What is the real-world clinical efficacy of SSRIs and other antidepressant medications compared to RCT placebos?
CONVERSATIONS IN CRITICAL PSYCHIATRY
Conversations in Critical Psychiatry is an interview series that explores critical and philosophical perspectives in psychiatry and engages with prominent commentators within and outside the profession who have made meaningful criticisms of the status quo.
Dan J. Stein, MBChB UCT, FRCPC, PhD, DPhil, is professor and chair of the Department of Psychiatry at the University of Cape Town (UCT), Cape Town, South Africa. To avoid compulsory service in the all-white South African army, he left for the United States, where he completed his residency in psychiatry and a postdoctoral fellowship in psychopharmacology at Columbia University. After Nelson Mandela was democratically elected president, Dr Stein returned to South Africa, where he has remained since. His research work has focused on anxiety and related disorders, including obsessive-compulsive and related disorders, and trauma- and stressor-related disorders. He chaired the DSM-5 and the ICD-11 workgroups on obsessive-compulsive and related disorders. Recognized for his contributions to multiple fields, he has received the Ethics in Psychopharmacology award from the International College of Neuropsychopharmacology and the Lifetime Achievement Award in Biological Psychiatry from the World Federation of Societies of Biological Psychiatry.
Dr Stein has been interested in both psychiatry research and philosophical writing since his residency. As a resident, he won the Karl Jaspers Award from the Association for the Advancement of Philosophy and Psychiatry in 1991. As part of the DSM-5 revision process, he wrote an article, collaborating with a number of leading figures in philosophy and psychiatry, titled “What is a mental/psychiatric disorder? From DSM-IV to DSM-V” that has been cited nearly 500 times.1 In 2008, he brought together his interests in psychopharmacology and philosophy in Philosophy of Psychopharmacology, and this year he has further extended his work in philosophy with the publication of Problems of Living: Perspectives from Philosophy, Psychiatry, and Cognitive-Affective Science. This is an ambitious book, tackling questions not only about the nature of mental disorders, but also about the mind-body problem, the relationship between reason and emotion, happiness and suffering, morality and truth, and the meaning of life.
AFTAB: You are the first African author I have interviewed for this series. Does being South African influence your work on philosophy and psychiatry?
STEIN: Well, it is notable that South Africans have made some really important contributions to psychiatry. The work of Joseph Wolpe, MD, developing behavior therapy comes to mind, as does Isaac Marks, MD’s contribution to anxiety disorders (others are detailed in a review I once wrote).2 On the other hand, critiques of psychiatry have had particular resonance here, emphasizing how social determinants and health systems are closely bound up with the history of apartheid and continue to influence mental health.
AFTAB: Your specific interest in the philosophy of psychopharmacology distinguishes you from many other authors and commentators in this area. Psychopharmacology too is a field where there have been advances but also important limitations.
STEIN: Yes, I fully agree. The introduction of antipsychotics, antidepressants, anxiolytics, and mood stabilizers in the 20th century was a complete game-changer for psychiatry. At the same time, the same receptors targeted by early agents continue to, by and large, remain the focus of current clinical psychopharmacology. Neuroscience has become increasingly sophisticated, and yet our understanding of how psychotropics affect symptom relief remains somewhat rudimentary. We should celebrate the fact that appropriate diagnosis and pharmacotherapy changes many individuals’ lives for the better. But we must remain aware that there is massive underdiagnosis, particularly in low- and middle-income countries, that not all patients respond to pharmacotherapy or other interventions, and that overdiagnosis and overtreatment is also an issue.
AFTAB: Selective serotonin reuptake inhibitors (SSRIs) and other antidepressant medications have been the subject of a lot of controversy in recent years. There is the perpetual question: Why have they performed so poorly when compared to placebos in randomized controlled trials (RCTs), and what does that say about their real-world clinical efficacy? And there is increasing awareness of the prevalence and severity of antidepressant withdrawal and other adverse effects. As someone who approaches psychopharmacology through a philosophical lens, how do you view these developments?
STEIN: In my thinking about these sorts of issues in psychopharmacology and related questions in philosophy of psychiatry, I find myself always trying to walk the line between overly hagiographic accounts and overly critical views of psychiatry. When I think of how psychotropics can impact thinking and feeling, and be so therapeutic, I am filled with awe (about the complexity of the relevant mechanisms) and with gratitude (that we are able to help individuals suffering from mental disorders). But I am also very aware of the robust criticisms of psychopharmacology’s evidence base, of iatrogenic illness, and of how far we still have to travel in psychopharmacology. I don’t think there’s a deep and readily addressed conceptual solution in psychopharmacology research. We have long been aware, for example, that neurotransmitters cut across dimensions of behavior, and that, while psychopharmacological dissection may be a useful tool, the idea that there is going to be a specific psychotropic that is particularly effective for each disorder is way too simplistic.
I do think, though, that in clinical practice it may be helpful to think about psychopharmacology not only from a molecular perspective but also from an evolutionary medicine perspective. This helps explain why anxiety is so common, why there are endogenous anxiogenic and anxiolytic mechanisms (which we can then target or mimic), why medications that target adaptive defenses can be clinically useful (an antitussive can reduce symptoms even though cough is highly adaptive), and why the motto “a pill for every ill” is far from the solution.
From a research perspective, while I love the current idea that clinical trials can be based on translational neuroscience approaches (eg, testing if a drug alters an important biomarker or endophenotype), successful bench-to-bedside advances remain fairly unusual in psychiatry, and I worry that we do not put commensurate attention and funding into pragmatic clinical trials. The United Kingdom’s Recovery Trial to quickly test drugs for efficacy against COVID-19 in day-to-day practice is inspiring. Should we not be doing the same sort of thing for mental disorders?
AFTAB: You have often differentiated among the classical, critical, and integrative positions. Tell us a bit more about these, particularly as you envisage them with regards to psychiatry.
STEIN: I have used these terms in part to find a middle path, avoiding both overly hagiographic and overly critical views of psychiatry and psychopharmacology. I have also used them as a way of integrating key philosophical views on science, language, and medicine. Thus, I use the term classical to refer to positions that emphasize essential natural kinds and scientific laws, holding up, say, the periodic table as an example of how science should work, and arguing that diseases too have essential features, which we need to explain. And I use the term critical to refer to positions that emphasize social construction and hermeneutic methods, pointing out that our concepts vary from time to time and place to place, arguing that mental disorders are socially constructed, and that the experience of being ill needs to be understood. I try to put forward an integrative approach which avoids the scientism of the classical view and the skepticism of the critical view, and which sees psychiatric science as both a social activity and a powerful account of the structures, processes, and mechanisms underlying phenomena, including disorders.
AFTAB: Your most recent volume is Problems of Living. Would you like to introduce the book to the readers in your own words? What are some of the major themes and conclusions of the book?
STEIN: It has been more than a decade since I wrote Philosophy and Psychopharmacology, and I have been wanting to get back to thinking about philosophy and psychiatry. I see the volume as expanding on my earlier work in a few key ways. First, whereas my earlier volume was on psychopharmacology, here I draw on a whole range of different scientific findings about the brain-mind. Second, my earlier volume spoke mainly about scientific naturalism and explanatory pluralism, but here I expand more on moral naturalism and value pluralism. Third, my earlier volume spoke mainly to the philosophy and ethics of psychopharmacology, whereas here I expand to cover the philosophy and ethics of a range of aspects of human life, including the question of the meaning of life. There are also key continuities between the volumes. The possibility of a middle way, of a balanced approach, remains a central issue for me, and I hope the volume is useful for readers also interested in that kind of path.
Given my interest in embodied cognition, I am very aware that expressions such as “a middle way forwards” and “a balanced approach” employ metaphors. My last chapter in Problems of Living is a brief reflection on the metaphors we use for thinking through life, the big questions and hard problems that it raises, and ultimately its meaning. I suggest that the metaphor of life as a journey may be a particularly useful one, and I spend some time on fleshing it out, and encouraging a course that avoids both unbridled optimism and relentless pessimism. It is a bit whimsical in spirit, but I hope it appeals to at least some readers.
AFTAB: You use the notion of wetware to talk about brain-minds. Can you tell us more about it and what you see as the advantage of employing this metaphor?
STEIN: The mind-body problem includes the hard problem of consciousness, and key philosophical positions include physicalism, dualism, and functionalism, which relies in part on the hardware-software distinction in cognitive science. We increasingly use the hardware-software metaphor in everyday life, as well as in psychiatry. It is easy for us to talk about medications as changing our hardware, and psychotherapy as changing our software. But while brain-as-thinking-machine metaphors can be useful, they also lead to important errors: psychiatry needs to remain vigilant and avoid brainless and mindless approaches. For me, the term wetware helps emphasize how the brain-mind (a term I think we should use more often) is biological through and through, with cognitive-affective phenomena embodied in brain processes and embedded in social activity.
AFTAB: At one point you write, “What about the fact that much psychotherapy is aimed not at specific mental disorders, but rather at ‘problems of living’? Can we really make progress in providing help for this sort of issue?”3 I think you are right that a lot of psychotherapy is aimed at problems of living, but it seems to me that a lot of contemporary pharmacotherapy is also aimed at problems of living, especially the use of SSRIs in primary care settings for the treatment of depression, anxiety, stress, etc. According to the Centers for Disease Control and Prevention, between 2015 and 2018, 13% of American adults were prescribed an antidepressant medication.4 It just does not seem that way because we are able to hide the distress and impairment behind all sorts of diagnostic labels. I am not taking the extreme Szaszian view here that all psychiatric disorders are problems of living, but more of a gentle skeptical view that there is no natural distinction to be found. Would you agree with that?
STEIN: Your point that both psychotherapy and pharmacotherapy address problems of living is a trenchant one. And I am with you with regards to a gentle skeptical view that there is a spectrum from psychiatric disorders through to problems of living, and my sense is that this is increasingly recognized both in neuroscience (eg, in the Research Domain Criteria framework) and in global mental health (which often speaks of the spectrum from illness to health). In Problems of Living, I often turn to Aristotle. I trust we are better at treating bipolar disorder than the ancient Greeks, but I suspect that the ancient Greeks were as good as helping individuals with problems in human relationships as we are, demonstrating the sort of practical wisdom (phronesis) that is required in medicine and psychiatry. Although advances in obsessive-compulsive disorder inspired me to go into that field, and, although I am proud of the ongoing progress the field has made, I suspect that Aristotle and his physician father would have some good techniques up their sleeves to manage some quite serious mental illnesses. Certainly, Aristotle’s thinking about mental disorders is sometimes very prescient.
AFTAB: As I was reading your discussion of metaphors, I thought of a quote by Derek Bolton, PhD, and Grant Gillett, MSc, DPhil, from their book on the biopsychosocial model. They write at one point: “What is missing from and obscured by these two-dimensional picture metaphors of levels and nested domains is the temporal, evolutionary and developmental, parameter…no static metaphor, whether in terms of levels or nested systems, capable of being drawn on a page, does justice to the new systems sciences, which essentially invoke dynamical interaction in present time, on the basis of co-evolution through deep time.”4
I think this shows us the power of metaphors to constrain us as well as liberate us. Our historical understanding of biopsychosocial complexity has been constrained by static metaphors, while new metaphors (such as baking a cake as a metaphor for organizational causality by Sanneke de Haan, PhD) free us from old mechanical ways of thinking. What is your view on the use of metaphors in philosophy and psychiatry?
STEIN: Dr Bolton co-supervised my dissertation in philosophy, and I am a fan of his work as well as of enactive approaches to psychiatry. I fully agree with your view that metaphors can constrain as well as liberate us. I have been interested in how metaphors work in our distinctions between typical and atypical disorders. In a typical disorder, metaphors such as being attacked work well: someone with pneumonia is attacked by a bug, we fight back with a drug, and they are not blamed but rather deserve the sick role. However, in an atypical disorder, these metaphors work less well: someone with alcoholism is not simply attacked by an external agent, rather they have to take some responsibility for their illness, and there is debate about the extent to which they deserve the sick role. It is as if we shift from medical to moral metaphors for conditions such as alcoholism. So, I like the idea of metaphors of addiction that bridge the medical and moral in order to avoid blame but also to emphasize responsibility.
AFTAB: Your experiences with professors of psychoanalytic orientation vs those of neurobiological and nosological orientation during your psychiatric residency seem to have left a deep mark on you. The notable schisms that I think our field is confronting now are between quite different players. Schisms between so-called evidence-based technological approaches (pharmacotherapy, CBT, etc) vs existential-humanistic-psychodynamic approaches; biomedical models vs interpersonal-relational models; and the epistemic authority of medical professionals vs epistemic authority of users of psychiatric services (exemplified by movements such as neurodiversity, mad pride, service user/survivors/ex-patients, etc). My approach to these schisms is in alignment with the same pluralistic and integrative approaches that you adopt.
However, a concern increasingly comes up when I discuss these things: within a pluralistic-integrative framework integrating these polarities, it is no longer obvious that psychiatry as a medical profession—that has increasingly specialized in psychopharmacology and clinical neuroscience over the last 3 decades—serves as the suitable umbrella profession for the integrated domain, instead of, say, clinical psychology, or social work, or even efforts led by service users. If neuroscience and psychopharmacology will no longer be of central importance in the new pluralism (at least it’s not obvious), then why should psychiatry continue to claim its existing power?
STEIN: I agree with you about the importance of the schisms that you mention (my sense is that these partly reflect aspects of the biological-psychoanalytical schism), and I am glad that you are in alignment with pluralistic and integrative approaches to address them.
In Problems of Living, I emphasized the importance of epistemic humility and of owning our fallibility; so absolutely we need to be open to entirely new ways of explaining, understanding, and improving mental health. Certainly, mental health care is too important to be left solely to psychiatrists. My work on trichotillomania has clearly taught me how much service users know, and how valuable they are in creating solutions.
At the same time, I would want to appropriately acknowledge the breadth and depth of psychiatry. So, with regard to sharing hegemony, I may be a bit more conservative than you would like. In my book, I refer a few times to the work of Jonathan Haidt, PhD, who, as you know, has argued for diversity of political positions; I do wonder if greater balance between conservativism and progressivism in general may not be useful, as we move forwards.
AFTAB: What do you see as some of the challenges we face in the pursuit of an integrative and pluralistic approach to psychiatry, and how can psychiatrists, especially trainees, better prepare for these challenges ahead?
STEIN: Another great question. From your columns I know you have a knack for making thinkers think harder. In line with my view that despite its important limitations, psychiatry does have extraordinary breadth and depth, I would argue that our field does already exemplify explanatory pluralism, and that a good clinician is necessarily taking an integrative approach. I do think that explicitly providing residents conceptual frameworks, as you have advocated for, is a good idea; this might be useful in seeing the explanatory pluralism we use as something to be proud of rather than concerned by. I also think that explicitly providing residents with exposure to good clinicians and researchers, who are able to explain how they integrate different ideas and approaches, is useful.
Finally, although I appreciate that it is important to be hopeful about the future, I also think that more explicit humility might be helpful at times; in our understandable zeal to address suffering, we may run the risk of overselling what we can do with any particular treatment approach, or any particular research program. In sum, I go back to a favorite metaphor: a balanced approach is key!
The opinions expressed in the interviews are those of the participants and do not necessarily reflect the opinions of Psychiatric TimesTM.
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 TimesTM Advisory Board.
Dr Aftab has no relevant financial disclosures or conflicts of interest. Dr Stein discloses that he has received research grants and/or consultancy honoraria from Johnson & Johnson, Lundbeck, Servier, and Takeda.
1. Stein DJ, Phillips KA, Bolton D, et al. What is a mental/psychiatric disorder? From DSM-IV to DSM-V. Psychol Med. 2010;40(11):1759-1765.
2. Stein DJ. Psychiatric contributions from South Africa: ex Africa semper aliquid novi. Afr J Psychiatry (Johannesbg). 2012;15(5):323-328.
3. Brody DJ, Gu Q. Antidepressant use among adults: United States, 2015-2018. Centers for Disease Control and Prevention. September 2020. Accessed September 9, 2021. https://www.cdc.gov/nchs/products/databriefs/db377.htm
4. Bolton D, Gillett G. The biopsychosocial model 40 years on. In: The Biopsychosocial Model of Health and Disease: New Philosophical and Scientific Developments. Palgrave Pivot; 2019:1-43. ❒