The Nocebo Effect In Antidepressant Trials

Early in my career I was an assistant to principle investigators who were doing clinical trials of drugs to treat generalized anxiety disorder, major depression, schizophrenia, and Alzheimer's Disease.  My job was top screen patients, do medical histories and physical examination, and follow them throughout the research protocol.  That is not an easy job.  The difficult part is making sure that the research patients are not getting any medical complications from a new and experimental drug in addition to assessing any possible therapeutic effects.

One of the main complications was the nocebo effect.  With all of the hype about placebo effects with antidepressants, I have always found it curious that few mention the nocebo and how it affects clinical research.  In those early days it was possible to break the blind and if research subjects withdrew from the protocol to let them know if they were taking active drug or placebo.   An adverse reaction to placebo is the nocebo effect.  It was common in these protocols for research subjects to either stop the protocol due to adverse effects or describe severe side effects while they were taking placebo.

One of the main problems I encountered with this effect in clinical trials that is an even bigger problem today is loss of research subjects who terminated early due to nocebo effects.  In the example I gave the patients developed significant side effects in response to a placebo, but people can also develop dramatic side effects to the active research medication.  Whether they are more likely to get the effect from active drug or an active placebo over the active study drug has not been actively studied.  These are critical questions because FDA trials now require and Intent To Treat Analysis for clinical trials.  That means all of the research subjects who did not complete the protocol for whatever reason need to be included in the analysis.  That becomes a problem when any subject has not been treated with the active drug - both in terms of true response but also side effects reporting.  All FDA package inserts contain detailed information on medication side effects.  Today in many cases there is a side effect comparison between active drug and placebo. Nocebo related data can skew the side effect data reported in the package inserts.    

I always thought that antidepressant trials were the ideal setting to study nocebo effects and came across a paper two years ago that does that (1).  That time frame over the last two years was an interesting one.  We saw all of the speculations about the release of the DSM-5 in the summer of 2015.  Much of that speculation involved sensational articles in the media suggesting that antidepressant medications did not work or ate least were no better than the placebo effect. Further speculation suggested that pharmaceutical manufacturers and the American Psychiatric Association (via the DSM-5) had an interest in broadening the market for antidepressants and increasing their use. At no point did any of the critics suggest that their may be a serious problem with clinical trials based on the nocebo effect.  And most interestingly, many of the critics in non-professional forum complained mostly about the side effects of these medications.  In some cases they described these medications as very dangerous.

The paper in reference 1 looks only at people receiving placebo in a pooled sample of placebo-arm data from 20 industry-sponsored multi-site randomized clinical trials of antidepressant medication in the treatment of acute major depression.  Adverse event data was recorded for all 20 clinical trials.  Adverse events (AE) can be pre-existing nonspecific somatic symptoms.  Treatment emergent adverse events (TEAE) were events that occurred or worsened during placebo treatment.  The adverse events were obtained by open ended questioning and in clinical trials from that period (1993-2010) were listed on standard forms.  Five endpoints were studied including any AE, any treatment related AE, any severe AE, any serious AE resulting in discontinuation from the study, and discontinuation form the study for any reason.  Worsening of clinical symptoms was also measured and defined as any increase in the depression rating score on any scale used for that particular study.

The main results included:

1.  TEAEs from placebo were reported in 1,569/2,457 or 63.9% of the study participants.

2.  11.2% (274) of the participants had worsening depression rating scores during the placebo treatment.

3.  4.7% (115) of the participants discontinued the study due to an AE during the placebo treatment.     

Just considering those results and nothing more illustrates the nocebo problem with current state-of-the-art clinical trials technology.  If 63.9% of the placebo-treated subjects experience side effects - what does that translate to in terms of subjects taking the active drug getting side effects unrelated to that drug?  Although untreated depression might be expected to worsen - how much of that is nocebo modulated and how much crosses over to the active drug.  A significant number of people dropped out of the trial due to the nocebo effect.  The main results suggest that in randomized placebo controlled trials of efficacy and safety - the nocebo effect is substantial.  Since the observed TEAEs and percentage of research subjects worsening on placebo was substantial - extension to TEAEs, worsening, and dropping out in clinical practice could be expected.  That would be a very difficult problem to research due to a lack of standardization across practices.

The authors did not stop with those results.  They looked at additional variable to see if there was any evidence to confirm either of the two major hypotheses about the nocebo effect.  The first is a conditioning hypothesis.  In this effect, prior exposure results in the expectation of an associated effect.  They cite as an example, women receiving chemotherapy for breast cancer and how an associated stimulus led to more nausea in the conditioned group (4).  In this case they looked at previous treatment with antidepressants as a possible conditioning effect and did not find any significant associations.

The other major hypothesis regard the nocebo effect is an expectation hypothesis.  They cite an example where a sample of college students were given inert placebo and told that it was an herbal supplement for cognitive enhancement (5).  They were provided with a fictitious list of potential benefits and side effects.  Symptoms were endorsed by most students but the students who believed that they received the active supplement endorsed more symptoms suggesting that their expectation of supplement and effect affected their perception.  They found some support that previous treatment with Hypericum perforatum (St. John's Wort) may have been associated with a greater likelihood of reporting TEAEs and suggest that users of complementary medications may be more suspect of medical pharmacotherapy.

The paper is a fairly concise review of demographic and neurobiological factors associated with the nocebo effect.  On the neurobiological side they cite the work of Enck, et al (6).  Elman and Borsook (7) have an interesting paper that looks at addiction, pain, and several common substrates of the placebo and nocebo effects.             

The take home message for me is what I have known for over a decade at this point. Current clinical trials technology in psychiatry and medicine is general is very primitive.  The evidence-based movement has had its day if this is the kind of evidence they are considering.  Why would anyone expect much more than a mild to moderate effect from a medication used for heterogeneous disorders when the true effect of the medication is significantly affected by two factors that are never measured?  This suggests areas for improvements in clinical trials that could render much of what has been collected so far - obsolete.

A final observation comes to mind and that is a phenomenon that I wrote about on this blog many years ago.  People with little to no expertise in psychiatry or medicine don't hesitate to criticize the field.  A good example would be people who have never treated a single case of depression much less thousands of cases who do a meta-analysis and claim that antidepressants are placebos.  I don't recall any of these critics in the popular press considering the limitations of clinical trials.  Without that basic consideration any theory that fits the apparent data can apply.

What would be useful at this point would be detailed analyses of the placebo arm of all clinical trials and a discussion of how these effects might bias the data.  Actual interventions to quantify or eliminate these effects in future trials is the next step.  These are more practical steps than hoping for mythical large clinical trials with slightly more sophisticated clinical trials technology that epidemiologists and the Cochrane Collaboration routinely recommend.         


George Dawson, MD, DFAPA

References:

1: Dodd S, Schacht A, Kelin K, Dueñas H, Reed VA, Williams LJ, Quirk FH, Malhi GS, Berk M. Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. J Clin Psychiatry. 2015 Jun;76(6):702-11. doi: 10.4088/JCP.13r08858. PubMed PMID: 26132671.

2:  Gupta SK. Intention-to-treat concept: A review. Perspectives in Clinical Research. 2011;2(3):109-112. doi:10.4103/2229-3485.83221.

3:   Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia” by A. Tinnermann, S. Geuter, C. Sprenger, J. Finsterbusch, C. Büchel in Science. Published online October 5 2017 doi:10.1126/science.aan122

4:  Bovbjerg DH, Redd WH, Jacobsen PB, Manne SL, Taylor KL, Surbone A, Crown JP,Norton L, Gilewski TA, Hudis CA, et al. An experimental analysis of classically conditioned nausea during cancer chemotherapy. Psychosom Med. 1992 Nov-Dec;54(6):623-37. PubMed PMID: 1454956.

5: Link J, Haggard R, Kelly K, Forrer D. Placebo/nocebo symptom reporting in asham herbal supplement trial. Eval Health Prof. 2006 Dec;29(4):394-406. PubMed PMID: 17102062.

6: Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron. 2008 Jul 31;59(2):195-206. doi: 10.1016/j.neuron.2008.06.030. Review. PubMed PMID: 18667148.

7: Elman I, Borsook D. Common Brain Mechanisms of Chronic Pain and Addiction. Neuron. 2016 Jan 6;89(1):11-36. doi: 10.1016/j.neuron.2015.11.027. Review. PubMed PMID: 26748087.



Attributions:

Figure at the top is stock photo from Shutterstock per their licensing agreement by kasezo entitled:

Stock illustration ID: 284558927   conceptual 3d design of false pill.( placebo and nocebo effect.red and green colored version)

Placebo - Nocebo Implications For Psychiatric Research and Clinical Care

The words popped up this week in two separate journals that I read regularly.  In the New England Journal of Medicine, there was an opinion piece on Placebo Effects in Medicine.   In the Journal of Clinical Psychiatry there was an article on Nocebo Effects in the Treatment of Major Depression.  Most people are familiar with the definition of placebo, or an apparent therapeutic effect from an otherwise inert medication or therapeutic intervention.  Even though the nocebo effect has been known for some time, it is less familiar.  A nocebo effect is an apparent adverse reaction to an inert substance.  I first became aware of it about 30 years ago as a clinical investigator working on a double blind placebo controlled study of an experimental anxiolytic medication.  In that study, the blind could be broken and the research subject informed of whether they were receiving active drug or placebo.  I had to inform several distressed subjects that they were receiving placebo after they insisted on stopping the study due to medication side effects.  In clinical practice, nocebo effects are also apparent typically as adverse reactions to low doses of medication or very atypical responses to medication.  In clinical practice, the determination is always probabilistic because placebos can't be given.

In the nocebo paper (1),  the authors analyze treatment-emergent adverse events (TEAEs) in 1,565 or 2,457 placebo treated participants in 20 industry sponsored, randomized, placebo controlled trials of duloxetine.  There were 16 different study designs typically in terms of length.  The Hamilton Depression Rating Scale (HDRS) was the primary outcome measure in 17 of the trials.  The authors looked at worsening ratings of depression score,  TEAEs, and discontinuation rates.  The authors hypothesized that prior conditioning by previous treatments (especially within the same class of drug) and negative expectations regarding treatment might predict nocebo responses.  They could find no  results to support either of these theories.  

The nocebo response has clear implications for interpreting the results of clinical trials in psychiatry and clinical practice.  Nocebo has really not been a term in the discussion, even by some authors who have basically declared that there is no antidepressant response (3).  Practically all of the naysayers doing meta-analyses to prove that antidepressants don't work don't include any discussion of it in their work.  All that you hear is that there is really no difference or not much difference between active drug and placebo.  What if 10% of the worsening depressive symptoms and 5% of the dropouts were due to a nocebo response?  That is a significant proportion of the trial subjects carried forward in an intent-to-treat design.

Should nocebo response rates be calculated for all clinical trials?  I think that they should and that data should be collected in a standardized manner as a part of clinical trials redesign in psychiatry.

What happens in clinical practice?  If a patient tells me that he or she is cutting up the lowest dose of a medication into sixteenths and can only tolerate 1/16 at a time due to side effects, I am not going to tell them to gradually titrate the dose up by sixteenths.  I know that this is probably a nocebo response, and it will likely occur with other medications.  I tell them to stop whatever they are doing immediately and we will try something else.  That could be a treatment focus on insomnia, supportive psychotherapy, exercise, meditation, relaxation techniques, mindfulness approaches -  anything but that medication.  If a patient tells me that they are basically "allergic to everything" my approach is the same.  I have no interest in prescribing a medication that makes a patient feel worse, irrespective of the purported clinical phenomenon.  Often, the patient's response is surprise.  Many people with these reactions are accustomed to physicians anguishing with them over the fact that they "cannot take any medication" and going through all of the excruciating misadventures associated with that nocebo response.  I certainly don't.  There are many other approaches and many other doctors who they can see.  One of the behaviors that I have observed in this population is a tendency to seek out complementary medicine providers where there is a risk that nocebo responders will find other treatments that may be more expensive with no proven efficacy in the context of improved tolerability.  There is also a tendency for non-psychiatrists to "kick the can down the road" and tell the patient experiencing a nocebo response that they have a psychiatric problem and need to see a psychiatrist.  I think it is useful to discuss the placebo and nocebo effects with patients and provide them with as much detail as possible.  I tend to focus on what is known rather than speculative neurobiology, especially in any conversation about endorphins.  Endorphins have already been excessively hyped as being associated with the "high" associated with exercise but the evidence is weak (4).

The opinion piece on placebo effects (2) is an interesting contrast.  One of the authors of this piece is associated with the Program in Placebo Studies & Therapeutic Encounter (PiPS).  A white paper on their web site describes their observations about the placebo effect and an action plan to conduct further research and a possible introduction of it as an action plan in medicine.  In the opening paragraphs they allude to the theoretical neurobiology of placebo effects including the early genetics of placebo responders.  They summarize three major findings of current research on placebo effects.  The first is that they are not curative.  The best example of this was the placebo effects with asthmatics.  Their subjective symptoms are relieved but their forced expiratory volume in one second (FEV_1.0) - stays the same.  The same is true of placebo in cancer treatment where the side effects of treatment improve but there are no changes in tumor size.  The second is the expectation effect, best illustrated by an example the authors give having to do with rizatriptan - a standard migraine medication.  If the active drug is labeled "placebo" the results are no better than placebo.  If the active drug is correctly labeled the antimigraine effect increases by 50%.  They list a number of medications with similar expectation effects.  Lastly, they touch on the nocebo effect as "the psychosocial factors that promote therapeutic placebo effects also have the potential to cause adverse consequences."  In a clinical trial of finasteride for benign prostatic hypertrophy, patients informed of sexual side effects report them at three times the rate of men who have not been informed.  They quote the statistic that 4-26% of placebo treated patients in clinical trials discontinue the study due to perceived side effects.  The philosophical aspects of this commentary are probably the most interesting.  The authors correctly point out that the placebo effect has pejorative connotations.  There is perhaps no better example than in psychiatry.  They suggest a further understanding and application of the various facets of this response to create a better therapeutic alliance with patients and alleviate their suffering.

This is a fascinating area of psychiatry.   I am generally compulsive about informed consent in general and more so in high risk situations.  For the highest risk warnings that I give patients - serotonin syndrome, tardive dyskinesia, agranulocytosis, cardiovascular complications, seizures, renal failure, and liver failure - I have never seen a nocebo effect.  That may have to do with the clear objective markers of these problems or the fact that I describe them as rare complications.  On the issue of sexual side effects, I clearly explain what they are and give people the exact numbers from clinical trials.  When it comes to explanations about medication side effects, the one that leads to the most problems is increased appetite and weight gain.  Even though that side effect is common with medications that psychiatrists prescribe, people tend to flee from it independent of the statistics and how much weight they have recently lost or gained due to either the primary psychiatric diagnosis or substance use.  It seems that most people who are likely to be nocebo responders, are well known before it gets to the informed consent stage.  In the initial evaluation stages they have clear histories of not be able to tolerate much of anything and the side effects described are very atypical.  

Another area where placebo-nocebo comes into play is when the primary disorder has been treated and a patient presents with the idea that the "medication has lost its effect".  There are papers written on this effect and some give statistics about how often it occurs.  In my experience, these outcomes are most often not due to a medication, but prevailing psychosocial factors and/or substance use.  Clarifying and addressing those issues frequently leads to better outcomes than changing medications or adding another one.  In many way it seems that some elements of a placebo response are an antidote to psychosocial stressors that affect medication responses.

Translating life into a medication mediated process needs to be averted at all costs.  




George Dawson, MD, DFAPA


References:

1:  Dodd S, Schacht A, Kelin K, Dueñas H, Reed VA, Williams LJ, Quirk FH, MalhiGS, Berk M. Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. J Clin Psychiatry. 2015 Jun;76(6):702-11. doi: 10.4088/JCP.13r08858. PubMed PMID: 26132671.

2:  Kaptchuk TJ, Miller FG. Placebo Effects in Medicine. N Engl J Med. 2015 Jul 2;373(1):8-9. doi: 10.1056/NEJMp1504023. PubMed PMID: 26132938.

3:  Ioannidis JP. Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?  Philos Ethics Humanit Med. 2008 May 27;3:14. doi: 10.1186/1747-5341-3-14. PubMed PMID: 18505564.

4: Harbach H, Hell K, Gramsch C, Katz N, Hempelmann G, Teschemacher H.Beta-endorphin (1-31) in the plasma of male volunteers undergoing physical exercise. Psychoneuroendocrinology. 2000 Aug;25(6):551-62. PubMed PMID: 10840168.


Attribution:

The graphic in this case is from 2,000 Plus Royalty Free Images from the Apple App store.