Hero

Videos

Slideshows

Articles

Podcasts

Poll

The next time one of psychiatry’s detractors tells you that psychiatrists do not treat real diseases because we have not identified the precise pathophysiology of schizophrenia, bipolar disorder, or other psychiatric illnesses, try this: Ask the skeptic to explain the precise pathophysiology of migraine or cluster headaches. Follow up by asking what laboratory test or neuroimaging study neurologists use to diagnose these devastating conditions. At that point, the critic should be either blushing or blanching.

For the coup de grace, ask them why the late Thomas Szasz, MD—who insisted that real diseases always entail the identification of specific morphological or physiological abnormalities—did not write a book titled 

 as a sequel to his famous (or infamous) 1961 work 

. (Disclosure: Szasz was one of my teachers during residency and an intellectual 

—our mutually agreed-upon term—for decades afterward).

 readers will know that the precise pathophysiology of migraine and cluster headaches is not known, despite notable advances in our understanding; and that there is no laboratory test or neuroimaging study that reliably or usefully identifies 

 Both diagnoses are made largely on the basis of the patient’s subjective report and the exclusion of other neurological causes. (Cluster headaches are often, but not always, associated with ipsilateral cranial autonomic signs, such as eyelid edema or facial flushing).

 As for Szasz and migraines, to the best of my knowledge, he never disputed the reality of this affliction, even though its precise pathophysiology remains incompletely understood.

Let us take note of the excellent piece by journalist and headache sufferer Tom Zeller Jr, who 

 his own struggles with cluster headaches.

 Technically, these are a subset of a group of conditions known as the 

 (TACs). Although this hifalutin name may suggest that scientists have pinned down the etiology and pathophysiology of TACs, this is simply not the case.

To be sure, plausible theories abound, including, most recently, linking TACs to “dysfunction in the trigeminal and cranial autonomic systems and their connections, modulated by the hypothalamus.”

 Yet, as headache specialist Stephanie J. Nahas, MD, has acknowledged, “The pathophysiology of TACs is complex and incompletely understood.”

 And, as a rule, morphological and anatomical abnormalities in the brain are lacking in TACs; for example, investigation rarely yields abnormalities on magnetic resonance imaging or computed tomography imaging. (However, vascular loop compression and pituitary abnormalities are sometimes found in patients with short-lasting, unilateral neuralgiform headache attacks or SUNHA.

) Furthermore, to my knowledge, TACs are never noted on autopsy reports, contrary to Szasz’s erroneous claim that “Every ‘ordinary’ illness that persons have, cadavers also have.”

 may reasonably be applied to the TACs, which Nahas has called, “a distinct set of headache diseases.”

 This is so, even though, as Zeller rightly noted, “any neurologist working today will readily admit that we remain the in the Stone Age with regard to many aspects of these most common disorders.”

 may reasonably be applied to schizophrenia, bipolar disorder (BD), and other incapacitating psychiatric afflictions, even though the etiology and pathophysiology of these heterogeneous conditions are not yet well understood. There are, however, 

 showing a variety of morphological and physiological abnormalities in both schizophrenia and bipolar disorder.

By and large, physicians are a practical lot, anxious about evaluating everybody sitting in their overcrowded waiting rooms. Most physicians do not scratch their heads, pondering the question, “Will my next patient have a disease, a disorder, a malady, an illness, a morbus, an affliction, or a syndrome?” The subtle differences among these terms are of far less clinical importance than the presence of substantial and/or enduring suffering and incapacity in the patient—arguably, the hallmarks of disease (dis-ease) as commonly understood throughout the 

 (I am well aware that not all states of suffering and incapacity are ordinarily viewed as disease, including instances of torture, physical or psychological abuse, and the like).

Cluster headaches and related diseases certainly fit the criteria of substantial and/or enduring suffering and incapacity; indeed, cluster headaches are ominously known as 

 It hardly needs mentioning that serious psychiatric disease states like schizophrenia, BD, and various psychoses also produce substantial and/or enduring suffering and incapacity—and all too often lead to 

Citing the work of sociologist Joanna Kempner, PhD, Zeller noted that migraine headaches, in particular, “have been given inadequate consideration by the medical and scientific establishments,”

 which Kempner attributed partly to the disproportionate number of women afflicted by migraines. Ironically, Zeller noted, their physical pain “was often ascribed a psychological or emotional origin.”

Like the TACs described by Zeller, psychiatric disease is too often dismissed or disparaged, and psychiatric patients are often 

 Sadly, this is due in part to the influence of Szasz and others who have relegated psychiatric diseases to the status of myths, problems in living, or—as Szasz once argued—forms of lying.

Despite Szasz’s widespread influence, his ideas have come in for heavy criticism. For instance, psychiatrist Tony Benning, MBChB, MSC, MRCPsych, FRCPC, PhD, 

the views of another psychiatrist, R.E. Kendell, MD

As Kendell pointed out in his rebuttal of Szasz’s claim that mental illnesses fail to conform to the definition of disease, Szasz’s notion of disease, influenced by [Rudolph] Virchow, was overly narrow, for it placed excessive importance on the criterion of ‘cellular pathology.’ Kendell also claimed that Szasz’s argument understated the extent to which ‘suffering and incapacity are fundamental attributes of disease’. He brought attention to the fact that in medicine generally there is no universally agreed upon definition of disease, and if Szasz’s criterion were to be widely adopted, several diseases widely recognized in medicine, such as migraine and torticollis (neither of which [is] associated with lesions or cellular pathology) would fail to qualify.

 is defined in many different ways, depending on the needs, training, and expertise of the observer. For the pathologist, the term generally means something quite different than what it represents for the primary care physician, the epidemiologist, or the forensic psychiatrist. Yet one thing is clear: Physicians in general view disease in pragmatic and humanistic terms, applying the term to a very broad spectrum of human suffering and incapacity. One remarkably sweeping definition was provided in no less a source than the 8th edition of Harrison’s 

 (italics added for emphasis): “The clinical method has as its object the collection of accurate data concerning all the diseases to which human beings are subject; namely, 

 conditions that limit life in its powers, enjoyment, and duration.”

Just as we recognize trigeminal autonomic cephalalgias as instantiations of disease, so too must we recognize the most serious psychiatric conditions as disease states. And just as patients with TACs must be taken seriously, so too must those afflicted by psychiatric disease.

is professor emeritus of psychiatry and lecturer on bioethics and humanities, SUNY Upstate Medical University; clinical professor of psychiatry, Tufts University School of Medicine; and Editor in Chief emeritus of

1. Pies R. On myths and countermyths: more on Szaszian fallacies. 

2. Pies R. Thomas Szasz and the language of mental illness. In: Haldipur CV, Knoll JL, and Luft E vD, eds. 

. Oxford University Press; 2019: 155-168.

3. Wei DY, Yuan Ong JJ, Goadsby PJ. Cluster headache: epidemiology, pathophysiology, clinical features, and diagnosis. 

4. Nahas SJ. Cluster headache and other trigeminal autonomic cephalalgias. 

5. Zeller T. There has never been a better time to have a headache. 

. July 23, 2021. Accessed July 28, 2021. 

7. Clay HB, Sillivan S, Konradi C. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. 

8.Nakahara S, Matsumoto M, van Erp TGM. Hippocampal subregion abnormalities in schizophrenia: A systematic review of structural and physiological imaging studies. 

9. Kendell RE. The concept of disease and its implications for psychiatry. 

10. Kendell RE. The myth of mental illness. In: Schaler JA, ed. 

Szasz Under Fire: The Psychiatric Abolitionist Faces his Critics

11. Baldessarini RJ. Epidemiology of suicide: recent developments. 

12. Thornicroft G, Rose D, Kassam A. Discrimination in health care against people with mental illness. 

The Meaning of Mind: Language, Morality and Neuroscience

14. Benning TB. No such thing as mental illness? Critical reflections on the major ideas and legacy of Thomas Szasz. 

Harrison’s Principles of Internal Medicine

, 8th ed. G.W. Thorn et al, eds. McGraw-Hill; 1977.

How is “disease” defined? A popular criticism of psychiatry gets debunked. 

Why Thomas Szasz Did Not Write The Myth of Migraine

Alzheimer disease (AD) remains one of the most dreaded diagnoses a patient can get. The US Food and Drug Administration (FDA) raised hopes when it approved aducanumab, which promised to be the first disease-modifying drug for AD. But the approval immediately proved controversial. Three FDA board members 

 its patient label, and in mid-July, major hospitals announced that they would not administer the 

, Helen Lavretsky, MD, MS clarifies the issues in the aducanumab debate and offers guidance for clinicians whose patients may ask about it. Going beyond pharmacology, she points out that other treatment options, including mind-body interventions and diet changes, have been shown to slow AD’s progression.

Advice for talking to patients and caregivers about aducanumab and other novel pharmacological options

Mind-body and lifestyle interventions for AD

AD prevention programs, including nutrition, exercise, and stress reduction

Taking care of caregivers, including psychiatrists and other medical professionals

is a professor in-residence in the Department of Psychiatry at the University of California, Los Angeles. Her work on geriatric depression and integrative mental health using mind-body interventions has received national attention, and she has won numerous grants supporting that work. A distinguished fellow of the American Psychiatric Association and a fellow of the American College of Neuropsychopharmacology, she is also on the board of 

Although the new drug aducanumab has grabbed all the headlines, the future of Alzheimer treatment may be just as much about public health campaigns as it is about psychopharmacology. In this episode of Psych Pearls, we find out why.   

What Will the Future of Alzheimer Disease Treatment Look Like? 

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 

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

Neuropsychiatry

Why Thomas Szasz Did Not Write The Myth of Migraine

What Will the Future of Alzheimer Disease Treatment Look Like?

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