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MDD is a highly prevalent mental health condition. There is evidence that, in China, co-occurring somatic symptoms, including headache and stomachache might contribute to misdiagnosis of depression and delayed 

 Previous studies of somatic symptoms in MDD have yielded conflicting or inconclusive results, although there is some evidence for increased gastrointestinal 

 Given growing evidence for the microbiota-gut-brain axis in depressive disorders, GI symptoms might be a marker for 

Huang and colleagues estimated the frequency and clinical correlates of GI symptoms during depressive episodes in a large, nationwide sample of patients with 

 They hypothesized that the presence of GI symptoms would be associated with comorbidity in MDD, including insomnia, hopelessness, anxiety, and suicidal ideation. Study participants were from the National Survey on Symptomatology of Depression (NSSD) in China, which included inpatient and outpatient participants 18 years or older with a current DSM-IV episode of MDD.

Exclusion criteria were a lifetime diagnosis of bipolar or psychotic disorder, imminent risk of suicide or homicide, received electroconvulsive therapy within the past month, current pregnancy or breastfeeding, and substance use disorder over the past year. Patients were interviewed by trained psychiatrists on a broad range of symptoms, including depression and somatic symptoms, over the previous 2 weeks. Sociodemographic and clinical characteristics between patients with different severity of GI symptoms were performed with 1-way analysis of variance. Multiple linear regression analysis was used to analyze associations between GI symptoms and psychopathology, adjusting for potential confounding factors.

A total of 3256 patients (mean age 41, 40% male) were included in the analyses. Of those, 1750 patients (71%) had GI symptoms, with a frequency of several days/week for 38%, more than half of days for 23%, and almost daily for 10%. Patients with more GI symptoms had a significantly increased prevalence of anxiety; insomnia; poor concentration; limb and body pain; hopelessness; anger and irritability; and feelings of failure. In linear regression, suicidal ideation, anxiety, insomnia, anger, feelings of failure, and body pain were independently and significantly associated with GI symptoms in patients with MDD (

The authors concluded that more than 70% of patients with MDD reported GI symptoms during depressive episodes. Strengths of the study include the large, nationwide sample. Limitations include the cross-sectional nature of the study design, unmeasured and residual confounding factors, as well as the absence of data on specific GI symptoms. These findings are germane to investigations of the microbiota-gut-brain axis in depressive disorders.

“Mr S” is a 26-year-old Caucasian male with a history of recurrent major depressive disorder (MDD) and anxiety disorder. The onset of his depressive illness began when he was 19 years old. For the past 2 to 3 months during an exacerbation of his depression, he reports significant nausea and vomiting on a daily basis, particularly in the morning, which was not attributable to increased anxiety. Mr S reports that his gastrointestinal (GI) symptoms did not respond to treatment with either H-2 blockers or a proton-pump inhibitor. Subsequently, his antidepressant was changed to a different selective serotonin reuptake inhibitor, and a low-dose long-acting benzodiazepine was also added for anxiety. Over the next month, he reported significant improvement in not only mood and anxiety, but also nausea and vomiting, such that he was able to return to full-time employment.

Gastrointestinal symptoms are common in the clinical presentation of MDD. GI symptoms may be associated with the onset and clinical severity of depression, which could be a potential ancillary indicator in the management of MDD.

 is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Smith K. Mental health: a world of depression. 

2. Harshaw C. Interoceptive dysfunction: toward an integrated framework for understanding somatic and affective disturbance in depression. 

3. Bruce-Keller AJ, Salbaum JM, Berthoud HR. Harnessing gut microbes for mental health: getting from here to there. 

4. Guo F, Cai J, Jia Y, et al. Symptom continuum reported by affective disorder patients through a structure-validated questionnaire. 

A study estimates the frequency and clinical correlates of GI symptoms during depressive episodes in a large, nationwide sample of patients with MDD in China.

Gastrointestinal Symptoms During Depressive Episodes

The Mighty Blueberry

Studies suggest blueberries may have the power to treat depression...

has identified a potential new mechanism for treating depression. 

The study, conducted by researchers at the Icahn School of Medicine at Mount Sinai, used the drug ezogabine to open the KCNQ2/3 potassium channels in participants’ brains. The results showed significant improvements in 

 Because anhedonia is associated with poor response to antidepressant medication, worse overall outcomes, and increased suicide risk, this finding is especially important. 

“Our study is the first randomized, placebo-controlled trial to show that a drug affecting this type of ion channel in the brain can improve depression and anhedonia in patients,” said the paper’s lead author, James Murrough, MD, PhD, associate professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai. “Targeting this channel represents a completely different mechanism of action than any currently available antidepressant treatment.”

The study included 45 participants with high levels of anhedonia and divided them into 

 The treatment lasted 5 weeks, with clinical measures of depression and anhedonia taken at weekly visits. Although the study did not meet its primary endpoint at the 5-week mark, it found that participants on ezogabine had increased reward anticipation and large improvements on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), compared with the placebo.

The United States Food and Drug Administration approved ezogabine in 2011 as an anticonvulsant for epilepsy, but this is the first study to test it as a depression treatment. The drug acts on the KCQ2/3 channel, which affects brain cell function by regulating the movement of electrical charges across cell membranes.

A previous study led by co-author Ming-Hu Han, PhD, found that changes in KCNQ2/3 potassium partially determined whether mice showed 

signs of depression and anhedonia following stress

 Mice with increased KCNQ2/3 channels in their brains appeared resistant to depression. When the mice were given drugs to increase KCNQ2/3 channel activity, previously depressed mice no longer showed depressive or anhedonic behaviors.

“The fundamental insight by Dr Han’s group that a drug that essentially mimicked a mechanism of stress resilience in the brain could represent a whole new approach to the treatment of depression was very exciting to us,” said Murrough.

 The previous study by Han’s group paved the way for the current study.

“I think it’s fair to say that most of us on the study team were quite surprised at the large size of the beneficial effect of ezogabine on clinical symptoms across multiple measures related to depression,” Han said of the current study.

 “We are greatly encouraged by these findings and the hope they offer for the prospect of developing novel, effective treatments for depression and related disorders.”

1. Mount Sinai Health System. Researchers identify brain ion channel as new approach to treating depression. 

. March 1, 2021. Accessed April 7, 2021. 

https://www.newswise.com/articles/researchers-identify-brain-ion-channel-as-new-approach-to-treating-depression?sc=dwhr&xy=5013482

2. Costi S, Morris LS, Kirkwood KA, et al. Impact of the KCNQ2/3 channel opener ezogabine on reward circuit activity and clinical symptoms in depression: results from a randomized controlled trial. 

3. Friedman AK, Juarez B, Ku SM, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. 

Opening certain potassium channels in the brain reduces depressive symptoms and anhedonia. 

Is There a New Mechanism for Treating Depression?

In 2018 more than 20 million Americans met criteria for substance use disorder, particularly alcohol abuse (73%). During the COVID-19 pandemic, alcohol sales have risen sharply, up 54% from the previous year.

In this Mental Health Minute, Judith J. Prochaska, PhD, MPH points out that the pandemic has made it difficult for patients to seek traditional forms of counseling. She discusses a digital therapeutic that can be an adjunct for traditional therapies, and 

 on the treatment’s efficacy for substance abuse and mood disorders.

 is a professor in the department of medicine at Stanford University with the Stanford Prevention Research Center and a member of the Stanford Cancer Institute.

Would you recommend a digital therapeutic to your patients? 

Share comments with your colleagues by emailing 

. Comments may be shared online pending review and editing for style.

A recent study tested a new digital therapeutic for effectiveness on both substance abuse and depression. 

Could Artificial Intelligence Improve Cognitive Behavioral Therapy?

The way to treat anxiety in bipolar disorder is to treat the bipolar disorder. Anxiety is a synonym for distress, and nearly all mental disorders cause distress, except perhaps the classic, euphoric manias that lift the patient into a carefree state of bliss.

Some mood episodes are more anxiety-provoking than others, and at the top of the list are mixed states. Although anxiety does not appear in the criteria for mixed states, it is often created when 

 The International Society for Bipolar Disorders has even calculated the exact proportions for this troubling recipe. It takes only 1 manic symptom during a depression, or 2 depressive symptoms during a mania, to spark anxiety.

Mixed states tend to respond better to anticonvulsants and atypical antipsychotics than to lithium, which may be why anxiety predicts resistance to lithium in 

 There are, however, 2 exceptions to this rule: suicide and panic disorder. Both mixed states and anxiety raise the risk of suicide in bipolar disorder, and lithium 

 This preventative effect is independent of lithium’s mood benefits, so it is worth considering lithium in patients who are suicidal, even when it has a lower chance of reducing the core symptoms.

Although the classic lithium-responsive patient tends to have pure manias and hypomanias and no anxiety disorder comorbidities, a recent study identified panic disorder as a 

 Although anxiety is low in pure mania and hypomania, these patients are on high alert for threat, which is the essence of panic disorder. One study found that they had more phobias of panic sensations than patients in 

The next step in treating mixed states is to reduce antidepressants and anything else that contributes to manic symptoms (eg, drugs of abuse, steroids, and irregular circadian rhythms). Most patients who are in a mixed state have been on an antidepressant for a long time, and it can be difficult to tell if the drug is exacerbating the mixed presentation. Given these uncertainties, it is best to taper slowly, 

 Rapid discontinuation can trigger mania and other mood symptoms. The work is much like tapering a benzodiazepine. If the symptoms worsen, raise back the dose and slow down the taper.

In bipolar disorder, anxiety is a non-specific symptom with 

, including mood episodes, stress, and comorbid anxiety disorders. With so many different causes, can any mood stabilizer truly be said to be anxiolytic? Probably not, but we do have a few trials that may point the way when selecting a mood stabilizer for a patient with significant anxiety.

Among the anticonvulsants, valproate and lamotrigine improved anxiety in small controlled trials of 

 Valproate’s evidence here is more robust, and this medication also improved anxiety in patients who do not have bipolar disorder, perhaps because of its benzodiazepine-like 

 Lamotrigine may also treat obsessive compulsive disorder through glutamatergic effects, based on a small placebo controlled and several uncontrolled studies.

The atypical antipsychotics can also improve anxiety. Quetiapine and olanzapine reduced anxiety in large, randomized, placebo-controlled trials of patients with bipolar depression and non-specific anxiety (both were secondary analyses). The effect sizes were large enough to make them noticeable to the casual observer (

0.35 for olanzapine and 0.56 for quetiapine

 Quetiapine had similar anxiolytic effects in the 300 mg and 600 mg doses, and olanzapine had similar anxiolytic effects as monotherapy or when paired with fluoxetine.

These anxiolytic properties do not seem to extend to other atypical antipsychotics. Ziprasidone and risperidone both failed in placebo-controlled trials of bipolar disorder with anxiety, and risperidone actually worsened anxiety in a study of bipolar with comorbid panic disorder.

The unanswered question here is whether these medications were targeting anxiety directly or treating mild mixed states. Most of the patients had 1 to 2 manic symptoms along with their depression, judging from their average Young Mania Rating Scale of 5, and anxiety was higher as the 

 On the other hand, quetiapine has a large effect size in generalized anxiety disorder (GAD), suggesting 

 Quetiapine came close to FDA approval in GAD, but was held back because the FDA did not think this disorder was severe enough to warrant all the risks of an antipsychotic. That lesson applies to bipolar disorder as well. Quetiapine may be very effective for anxiety, but it should not be used in mild cases.

Anxiety may not offer a direct path to pharmacotherapy in bipolar disorder, but it does tell us something about the care of the patient. These patients are at greater risk for treatment dropout, adverse effects of medications, substance abuse, and suicide. Supportive psychotherapy, fast-acting treatment, and an extra phone call to make sure they are tolerating any new medication go a long way in these cases.

is the Mood Disorders Section Editor for 

 and the director of the Mood Treatment Center. He has written several books on mood disorders, most recently 

The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis.

2. Swann AC, Secunda SK, Katz MM, et al. 

Lithium treatment of mania: clinical characteristics, specificity of symptom change, and outcome.

Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment.

4. Nunes A, Ardau R, Berghöfer A, et al. 

Prediction of lithium response using clinical data.

5. Simon NM, Otto MW, Fischmann D, et al. 

Panic disorder and bipolar disorder: anxiety sensitivity as a potential mediator of panic during manic states.

Treating anxiety by discontinuing antidepressants: a case series.

Treating nonspecific anxiety and anxiety disorders in patients with bipolar disorder: A review.

Divalproex in the treatment of bipolar depression: a placebo-controlled study.

9. Sheehan DV, Harnett-Sheehan K, Hidalgo RB, et al. 

Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient.

10. Bach DR, Korn CW, Vunder J, Bantel A. 

Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.

Valproate (depakine-chrono) in the acute treatment of outpatients with generalized anxiety disorder without psychiatric comorbidity: randomized, double-blind placebo-controlled study.

12. Bruno A, Micò U, Pandolfo G, et al. 

Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study

. J Psychopharmacol. 2012;26(11):1456-1462.

13. Lydiard RB, Culpepper L, Schiöler H, et al. 

Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies.

14. Tohen M, Calabrese J, Vieta E, et al. 

Effect of comorbid anxiety on treatment response in bipolar depression.

15. Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N. 

Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis.

Some mood episodes are more anxiety-provoking than others, and at the top of the list are mixed states.

How to Treat Anxiety in Bipolar Disorder



In this installment of PsychPearls and the Columbia University Breakthrough Session, hosts Angela Coombs, MD, and Jennifer Sotsky, MD, discuss anxiety with 

Anxiety as cultural phenomenon vs individual illness

Help-seeking as a sign of strength and self-knowledge


Dr Albano is professor of medical psychology (in Psychiatry) at Columbia University and director of the 

Columbia University Clinic for Anxiety and Related Disorders

 (CUCARD). She is a clinical psychologist and board-certified in clinical child and adolescent psychology. In addition to serving as director of CUCARD, she also conducts research and trains residents, fellows, and psychology postdoctoral fellows and interns. Her research is focused on the development and testing of psychosocial treatments for anxiety and mood disorders, and in understanding the impact of these disorders on the developing youth. Dr Albano devotes her career to the study and treatment of anxiety and mood disorders in children, adolescents, and young adults. She is an expert diagnostician and cognitive-behavioral therapist. Dr. Albano co-developed a cognitive behavioral treatment program for adolescents with social phobia. She has published more than 90 articles and chapters and is the coauthor of several cognitive behavioral treatment manuals, including 

Anxiety Disorders Interview Schedule (ADIS-IV) Child and Parent Interview Schedules.

is a board-certified psychiatrist and assistant professor in Clinical Psychiatry at Columbia University Medical Center and the New York State Psychiatric Institute. She serves as the medical director and team psychiatrist at ONTrackNY Washington Heights Community Service clinic. She completed her public psychiatry fellowship and adult psychiatry residency at Columbia University where she was a chief resident and co-organized the curriculum on racial/ethnic mental health disparities. In addition to her clinical work in the public sector, she also works in Columbia's psychiatric emergency room and has a private practice in Upper Manhattan. 

 is a fellow in consultation-liaison psychiatry at Columbia University Irving Medical Center with a part time private practice. She was formerly a chief resident at Columbia’s psychiatry residency program. Before medical training, she received an MS in Narrative Medicine, an interdisciplinary field that studies illness through a humanities lens. She is co-author of 

Conquering Lyme Disease: Science Bridges the Great Divide

 and has interests in medical education, psychotherapy, and medical humanities.



Thanks to Columbia University Department of Psychiatry for allowing us to present the Breakthrough Session podcast with experts in the field of psychiatry.



A discussion with professor of medical psychology and director of the Columbia University Clinic for Anxiety and Related Disorders.

Anne Marie Albano, PhD: A Conversation on the Spectrum of Anxiety

Susan J. Noonan, MD, MPH, talks about the differences between loss, bereavement, and a prolonged grief response. 

is a physician consultant and Certified Peer Specialist in the Department of Psychiatry at McLean Hospital and the Massachusetts General Hospital. She is the author of four books and a blog on managing depression, most recently 

Helping Others With Depression: Words to Say, Things to Do (December 2020)

. Dr Noonan offers peer counseling to fellow patients, including physicians and other professionals, and can be confidentially reached through her website at 

Loss: the most common experience of all people, across all cultures...

Loss, Bereavement, and Prolonged Grief

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.

, is professor of critical and social psychiatry at University College London and works as a consultant in community psychiatry in London. She has researched and written about theories of drug action, drug efficacy, the subjective experience of taking psychiatric drugs; decision-making; the history of drug treatment; and the history, politics, and philosophy of psychiatry more generally. She is currently leading a United Kingdom (UK) government-funded study of antipsychotic reduction and discontinuation, called the RADAR study (Research into Antipsychotic Discontinuation and Reduction). She is one of the founders and the co-chairperson of the Critical Psychiatry Network. She has authored numerous papers and several books including 

The Bitterest Pills: The Troubling Story of Antipsychotic Drugs

A Straight-Talking Introduction to Psychiatric Drugs

Moncrieff’s views on psychopharmacological mechanisms of action, although controversial, have been influential within the critical psychiatry community. We have discussed some implications of the drug-centered model in an earlier interview with Sandra Steingard, MD. Moncrieff’s ongoing randomized controlled trial investigating the long-term impact of gradual antipsychotic dose reduction and discontinuation in schizophrenia on outcomes such as psychotic relapse and social functioning (versus maintenance treatment) could alter how the field approaches management of chronic psychotic disorders.

This interview, however, largely focuses on conceptual concerns, exploring her views on the nature of psychiatric suffering. My first conscious exposure to Moncrieff was at the 2017 annual meeting of the Association for the Advancement of Philosophy and Psychiatry, where Moncrieff gave the keynote lecture titled “Many Ways of Being Human,” in which she challenged the medical view of mental disorders and argued that medical and psychiatric conditions have a different relationship to agency, responsibility, and selfhood.

Moncrieff's ideas carry on the legacy of Thomas Szasz, MD, and given my own disagreements with how Szasz conceptualizes the notion of disease, this interview also represents an attempt on my part to understand how deep our philosophical disagreements go.

 referred to by Moncrieff was in press at the time this interview was conducted but has since been published online. I would also like to add that there is a large body of literature critically engaging with the ideas of Thomas Szasz, such as the 2019 book 

 (International Perspectives in Philosophy and Psychiatry; 2019), which I would encourage readers to explore.

 Can you briefly tell us about the Critical Psychiatry Network? Its mission and how it has impacted British psychiatry over the years?

When I was a trainee in psychiatry, I felt the way psychiatry was portrayed in the mainstream—in textbooks and medical journals—did not match my ideas about the nature of mental health problems or my experience of individuals who were deemed to have such problems. I was aware that other trainees felt like this too, so I started a club while I was at the Institute of Psychiatry in 1997. Initially we had discussions about interesting books and articles, and then we organized meetings, in conjunction with the Maudsley Hospital service-users group, with outside speakers, including the likes of Szasz, Nikolas Rose, PhD, and Andrew Scull, PhD. Around this time, we were contacted by some psychiatrists from another part of the UK, who were concerned about the upcoming review of the Mental Health Act. We got together to submit evidence to this review, and that was the start of the 

. Since that time, it has functioned as a forum for mutual support, and as a mechanism for contributing a critical view of psychiatric practice to various parliamentary and governmental reviews, the media, and other organizations. Have we had any impact? I think the fact that members of the psychiatric profession are challenging mainstream views, particularly the dominance of the biological paradigm in psychiatry, is important, and helps to support broader movements that are trying to imagine and establish alternative approaches.

 Models of drug action have been an important focus of your work—in particular, the distinction between the disease-centered model and drug-centered model. In the disease-centered model, drugs help correct an abnormal brain state and the therapeutic effects of drugs are derived from their effects on an underlying disease process. In the drug-centered model, drugs are psychoactive agents that create an abnormal brain state, and therapeutic effects are derived from the impact of drug-induced states on behavioral and emotional problems. Can you elaborate for us how ignoring this has distorted our understanding of the treatment of psychiatric conditions and has biased our assessments of risks and benefits?

The assumption that drugs work by acting on the underlying biological mechanisms of mental symptoms, the disease-centered model, has obscured the fact that the drugs we use in psychiatry are psychoactive drugs—that is, drugs change the brain in ways we do not fully understand and, by doing so, produce more or less subtle alterations to normal mental experiences and behavior—what I have called the 

 model of drug action. Because we have ignored the fact that psychiatric drugs are psychoactive substances, we have not bothered to properly research or even describe the physical and mental physical alterations they produce and all the short- and long-term consequences of these. Therefore, we are not making fully informed assessments of the benefits and harms of drug treatment, and because we assume we are rectifying an underlying abnormality, we tend to over-estimate the benefits of treatment and understate its harms.

Although I think there are some situations in which some drugs can be useful—eg, antipsychotics in acute psychosis, 

 in acute agitation—this has led to millions of individuals who are taking drugs that are doing them little or no good, but are causing them harm; both harm that we know about and harm that we have not properly researched yet.

 I wonder if the disease-centered model conflates instances of disease processes with biological mechanisms. Let us consider a thought experiment. Assume that in patient A, biological mechanism X mediates the subjective experience of anhedonia. We are not qualifying mechanism X as an abnormality or disease, we are simply saying that it is a mechanism, among others, of generating anhedonia. Patient A takes a medication M, which has a direct action on X that leads to an improvement in anhedonia. Again, we are not saying that M is fixing an abnormality in X, just that it has a direct action on mechanism X. In this thought experiment, M is neither correcting a disease process nor is it producing a therapeutic effect indirectly from a drug-induced state; it is producing a therapeutic effect by a direct action on a mechanism that is not necessarily abnormal but is nonetheless directly involved in the experience being targeted. How would your framework incorporate such hypotheticals?

I think I make it clear in my writings that the disease-centered model I have outlined is not restricted to what we think of as diseases, especially as the use of this term in psychiatry is not clear-cut. The disease-centered model consists of the idea that drugs work by targeting underlying biological mechanisms that produce what we call the symptoms of mental disorders. Hence, your thought experiment is an example of the disease-centered model as I have noted.

My response to your example is this: First of all, we have no idea what biological mechanism mediates anhedonia or almost any other subjective experience. The idea that we can pin down the biological mechanisms of complex human thoughts, feelings, and behaviors is part of the problem with our thinking. We cannot do this now, and we have no indication that we will be able to do so in the future—a view put forward in critical 

Second, if you give a drug that affects mechanisms P, Q, R, S and some others, and through its action produces an altered mental state in anyone who takes it regardless of diagnosis, allowing for individual variation, you will get some impact on emotions, including feelings of anhedonia. This may involve mechanisms related to anhedonia, including your hypothetical mechanism X, but it may not, since any significant alteration of mental state and activity will affect emotions in some way. Now this is a drug-centered action, and this is what I propose is happening when we use psychiatric drugs.

We recognize the fact that psychoactive substances such as alcohol and heroin change our mental states and can therefore interact with unwanted mental states and feelings. We talk of using alcohol to drown our sorrows, but we do not consider alcohol to be targeting the biological basis of misery in any specific way. When we recognize that psychiatric drugs have psychoactive properties, then we can start to understand what they are doing in individuals who suffer from mental health problems, and we can start to make a thorough and informed judgement about the pros and cons of using them.

 When you say, “The idea that we can pin down the biological mechanisms of complex human thoughts, feelings, and behaviors is part of the problem with our thinking in my view. We cannot do this now, and we have no indication that we will be able to do so in the future,” do you say that in an epistemological sense, that is, reflective of the limits of human knowledge and understanding, or do you say that in an ontological sense, that is, you do not think that complex human thoughts, feelings, and behaviors are mediated by biological mechanisms? By 

 I mean that biological mechanisms are part of the causal chain that eventually generates human thoughts and behaviors; I am not implying that human thoughts and behaviors can be reduced to or entirely explained by biological mechanisms.

It depends what you mean by mediate. The Wittgenstein scholar, Peter Hacker, PhD, puts this issue well. For Hacker, the mind is a set of capacities of the human organism, like Aristotle’s psuche or psyche. The human brain working as a whole is necessary to generate these capacities, but individual mental processes cannot necessarily be pinned down to specific brain mechanisms. Think of emotional states like anger, elation, anxiety, and fear. They are all associated with increased adrenaline and other arousal mechanisms, but they have their own character, and this character derives from how the individual appraises their worldly situation, not from the nature of the biochemical or physiological reactions.

 medications as having disease-centered effects as well as drug-centered effects. Given that our understanding of causal mechanisms of serious mental illness as well as mechanisms of drug action is less than comprehensive, how do we know that such dual effects are not the case in at least some individuals with serious mental illness? Because that is an empirical matter, I do not think we can rule this possibility out on an a priori basis.

 There are many things we cannot rule out, but that does not mean they are useful ideas. The drug-centered model provides an adequate explanation of drug action in mental disorders. There is no need to postulate a hypothetical disease-centered action alongside it.

What is your view of the philosophy of psychiatry literature that has emerged, in great part thanks to British academics such as Bill Fulford, PhD, and Tim Thornton, PhD? I am particularly thinking of the body of work that is devoted to questions of whether the boundary between supposedly normal and pathological can be drawn on the basis of objective, scientific facts, and what is the relationship between meaning and disease, ie, Derek Bolton, PhD; and how to best understand and explain causal mechanisms in psychiatric conditions, ie, Ken Kendler, MD, and Peter Zachar, PhD. This body of work seems to have great relevance to your interests; have you engaged with it in your writings?

 I have followed the work of Fulford and, to a lesser extent, the others you mention in detail over the past few decades and I am about to have a paper 

 However, I think it was Szasz, who I met a couple of times in my life, who identified the main problem with psychiatry, and few modern philosophers seem prepared to engage with his core arguments, with the exception of Fulford.

For Szasz, there is a key distinction between a condition of the body and a situation that is characterized by self-directed, human behavior, as opposed to involuntary behavior caused by a biological process or event. In this, he follows antipositivist philosophers, including the later work of Ludwig Wittgenstein, PhD, who stress the differences between the natural world and the human world, and how these entail different forms of knowledge. Szasz argues that psychiatry mostly deals with self-directed behavior and is therefore different from other parts of medicine that deal with bodily conditions.

Much of the psychiatric establishment clearly agrees with Szasz’s distinction, because it wants to demonstrate that psychiatry too deals with bodies—or more specifically brains—and that psychiatric disorders are, in fact, brain diseases. I agree with both Szasz and the biological psychiatrists that it is important to know whether behavior is the direct result of a specific biological mechanism or not. However, I do not think research that finds a slightly higher rate of this or that biological feature in the brains of individuals with a psychiatric diagnosis compared to allegedly healthy controls demonstrates that mental disorders originate in the brain, as opposed to in the individual’s agency or character.

But I also do not think that the behavior that characterizes some mental disorders is quite the same as fully volitional behavior as Szasz suggests. The thinking and behavior characteristic of psychosis, for example, is not rational in a clear-cut way. Individuals with psychosis do not respond to environmental cues and evidence in the usual way, and their purposes are not easily and immediately discernible to others. They may not have as much control over their behavior as individuals ordinarily do, either.

Although the behavior we associate with mental disorder is not simply the same as everyday behavior, I do not think it is distinct either. It is not a biological reflex, and therefore it can be viewed as part of the self or character, just as other, more clearly voluntary behavior is. This is why I refer to mental disorder as “part of the range of ways in which human beings live within, and interact with, their world.”

 What about psychological experiences that are involuntary, unwanted, and distressing, such as auditory 

 and obsessions? At least in some instances, they are perceived to be intrusive and threatening to their sense of selves and lead to help-seeking behaviors. Do you think of those experiences as parts of the self or reflective of the individual’s values, desires, and intentions?

 This is a good question, and it highlights the complexity of our human nature, which I cannot do justice here. Certainly, some mental processes are not straightforwardly voluntary. Our moods and emotions, for example, are not brought on at our demand. Yet, although feelings are usually unbidden, we can nevertheless usually exercise some control over how we behave in response to them, and, often, with time and experience, over the feelings themselves. In the normal course of things, we see our moods and emotions as being part of ourselves or our character. As I put it in my recent paper “the way we express our emotions is part of what is characteristic about us as individuals.”

Many symptoms of mental disorders, including extreme or prolonged moods, but also obsessional thoughts and hallucinations, are of the same nature. Individuals who end up in services may find their experiences difficult to resist and control, but that is true to some degree of many mental states and does not mean they are simply the meaningless byproducts of biological events.

We know that psychosis can occur in conditions such as Parkinson disease and Alzheimer disease, and there are phenomenological similarities between psychosis in these instances and the psychosis experienced in 

. I assume you consider the former pair to be diseases but the not the latter. If we restrict ourselves to examining the psychotic experiences only, without considering the concomitant presence of motor or cognitive symptoms, is there anything in the nature of these psychotic experiences that tells you whether they should be considered a disease or not?

 Physical states can occasionally mimic psychological ones. Thyroid hormone deficiency is famously said to cause depression. Often there are some phenomenological differences, but probably not always. Amphetamine abuse can cause 

. Again, there are some phenomenological differences if you were to look at a group level, but you cannot necessarily distinguish amphetamine-induced psychosis from an idiopathic psychotic episode on the basis of symptoms alone. However, this does not mean that the majority of instances of psychosis and depression are of the same nature.

As I have said before, many philosophers have pointed to how human emotions and mental states cannot be understood in a mechanical sense as isolated phenomena or events. They are intrinsically connected to the whole life history and experience of the individual, and the society in which that individual has grown up. Whereas thyroid deficiency may provide an adequate explanation of an episode of depression brought on by hypothyroidism, and thyroid hormone will usually provide an adequate treatment, an episode of depression has to be understood and treated in quite a different way, as a human reaction that requires a human-level response.

 You seem to suggest that if a behavior or experience can be seen as a meaningful response to experiences, environment trauma, social alienation, and so on, then it should not be considered the product of a brain disease. Two questions: One, human minds are great at conjuring explanations where none may exist. How can we ensure that our attributions of meaning are not simply instances of creative storytelling? Second, there is no philosophical reason why meaning and biological abnormalities should be considered mutually exclusive. Someone who is experiencing paranoia as a result of cocaine use can still find that paranoia as imbued with meaning and distorted reason, but there is no denying that it was the result of a brain aberration. Your thoughts?

We can never be sure about meaning. It is not a categorical thing—this is one of the many aspects in which the activity of human beings differs from the natural world and the form of our understanding needs to reflect this difference. 

 is premised on the idea that meaning is opaque and contested. The therapist’s interpretation of feelings and events may be quite different from the subject’s and this is not an arena where we can ever know the truth as we know it in a physical science.

I take issue with your statement that “there is no philosophical reason why meaning and biological abnormalities should be considered mutually exclusive,” and I argue this point in my recent paper.

 We are biological beings, and our behavior and activity is reflected in our biology, so of course “meaning and biological abnormalities” coexist. Yet, when we think of behavior, biological causation trumps meaning and agency. If an action—a twitch or a seizure, for example—is caused by a biological process, this removes it from the realm of agency. It does not make sense to think of an action as both caused by a biological reflex and initiated by the self in an intentional fashion. They are mutually incompatible situations.

Biological processes are not meaningful, but biology is the context in which human agency takes place, and it sets the limits of possibility. Individuals with intellectual disability, Alzheimer disease, or other brain diseases may make meaningful choices, but their agency is circumscribed, as it is for all of us, by the nature of their brains. And so it is for those under the influence of substances. The biological limitations are not meaningful in themselves, but within these limits, individuals may still be able to make choices and act in an intentional fashion. However, the extent to which behavior is driven, changed, or limited by a brain disease is not meaningful.

As I show in my recent philosophical paper, Szasz was trying to highlight how this distinction plays out in the difference between disease and behavior. Only when behavior is the product of a specific physical process, such as a brain tumor, can it be thought of as the symptom of a disease, and in this case, it is not meaningful. Otherwise it is part and parcel of the individual’s character; it reflects the individual’s values, desires and intentions—in other words it has meaning.

 When it comes to schizophrenia, a large body of research literature shows that there is a robust genetic component, that there are well-replicated associations with obstetrical complications, infections, inflammatory processes, cannabis use, and as a group, individuals with 

 show differences in brain volume and cognitive functioning. I agree, there is no specific abnormality of brain structure or function, but there is a range of non-specific neurobiological factors that have been implicated as risk factors on a consistent basis. If schizophrenia was merely a problem in living or a different way of being human, why would we observe this risk factor profile in research studies?

 I would put it another way. Despite decades of extremely well-funded research, we have yet to identify any specific biological factor associated with any type of mental disorder, including schizophrenia. There is a genetic component to many things, and it is likely this includes some aspects of character or temperament that are associated with developing schizophrenia. As far as other research goes, despite what you and others say, findings are not well replicated, and the research has failed to control for crucial confounding factors such as drug treatment, social class, stress, and IQ.

There are myriad reasons why individuals who show unusual behavior that is classified as schizophrenia are likely to have higher rates of obstetric complications, inflammatory markers, dopamine abnormalities, drug use, etc, when compared with stable, employed, middle class individuals that become the normal controls in biological studies. The most consistent and well-replicated finding in individuals with schizophrenia is the evidence of smaller brain size and larger brain ventricles, yet after years of talk about “schizophrenic brains,” it transpires that this is, at least in large part, caused by antipsychotic drug treatment.

Conversations in Critical Psychiatry’s aim is to engage prominent experts within and outside the profession who have made meaningful criticisms of psychiatry and have offered constructive alternative perspectives to the current status quo. The opinions expressed in the interviews are those of the participants and do not necessarily reflect the opinions of Psychiatric TimesTM.

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

Drs Aftab and Moncrieff have no relevant financial disclosures or conflicts of interest. Dr Moncrieff discloses that she is the cochairperson of the Critical Psychiatry Network, a board member of the Council for Evidence-Based Psychiatry, chief investigator on the RADAR study of antipsychotic reduction funded by the UK government’s National Institute of Health Research (NIHR) and co-investigator on the REDUCE study of antidepressant discontinuation also funded by the NIHR.

An extended version of this article was posted online ahead of print as 

Psychiatry and the Human Condition: Joanna Moncrieff, MD

Philosophical Foundations of Neuroscience. 

The neural antecedents to voluntary action: a conceptual analysis

Aping Mankind: Neuromania, Darwinitis and the Misrepresentation of Humanity. 

“It Was the Brain Tumor That Done It!” Szasz and Wittgenstein on the Importance of Distinguishing Disease from Behavior and Implications for the Nature of Mental Disorder

How can we ensure that our attributions of meaning are not simply instances of creative storytelling? 

Exploring Psychiatry and the Human Condition: Joanna Moncrieff, MD

Body dysmorphic disorder (BDD) is a mental health disorder in which you cannot stop thinking about perceived defects or flaws in your appearance, flaws that are often minor or even invisible to others. This condition currently affects around 2-3% of the general population.

, we speak to Katharine Phillips, MD, about how her pioneering research on BDD, she books on the topic, and options for treatment.

is currently professor of psychiatry, DeWitt Wallace Senior Scholar, and Residency Research Director for the Department of Psychiatry at Weill Cornell Medicine. She is also an attending psychiatrist at New York-Presbyterian Hospital and adjunct professor of Psychiatry and Human Behavior at the Alpert Medical School of Brown University.

Millions of Americans have a skewed view of their own bodies, leading to serious depression and suicidality.  

Body Dysmorphic Disorder: Widespread and Potentially Deadly

In the years after World War II, there were no effective medicines for schizophrenia, bipolar disorder, or major depression. There were not even names for such things. The word 

 was first used at a medical meeting in 1956, 

The war experiences of physicians and scientists shaped their research agendas.

Depression