An interview about the problematic success of antidepressant drugs
Dr Michael P. Hengartner is graduate psychologist and researcher at the Zurich University of Applied Sciences in Switzerland. He was research associate at the Psychiatric University Hospital of Zurich from 2009 till 2014. Since 2015 he is also teaching psychosocial medicine at the University of Zurich and psychopathology at the University of Applied Sciences and Arts of Northwestern Switzerland. His major research areas are clinical psychology, social psychiatry, and the frequency (epidemiology) of mental disorders.
Important note of the author: The discontinuation of antidepressant drug treatments can lead to withdrawal symptoms or an increase in severity of the symptoms. Please do not take such steps without the supervision of an experienced physician of trust.
Dr Hengartner, how did you become interested in the research on antidepressant drugs?
Michael P. Hengartner: I have been interested in research methods and the theory of science for a very long time. How reliable is research as altogether? But in particular also the research in psychology and psychiatry? I was further interested in statistics and the ways in which some researchers are misusing or misinterpreting statistical methods.
And then we obviously had the replication crisis in psychology: Why do the results of so many studies not replicate? In addition to that there seems to be a "publication bias" everywhere. That is, positive results are overestimated and published, while negative results vanish in the file drawer. Many scientists try to advertise their field of research - and that is why they are biased.
I also took a closer look at studies on the efficacy of psychotherapy. Then I found the critical reports on the efficacy of antidepressant drugs by the British psychiatrists David Healy and Joanna Moncrieff, by the American psychologist Irving Kirsch, and by the Danish physician and director of the Nordic Cochrane Center Peter Gøtzsche. I was shocked about the extent of methodological biases in these antidepressant trials.
In your recent review article you are drawing the conclusion that antidepressant drugs - in particular the popular drugs of the types SSRI and SNRI - are largely ineffective and potentially harmful. Can you explain that briefly?
Michael P. Hengartner: The major problem of the studies on antidepressant drugs is that they are flawed by design. Already before the actual trials begin, much has been done such that they will yield a statistically significant effect in favor of the antidepressant drug. Yet, randomized and placebo-controlled studies should avoid such biases.
One example is that participants who are strongly responding to the placebo substance are excluded before the trials officially begin. Why are researcher doing that? Because this increases the likelihood that the investigated drug will eventually seem to have a higher efficacy than the pharmacologically ineffective placebo pill.
Treating Withdrawal Symptoms
Can you explain that in a bit more detail?
Michael P. Hengartner: Patients with a diagnosed depression often already have a prescription for another drug. To avoid that a study’s results will be biased by that medication, they will get a placebo a few days before the outset of the randomized trial. This is called the placebo-washout. The idea is to wash the old drug out of the body. Those showing an improvement in that period, that is, those who are strongly responding to the placebo, are excluded from the actual trial.
Another problem is that the discontinuation of the old medication can lead to withdrawal symptoms, such as mood swings, irritability, anxiety, or sleep problems. The few days of placebo-washout right before the actual trial are often too short for these symptoms to disappear. Now one must understand that these very symptoms are also used to measure the severity of depressive disorders.
That means that some patients in the placebo group have higher depression scores at the beginning of the trial due to the discontinuation of their original medication. Conversely, in participants receiving the active drug an improvement occurs right from the beginning, because the antidepressant drug stops the withdrawal syndrome immediately. So if in trials of four to six weeks duration patients in the drug group show a slightly higher symptom reduction than patients in the placebo group, this is possibly unrelated to the antidepressant property of the investigational drug, but instead resulting from the abatement of the withdrawal syndrome.
One cannot distinguish the true drug effect on the depressive symptoms from that on the withdrawal symptoms in the data. Some patients in the placebo group will have withdrawal symptoms right after discontinuation of the previous medication, that is during the washout phase, but others just after days or a few weeks, that is during the trial period. We know from studies that between 10 and 50 percent of the patients can suffer from such withdrawal symptoms.
A similar problem is that patients in some studies additionally receive tranquilizers, such as benzodiazepines. Their doctors are free to treat restlessness or sleeping problems, which are typical side effects of antidepressant drugs, with such tranquilizers. The effect attributed to the new antidepressant medication therefore might simply be due to the prescription of these other drugs.
Which role do the experts play who are carrying out the studies?
Michael P. Hengartner: A classical finding from psychology is that there is an observer effect in experimental studies. That is, if the study participants or the researchers know to which experimental condition they belong, then the result of the study will be different. That is precisely the reason why neither the patients nor the experimenters should know in such studies who gets placebo and who the active medication. This is called double-blinding.
But this often does not work: Both the patients and the experimenters usually have years of experience with the effects of psychopharmacological drugs. Thus, if a patient does not report some of the common side effects, such as a dry mouth, then both suspect that a placebo is used in this case, even if nobody knows this officially.
This can bias the study’s findings. After all, the experimenters ask the patients questions and assess the severity of the symptoms - whether they are mild, moderate, or severe -, from which then a general depression score is calculated. There are studies which have shown that about 90 percent of the experimenters know after a while who is getting placebo and who the active drug. This severely undermines the trustworthiness and validity of the study.
In some studies the patients were allowed to fill out questionnaires to assess their symptoms themselves. In such cases, the effects became smaller or disappeared completely. Clinicians and patients thus have different opinions about the drug effects. Besides that, the questionnaires commonly used often fall short of measuring the problems in the patients’ real life. Can they work? How are their relations with other people? These are the things that really matter to the patients, independent from the severity of their symptoms.
And in which respect can the studies said to be representative?
Michael P. Hengartner: That’s another important point. In addition to people who are strongly responding to placebo, those who have other problems like anxiety or substance abuse disorders, like alcohol or drug addiction, are excluded from the trials. We call this comorbidity. Usually patients suffering from psychotic symptoms or suicidal thoughts are excluded, too.
Yet, every clinician knows that patients with severe depression often have a variety of problems. The studies would thus have to show which effect the antidepressant drugs have in this typical group of patients, but they are investigating a carefully selected subgroup instead. Therefore the results of these placebo-controlled trials cannot be generalized.
You also write that antidepressant drugs can increase the suicide risk and damage health. Could you explain that?
Michael P. Hengartner: This discussion is more than twenty years old. It has actually been found right from the early 1990s that the then new selective serotonin re-uptake inhibitors (SSRIs) can cause extreme psychomotor agitation and suicidal behaviors, in healthy people as well as in those with a mental disorder. That is, people can get uncontrollable aggressive impulses, suicidal ideation, or take steps to harm themselves.
One problem was that the efficacy trials included too few subjects for these effects to become statistically significant. One must know that the scientific community takes the 5%-threshold of significance more important than justified by the statistical theory. Thus only later meta-analyses with the data of thousands of people confirmed that antidepressant drugs can lead to an increase of suicidality. David Healy, whom I already mentioned, pointed that out very early and got many enemies because of that.
Moreover, when suicide attempts occurred in the previously mentioned washout-phase, then they were attributed to the placebo group. That made it less likely that such problems were noticed when they were caused by the investigational drug. It is also difficult to measure them, leaving aside lethal suicide attempts. In some studies suicidal ideation or self-harm were simply recorded as "emotional lability" or "worsening of depression" to conceal that problem.
And what do you mean by possible damage to one’s health?
Michael P. Hengartner: This is related to the long-term use of psychopharmacological drugs, thus for a period of many years. One must take into account that these are psychoactive substances. That is, these drugs do have effects in the brain, even though, in my opinion, they do not have specific anti-depressive properties.
It is also known that serotonin has various effects in the whole body and that it influences the immune system and metabolism for instance. This can eventually lead to a dysfunction of basic bodily processes. And of course to neurobiological disorders owing to enduring changes in neurochemistry.
I don’t want to condemn psychopharmacological drugs. One has to deal with them more consciously, though, and to consider how the substances work in the whole body. This has to be included in the risk-benefit analysis. By now several studies have demonstrated that the long-term use of psychopharmacological drugs increases certain health risks.
What you are summarizing in your article is the result of many years of research. These are scientific publications that have been available in libraries for many years. Why is so little of that knowledge disseminated to the public?
Michael P. Hengartner: One has to realize that mainstream psychiatry has made itself very much dependent on biomedical concepts and the prescription of psychopharmacological drugs. These are the disease models investigated most frequently and the treatments prescribed most often. This message is also spread successfully in the media and marketed aggressively. The hopes in Biological Psychiatry have been and still are very high. Opposing views, by contrast, have been ignored for a very long time.
This is also due to the systematic biases described earlier. We now know that some studies found a meaningless difference of one to two points on a depression scale of 52 points between the placebo and the antidepressant group. However, the actual publication eventually reported a difference of more than ten points, because only a selected subset of the patients has been included in the analysis. Physicians and researchers then read these biased reports and got a wrong impression.
It goes without saying that those working in the clinics or hospitals have a great wish to offer patients something that really helps. The doctors prescribing the drugs do not want to give up the belief in their effectivity.
But why are still so many antidepressant drugs prescribed? You even say that the prescriptions are still increasing.
Michael P. Hengartner: There is probably more than a single cause. I think that the helplessness in clinical practice also plays a role. What didn’t clinicians already try with severely suffering patients? They want to help people, after all, such that they feel better.
Additionally, resources and alternative possibilities are scarce. Psychotherapy is difficult, for example, in the case of an acute and severe depression with psychotic symptoms. The patients might not participate or stop the treatment quickly under such circumstances.
Another reason is, as I already said, that the effectivity is of the medications is overestimated. Because this opinion is so widespread, critical studies have more difficulties to get through the peer-review process. The referees, who should actually be neutral and independent, consider the critical view as wrong and thwart their publication. One can also be marginalized quickly as an irrational polemic or even sectarian.
How about the official treatment guidelines? Are they clear?
Michael P. Hengartner: These express another problem, that there are different opinions at different places about the best treatment. For example, the guideline of the American Psychiatric Association instructs doctors to prescribe antidepressant drugs already in cases of mild depression. By contrast, the respective British committee strictly advises against this and states that one should rather wait and carefully observe in such cases.
It is interesting that both committees, the American and the British psychiatrists, more or less refer to the same studies - but draw completely different conclusions from them. Thus, what should a physician do? Also consider that he or she participates in continuing medical education that is mainly funded by the pharmaceutical industry, where somebody comes to praise medications.
Conflicts of Interest
To what extent do financial conflicts of interest play a role?
Michael P. Hengartner: They are a very big problem. We now know that the key opinion leaders in psychiatry heavily depend on the money of the pharmaceutical industry. Some of them have financial ties with six to eight different companies.
In some cases it has been documented that someone could earn hundreds of thousands of dollars within a couple of years with giving talks, working as an advisor, or in other functions. Some even are shareholders of the companies, whose products they are supposed to investigate neutrally and independently. Such people and their employees then produce the results which are required by the regulatory agencies for market approval.
In addition to that, the pharmaceutical industry funds the majority of the trials. Also conferences and education are supported financially and stuffed with pro-drug content. How should a neutral, critical opinion, as we expect it of science, be still possible under such conditions?
One anecdote to illustrate the problem: Marcia Angell, former editor-in-chief of the New England Journal of Medicine, one of the leading medical journals, once was looking for a well-known psychiatrist without a conflict of interest. He or she should write an editorial for a particular research topic. However, it was virtually impossible to find someone like that among the leaders of the field.
But there are also patients who are convinced that the drugs helped them. How do you explain such cases?
Michael P. Hengartner: As I said, antidepressant drugs are psychoactive substances, which have mental and physiological effects. SSRIs, for example, have activating effects in some people. Those patients suffering from lethargy can experience that as very helpful.
In others this activation can lead to agitation, manic thoughts and sleeplessness. I do not doubt that antidepressant drugs have effects, but just that they are specifically anti-depressant. And I also think that their effects can cause harm in the long term.
Besides that, for some patients the belief that one is getting treatment is helpful. It is frequently neglected that people get attention in addition to the drugs, which is also a medical service. Somebody is assessing one’s symptoms, asking how they feel.
This alone can already improve the symptoms. Probably many patients, had they received a placebo instead of an antidepressant drug, would have had very similar experiences. In clinical practice, though, this is not feasible for ethical reasons.
And finally: Your summary of the research draws a rather disconcerting image of psychiatry and psychopharmacology. Do you have an idea what a better alternative could look like?
Michael P. Hengartner: Personally I think that the pharmaceutical industry should no longer be allowed to determine the effectivity of their own drugs. Imagine that a football team would be allowed to appoint its own referee! Everybody immediately understands that sports would not work like that.
Why is it then different in science? There has to be a completely independent agency carrying out the study from beginning to end, including the publication. This means that the dependency on the pharmaceutical industry, which has unfortunately reached a catastrophic dimension, has to be reduced.
The conflicts of interest already arise where experts think about the definition and diagnosis of mental disorders. As a result, grief and strain due to stressing life events have been turned into a mental disorder in some cases, which are then treated psychopharmacologically. Also, the treatment guidelines should not be written by experts who are earning thousands or perhaps even hundreds of thousands of dollars with their additional business for the pharmaceutical industry.
This is still argued from the experts' perspective. Is there something you can recommend with respect to patients?
Michael P. Hengartner: It is important to raise awareness for these issues among doctors and patients. There are alternatives to medical treatment particularly for mild forms of depression. In addition to that, more than half of antidepressant drugs are prescribed to people who don’t even have a diagnosis of depression.
For such people without a diagnosis and for those with mild forms of the disorder, one should rather consider social or psychological interventions. One should certainly not understand the drugs as "happy pills." It is concerning that nowadays in the USA about 20 percent of women aged 40 to 60 receive prescriptions for antidepressant drugs!
Many such people are simply overstrained, frustrated, or stressed out. Then one should consider the circumstances in one’s life, sleep hygiene, and diet. We also know that outdoor activities and exercise can help many people. That should be the first-line treatment in milder cases.
And even in severe cases of depression psychotherapy has been proven an effective alternative to medication. Psychotherapy seems to be superior to psychopharmacological treatment particularly in the long term, as it can also help people to find a job, for example. That is something the drugs cannot do. Another advantage of psychotherapy over pharmacotherapy is that it cannot cause severe somatic disorders.