One night I was laying down, I heard mama and papa talkin’. I heard papa tell mama to let that boy boogie woogie ’cause it’s in him and it got to come out.
-John Lee Hooker, “

my psychiatrist’s door always opened wide,

and the smell and feel of the chair’s skin

stacked ceiling high in my father’s factory,

soaked into the stained flesh of his hands.

Dead from cancer, I longed to have him back,

to talk man to man, but what I got instead

one of my father’s sweatbands sewn inside,

The Hook teaching me to play “Boogie Chillen”

on my father’s old D’Angelico guitar.

the tissue box until I could finally feel

believed I could boogie. I learned to play

my father’s songs, the jazz chords he loved,

when I greet my patients with music I heard

Articles

Our time was Thursday, 5 o’clock, my psychiatrist’s door always opened wide, him wearing a wool sweater, sipping tea, lights dimmed to an endless twilight...

Boogie Child

This activity offers CE credits for:
	1. Physicians (CME)
	2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

To understand the various classes of antidepressants: their kinetics, dynamics, and mechanisms of action as well as future novel formulations.

At the end of this CE activity, participants should be able to:

• Understand the pharmacokinetic and pharmacodynamic heterogeneity of current antidepressants

• Describe the mechanism of action of antidepressants with a focus on the serotonin system

• Identify novel drugs in development for depression

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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CME Outfitters designates this enduring material for a maximum of 1.5 

. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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In this 2-part series, the origins of antidepressants in the early 1900s and the discoveries that led to FDA approval of the first antidepressant in 1958 were reviewed in 

, October 2017). The development of the monoamine hypothesis of depression, our current FDA-approved armamentarium, and antidepressant augmentation strategies as well as the first FDA approval of an augmenting agent in 2007 were discussed.

Part 2 explores the significant pharmacokinetic and pharmacodynamic heterogeneity of current antidepressants and provides a review of the many potential drug targets that exist-with a focus on the serotonin system as we now understand it. Part 2 concludes with an overview of antidepressant drug development that is currently underway to hopefully provide novel agents.

Pharmacokinetics and pharmacodynamics: variety is the spice of life

No single antidepressant is considered superior. As such, choosing which antidepressant to prescribe to a patient is the result of a thoughtful analysis that includes many factors, both pharmacokinetic and pharmacodynamic. The analysis follows a careful history (

). In addition, the patient’s understanding of depression as a psychiatric disorder that may improve with antidepressant treatment, his or her opinion about the use of antidepressant medication, ability to comply with a structured medication regimen, and competent understanding of the risk-to-benefit ratio of antidepressant treatment must be considered.

The criteria for a major depressive episode include both insomnia and hypersomnia, psychomotor retardation and agitation, decreased and increased appetite, and weight gain and loss. Hence, the specific symptoms of the patient’s depressive episode can inform which antidepressant choice may best improve these symptoms and which may worsen them. A comorbid psychiatric diagnosis can inform the choice of an antidepressant, which may help symptoms of both diagnoses. Family history can provide many clues about the likelihood of medication response, as shared genetic factors can contribute to the response to a particular antidepressant.

It is vital to obtain an accurate list of all current prescription medications, along with the reason it is being prescribed, its dose, and the duration of treatment. Factoring in the potential for drug-drug interactions on the basis of pharmacokinetics and pharmacodynamics can prevent significant adverse effects and possibly life-threatening outcomes.

Herbal supplements that patients often forget to list can have a major effect on a drug. One example is St John’s wort, which is a serotonin reuptake inhibitor and also a potent inducer of cytochrome P450 (CYP450) 3A4-the most common metabolic pathway of all prescription drugs. St John’s wort can dramatically lower the serum level of a medication that is metabolized by CYP450 3A4, which renders it less effective and possibly ineffective. Moreover, the use of an antidepressant that also has activity as a serotonin reuptake inhibitor can increase the risk of serotonin syndrome.

Many recreational drugs can contribute to antidepressant failure. Not uncommonly, use of the recreational drug may significantly contribute to the patient’s presenting symptoms. Alcohol use disorder can result in significant depression and anxiety. Excess caffeine intake can contribute to insomnia and psychomotor hyperactivity. Cigarette smoking (the smoke, not nicotine itself) results in significant induction of CYP450 1A2 levels, which will hypermetabolize any drug that utilizes this pathway. Methadone can cause depression and weight gain. Cocaine withdrawal can mimic a major depressive episode. These are just a few common examples.

If a patient has a history of nonadherence or poor adherence to treatment, consideration should be given to the use of a drug with a long half-life. Alternatively, recruiting a partner, friend, or family member to monitor medication adherence can have a huge impact on treatment effectiveness. Assessing the patient’s capacity to manage the medication regimen is also important. A person with psychomotor retardation, poor motivation, or cognitive impairment is less likely to successfully comply with treatment. Finally, a patient’s access to a particular treatment needs to be considered. Lack of health insurance, lack of medication coverage, rigid formularies, and geographical isolation can create barriers to access of medications. 

 list pharmacokinetic and pharmacodynamic issues that need to be considered when choosing an antidepressant.

In the early days of antidepressants, the 3 monoamines that helped transform our understanding of depression-serotonin, dopamine, and norepinephrine-created the hypothesis that changes in the brain levels of these neurotransmitters could treat depression. The importance of these 3 monoamines gained greater momentum in our understanding of mental illness as our medication armamentarium grew.

With the antipsychotic efficacy of chlorpromazine, it was discovered that too much dopamine in one part of the brain (mesolimbic tract) seemed to be related to psychosis and mania. Too much norepinephrine in another part of the brain ramped up anxiety and panic. Too little dopamine in the prefrontal cortex resulted in cognitive dysfunction and inattention. Decades of research in the basic science laboratories of universities around the world began to unravel the complexity of the monoamine story, which went far beyond a monoamine and its associated receptor communicating in a synapse of a neuron in the brain.

The completion of the human genome project in 2003 allowed for the identification of the many subreceptors, gene promoter variants, and single nucleotide polymorphisms that all contributed to individual variations to drugs. More recently, the field of epigenetics has exploded, which adds yet another complex layer to gene expression. Significantly, an individual’s experiences throughout life have been shown to affect and change these epigenetic factors.

To appreciate just how far we have come since the FDA approval of iproniazid in 1958, let us explore the peeling of just the serotonin onion (

). Three scientists who were studying hypertension at the Cleveland Clinic in 1948 discovered a molecule released from platelets that resulted in vasoconstriction, synergistically working with the platelets to stop bleeding. They named this new vasoconstrictor serotonin. Subsequently, it was established that 90% of serotonin is in the gastrointestinal tract, and the remaining 10% is in the brain and in platelets.

The next challenge was to discover serotonin’s role in the 3 organ systems. A serotonin receptor was discovered, which created a logical sequence of information flow: serotonin is released from a presynaptic serotonin neuron and through entropy drifts across the synapse (

). As it drifts, some of the serotonin binds to and activates the serotonin post-synaptic receptor. Binding to this receptor activates a change across the post-synaptic neuron’s membrane. If the receptor is ionotropic (an ion channel that is opened or closed), the receptor affects the influx or outflux of a particular ion relevant to that receptor. If the receptor is metabotropic (a G-protein transmembrane-linked receptor), it results in many possible intracellular processes that can ultimately affect induction or suppression of gene expression, or activation or suppression of numerous intracellular processes.

The first serotonin receptor discovered was named the 5HT-1 receptor. Further research found a distinct second serotonin receptor, named 5HT-1B, while the first serotonin receptor was renamed 5HT-1A. In addition, a third serotonin receptor was identified: 5HT-1C. Careful analysis of these receptors’ amino acid sequences, and the discovery of additional serotonin receptors, indicated that there were different “families” of receptors that bound serotonin. Consequently, because of differences in their amino acid sequences, these serotonin receptors could be subdivided by similarities and differences.

The 5HT-1C receptor was structurally more similar to the 5HT-2A and 5HT-2B receptors than to the other 5HT-1 receptors, so it was renamed 5HT-2C. To this day, there is no 5HT-1C receptor, but we now have 5HT-1D, 5HT-1E, and 5HT-1F receptors.

In 1993 the seventh and final family of serotonin receptors was discovered, appropriately named the 5HT-7 receptor. With the completion of the human genome sequencing in 2003, it is well accepted that there are no additional families of serotonin receptors. Having so many variations for the activation of any given G-protein at the cell surface allows for infinite possibilities of post-synaptic neuronal response to a single neurotransmitter, such as serotonin.

However, it would be too easy if the story ended here. Each gene that codes for the mRNA of each receptor contains introns and exons, which allows each serotonin subreceptor to be spliced in alternative sequences, providing another layer of complexity.

A single gene for a single receptor can have a range of single nucleotide polymorphisms (SNPs) that preserve the functioning of the gene but result in a range of binding affinity variability or response variability for the same neurotransmitter-in this case, serotonin. The change in a single nucleotide of one gene can occur in many different locations, each of which can alter the gene’s function in different ways. The SNPs can occur on the promoter sequence preceding the gene, which can affect the number of gene products transcribed-affecting the final number of receptors in the neuron’s membrane.

Alternatively, SNPs can occur at some structural site in the gene, which can directly affect the 3-dimensional structure of the neurotransmitter-receptor interface, or have a distant allosteric effect on the receptor that also influences receptor function. In both cases, the SNP on the structural region of the receptor’s gene can result in 3 different outcomes: no change in receptor activity, a decrease in receptor activity, or an increase in receptor activity.

One of the many studies that resulted from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial supports this idea of heterogeneity. McMahon and colleagues

 report, “Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment, compared with those homozygous for the other allele.”

A comprehensive review summarized much of the science related to the impact of epigenetic changes on depression, and how these epigenetic modifications appear to be reversed with current antidepressant treatments. This ongoing research provides a glimpse into the evolving understanding of the relationship between epigenetics and depression.

 Epigenetic modifications that affect levels of brain-derived neurotrophic factor (BDNF) and the glucocorticoid receptor have been most studied. When the brains of individuals who had a history of childhood abuse and committed suicide were examined, variations in the degree of methylation of the promoter sequence of the glucocorticoid receptor were discovered. Several studies demonstrated a decrease in DNA methylation (which would increase gene transcription) associated with an increase in BDNF in individuals treated with various antidepressants.

An important paradigm shift occurred when drug development moved from a focus on blocking serotonin reuptake pumps to targeting specific serotonin receptors. Arguably, blocking a serotonin reuptake pump is a very crude way to modulate the serotonin system. The result is a global increase in synaptic serotonin, which results in the agonism of all 7 serotonin receptor families and their associated subreceptors.

Post-synaptic serotonin receptors can execute their message on many different neuronal types. Post-synaptic serotonin receptor modulation may ultimately result in changes in concentration of a different neurotransmitter in a different part of the brain. Downstream effects of serotonin receptor activity may increase or decrease synaptic levels of serotonin, dopamine, norepinephrine, acetylcholine, glutamate, and GABA. In addition, serotonin receptors can regulate prolactin, oxytocin, cortisol, and substance P, just to name a few.

When you extrapolate the complexity of the serotonin system to all neurotransmitters that may affect depression, an infinite possibility of drug targets exists. This is very good news for the future of drug development to treat depression-thus far, we have only scraped the surface of potential mechanisms of action.

Looking to the future: opioids, magic mushrooms, and Special K

Research on novel antidepressant molecules that function outside of the monoamine hypothesis of depression has been somewhat of a roller coaster over the past 3 decades. Initially promising drug classes such as neuropeptide Y modulators, substance P analogs, corticotropin-releasing hormone (AKA factor) receptor antagonists, and metabotropic glutamate receptor agonists (especially subtypes 2 and 3) ultimately failed as treatment options. One continued frustration and clinical limitation of our current antidepressants that follow the monoamine mechanism is that it can take from 2 to 8 weeks to achieve an adequate antidepressant effect. It appears that a common denominator of the delayed antidepressant response correlates with increasing levels of BDNF as the depression lifts. This increase in BDNF is associated with increased synaptogenesis in the brain’s hippocampus-a crucial gateway connecting memories and emotions-which may often be atrophied in cases of chronic depression and chronic stress. When the depression has resolved, the hippocampus increases in size.

The recent excitement about ketamine is that it has been shown to have immediate antidepressant effects, which correlate with increasing brain levels of BDNF.

 Ketamine is a racemic mixture of S-ketamine (esketamine) and R-ketamine (arketamine), and both molecules are antagonists at the glutamate NMDA ion channel. Esketamine is 3 to 4 times more potent than arketamine. Arketamine appears to have a greater antidepressant effect than esketamine. Ketamine continues to be aggressively studied as a possible “next-generation” antidepressant, and the racemate esketamine delivered intranasally is likely to be the first formulation to apply for FDA approval.

Both esketamine and arketamine are metabolized to hydroxynorketamine, which activates the glutamate AMPA ion channel. Increasing AMPA glutamate ionotropic receptors may produce an antidepressant effect, and with no dissociative adverse effects and no abuse potential. This metabolite has no activity on the NMDA glutamate ion channel and may be responsible for the increase in BDNF.

 The discovery in 2016 that hydroxynorketamine has antidepressant efficacy in mice (likely related to increased BDNF), without the abuse potential or dissociative adverse effects of ketamine, may provide a new avenue for drug development.

The clinical use of ketamine for the treatment of refractory depression is still considered experimental, and much remains to be learned about optimal dosing, delivery mechanisms, short- and long-term adverse effects, and duration and frequency of treatment.

Another class of drugs with a resurgence of interest for the treatment of refractory depression is the hallucinogens. Psilocybin, LSD, and mescaline are all serotonin analogs that have significant agonism at the 5HT-2A receptor. Most of the recent studies in refractory depression have involved psilocybin.

In one study, patients with treatment-resistant depression received 2 oral doses of psilocybin (10 mg and 25 mg in a supportive setting, 7 days apart). One week after they received the second dose, 67% of patients had an improvement in symptoms, and 58% maintained this response at 3 months.

 Although the data on psilocybin are in the early stages, and the current studies are open label, the findings are very intriguing.

The buprenorphine-samidorphan combination results in kappa-opioid antagonism. Buprenorphine is an antagonist/partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor (this is the putative antidepressant action of the combination drug). Samidorphan is an antagonist at the mu-opioid receptor, with tighter binding affinity than buprenorphine; hence, it prevents the mu-opioid analgesic effect of buprenorphine.

Rapastinel is being studied as an augmentation agent for treatment-resistant major depression. It received FDA fast-track status on March 3, 2014, and has a novel mechanism of action by selectively binding as an antagonist/partial agonist at an allosteric site on the glycine binding region of the NMDA glutamate receptor. Rapastinel is administered intravenously and is a rapidly acting drug that demonstrates antidepressant as well as cognitive-enhancing properties likely related to its activity as an antagonist/and partial agonist of the glycine binding site on the NMDA glutamate ion channel.

There has been increased interest in the role of inflammation in causing depression, exacerbating depression, and/or contributing to non-response in patients with treatment-resistant depression. Raison and colleagues6 looked at infliximab, a monoclonal antibody that inhibits the inflammatory cytokine tumor necrosis factor, in a cohort of 60 outpatients whose depression was moderately resistant to antidepressants. The subgroup of patients with elevated baseline levels of inflammatory biomarkers, including tumor necrosis factor and high-sensitivity C-reactive protein, demonstrated some improvement in their depressive symptoms compared with patients whose baseline levels of inflammatory biomarkers were not elevated.

Conclusion: looking forward to the next 100 years

MDD is a common and often disabling mental illness that has plagued humanity since the existence of historical records. The past 100 years has been a time of impressive advances in medicine, neuropsychiatry, pharmacology, and our understanding of the circuitry of the brain.

The birth of the monoamine hypothesis of depression in the early 1960s revolutionized our understanding of, and ability to treat, depression. However, full remission from a major depressive episode is hard to achieve, and even obtaining a 50% response in patients with depressive symptoms can be challenging.

All of our FDA-approved antidepressants have mechanisms of action that are grounded in the monoamine hypothesis. Over the past several decades, there have been exciting breakthroughs of novel mechanisms of action-all too often followed by disappointment after extensive basic science research and early-phase clinical trials. However, we must always look to the future with optimism. We never know when a new molecule discovered by serendipity or an idea coalescing in the mind of some graduate student will bear the fruit of our next paradigm-changing antidepressant.

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The author explores the significant pharmacokinetic and pharmacodynamic heterogeneity of current antidepressants and reviews the many potential drug targets that exist-with a focus on the serotonin system.

Antidepressants, Part 2: Kinetics, Dynamics, Mechanisms of Action, and the Future

No, for a change, I’m not talking about the inundation from the 24-hour-a-day news. I’m thinking about psychotherapy and want to discuss 2 related things. The October issue of the 

 published 2 articles of major importance for those interested in strengthening the evidence base for psychotherapy.

 Over the past 5 decades, for a variety of reasons, the training in and availability of psychodynamically focused psychotherapy has been diminishing. Since the publication of the Institute of Medicine’s report on evidence-based medicine, the pace of the decline has increased. Why?

In large part the decline has occurred in association with several factors related to cognitive behavioral therapy (CBT) and psychoanalysis. The first is that a large cadre of CBT faculty expertise became available in training programs to broaden the reach of teaching that modality, and at the same time psychoanalysts were leaving academia. The second factor is that the more standardized clinical approach embodied in CBT practice made outcomes research for CBT much more easily done than for psychodynamic psychotherapy research. A further factor was significant resistance from psychoanalysts-of which I’m one, so I can say this-to engage in modern outcomes research. I bemoaned this some years ago in an article I published in the 

Journal of the American Psychoanalytic Association

 which not surprisingly to me, had little impact.

For many years, Dr. Barbara Milrod has been on the forefront of attempts to rectify the imbalance of clinical outcomes research in psychodynamic therapy compared with CBT. In her current article, she highlights the difficulties in doing a good meta-analysis, especially one that deals with psychotherapy treatment outcomes.

 These include ensuring not only similar diagnostic criteria and inclusion of patients across studies, but also more important for psychotherapy research, ensuring that clinical interventions are comparable within a study and across studies. Lack of such uniformity across studies has impaired high-quality meta-analytic studies analyses in many areas, but especially in psychotherapy.

It was, therefore, reassuring that her assessment of the Steinert meta-analysis was that it met a very high standard. Thus, Steinert and colleagues’ finding of essential equivalence between CBT and psychodynamic therapy was satisfying to me and many other psychodynamically inclined therapists-and was important for patient care. Milrod cites several other important studies that demonstrated positive outcomes for psychodynamic therapy, and there have been a number of others in recent years, mostly focusing on depression treatment.

The importance of the Steinert study is that it looked across diagnoses and used high inclusion standards for individual research reports. Yes, the sample sizes in the studies are small and the number of studies that could be included is small because so few met the high standard for inclusion in the meta-analysis, but this is an important contribution. And maybe this and similar reports to come will help slow the decline in the training of the next generation of clinicians in psychodynamic therapy.

The reality is that other individual studies such as the Driessen

 study that compared CBT and psychodynamic therapy show equivalence of outcome in depression treatment. But their finding that only about 25% of patients improved with either treatment, and the fact that no one else has thus far found any formula to help a clinician determine which treatment will be more likely to succeed in any one patient, means there is still a long way to go to convince payers in the US to more appropriately reimburse for psychotherapy treatment.

The slow advances in psychotherapy research, contrasted with decades of clinician experience that support clinical improvement with such treatment, pertain directly to my second topic. Over the summer, 

 reported on a major shift in support for psychotherapy as an essential clinical intervention.

 Unfortunately for our patients, at least for now, this didn’t come from the US but from the UK. Their National Health Service has embarked on what the 

 called “the world’s most ambitious effort to treat depression, anxiety, and other common mental illnesses.”

And how are they doing this? By essentially making unlimited psychotherapy available free of charge at clinics throughout England when the patient’s clinical condition indicates it is a necessary treatment. The goal is to eventually expand this throughout the entire UK. And, the report notes, there was widespread publicity about the initiative, including a video from Princes Harry and William talking about their own struggles after the death of their mother, Princess Diana, as well as comments from Princess Kate. The clinical head of mental health for the National Health Service is quoted as saying that the project-and its attendant publicity-has already led to a reduction in stigma among Millennials.

The program’s origins go back just over a decade, when it started on a smaller scale. Of course, the first comment we’d hear from insurers and the government about this in the US is that we can’t afford it. But given that the World Bank’s analysis of the global economic burden of all diseases will have depression at the top of the list within a few years, the predictable costs of not providing adequate treatment for all of the most common psychiatric disorders are unimaginably high-not to mention the personal and societal costs, which are much harder to quantify.

Not surprisingly, the English program has been inundated with demand, although therapy is only generally available after an appropriate clinical evaluation. Their 1-month wait time for a therapy appointment has been a cause of great concern, but they should look at the situation in the US. We don’t have very good data on wait times here because we have such a decentralized system and can’t gather it. But I think in nearly every location in the US, the wait time to begin therapy is undoubtedly much longer. I do know that yesterday I evaluated about 10 patients in our clinic and thought at least half of them would benefit from immediate therapy. Of course, they will wait much, much longer than a month to begin.

There is little chance that such an important initiative would even be seriously considered on such a grand scale in the US in the foreseeable future. Aside from the usual stigma-related discrimination against psychiatric treatments, the inability to project the cost of this type of program is a major impediment. But the experiment in the UK is gathering clinical tracking data and will at some point have direct cost data, so a cost/benefit analysis will eventually be available. I’m pretty optimistic the data will show this type of program is worth the effort not only on economic, but also on quality-of-life measures. However, much more important is that with all the therapists practicing in the US today, demand already exceeds capacity. So who would deliver all that new care?

 Milrod B. The evolution of meta-analysis in psychotherapy research. 

 Steinert C, Munder T, Rabung S, et al. Psychodynamic therapy: as efficacious as other empirically supported treatments? A meta-analysis testing equivalence of outcomes. 

 Tasman A. Beyond the single case study: it’s time to do our homework. 

 Driessen E, Van HL, Don FJ, et al. The efficacy of cognitive behavioral therapy and psychodynamic therapy in outpatient treatment of major depression: a randomized clinical trial. 

 Carey B. England’s mental health experiment: no-cost talk therapy. 

https://www.nytimes.com/2017/07/24/health/england-mental-health-treatment-therapy.html

Know about these two articles of major importance for those interested in strengthening the evidence base for psychotherapy?

You Are Always on My Mind

How does a psychiatrist tell a good psychiatric app from one that could harm a patient?

 Where to turn for guidance about MOC? Or for help with the tough ethical and clinical calls? How can psychiatrists keep abreast of the truly important clinical studies? Where does an early career psychiatrist become financially literate and learn about setting up his or her own practice? Where can a solo practitioner turn for expert “how I do it” guidance that’s concise and down to earth-not ivory tower?

These are just some of the editorial ideas our newly convened advisory board-made up of 7 early career psychiatrists-came up with recently . . . ideas this group will help us translate into published work in the coming months.

It’s my pleasure to introduce these extraordinarily accomplished young physicians, who were hand-picked by our editors in chief-Drs. Allan Tasman and Michelle Riba-from a pool of applicants. After reviewing their resumes, Allan and Michelle commented, “These young psychiatrists are amazing! It is wonderful to welcome them to our team with their innovative and interesting ideas.”

We asked each advisory board member to write a short “bio” to tell readers a little about themselves. I think you’ll enjoy the read.

Welcome, Drs. Awais Aftab, Noel Amaladoss, Kristel Carrington, Ralph de Similien, Jessica Gold, Desiree Shapiro, and John Torous!

I am a PGY4 and Chief Resident for Education and Research at Case Western Reserve University (CWRU)/University Hospitals Cleveland Medical Center. I am an APA Leadership Fellow, and a fellow member of the APA Council of Research and have received fellowship awards from AADPRT as well as the Association of Academic Psychiatry. I have authored more than 2 dozen peer-reviewed publications and am the principal investigator for a Practice Based Research Network study investigating how the experience of psychiatric hospitalization affects trust and relationships with outpatient psychiatric providers. I’m also involved in an RCT investigating pioglitazone as a treatment for bipolar depression.

I am keenly interested in the myriad ways in which psychiatry is subject to philosophical inquiry and have developed a 6-part didactic course on the intersection of philosophy and psychiatry, which I have taught to psychiatry residents. The course covers topics such as the nature of mental disorder with regards to the debate between naturalism and normativism, the antipsychiatry movement, pluralism in psychiatry, and philosophical issues in psychiatric nosology. I am the founder and chief curator of the resident-led newsletter 

, which has been featured by APA’s Ohio district branch, and received the 2017 CWRU Scholarship in Teaching award.

In my spare time, I listen to indie pop/indie rock music on Spotify, enjoy fiction and non-fiction (most recently 

 fantasy series and a biography of Philip K. Dick), peruse the Sunday 

Dr. Amaladoss is Assistant Professor at McMaster University, Department of Psychiatry and Behavioral Neurosciences, and a Staff Psychiatrist at the Advanced Mind Clinic in Burlington, Ontario, whose main clinical interests are medical education, anxiety disorders, ADHD, psychopharmacology, and physician and corporate mental health. He earned his MB and ChB degrees from the University of Stellenbosch, Tygerberg Medical School, in Cape Town, South Africa, completed a psychiatry residency at Queens University in Ontario, and his fellowship at the Royal College of Physicians and Surgeons of Canada.

I grew up in Brooklyn, NY, and am of Guyanese heritage. I’ve wanted to be a doctor since the age of 3, and I fell in love with psychiatry once I got to medical school. I received excellent training at NYU and got the full experience of the diversity psychiatry offers. Now that I have completed my training, my main career goal is to be able to experience the diversity of psychiatric practice as much as possible. I do part-time work as a locum in an outpatient clinic, I have a part-time private practice, and I also moonlight in a psychiatric emergency department.

When I’m not at work, I’m usually at home relaxing with my partner and our 2 cats. I love playing video games and find them very relaxing and therapeutic-especially the first-person shooters! I also enjoy traveling, seeing natural beauty, and taking very amateur nature pics. One of my big passions is financial literacy for MDs. Doctors are horrible at managing finances, so I am big on educating early career MDs about topics such as retirement planning, safe investing, and basic budgeting.

I am currently a Fellow in the Public Psychiatry Fellowship at Yale University. I earned my medical degree from Wayne State University School of Medicine in 2013 and completed psychiatry residency at Howard University Hospital in 2017. I am an alumnus of Teach for America and AmeriCorps and a former elementary school teacher. My interests include public and community psychiatry, education administration, and addressing the social determinants of mental health and persistent mental illness in the transitional/college-age patient population.

I am a fourth-year Resident and Chief in Psychiatry at Stanford University. As an undergraduate, I majored in anthropology at the University of Pennsylvania, where I was a Benjamin Franklin Scholar and graduated Phi Beta Kappa in 2009. I also received a Master’s in Science in anthropology from Penn at the same time, using qualitative methods to study premedical education for my thesis work. I received my medical degree from the Yale School of Medicine and graduated in 2014. While at Stanford, my primary interests are medical education, physician wellness, and the media portrayal of psychiatry as it relates to stigma.

I enjoy both academic and popular press writing, frequently blogging for the 

.” In my spare time, I spend time with my dog, friends, playing bar trivia, and my growing extended family of 7 nieces and nephews.

I am an Assistant Clinical Professor of Child and Adolescent Psychiatry at the University California, San Diego. I help patients and families in psychiatric crises on an in­patient unit, in the emergency department, and in a crisis stabilization unit at Rady Children’s Hospital. I love working on teams and with trainees to help youth and their families create a recovery plan.

I have been involved in organized medicine through the APA and AACAP and served as President of the APA Leadership Fellowship, which was an incredibly rewarding experience. I am passionate about child and adolescent psychiatry and feel fortunate to care for youth and their families. I have many interests but currently am focused on prevention and early intervention, systems of care, teaching, mentorship, and positive psychiatry.

In my spare time, I enjoy being with my 21-month-old and family. Being a mom is the hardest and greatest adventure I’ve ever had; playing with my little girl is my greatest joy! I am excited about being a part of the Editorial Advisory Board for 

I am a board-certified psychiatrist and researcher at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School. I completed a computer sciences degree at UC Berkeley, medical school at UC San Diego, residency at BIDMC, and currently am completing a master’s degree in biomedical informatics at Harvard Medical School. My research focuses on smartphone-based passive data sensing (monitoring mobility, social, and cognitive data streams) for relapse prediction in patients with depression and schizophrenia. I’ve published over 40 peer-reviewed papers on digital technology in psychiatry. I chair the APA’s workgroup on smartphone app evaluation, advise on smartphone apps for the Precision Medicine Initiative, and co-direct the digital psychiatry program at BIDMC.

Here's a warm welcome to the 7 members of our new Advisory Board. 

The Future of Psychiatry

The uncanny eludes facile definition. Savants diverse as Nietzsche, Poe, Freud, and Jung have had a go at those mysterious creeps that prick up your hair and unsettle your mind. However trenchant, speculations about the nature and causes of the uncanny somehow end up wide of the mark.

At base, uncanny experiences are rooted in the realm of the unconscious-individual or collective (if your bent is Jungian). And the workings of the unconscious 

 refuse tidy explanation because they’re recoverable only in conscious “traces”-eerie moments of deja vu, slips of the tongue, and in the waking residue of our dreams.

In high or popular art, the uncanny customarily summons up midnight graveyards, unquiet ghosts, doppelgangers, the living dead. Freud’s famous essay, 

, (1919) itself possesses an uncanny cast: his usually incisive prose is strangely prolix; his speculations uncharacteristically equivocal.

Freud cites several examples of the uncanny in literature-eg, Olympia, the exquisite mechanical simulacrum of a human ballerina, in E.T.A. Hoffmann’s 

. He goes on to posit an intimate relationship between the comfortable (

) feelings related to ordinary things and events, and the uncomfortable, even dreadful (

) sensations the same objects and events generate. These may occur in stressful circumstances, but sometimes emerge unbidden, ex nihilo.

 perceptions are precipitated by the activation of repressed childhood “complexes,” oedipal, pre-oedipal, so forth. I’ve found little clinical evidence to back up this speculation. But I do believe that horror fiction, painting, and cinema are often most frightening when quotidian reality gives way to a vastly troubling perception that the real world comprises a thin scrim, overlaying a rich, numinous, and often terrifying underworld.

Stephen King is today’s foremost adventurer into that 

 nether region. King is astonishingly prolific. He has published at least 50 novels and 200 short stories in the horror/sci fi genres. He has also written children’s books, 

, and private eye mysteries, an autobiography, and diverse essays-one of the best on the vicissitudes of writing.

King’s genre work ranges across the broadest spectrum of the horrific and uncanny. He has borrowed honorably from masters like Poe and Bram Stoker; repurposed classic inhabitants of monster alley like 

, 1975), and created his own creatures of the night, including a shapeshifting satanic clown-of which more presently.

He has probed virtually every parapsychic phenomenon-eg, precognition, in 

 trope often figures prominently in his oeuvre, eg, the gleaming roadster, come murderously alive in 

King has always drawn abundantly from his own childhood and adult experiences. Abandoned at age 2 by a merchant marine father, he was raised by his working-class mother under harsh circumstances, mostly in a small Maine town. The Maine hamlet of “Derry” is its replication, and frequently appears in his work.

King is singularly adept at capturing the vicissitudes, mores, and speech of pre-teenagers (particularly boys) throughout his writing-most notably in one of his longest novels, 

 (1986). Adapted for an uninspired television miniseries in 1990, 

 has been re-adapted again for the screen. As I write, the current film remains immensely popular and has generated blockbuster box-office across the world.

 is set in Derry. The town and its verdant countryside first appear Grandma Moses’ 

. Everybody knows everybody. Derry people seem folksy-nice enough-if sometimes given to gossip, and a bit quick to make hurtful judgment. But a wave of child disappearances is afflicting the town, not for the first time. And the facade of the tidy houses can conceal cruel, perverse deeds, perpetrated by parents upon their children or vice versa; or-this being Kingland-by sundry ghoulies and ghosties and things that go bump in the night.

’s protagonists are the Losers-so named by their yahoo peers-a fetching group of 6 boys and one tomboy. Each is an outsider in some fashion, often denigrated: variously, the tomboy, a stutterer; Jew; brainy nerd; off-putting chatterbox. Each comes from a troubled social or family background. For instance, the tomboy is savagely mocked by mean girls for being dykish and a slut. (She’s not.) At home she’s tyrannized by a father seething with repressed incestuous desire.

For all their jibing, the Losers are touchingly supportive and winningly decent (King always treasures a kind heart). The members of such a group typically grow more whole psychologically as it evolves. The group identity forged is stronger than its parts. Before the film’s opening, one senses the youngsters have already begun drawing upon each other’s strengths, as they care for each other’s psychological bruises.

’s opening sequence skillfully encapsulates the terror to come. A winsome boy in a yellow slicker pursues his paper boat racing down the gutter in a drenching rain. It disappears into a sewer. A garishly painted clown head pops up behind the drain gate. Pennywise-so he calls himself-is merry, insouciant, and beneath his seductive affability, ineffably frightening.

He invites the boy, by name, to join his subterranean circus: “We all float down here” (a typical uncanny King catchphrase-how and why would you float in a sewer’s depths?). The youngster backs off, Pennywise gulls him into reaching for his boat-and bites off his arm, killing him!

After the dead boy’s agonized brother (the stammerer) also sees the clown, each of the kids has a different, traumatic supernatural experience: a torrent of blood explodes from a bathroom sink; the elongated woman in a Modigliani-like portrait writhes into horrid life. During each manifestation, Pennywise is seen, heard, or his presence intimated by an eerily floating, blood-scarlet balloon.

Pennywise comprises King’s powerful reinvention of the “Evil Clown,” a signal example of the 

 binary, uncannily conflating humor and horror. It’s been widely observed that a clown’s gaping grin and bumptious behavior are more likely to provoke angst rather than laughter in children. (Jungian researchers link the Evil Clown to the archetype of the benevolent/malevolent “Trickster” of many cultures.)

Delving in the library by the Losers’ quondam historian reveals that Derry’s 

 reality is, and has always comprised a scrim over Pennywise’s 

 inferno since the town was founded. Over several centuries, scores of children have disappeared or died in a succession of catastrophic fires, factory explosions, et cetera.

Derry turns out to be situated over a maze of ancient sewers, converging into a central pumping station. Once prized as a symbol of civic progress, it has decayed into the genre’s staple-the dark old house, where inchoate evil lies “below.” At some point the main sewer conduit became the entrance of Pennywise’s underground charnel house, in which his young victims “float.” (King perennially taps into the creepy horror of “what lies beneath”; Pennywise’s noxious domain evokes Gehenna; Hades; and sundry Christian, Islamic, and Buddhist infernal regions.)

The Losers eventually realize that Pennywise flourishes by feeding off their fears, and will only be conquered by descending into the sewer’s hellmouth and destroying him.

In Pennywise’s labyrinthine lair, they run a gauntlet of loathsome monsters and funhouse grotesqueries, until the tomboy’s slingshot turns magical, pierces Pennywise’s facade. The other Losers then attack him with whatever makeshift weapon at hand, until the earth swallows him up.

All this seems the stale stuff of hoary fairy tales. But a source of King’s success is his remarkable ability to newly mint fairy tales, myths, and sagas, notably those in which an omnipotent jabberwock-monster is defeated by a seemingly weak or inept child-or child-like-adversary.

Bettelheim was not the first to address the therapeutic value of these enduring narratives to children. King’s heroes, young or old, regularly undergo analogous quests, culminating in a newfound maturity, while satisfyingly scaring us out of our collective knickers.

Pennywise has only been vanquished for the present. As he sinks back into his cloacal sewer, he cackles that his clown persona is just another mask, concealing a being infinitely more malignant, that will return again. It testifies to their maturity that they recognize his threats conceal his fears-of them.

In the final scene, the Losers link arms in a charmed circle; swear a blood oath to return to Derry, no matter where they are, to confront Pennywise in his next cycle. Then, poignantly, each fades away.

 (1983). But the film is well directed (Andy Muschietti), scripted, and acted. The children’s performances are particularly fine.

Tim Curry’s Pennywise was greatly stroked, but Bill Skarsgard’s Evil Clown is much more nuanced, his voice shifting supply between merriment and menace. The CGI and other special effects are beyond awesome.

 honors the unwritten contract between maker and viewer since the genre’s inception to scare us, but never to death. Such is not the case with a sub-genre of “cruel cinema” I’ve analyzed elsewhere, in which the horror picture so assaults viewers as to become a nightmare from which one doesn’t easily awaken so easily.

As a stoned buff of horror movies since adolescence-like King himself-I myself savor gorefest classics like 

 (1968). But I wouldn’t recommend such grisly fare to the faint of heart.

A note on the trashing of King’s work by literati like Harold Bloom. Bloom was said to be incensed when King was granted a lifetime achievement award from the National Book Awards association. A mere scribbler doesn’t get published in 

. I predict that if we manage to survive the very real horrors of our present world, a century from now, King-like Poe, Hawthorne, Philip K. Dick, and H. P. Lovecraft-will be treasured, long after Bloom and his censorious lot have been consigned to the dustbin of history.

-The movie, like the novel, adroitly interpolates flash-forwards of the adult Losers, preparing to encounter Pennywise when he has emerged from his 27-year hibernation. In the next film, already in production, they confront the shapeshifting malignancy definitively. I won’t reveal the outcome, but one doesn’t have to be Nostradamus to predict a repeat of the current film’s staggering popularity and profitability.

From the beginning, Freud’s clinical investigations were augmented by the new discipline he called “applied analysis” of the arts.

 My writing in this field has chiefly focused on cinema, but I’ve also addressed literature, painting, and music elsewhere. 

 recently asked me to cast a wider critical net in these pages, via a column. My spectrum will be broad and, for the most part, current and reasonably available via the usual sources, the internet, and theatrical telecasting of drama, opera, art exhibitions, and so forth. Reader suggestions are always welcome.

Dr. Greenberg practices psychiatry in Manhattan, New York. He continues to publish frequently on film, media, and popular culture. For many years, his cinema column appeared in 

King is singularly adept at capturing the vicissitudes, mores, and speech of pre-teenagers (particularly boys) throughout his writing-most notably in one of his longest novels, IT. 

Vol 34 No 11

Boogie Child

Antidepressants, Part 2: Kinetics, Dynamics, Mechanisms of Action, and the Future

You Are Always on My Mind

The Future of Psychiatry

IT: On the Unheimlich Maneuvers of Stephen King

Personalized Medicine in Psychiatry: The Tangible and Immeasurable Benefits of Measurement-Based Care