Hero

Videos

Slideshows

Articles

Podcasts

Poll

The English word apathy originates from the Greek word apathes, which means “without pathos or feeling,”

 but scholars have shared various definitions. For example, Robert S. Martin, MD, defined apathy as a syndrome of primary motivational loss that is not attributable to emotional distress, intellectual impairment, or 

 According to Drs Richard Levy and Bruno Dubois apathy is the quantitative reduction of self-generated voluntary and purposeful behaviors, which are observable and can be quantified.

 In addition, the underlying mechanism(s) responsible for apathy may be seen as dysfunctions occurring at the level of elaboration, execution, and control of goal-directed behaviors. According to an international consensus criterion, apathy is defined as a disorder of motivation in which the symptoms are present for at least 4 weeks.

 In addition, 2 of the following 3 should be present: reduced goal-directed behavior, reduced goal-directed cognitive activity, and reduced emotions. Furthermore, these symptoms cause clinically significant impairments in personal, social, occupational, or other important areas of functioning, with such symptoms not exclusively explained by or due to other causes (ie, physical disabilities [such as blindness or loss of hearing], motor disabilities, diminished level of consciousness, or direct physiological effects of a substance [such as a drug of abuse or a medication]).

 of individuals who have no cognitive deficits.

 It is also seen among individuals with major depressive disorder, schizophrenia, strokes, multiple sclerosis, and traumatic brain injury. Apathy is more prevalent among individuals with neurodegenerative disorders than in those free of such disorders.

Apathy has been noted throughout the spectrum of neurocognitive disorders (

 The prevalence rates for apathy among individuals with mild cognitive impairment ranges from 

 Apathy is also the most frequently reported behavioral symptom among individuals with dementia. The results of one study showed that individuals with frontotemporal dementia (FTD) and vascular dementia (VaD) report more severe apathy than individuals with Alzheimer disease (AD).

Apathy usually appears early in dementia and tends to persist throughout; it is associated with longer illness duration and it worsens with the 

 Risk factors for developing apathy include older age and greater severity of cognitive impairment. Akyol et al found that apathy was correlated with the degree of cognitive impairment among individuals with AD and VaD, but not with FTD; but apathy did not correlate with age or gender in individuals with AD, FTD, and VaD. Additionally, the degree of apathy correlated with the level of functional impairment and dementia severity across all 3 types of dementia.

Individuals with dementia who present with apathy often have more rapid cognitive decline and are more impaired in their activities of daily living.

 In addition, apathy increases the risk for earlier institutionalization among individuals with dementia.

 Distress is also significantly higher among caregivers of individuals with dementia who have apathy, when compared with individuals with dementia without it.

Emerging evidence indicates that apathy in individuals with dementia occurs due to a complex interaction among neuroanatomy, neuropathology, neurochemistry, and genetics.

 Among individuals with AD, apathy is associated with an increased neurofibrillary tangle burden in the parahippocampal, frontal, and parietal regions, in addition to the anterior cingulate gyrus. Emerging evidence indicates that the severity of apathy is also associated with amyloid plaque burden, especially in bilateral frontal cortices and the right anterior cingulate gyrus along with 

One study that evaluated the cerebrospinal fluid (CSF) biomarkers among individuals with AD showed that apathy was significantly correlated with tau and p-tau, but not with amyloid β١–٤٢.

 Another study examined regions of cortical thinning and CSF biomarkers (amyloid-β ١-٤٢, total tau, and phosphorylated tau) among 3 groups—clinically normal elderly individuals, individuals with mild cognitive impairment, and individuals with mild AD dementia with apathy—and found that reduced baseline inferior temporal cortical thickness was predictive of increasing apathy over time.

 The investigators of this study did not find any association between CSF biomarkers and the severity of apathy in cross-sectional or longitudinal analyses.

Another study found that individuals with AD and apathy had a loss of white matter integrity in the genu of the corpus callosum when compared with individuals with AD without apathy.

 In addition, the loss of white matter integrity in the genu, body, and splenium of the corpus callosum was negatively correlated with the severity of apathy among individuals with AD. Neuroradiological studies indicate that the dysfunction of the anterior cingulate cortex is the strongest anatomical correlate of apathy in AD, whereas lesions of the basal ganglia are the most common correlates of apathy in cerebrovascular disorders.

Neuroimaging studies indicate that the apathy among individuals with behavioral variant of FTD is associated with prominent atrophy in: the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, right caudate (including the ventral striatum), right temporoparietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum-anterior insula region.

A recent meta-analysis that analyzed data from 41 studies indicated that apathy is associated with hypometabolism and a decrease in gray matter volume in the left inferior frontal gyrus.

 The investigators also found altered brain perfusion and decreased gray matter volume in the anterior cingulate cortex among individuals with AD, and decreased gray matter volume in the inferior frontal gyrus and parietal cortex among individuals with FTD. These findings indicate that apathy occurs due to a cortical dysfunction of areas involved with executive cognitive processing (action planning) and emotional regulation (autoactivation and reward processing).

Individuals with AD and apathy have been found to have reduced dopaminergic activity in the putamen, reduced acetylcholine in the lateral frontal cortex, and lower levels of plasma gamma-aminobutyric acid.

 In evaluating the association between apolipoprotein E ɛ4 allele and apathy in probable AD, investigators found that the presence of this allele was indeed significantly associated with apathy in these individuals.

Among individuals with dementia, the assessment of apathy is often complicated. It is particularly difficult to distinguish between reduced motivation to do things due to apathy and the loss of ability or motivation secondary to cognitive dysfunction. Additionally, there may be overlap between symptoms of apathy and depression (

 Often, as well, psychotropic medications (ie, antipsychotics, antidepressants) are used to treat neuropsychiatric symptoms (NPS) of dementia, and the adverse effects of these medications include fatigue, lethargy, listlessness, and decreased initiative to respond to external stimuli. These AEs can mimic symptoms of apathy among individuals with dementia.

The scales that have been developed for the assessment of apathy include the Apathy Evaluation Scale (AES), the Structured Clinical Interview for Apathy, the Apathy Scale, the Apathy Inventory, the Dementia Apathy Interview and Rating (DAIR), and the Lille Apathy Rating Scale (LARS).

 Among these scales, only the DAIR was designed for use among individuals with dementia. The Apathy Scale for Dementia Patients in Nursing Homes was designed to measure apathy among individuals with dementia who live in institutional settings.

 The Neuropsychiatric Inventory (NPI) is considered the gold standard for the assessment of NPS among individuals with dementia. However, the use of a single domain from the NPS prevents a comprehensive assessment of all dimensions of apathy among individuals with dementia. A recent systematic review found that the DAIR, the AES–clinical version (AES-C) in AD, and the LARS in Parkinson disease (PD) had psychometrically favorable qualities and the highest quality among the scales used to assess apathy among individuals with neurodegenerative disorders.

Available evidence indicates that both nonpharmacological and pharmacological treatment modalities can benefit individuals with dementia who present with apathy (

A systematic review by Brodaty et al found that therapeutic activities—including stimulation, creative activities, cooking, Montessori methods, music, exercise, multisensory stimulation, and pet therapy—as well as placement in special care units may improve apathy among individuals with dementia.

 Another recent systematic review by Cai et al, evaluating the effectiveness of nonpharmacological interventions among individuals with dementia and apathy, also found that multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are useful in improving symptoms of apathy.

 Cai et al found limited evidence as well for the efficacy of art, exercise, reminiscence, and occupational therapies; dementia special care units; comprehensive interventions; nursing staff education; and behavioral management techniques (ie, therapeutic conversations, progressive muscle relaxation). They found that the effects of psychomotor therapy and validation therapy were still unclear; evidence also indicates that receptive music therapy is better than interactive music therapy. Pet therapy that includes the introduction of domestic pets and companion robots tends to reduce loneliness and improve well-being. Tailoring the overall lifestyle of individuals with dementia to increase recreational activities, physical exercise, cognitive stimulation, and social activities also reduces apathy.

Various pharmacological agents have been trialed for the treatment of apathy,

 including acetylcholinesterase inhibitors (ChEIs), memantine, stimulants, calcium antagonists, and antipsychotics.

 In their systematic review and meta-analysis, Sepehry et al found a total of 15 randomized controlled trials that assessed the efficacy of pharmacotherapy.

 For cognitive enhancers (donepezil and galantamine), there was no was significant effect of treatment on apathy (Hedges’ g = –0.055; 

 = .687). The average donepezil dosage was 10 mg/day, while galantamine dosage ranged between 16 mg/day and 32 mg/day. All but 1 study used the NPI-apathy subscale as an outcome measure, and these trials included individuals with mild-to-severe AD.

For memantine, the investigators found a small and nonsignificant benefit for apathy (Hedges g = .092; P = .423). The average dose of memantine was 20 mg/day, and the trials included individuals with moderate-to-severe AD and used the NPI-apathy subscale. The effect of psychostimulants on apathy was small and nonsignificant when compared with placebo (Hedges’ g = –.063; 

 = .903). All stimulant trials included individuals with mild-to-moderate AD, used multiple scales including the NPI-apathy and Frontal Systems Behavior Scale (FrSBe) apathy subscale, and included mixed drugs with noncomparable dosages. The investigators did not find enough individual studies to do a meta-analysis for antipsychotics and drug classes with antidepressant properties, but the data from the individual atypical antipsychotic studies did not support their use for apathy in AD. The investigators indicated that the analysis for cognitive enhancers and memantine were appropriately powered, whereas the psychostimulant studies were underpowered due to limited patient enrollment in each arm of the trials.

In another quantitative meta-analysis, Ruthirakuhan et al included data from 21 studies.

 The investigators found that methylphenidate may improve apathy when compared with placebo; this held true when apathy was assessed using the AES (mean difference [MD] = – 4.99) but not when using the NPI-apathy subscale (MD = –.08).

The investigators further found that methylphenidate may also improve cognition (MD = –.08) and instrumental activities of daily living (MD = 2.30), when compared with placebo. There was no difference between methylphenidate and placebo in the risk of developing an adverse event (risk ratio = 1.28). The investigators indicated that there was insufficient evidence from a small study of modafinil to determine its effect on apathy assessed with the FrSBe-apathy subscale (MD = 0.27). They reported that in all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. The investigators considered the evidence on apathy from these studies to be indirect and associated with publication bias. They reported that there was low or very low quality of evidence on ChEIs, ChEI discontinuation, antipsychotics, antipsychotic discontinuation, antidepressants (2 studies), and valproate for the treatment of apathy in dementia.

A recent systematic review by Theleritis et al evaluated data from 90 unique studies and relevant reviews but noted that in many studies, apathy was not considered the primary outcome measure.

 They concluded that after considering the amount of evidence, ChEIs may be the best available pharmacological treatment choice for the treatment of apathy, while data from 3 studies indicated that gingko biloba may also be effective. The investigators found weaker evidence for memantine’s efficacy. Stimulants like methylphenidate alone or in combination with ChEIs were found to be beneficial in treating apathy. Atypical antipsychotics, however, appear to have limited benefit for this purpose, and their long-term use is not recommended due to their adverse effect profile. Data from one study indicated that the combination of citalopram and memantine reduced apathy among individuals with AD when compared with placebo.

Apathy can be described as the quantitative reduction of self-generated voluntary and purposeful behaviors that are observable and quantifiable. Apathy commonly presents in individuals with many different illnesses, including major depressive disorder, schizophrenia, strokes, multiple sclerosis, and traumatic brain injury. However, apathy is more prevalent among individuals with neurodegenerative disorders, including dementias. Among individuals with dementia, apathy is considered to be the most frequently reported behavioral symptom. Apathy worsens morbidity and mortality in AD and is associated with greater caregiver distress.

The exact neurobiological mechanisms associated with apathy in dementia are unclear, but emerging evidence indicates a complex interaction among neuroanatomy, neuropathology, neurochemistry, and genetics. The assessment of apathy is often complicated, and it is difficult to distinguish between reduced initiative to do things due to the loss of cognitive ability vs the loss of motivation due to apathy. In addition, there may be an overlap between symptoms of apathy and depression. Among the many scales that have been developed to assess apathy, the DAIR, the AES-C in AD, and the LARS in PD have the highest quality. Emerging evidence indicates efficacy for both nonpharmacological and pharmacological treatments for improving apathy. Multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are beneficial nonpharmacological treatments; and among pharmacotherapy options, ChEIs may be the best available treatment choice, followed by gingko biloba, memantine, and stimulants like methylphenidate either alone or in combination with ChEIs.

Future directions in the evaluation of apathy in dementia should include the study of animal models as well as genetic studies that improve the knowledge of the neurobiological mechanisms underlying this condition. In addition, well-designed clinical trials of nonpharmacologic and pharmacological interventions that exclusively target apathy in dementia are needed. These trials should assess not only the symptomatic improvement of apathy but also evaluate its effect on the individual’s functioning and on caregiver burden. These studies should use advances in both neuroimaging techniques and biomarkers to provide surrogate metrics for treatment response.

is chairman of the Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, Ohio; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Ohio; and professor of medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

1. Cipriani G, Lucetti C, Danti S, Nuti A. Apathy and dementia. nosology, assessment and management. 

2. Marin RS. Apathy: a neuropsychiatric syndrome. 

3. Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex–basal ganglia circuits. 

4. Robert P, Onyike CU, Leentjens AFG, et al. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. 

5. Harrison F, Aerts L, Brodaty H. Apathy in dementia: systematic review of recent evidence on pharmacological treatments. 

6. Theleritis C, Politis A, Siarkos K, Lyketsos CG. A review of neuroimaging findings of apathy in Alzheimer’s disease. 

7. Lanctôt KL, Agüera-Ortiz L, Brodaty H, et al. Apathy associated with neurocognitive disorders: recent progress and future directions. 

8. Sherman C, Liu CS, Herrmann N, Lanctôt KL. Prevalence, neurobiology, and treatments for apathy in prodromal dementia. 

9. Berman K, Brodaty H, Withall A, Seeher K. Pharmacologic treatment of apathy in dementia. 

10. van Dyck CH, Arnsten AFT, Padala PR, et al. Neurobiologic rationale for treatment of apathy in Alzheimer’s disease with methylphenidate. 

11. Mele B, Van S, Holroyd-Leduc J, et al. Diagnosis, treatment and management of apathy in Parkinson’s disease: a scoping review. 

12. Akyol MA, Küçükgüçlü Ö, Yener G. Investigation of factors affecting apathy in three major types of dementia. 

13. Sepehry AA, Sarai M, Hsiung G-YR. Pharmacological therapy for apathy in Alzheimer’s disease: a systematic review and meta-analysis. 

14. Mori T, Shimada H, Shinotoh H, et al. Apathy correlates with prefrontal amyloid β deposition in Alzheimer’s disease. 

15. Marshall GA, Donovan NJ, Lorius N, et al. Apathy is associated with increased amyloid burden in mild cognitive impairment. 

16. Skogseth R, Mulugeta E, Jones E, et al. Neuropsychiatric correlates of cerebrospinal fluid biomarkers in Alzheimer’s disease. 

17. Donovan NJ, Wadsworth LP, Lorius N, et al; Alzheimer Disease Neuroimaging Initiative. Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum. 

18. Hahn C, Lim H-K, Won WY, et al. Apathy and white matter integrity in Alzheimer’s disease: a whole brain analysis with tract-based spatial statistics. 

19. Starkstein SE, Brockman S. The neuroimaging basis of apathy: empirical findings and conceptual challenges. 

20. Massimo L, Powers C, Moore P, et al. Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration. 

21. Eslinger PJ, Moore P, Antani S, et al. Apathy in frontotemporal dementia: behavioral and neuroimaging correlates. 

22. Raimo S, Santangelo G, D’Iorio A, et al. Neural correlates of apathy in patients with neurodegenerative disorders: an activation likelihood estimation (ALE) meta-analysis. 

23. Agüera-Ortiz L, Gil-Ruiz N, Cruz-Orduña I, et al. A novel rating scale for the measurement of apathy in institutionalized persons with dementia: the APADEM-NH. 

24. Radakovic R, Harley C, Abrahams S, Starr JM. A systematic review of the validity and reliability of apathy scales in neurodegenerative conditions. 

25. Brodaty H, Burns K. Nonpharmacological management of apathy in dementia: a systematic review. 

26. Cai Y, Li L, Xu C, Wang Z. The effectiveness of non-pharmacological interventions on apathy in patients with dementia: a systematic review of systematic reviews. 

27. Ruthirakuhan MT, Herrmann N, Abraham EH, et al. Pharmacological interventions for apathy in Alzheimer’s disease. 

28. Theleritis CG, Siarkos KT, Politis AM. Unmet needs in pharmacological treatment of apathy in Alzheimer’s disease: a systematic review. 

29. Zhou T, Wang J, Xin C, et al. Effect of memantine combined with citalopram on cognition of BPSD and moderate Alzheimer’s disease: a clinical trial. 

Apathy occurs throughout the spectrum of neurocognitive disorders, but it is easy to mistake for other conditions, like depression. How can clinicians identify apathy, and treat it?

Addressing Apathy in Dementia

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.

, FRCPC, PhD, DPhil, is Professor and Chair of the Department of Psychiatry at the University of Cape Town (UCT), Cape Town, South Africa. Dr Stein did his undergraduate and medical training at UCT. 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 Mandela was democratically elected President, Dr Stein returned to South Africa where he has remained since. His training also includes a PhD in clinical neuroscience, and a DPhil in philosophy, both from Stellenbosch University. 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. His own research has been continuously funded since his residency, and has had significant impact, as evidenced by a Google scholar h-index>140, by the broad range of work led by his mentees, and by research awards including the Ethics in Psychopharmacology award by the International College of Neuropsychopharmacology. He has received the Lifetime Achievement Award from the World Federation of Societies of Biological Psychiatry.

Dr Stein has been interested in both psychiatry research and in philosophical writing since his residency. As a resident, he won the Karl Jaspers Award from the Association for the Advancement of Psychiatry and Philosophy in 1991 (I had the privilege of winning the same award in 2018). 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.

 In 2008, he brought together his interests in psychopharmacology and philosophy in 

 (Cambridge University Press, 2008) 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

 (Academic Press, 2021). 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.

: You are the first African author I have interviewed for this series. Does being South African influence your work on philosophy and psychiatry?

: 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 

 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. From early on in my studies I was aware of both the positive contributions of psychiatry, as well as of important critiques of the field, and wondering what to make of this.

: 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.

: 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 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 of 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 over-diagnosis and over-treatment is also an issue.

: 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? There is increasing awareness of the prevalence and severity of antidepressant withdrawal, and other adverse effects. There is the implosion of the popular idea that antidepressants exert their effect by correcting some biochemical abnormality in individuals with depression. And there is the escalating search for more potent psychopharmacological interventions for treatment resistance. As someone who approaches psychopharmacology through a philosophical lens, how do you view these developments? Are they reflective of a deeper malaise in the field of psychopharmacology? Have we been asking the right sorts of questions about efficacy, safety, and mechanism of action? Has there been something lacking in our mainstream conceptual understanding of psychopharmacology that is being reflected in these on-going discussions?

: 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 (the pioneering work of Herman van Praag, MD, PhD comes to mind), and that while psychopharmacological dissection may be a useful tool (one of my mentors was Donald Klein, MD!) 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 (Randolph Nesse, MD, is another of my mentors!). 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? (I hope Josh Gordon, MD, PhD, and Miranda Wolpert, PhD, are readers of your column!)

: I hope they are too! You have often differentiated between the 

 positions. Tell us a bit more about these, particularly as you envisage them with regards to psychiatry.

: I have used these terms in part to find a middle path that I mentioned earlier, avoiding both overly hagiographic and overly critical views of psychiatry and psychopharmacology. I have also used them to help find a way of integrating key philosophical views on science, language, and medicine. Thus, I use the term 

 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 

 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 

 approach which avoids the scientism of the classical view and the skepticism of the critical view, and which sees science (including psychiatric science) as both a social activity, and as providing powerful accounts of the structures, processes, and mechanisms underlying phenomena, including disorders.

: Among the philosophers who have had a formative influence on your intellectual development, you mention the British philosopher Roy Bhaskar, PhD, and his critical realism. What are some of the fundamental ideas of critical realism and what do you think they have to offer to our philosophical understanding of science and psychiatry?

: Bhaskar taught me that science is both a social activity and provides powerful accounts of real phenomena, and I continue to find his naturalistic account particularly persuasive. In arguing that this account can be extended to the social sciences, I see critical realism as integrating philosophical positions that focus on 

), mechanisms, and facts in the social sciences, together with positions that focus on the importance of 

), narratives, and values in these fields. In my mind, this kind of integrative approach is redolent of work of the psychiatrist-philosopher Karl Jaspers, who I also see as emphasizing the importance of both explanation and understanding.

: You have also been heavily influenced by pragmatic philosophers such as John Dewey, PhD, and by the work of George Lakoff, PhD, and Mark L. Johnson, PhD. Can you say more about why you see the work of these authors as important, and what you think they have to offer to our philosophical understanding of science and psychiatry?

: Bhaskar is interested in the success of science, and he provides a 

 account of this success. Lakoff and Johnson are particularly interested in the findings of cognitive science, which views mind as embodied (in the brain) and embedded (in society). For me, their 

 helps account for many additional phenomena, including for example our metaphors of disease. Dewey’s 

 is older than the work of these modern authors, but in my mind, it prefigures it. He emphasized, for example, how knowledge is not so much based on a representation of the world, but rather is more based on engagement with the world. The classical position is a naturalist one, but by seeing physics and chemistry as the exemplars of science par excellence, it runs the risk of scientism and reductionism. I see pragmatic, critical, and embodied realism as allowing a 

 that emphasizes the complexity of the world, the usefulness of multiple explanations of such multilayered concepts as disease, and the intertwining of facts and values in medicine and psychiatry.

: Jaspers’ methodological pluralism sees 

 as distinct methods with distinct advantages and limitations such that are both essential in the realm of psychology and psychopathology. However, in such a methodological pluralism, 

 remain incommensurable, coexisting, but without a meaningful connection or bridge. When you talk about the bridging the 

 divide, do you mean the same thing as Jasperian pluralism, or do you mean something different, perhaps a sort of naturalistic account which can explain how 

: That is a great question, that I suppose I am still struggling with. I see 

 as commensurable, and I am hopeful that scientific explanations, although multiple, can be integrated. Ken Kendler, MD, who like you and me is a fan of explanatory pluralism, has put forward the notion of 

 and perhaps this sort of idea is able to form the basis of a bridge. We sometimes forget how deeply metaphoric our concepts are, and I wonder if some of the gap between 

 is based on how they use different metaphors for science and for psychiatry. My intuition is that a more comprehensive metaphor of science and psychiatry would allow a better bridge, and more successful integration. I find the schema construct or metaphor particularly useful in bridging psychodynamic and cognitive-behavioral theory and practice, and I would suggest that work on schemas may also be useful in accounting for how humans including clinicians bring together 

. 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?

: It has been more than a decade since I wrote 

, and I have been wanting to get back to thinking about philosophy and psychiatry. I have been fortunate that a postdoctoral fellowship in philosophy and psychiatry was established in our department, and this has encouraged me to do so. 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. First, I continue to use the framework of classical, critical, and integrative positions to help frame philosophical and psychiatric debates. Second, I continue to be committed to scientific and moral naturalism, hoping that humans can achieve progress in both arenas through rigorous thinking-imagining, and paying attention to facts and values, and to principles and particulars. Third, I think I remain keenly aware of both the value and harms of science and psychiatry, and indeed the pros and cons of life more generally. The possibility of a middle way, of a balanced approach, is 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 

 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 

 may be a particularly useful one, and I spend some time in fleshing it out, and in advocating engagement with the world (rather than the sort of navel-gazing that some seem to advocate), and encouraging a course that avoids both unbridled optimism and relentless pessimism (of the sort that is seen in some self-help and philosophical literature). It is a bit whimsical in spirit, but I hope it appeals to at least some readers.

 to talk about brain-minds. Can you tell us more about it and what you see as the advantage of employing this metaphor?

: 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 

 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.

: Something I found really fascinating and insightful was your discussion of wetware and placebo response. You write, “the placebo response can be characterized as embodied in our particular wetware (and underpinned by a range of specific psychobiological mechanisms), and as embedded in our interactions with healers (which are powerfully meaningful for us). We might therefore propose a placebo Turing test: a computer may be considered to think and feel if it demonstrates a placebo response. Put differently, a key difference between wetware and hardware-software is that wetware entails the sort of structures, processes, and mechanisms that can produce a placebo response.”

Placebo response in this context is not a bug, not some pesky feature of our psychology that merely makes it difficult for researchers to conduct successful RCTs. Rather, it becomes an essential characteristic of our embedded, embodied, and enactive selves! I never thought of it that way.

: The Turing test, which asks that we interact with a computer, and decide whether it is a person or machine, is well-known. Stevan Harnad, PhD, has rigorously put forward variations of the Turing test, which help think through distinctions between humans and computers. For example, once robots can move around a room, and say dance with us, it becomes harder to distinguish persons from machines. Thinking about these issues as a psychopharmacologist, I was struck by the idea that even if machines can move and dance, there is yet another a level of human interaction that is captured by the placebo response, and that then helps us with distinguishing humans from machines. I am not sure that non-psychopharmacologists will find this the best way of arguing that human cognitive-affective processes are embodied and embedded, and so I particularly appreciate your being enthusiastic about this idea!

: 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?”

 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, between 2015 and 2018, 

 were prescribed an antidepressant medication!

 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?

: 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 

, 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 (

) 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.

: As I was reading your discussion of metaphors, I thought of 2 things. The first is a quote by Derek Bolton, PhD, and Grant Gillett, MSc, DPhil, from their book on the biopsychosocial model, a work you cite as well. They write at 

: “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.”

 De Haan has a wonderful ability to illustrate her arguments using metaphors. She has talked about vulnerability to mental illness using the metaphor of laying down 

: “once there is this path it is so much easier to walk that road again rather than go through all the trouble and hard work of making a new path. We slip into old patterns because they have become so engrained and come so naturally. Vulnerability is like having deeply engrained paths, making relapse probable, yet we are not destined to walk them.”

 One of her most delightful metaphors is that when we think of minds, we should “think cakes, not clockworks.” At the same time, like yourself, she argues that metaphors are never innocent and require eternal vigilance.

I think these 2 instances show 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) free us from old mechanical ways of thinking. What is your view on the use of metaphors in philosophy and psychiatry?

: 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 

 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. It is also interesting to me that we use the metaphor of 

 for thinking through healthiness and goodness, and indeed Aristotle and other writers of the Axial Age appropriately emphasized the importance of the golden mean, of moderation, and of balance.

: 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. I have observed that the biological psychiatry vs psychoanalysis divide was often thought of as the central schism of the field by several of my psychiatric professors as well. Fortunately, this schism has played less of a role in my own education. One of the features of the biological psychiatry vs psychoanalysis divide was that it was very much an internal schism, a divide within the psychiatric community. The notable schisms that I think our field is confronting now are between quite different players. Schisms between so-called 

 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? This is also a point that 

 with me: “I am a deep believer in pluralism, too, but I believe that a road to true pluralism will require the courage to share power. In other words, alongside becoming less reductionist, the field also could consider becoming less hegemonic… I have suggested that the field would be stronger and serve patients better if it functioned as one part—the medical part—of a cooperative ecosystem of mental health experts.”

: I agree with you about the importance of the schisms that you mention (my sense is that these partly reflect aspects of the biological-psychoanalytic schism), and I am glad that you are in alignment with pluralistic and integrative approaches to addressing them. In 

, I emphasize 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 is too important to be left 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.

: 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?

: 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 do 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 

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 

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. 

2. Stein DJ. Psychiatric contributions from South Africa: ex Africa semper aliquid novi. 

3. Kendler KS, Campbell J. Expanding the domain of the understandable in psychiatric illness: an updating of the Jasperian framework of explanation and understanding. 

5. Brody DJ, Gu Q. Antidepressant use among adults: United States, 2015-2018. The Centers for Disease Control and Prevention. September 2020. Accessed June 28, 2021.

6. Bolton D, Gillett G. The biopsychosocial model 40 years on. In: 

The Biopsychosocial Model of Health and Disease: New Philosophical and Scientific Developments

8. Aftab A. Sense-making and the enactive turn in psychiatry: Sanneke de Haan, PhD. 

. October 22, 2020. Accessed June 28, 2021.

9. Aftab A. The many histories of biological psychiatry: Anne Harrington, DPhil. 

Travelling the middle road between skepticism and scientism in psychiatric research and treatment.  

From Classic and Critical to Integrative Psychiatry: Dan J. Stein, MD, PhD, DPhil

Since its birth in the early 19th century, psychiatry has sought to ground its diagnoses in the same mechanistic explanatory models that were emerging as hallmarks of the other branches of modern medicine.

 Drawing on the nascent fields of genetics and Darwinian evolution, psychiatry entered a debate over the origins of human behavior: nature vs nurture? As the debate raged on, studies of human traits and behavior were co-opted by promoters of nefarious political agendas, with scientists at the center of numerous atrocities throughout the 20th century.

 For all their harms, genetic determinist models, which explained human variation purely in terms of nature (ie, genetics), bore disappointingly little fruit.

Social reductionist models, which explained human variation purely in terms of environmental factors, fared no better. Neither model could account for the pronounced changes in behavior and gene expression in response to events experienced over the course of an individual’s lifetime. Nor could they explain how such changes, conferring either vulnerability or resilience in the face of trauma, could be passed between generations.

By the mid-20th century, the burgeoning field of 

 had begun to bridge the divide between genetics and developmental biology,

 and, by the start of the 21st century, scientists increasingly turned to epigenetic approaches to disentangle the molecular mechanisms by which genes give rise to specific phenotypes; determine how the expression of genes could be modulated by stochastic factors; and establish how such modulations can be passed to offspring. Across fields of medicine, researchers today strive to elucidate the mechanisms by which adverse life experiences shape the development of disease and devise novel therapeutic interventions to supplant currently inadequate treatment and prevention paradigms. Nowhere is this work more necessary than in psychiatry, where diagnoses continue to elude biological definition and where remedies are frequently inadequate to address widespread suffering.

Because the models employed by researchers and clinicians in the study and treatment of disease shape patients’ understanding of their own suffering, the dominance of reductionist models can leave both patients and clinicians feeling powerless in the fight against fate, whether inscribed by circumstance or biology. The emergence of epigenetic models has generated a surge of optimism, opening new possibilities for psychiatric intervention.

The term epigenetics was coined in 1942 (prior to the discovery of the molecular basis of heredity) by developmental biologist 

, as a neologism combining epigenesis (embryonic development) and genetics.

 Waddington described epigenetics as “the branch of biology which studies the causal interaction between genes and their products [that] brings the phenotype into being”; this definition is broader than the one in use today.

 In the time since the identification of DNA as carrier of the genetic code, the definition of epigenetics has narrowed to refer specifically to heritable alterations in gene expression that do not involve direct changes in DNA sequence.

In the mid-1970s, investigators identified the first molecular mechanisms that might explain how patterns of gene expression could vary so dramatically among an individual’s different cell types, all of which contain the same set of chromosomes.

 and John E. Pugh proposed a molecular mechanism for this differential gene expression: Covalent addition of methyl groups at specific DNA sites sterically inhibit the docking of transcriptional machinery at those sites.

 DNA methylation was thus deemed an epigenetic marker of gene inactivation.

, demonstrated that the covalent modification of histone proteins was also a critical mechanism of gene regulation. Adding chemical groups (eg, methyl, acetyl) to histones adjusts how tightly DNA wraps around them to form chromatin, which thereby changes the accessibility of that DNA to transcriptional machinery.

 Subsequent work demonstrated additional epigenetic regulatory mechanisms of chromatin remodeling (eg, nucleosome sliding). Notably, epigenetic markers and mechanisms were shown to be heritable, not only clonally (ie, between generations of mature cell populations within an individual), but also between generations of individuals, passed from parent to offspring.

Although epigenetics would eventually be applied to study psychiatric illnesses in the search for so-called missing heritability, the observation that chronic mental states and/or behaviors can be passed down through generations had occurred decades earlier. Among the first to consider epigenetics in the context of psychiatry was psychoanalyst and developmental psychologist

 In his 1950 book Childhood and Society, Erikson articulated his theory of “ego epigenesis.” Borrowing the term epigenesis from the field of developmental biology, he described a staged model of individual identity (ego) formation analogous to that of embryonic development in utero. Erikson wrote that identity arose through an individual’s resolution of a predetermined series of conflicts and asserted that an individual’s specific resolution to these conflicts was shaped by both innate biological factors and environmental inputs. His version of epigenetics focused on psychosocial processes rather than biological mechanisms, and it suggested psychoanalysis as a primary intervention.

Epigenetics was first introduced into the field of psychiatric genetics by 

The emergence of epigenetic models has generated a surge of optimism, opening new possibilities for psychiatric intervention.





Neuropsychiatry

Addressing Apathy in Dementia

From Classic and Critical to Integrative Psychiatry: Dan J. Stein, MD, PhD, DPhil

Can Epigenetics Promote Resilience Without Genetic Reductionism?

The Neural Mechanisms Behind Effective Psychotherapy

A Skeptical Look at Aducanumab

Pride: A Driving Force

A Spirited Defense of ECT: From Our Readers

Liftoff! Brain Monitoring Startup Bound for Space

Exploring the Epigenetic Paradigm Shift

In Defense of ECT