A New Paradigm for Testing Psychiatric Drugs Is Needed

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.

Abstract

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.

Introduction

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.

Ineffective blinding

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 others^2,19-21 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.

Medication spellbinding

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.

Acknowledgment

I thank psychologist Marie Jensen for fruitful discussions and input on earlier drafts.

Conflicts of interest

None.

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MIA Reports are supported, in part, by a grant from The Thomas Jobe Fund.