"It is simply wishful thinking to believe that one course of treatment may entail the solution to problems that we encounter in complex cases," says Dr Fava. Dr Aftab explores a multitude of issues in psychiatry and science in this interview.
Awais Aftab, MD
Giovanni Andrea Fava, MD
CONVERSATIONS IN CRITICAL PSYCHIATRY
Dr Fava has authored more than 500 scientific papers and his work has been highly influential in the field in the psychiatry. His innovations include a novel psychotherapeutic approach for increasing psychological well-being (well-being therapy), the sequential model for combining pharmacotherapy and psychotherapy, the concept of staging in psychiatry, a new method of classification of psychosomatic distress (the Diagnostic Criteria for Psychosomatic Research), the concept of oppositional tolerance with antidepressant treatment, and the clinimetric approach to psychiatric evaluation. Since 1992, he has been the Editor in Chief of Psychotherapy and Psychosomatics, which ranks fourth in the Science Citation Index for psychiatry journals with an impact factor of 13.74 (and precedes the American Journal of Psychiatry). I particularly enjoy his editorials in Psychotherapy and Psychosomatics—a treat for any thoughtful psychiatrist—and I am a great admirer of his brilliant mind, intellectual integrity, and willingness to tackle complex clinical questions that few others are asking in the field.
Aftab: I feel psychiatrists are in a very tough spot. The way they are educated and trained, they are unaware of the systematic ways in which research studies and guidelines are heavily biased and misrepresented. They have to learn to critically appraise research literature for guidance, which is a hard thing to do for clinicians without research training, especially since it often means challenging the wisdom of their colleagues, conclusions of top researchers, and “key opinion leaders,” as well as established guidelines in the field.
To make matters worse, there is very little unbiased and generalizable research. This means psychiatrists have to rely on their clinical experience when working with individual patients, which is subject to biases and distortions of its own. Despite mountains of research data, it feels like we are in an impoverished state of knowledge. Am I being too nihilistic, or do you share some of these frustrations as well?
Fava: I agree; psychiatry is going through an intellectual crisis. This crisis is shared by other areas of clinical medicine and stems from a narrow concept of science that neglects clinical practice as a source of fundamental research questions. Fewer and fewer academic psychiatrists actually assess and treat patients. Most of published research has no relevance to practice. The progress of neurosciences in the past 2 decades has often led to the belief that clinical problems in psychiatry were likely to be solved by this approach. Such hopes are understandable in terms of massive propaganda operated by biotechnology and pharmaceutical corporations.
An increasing number of psychiatrists are wondering, however, why the cures and clinical insights promised by neurosciences have not come to fruition. Biological reductionism has resulted in an idealistic approach, which is quite far from the explanatory pluralism required by clinical practice. Neurosciences have exported their conceptual framework into psychiatry much more than serving as an investigative tool.
Aftab: You use the term iatrogenic comorbidity to refer to the lasting effects of previously administered treatments that negatively influence course, characteristics, and responsiveness to treatment. Can you share some examples to illustrate what you mean?
Fava: Like Moliere’s bourgeois who was surprised to speak in prose, the clinician may discover they are constantly faced with iatrogenic comorbidity. In pharmacological terms, let us just think of the case of switch into mania of a patient with allegedly unipolar depression treated with antidepressant drugs. You are faced with a modification of illness that is largely drug-induced and that is likely to affect treatment. Or, in psychotherapeutic terms, let us think of a patient who has been unsuccessfully in analysis for many years and is offered a course of cognitive behavioral therapy (CBT): their response is likely to be affected by the previous psychotherapeutic experience in terms of expectation, adherence, and motivation. The concept of iatrogenic comorbidity is simply an attempt to conceptualize the problem in a practical way.
Regrettably, psychiatrists, unlike other specialists, have been taught to consider comorbidity only in terms of diagnoses, and not as problems and treatment experiences. And they are unable to think “iatrogenic” in interpreting clinical problems, simply because they have not been exposed to the concept, which has been submitted to tight censorship by mainstream psychiatry.
Aftab: Clinicians and researchers have been taught and/or have learned to ignore and misunderstand antidepressant discontinuation symptoms, such that in many instances, withdrawal symptoms are interpreted as indicators of impending relapse. In fact, the vast majority of psychopharmacological maintenance randomized controlled trials appear to conflate withdrawal reactions with illness relapse to justify superiority of maintenance treatment over discontinuation. How can psychiatrists better differentiate between withdrawal and illness relapse, and how can maintenance studies be better designed to parse out this issue?
Fava: Psychopathology, the basic neglected method of psychiatry, allows differentiation of withdrawal syndromes from relapse. Specific diagnostic criteria have been developed by Guy Chouinard, MD, and Virginie-Ann Chouinard, MD, in 2015.5 These criteria allow differentiation of withdrawal syndromes from relapse, recurrence, rebound, and persistent post-withdrawal disorders. Maintenance studies with antidepressants are likely to confound withdrawal and relapse unless specific criteria are used. We need new studies with these criteria.
Aftab: It has been interesting that the psychiatric establishment insists on using the term antidepressant discontinuation syndrome, while researchers such as yourself and critics in the general public favor antidepressant withdrawal. Does this battle of terminology have any larger significance?
Fava: The term discontinuation syndrome applied to antidepressants, versus withdrawal syndromes with benzodiazepines, was a very smart method of the pharmaceutical industry to deny the problem. It is sad that most academic psychiatrists followed these leads. The evidence, based on systematic reviews and a large body of literature, is now pretty clear and the tide is turning.2 Selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors may cause withdrawal reactions (ie, new symptoms that were not present before) despite slow tapering; these reactions may be severe and do not necessarily subside in a few weeks. When I see a patient whose symptoms have been treated with paroxetine or venlafaxine, I am always looking for manifestations of iatrogenic comorbidity, which, unfortunately, I am very likely to find.
If you teach a psychiatric resident that symptoms that occur during tapering cannot be due to withdrawal, they are likely to interpret them as signs of relapse and to go back to treatment (exactly what “Big Pharma” likes). In the United Kingdom, the National Institute for Health and Care Excellence (NICE) guidelines are changing to reflect the potentially malignant outcome with SSRI and SNRI discontinuation. I do not see anything similar happening in the United States.
Aftab: Many clinicians seem to hold the view, implicitly or explicitly, that it is better to identify and treat depression when it is mild or even subthreshold because untreated depression will progress in severity. This is coupled with the assumption that at worst, the medication may not help but it certainly won’t cause disease progression. Do such clinicians have an unfairly malignant view of the natural history of untreated depression and an unfairly benign view of psychopharmacological treatment?
Fava: These clinicians perceive a state of distress in their patients but have been taught only to think in terms of harmless medications. They are often unaware of the major advances that have been made in psychotherapy in the past decades, which are far superior to the pharmacological ones. Mild or subthreshold depression should be primarily addressed with effective and short-term psychotherapies, such as CBT. Unfortunately, the prescribing clinician is driven by an overestimated consideration of potential benefits, paying little attention to the likelihood of responsiveness and to potential vulnerabilities in relations to the adverse effects of treatment, one of the spectacular achievements of “evidence-based medicine,” which has been transformed into the marketing arm of the pharmaceutical industry. These latter components outweigh potential benefits of antidepressants in mild depression.
Aftab: You seem to interpret the results of STAR*D as indicating that the use of switching and/or augmenting strategies propels depressive illness into a phase characterized by low remission, high relapse, and high intolerance to medications.3 You tie the poor outcomes seen in STAR*D to the use of psychopharmacological strategies while conventionally the poor outcomes have been viewed as a result of patient characteristics or characteristics of disorder pathophysiology. Is there anything in the data that supports one interpretation over another?
Fava: The findings of STAR*D were pretty clear. The aim of the trial was to apply the best pharmacological strategies for obtaining remission in major depression. Those who did not recover after a trial with citalopram were submitted to 4 sequential steps involving switching, augmentation, and combination strategies, based on available literature.
The results were rather disappointing. The cumulative rate of remission after 4 sequential steps was 67%. However, when sustained recovery (taking into account relapse rates while on treatment) was considered, the cumulative rate was 43%. This means the strenuous efforts after step 1 (open treatment with citalopram) yielded an additional 6% of sustained recovery. Remission rates decreased after each treatment step. Rates of relapse increased after each treatment step in patients who achieved remission. Further, intolerance (dropouts for any reason during the first 4 weeks, or adverse effects afterwards) increased after each treatment step.
STAR*D’s message should have been clear: Do not do what we have done. Regrettably, just the opposite came out. The findings can be interpreted in light of the oppositional model of tolerance. Continued drug treatment may recruit processes that oppose the initial acute effects of a drug. This may explain loss of treatment efficacy and the fact that some side effects (such as increased appetite and weight gain) tend to ensue only after a certain time. These processes may also propel the illness to a more malignant and treatment- unresponsive course, as with a bipolar manifestations or paradoxical reactions. When drug treatment ends, oppositional processes may encounter no more resistance, resulting in appearance of new withdrawal symptoms, rebound symptomatology, persistent post-withdrawal disorders, hypomania, resistance to treatment if it is reinstituted.
In the long run, antidepressants may increase chronicity, vulnerability to depressive disorders, and comorbidity. There is now extensive literature supporting this mechanism. In practice, you may encounter patients whose symptoms have been treated with a number of psychotropic drugs, particularly in combination, and who end up as in the STAR*D. What to do is a big problem. You can blame the illness and the patient, it is easy, but you should also think iatrogenic.
Aftab: You wrote, “Current diagnostic methods in psychiatry, both DSM-5 and the forthcoming ICD-11, refer to patients who are drug-free and do not take the issue of iatrogenic comorbidity into adequate consideration. They are suited for a patient who no longer exists.”4 How do you think the diagnostic manuals can take iatrogenic comorbidity into account?
Fava: Most of the patients we see in practice are already taking psychotropic drugs. If a primary care physician refers a patient to me, it is because the patient’s symptoms did not respond to the pharmacological treatment (generally an SSRI or SNRI) that had been started. Medications may affect clinical presentation of symptoms. In a naïve implicit formulation that runs counter to any modern insights into the plasticity of the brain, we may believe that after discontinuing an antidepressant everything goes back to the pre-treatment state. It does not, as any physician in the real world knows.
Treatment is a one-way street. We even subscribe to the hope of finding pre-treatment predictors (biomarkers), and we waste money on it. Everything changes in the course of treatment. This means we need to supplement DSM with a more comprehensive assessment that takes the issues of medication history and development of tolerance into consideration, using methods that pertain to clinimetrics, the science of clinical measurements, such as macroanalysis and staging.5
Aftab: It is very common for psychiatrists to encounter patients with complex presentations of multiple psychiatric comorbidities who are on multiple psychotropic medications but remain symptomatic with a mix of symptoms that does not fit into diagnostic categories and their psychopharmacological treatment history is a mess of one trial after another, consisting of medications that once worked but no more, medications that never worked, and medications poorly tolerated. Do you have any general clinical recommendations regarding how to approach evaluation and treatment in such cases?
Fava: These are exactly the patients who do not fit into any DSM category. You need to take the issue of iatrogenic comorbidity into account and spend a good deal of time for a full clinimetric assessment and use diagnoses only as temporary transfer stations that can be verified in the course of time. There is almost no research on these issues, as it happens with most of the truly important matters in psychiatry.
I can share with you what I do clinically. First, I use clinimetric assessment to capture clinically relevant information that is not included in the diagnosis. Based on the assessment, I try to taper and discontinue, very slowly, the multiple medications starting from those I judge as less important. I am also looking for counter-therapeutic elements (behavioral components) and attitudes that may affect response to treatment at the individual, family, and work levels using a framework that Karl Rickels, MD6, developed in the ’60s and that we have recently updated. I also pay a lot of attention to psychological well-being (ie, is there anything I can build on?). Then I introduce the type of psychotherapy (eg, CBT, brief dynamic psychotherapy, family therapy, well-being therapy) that may affect the targets I have identified. It is simply wishful thinking to believe that one course of treatment may entail the solution to the problems that we encounter in these complex cases. We need the sequential combination of different treatments, and this should be planned from the very beginning and subsequently modified as needed.
Aftab: What percentage of patients prescribed antidepressants would you say experience clinically significant effects related to oppositional tolerance? Why is there so much variability in how individuals are impacted by these medications?
Fava: It very much depends on the type of practice. In my practice, which is very much shifted to treatment resistant, difficult, unusual cases, the percentage of cases who present with the various manifestations of tolerance (eg, loss of clinical effects, paradoxical reactions, switching, persistent post-withdrawal disorders, refractoriness) is very high and may approach 1 case out of 2. But you do not have the same crowd, the percentage may be much lower. We need studies addressing these issues in a comprehensive manner in outpatient populations.
Aftab: Psychiatry is continuing its path of aggressive pharmacological treatment of “treatment resistance” in depression, and medications such as ketamine are being hailed as new miracle drugs. What is your perspective on these developments?
Fava: These types of studies reveal the methodological frailty and the narrow perspectives of much of current psychiatry. You test a drug in a highly heterogeneous sample of patients who do not respond to a certain treatment (the reasons for which could be so different) without any discrimination in terms of tolerance and questioning whether the treatment was appropriate (you just go by the book). Because you use a controlled design, you are convinced you are performing high-level clinical science. But the results are likely to be spurious and the outcome is monitored for a very short time.
For a clinician, a short-lived response does not mean much. It can also be achieved with non-specific ingredients, such as high expectations. One course of treatment, again, is unlikely to yield solutions to the complex situations of these patients. The claim of “miracle drugs” such as ketamine are only a sign of the intellectual crisis of psychiatry. I would like to see adequate assessments and articulated courses of treatment be tested for enduring results.
Aftab: Have you read or are familiar with Robert Whitaker’s book Anatomy of an Epidemic? If so, do you have any thoughts on what the book gets right and what it gets wrong?
Fava: Yes, of course. I think it was an excellent piece of investigative journalism that was highly effective in fighting the tight censorship that mainstream psychiatry endorsed against any vulnerabilities induced by psychotropic drugs. Subsequent developments (eg, Mad in America) had the recognized merit of addressing clinical problems, such as the withdrawal syndromes from SSRI and SNRI, that were and are still denied by professional organizations and scientific societies, as well as issues related to financial conflicts of interest.
However, the risk is forgetting that, if used properly, antidepressants, antipsychotics, and lithium are life-saving drugs, and benzodiazepines offer a rapid and safe relief for anxiety. The problem is their inappropriate application, like any other medication (eg, antibiotics).
Aftab: As you have discussed, forces and incentives in the world of academic publishing converge to reward mediocrity and discourage truly innovative research.8 What would be your advice to early career psychiatrists about surviving in academia without giving up independent thinking and creative integrity?
Fava: A young psychiatrist who reads our conversation may become convinced that this is the worst of times for psychiatry. As Dickens teaches us, however, it may also be the best of times. There are entire areas of clinical research, such as those related to the iatrogenic effects of medications and psychotherapy, that are largely unexplored. Neuroscientific methods applied to specific problems (eg, what characterizes withdrawal syndromes) may offer unprecedented opportunities but should be associated with clinimetric tools (eg, specific criteria).
The recent development of medicine-based evidence9 that integrates data from clinical practice with those of randomized controlled trials opens an important line of research. Psychiatrists, who in their clinical practice use sophisticated forms of clinical judgment and master techniques of interviewing and history taking, are geared to capture the components of medicine-based evidence. Fascinating vistas for psychiatrists who are skilful in differential psychopathology and have strong curricula in clinical pharmacology and internal medicine are emerging. They should be welcome to all those who are disillusioned with the meagre practical results of decades of mainstream psychiatric research and should become the preferred channel of funding and attention. Long-term outcomes of psychiatric disorders may be unsatisfactory, not because technical interventions are missing but because our conceptual models are inadequate.
Of course, a pathway characterized by independent thinking and creative integrity may be difficult and frustrating nowadays (eg, very few journals host contributions that may hit commercial interests), and it is certainly easier to make progress in academia with meta-junk. But, in my opinion, we may be close to a change of paradigms in psychiatry. Either you persist on the current mainstream road to nowhere that leads to frustrating clinical experiences (with ensuing aversion to patient contact) or realize that there is a world of new possibilities and pathways.
Aftab: Thank you!
Dr Aftab is a psychiatrist in Cleveland, Ohio, and clinical assistant professor of psychiatry at Case Western Reserve University. He is a member of the executive council of Association for the Advancement of Philosophy and Psychiatry and has been actively involved in initiatives to educate psychiatrists and trainees on the intersection of philosophy and psychiatry. He is also a member of the Psychiatric Times Advisory Board. He can be reached at email@example.com or on Twitter @awaisaftab. Dr Fava completed his medical education as well as his psychiatry residency training at the University of Padova, Italy. After working for several years in the United States, he returned to Italy in 1988, where he established an Affective Disorders Program at the University of Bologna. He is currently clinical professor of psychiatry at the State University of New York (SUNY) at Buffalo, NY. A full version of this article can be found online at https://www.psychiatrictimes.com/view/impoverishment-psychiatric-knowledge.
Dr Aftab and Dr Fava have no relevant financial disclosures or conflicts of interest.
The opinions expressed in the interviews are those of the participants and do not necessarily reflect the opinions of Psychiatric Times.
1. Chouinard G, Chouinard VA. New classification of selective serotonin reuptake inhibitor withdrawal. Psychotherapy and psychosomatics. 2015;84(2):63-71.
2. Hengartner MP, Davies J, Read J. Antidepressant withdrawal-the tide is finally turning. Epidemiology and psychiatric sciences. 2019;29:e52.
3. Fava GA. Rational use of antidepressant drugs. Psychotherapy and psychosomatics. 2014;83(4):197-204.
4. Fava GA, Rafanelli C. Iatrogenic Factors in Psychopathology. Psychotherapy and psychosomatics. 2019;88(3):129-40.
5. Fava GA, Rafanelli C, Tomba E. The clinical process in psychiatry: a clinimetric approach. J Clin Psychiatry. 2012 Feb;73(2):177-84.
6. Fava GA, Guidi J, Rafanelli C, Rickels K. The clinical inadequacy of the placebo model and the development of an alternative conceptual framework. Psychotherapy and psychosomatics. 2017;86(6):332-40.
7. Chouinard G, Samaha AN, Chouinard VA, Peretti CS, Kanahara N, Takase M, Iyo M. Antipsychotic-induced dopamine supersensitivity psychosis: pharmacology, criteria, and therapy. Psychotherapy and psychosomatics. 2017;86(4):189-219.
8. Fava GA. The Decline of Pluralism in Medicine: Dissent Is Welcome. Psychotherapy and Psychosomatics. 2019;13:1-5.
9. Lobitz G, Armstrong K, Concato J, Singer BH, Horwitz RI. The biological and biographical basis of precision medicine. Psychotherapy and Psychosomatics. 2019;88(6):333-40. ❒
An earlier version of this article was posted on March 30, 2020: The Impoverishment of Psychiatric Knowledge. -Ed
Previously in Conversations in Critical Psychiatry