, et al. Cumulative traumas and psychosis: an analysis of the national comorbidity survey and the British Psychiatric Morbidity Survey. Schizophr Bull 2008;34:193-9.
- Varese F, Smeets F, Drukker M, et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull 2012;38:661–71.
- Moncrieff J, Cooper RE, Stockmann T, et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 2022;June 20. https://doi.org/10.1038/s41380-022-01661-0.
- Gøtzsche PC. Critical psychiatry textbook. Copenhagen: Institute for Scientific Freedom; 2022.
- Demasi M, Gøtzsche PC. Presentation of benefits and harms of antidepressants on websites: cross sectional study. Int J Risk Saf Med 2020;31:53-65.
- Eveleigh R, Speckens A, van Weel C, et al. Patients’ attitudes to discontinuing not-indicated long-term antidepressant use: barriers and facilitators. Ther Adv Psychopharmacol 2019;9:1-9.
- Kemp JJ, Lickel JJ, Deacon BJ. Effects of a chemical imbalance causal explanation on individuals’ perceptions of their depressive symptoms. Behav Res Ther 2014;56:47–52.
- Read J, Cartwright C, Gibson K, et al. Beliefs of people taking antidepressants about the causes of their own depression. J Affect Disord 2015;174:150–6.
- Karp DA. Taking anti-depressant medications: resistance, trial commitment, conversion, disenchantment. Qual Sociol 1993;16:337–59.
- Gøtzsche PC. Mental health survival kit and withdrawal from psychiatric drugs. Ann Arbor: L H Press; 2022.
- Gøtzsche PC. Long-term use of antipsychotics and antidepressants is not evidence-based. Int J Risk Saf Med 2020;31:37-42.
- Gøtzsche PC. Long-term use of benzodiazepines, stimulants and lithium is not evidence-based. Clin Neuropsychiatry 2020;17:281-3.
- Whitaker R. Anatomy of an industry: commerce, payments to psychiatrists and betrayal of the public good. Mad in America 2021;18 Sept.
- Börjesson J, Gøtzsche PC. Effect of lithium on suicide and mortality in mood disorders: A systematic review. Int J Risk Saf Med 2019;30:155-66.
- Molina BS, Flory K, Hinshaw SP, et al. Delinquent behavior and emerging substance use in the MTA at 36 months: prevalence, course, and treatment effects. J Am Acad Child Adolesc Psychiatry 2007;46:1028-40.
- Swanson JM, Arnold LE, Molina BSG, et al. Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression. J Child Psychol Psychiatry 2017;58:663-78.
- Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing; 2013.
- Gøtzsche PC. Psychotherapy: Less expensive and better than pills, it’s what the patients want but don’t get. Mad in America 2022;Dec 22.
- Spielmans GI, Berman MI, Usitalo AN. Psychotherapy versus second-generation antidepressants in the treatment of depression: a meta-analysis. J Nerv Ment Dis 2011;199:142–9.
- Cuijpers P, Hollon SD, van Straten A, et al. Does cognitive behaviour therapy have an enduring effect that is superior to keeping patients on continuation pharmaco-therapy? A meta-analysis. BMJ Open 2013;26;3(4).
- Shedler J. The efficacy of psychodynamic psychotherapy. Am Psychol 2010;65:98-109.
- Furukawa TA, Shinohara K, Sahker E, et al. Initial treatment choices to achieve sustained response in major depression: a systematic review and network meta-analysis. World Psychiatry 2021;20:387-96.
- Bighelli I, Rodolico A, García-Mieres et al. Psychosocial and psychological interventions for relapse prevention in schizophrenia: a systematic review and network meta-analysis. Lancet Psychiatry 2021;8:969-80.
- Cuijpers P, Miguel C, Harrer M, et al. Cognitive behavior therapy vs. control conditions, other psychotherapies, pharmacotherapies and combined treatment for depression: a comprehensive meta-analysis including 409 trials with 52,702 patients. World Psychiatry 2023;22:105-115.
- McPherson S, Hengartner MP. Long-term outcomes of trials in the National Institute for Health and Care Excellence depression guideline. BJPsych Open 2019;5:e81.
- Hughes S, Cohen D, Jaggi R. Differences in reporting serious adverse events in industry sponsored clinical trial registries and journal articles on antidepressant and antipsychotic drugs: a cross-sectional study. BMJ Open 2014;4:e005535.
- Bielefeldt AO, Danborg PB, Gøtzsche PC. Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers. J R Soc Med 2016;109:381–92.
- Maund E, Guski LS, Gøtzsche PC. Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports. CMAJ 2017;189:E194-203.
- 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 ReAnalysis.” Psychother Psychosom 2019;88:373-4.
- Sharma T, Guski LS, Freund N, et al. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ 2016;352:i65.
MIA Reports are supported, in part, by a grant from The Thomas Jobe Fund.
1. footnotes 9 and 11 are the same text. probably some kind of mistake there.
2. “In other areas of healthcare, the researchers usually have a clear concept of what a healthy body is, and there are often objective signs and symptoms of the disease.” This should be “valid” instead of “objective”, imo. While objectivity is a problem with psychiatric disnosis, validity is a way bigger one. While a covid test is also more reliable and objective, the main difference to a psychiatric disgnosis is that it is valid and measures something that actually exists by a process we understand.
Comprehensive and damning.
Thank you for all you do, Peter, including making recommendations for how to improve “the system.” But we should also look at the bigger picture, and ask ourselves whether or not the “psychiatric system,” historically and today, benefits or harms society as a whole.
And if the answer is repeated harms, as I believe is the case with psychiatry. And since the medical evidence does seem to show that the psychiatric and psychological industries’ only primary job is silencing the legitimately “distressed” – which is mostly child abuse and rape survivors – which is illegal behavior. We should also ask ourselves whether or not these scientifically “invalid” industries / systems should even continue to exist.
I love your new paradigm Peter!
Letting go now. Letting go…
I have to go.
(so shall the Hoover Dam)
(according to the landscape in my balanced prophetic dreams).
I need to declare an interest. If mental disorders and personality disorders exist anywhere other than in the minds of those who believe them to, then I qualify for a very great majority of them, as previously I did for “sinfulness:” Obviously, I cannot allow any such myths to persist.
While I hugely admire Peter C Gøtzsche’s passion, zeal and dedication, and the intensity, sophistication and extent of his long, hard work, when I read him, I feel his work, stripping them of their quotation marks, throws “psychiatric diagnoses/disorders” and so psycho pharmacology a spurious legitimacy, an unearned and unjustifiable validity which not one of those “disorders” or that psycho pharmacology deserves.
Apart from any true neurological diseases (proven, irrefutably identified diseases of the brain/nervous system, various forms of dementia, as well as nutritional, infectious, parasitic, traumatic, anatomical, vascular, neoplastic etc. diseases included), and absent any objective evidence to support the notion that a single one of the so-called psychiatric or mental disorders exists other than in the minds of professional and/or other diagnosticians (their patients/those suffering and their cooperating families included), and while not one of these “conditions” – actually, better make that “disorders,” please, for the term “psychological condition” is used to describe burnout in physicians, I am not kidding you) has been shown to represent a demonstrable deficiency of any of the the neuroleptic agents used, it has been pointed out that “treating” any such “disorder” with any such drug amounts to inflicting a neurotoxin on people’s brains.
‘According to Ghaemi, one exception to the rule of psychiatry’s ineffective drugs is lithium.
“Only lithium has been proven to improve the course of any psychiatric illness. Further only lithium has been proven to prevent completed suicide in randomized clinical trials in psychiatry […] It is the only drug in psychiatry which is proven to be disease-modifying.”’ – from https://www.madinamerica.com/2022/06/psychiatric-drugs-not-improve-disease-reduce-mortality/
If it is true that, of all psychotropic drugs prescribed in those studies, lithium, alone, may be considered to possibly have shown some long-term benefit in terms of morbidity/mortality, one may wonder if any possible real benefits may have been thanks to some partial substitution by the lithium for the magnesium (and/or other metal/s) which people’s modern diets lack.
Use of nicotine, alcohol, benzodiazepines or other sedatives and of monoamine oxidase inhibitors or serotonin re-uptake inhibitors etc. to try and help relieve grief, hopelessness or any manifestation of the angst involved in playing human (oh, and sometimes, nowadays, also animal) roles may be perfectly understandable and acceptable.
To make the leap to assuming that any short-term alleviation of suffering, of unpleasant experiences, emotions or moods by any such drugs points to the existence of any elusive underlying disorder of the brain, let alone to any deficiency (in the usual medical/nutritional sense) of any such chemicals seems…well, brainless.
“…for we are all as God made us, and many of us [sometimes translated as and frequently”] much worse.” – Sancho Panza, some four centuries ago, with the tongue of Cervantes, at least, in his cheek, and reminding me that I am invariably at my very stupidest when I have once again lost any sense of humor I ever had.
“Oh, what idiots we all have been. This is just as it must be.” – Neils Bohr. And, given the terms of/surrounding the last big bang, wasn’t Neils right, as usual?
If “insanity” or folly (for the French, like the Germans and Hungarians, at least, have no word for “mind” and therefore none for “mental illness,” I believe) is anything, perhaps it may be said that
“La folie, c’est de n’avoir pas d’autres normes que soi-même:
Madness is conforming to one’s own norms, and no others”?
And “sanity,” then, is an arising recognition of one’s own folly/madness?
Many thanks to MIA, to Robert Whitaker and to Peter C Gøtzsche.
Using SSRI’s to treat depression is like endlessly using aspirin to treat a fever without ever looking for a cause.
Mental illness is almost always a symptom and never a disease. Psychological symptoms are no different than physical symptoms, it is simply a different way for your body to tell you something is wrong. The cause may be past trauma, it may be a pathogen, or a bowel problem, or just about anything that your body sees as a threat. Once we see past the symptoms only then can we begin to treat the illness.
I am not sure that there is not ever anything that goes awry with the brain, so as to manifest in weird ways to the self and others. Personal experience was, going into psychosis and being out of it was effectively like throwing a switch. The medication that was prescribed per protocols did seem to help to throw the switch back from “crazy” to something closer to previous brain function.
Impressions, in working with psychiatrists are: Many must be somewhat terrified of consequences for their patients of a recurrence of, if I might speak colorfully, going berserk. Social consequences of psychosis may be quite real: Once associates have experienced a person being in psychosis, these associates may not ever again trust the previously psychotic person to be sane.
Of tapering, personal learning experience has been, it makes sense to proceed with most exquisite and great caution and care, in the interests of best results. It might be socially incorrect to say this on this website, but, there are subjective elements of withdrawal for patients that can potentially work against explicit intent to reduce medication load. For example, anyone who has borne the aforementioned social consequences of psychosis has good reason to fear a recurrence of psychosis; but, it might be difficult to admit of such fears to a prescriber whom the patient knows to be predisposed to avoid all risks to the patient that the prescriber can discern.
I am not sure it always makes sense to opt for all psychotherapy and no psychiatry. Personal experience has been that psychiatrists may have knowledge, understanding and experience that psychotherapists lack. And, psychotherapists need back up from psychiatrists. To say this is by no means to intend any disparagement of important work psychotherapists do. It is to say, they should have support that psychiatrists can give to them.
“The Fragile Alliance” is the title of an old book about psychotherapy. In treatments of what are called ‘major mental illnesses,’ I would understand that the importance of provider-patient relationships is much more than what biological psychiatry now admits. In the arena of mental health, providers may incline to mistrust their patients, fearing the patients will seek to manipulate and lie to the providers. For best outcomes, trust is key: If providers are unable to hear what their patients report as to what is going on with them, providers will not be able to deliver competent care.
I enjoyed slogging through this paper by Peter Gøtzsche. I also note a report I heard this morning, to the effect that an agency of the U.S. government is inclining to think that the Covid-19 pandemic did, indeed, originate with a lab leak — as, I believe, both Peter Gøtzsche and Peter Breggin have maintained.
I do feel bad, over this, for Tony Fauci.
Thank you Peter for all your work.
Francey et al. 2020 (reference 7) is mentioned as where none of the patients had received a neuroleptic before randomisation.
I would like to add Morrisson et al. 2020: Antipsychotic medication versus psychological intervention versus a combination of both in adolescents with first-episode psychosis (MAPS): a multicentre, three-arm, randomised controlled pilot and feasibility study. «This trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis.» (https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30248-0/fulltext)
Further support of consequences of flawed drug-withdrawal design:
Bola et al. 2011: “With only a few studies meeting inclusion criteria, and with limited useable data in these studies, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that people with early episode schizophrenia treated with typical antipsychotic medications are less likely to leave the study early, but more likely to experience medication-related side effects. Data are too sparse to assess the effects of antipsychotic medication on outcomes in early episode schizophrenia.” (https://pubmed.ncbi.nlm.nih.gov/21678355/)
Norwegian Institute of Public Health 2019: Effectiveness of treatment for psychosis: evidence base for a shared decision making tool: “It is uncertain if antipsychotics compared to placebo affects symptoms in persons with early psychosis” (ISBN 978-82-8406-009-5: https://www.fhi.no/globalassets/dokumenterfiler/rapporter/2019/nytteverdien-av-behandling-for-voksne-med-primar-psykose-rapport-2018.pdf)
Since “mental illness” is clearly a fraudulent concept, ANY “testing” of drugs in the name of fighting such should be seen as equally fraudulent, and criminal.
The “new paradigm” should be that ALL such “testing” should be outlawed, period. Many laws prohibit fraudulent medical practice, so this should not be seen as new or radical.
On the other hand, if the current paradigm is to hold there should be no opposition to also promoting drugs and rituals meant to free one from demonic possession, etc.
Man-made chemicals will never cure a mental illness, no matter how high-tech they are. I agree 100% with what yinyang and LivingPast27 have just said: psychiatry is fraudulent. It isn’t designed to cure anyone, just suppress symptoms until the patient dies. It’s like giving cough syrup to a pneumonia patient and when he isn’t cured, the doctor says, “See? I told you pneumonia is incurable.” Restorative care, such as “orthomolecular medicine,” actually corrects the biochemical causes of patients’ mental health. The Amer Psych Ass’n has been FIGHTING orthomolecular medicine for 80 years. It’s what I treated my family member with and he recovered completely. There is NO federal law that says the APA must even try to uncover the physical or energetic cause of a patient’s illness. The leaders of the APA are free to use any approach they choose, and what they choose is what brings in the most money. The APA isn’t legally required to even try to cure any patient so, no surprise, they don’t. Profits are way more important than the patients. –Linda at FB “Real Recovery for Mentally Ill Loved Ones.”