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The authors of the 3 articles in this Special Report have done a commendable job. Not only will you, the reader, benefit from reading these discussions, but, ultimately, so will your patients.

A few comments may help to put the issue of treatment resistance in perspective:

 is describing the illness the patient has rather than the patient being resistant. The importance of this distinction cannot be overstated. Caveat: There are patients who may decline treatment, but that is a different topic for a different time.

2. Patients do not fail treatments. Instead, treatments fail patients. This distinction also cannot be overstated.

3. Pharmacotherapy and psychotherapy are complimentary rather than antagonistic modalities. When explaining the relationship, I use the analogies of computer science in terms of hardware and software in computer science and/or orthopedic procedures (eg, casts) and physical therapy to explain the interrelationship between pharmacotherapy and psychotherapy.

, like physical therapy, may be the only treatment the patient needs; however, it is rarely the case that a patient only needs 

 without some form of psychotherapy, even if it is limited to supportive, educational psychotherapy.

4. There are 4 levels to diagnostic sophistication arranged like a pyramid.

 The first level is symptomatic diagnosis, which is what patients say when they present to a health care provider (HCP) (eg, “I have a headache.”). Moving up in the pyramid, the second level is syndromic, which is a cluster of symptoms and/or signs (ie, physical findings), and the HCP may say to the patient : “You have a 

.”). The third level up is pathophysiology, which is based on laboratory findings, such as elevated levels of norepinephrine in the bloodstream that causes the headache. The fourth level and top of the pyramid is pathoetiology, which is the cause of the patient problem. In our example, a tumor, a pheochromocytoma, could be causing the high levels of norepinephrine which increased the patient blood pressure resulting in the headache.

As one can see, the higher the level of the diagnosis, the greater the understanding of the problem, what is causing the problem, and how to most effectively treat it. The lowest 2 levels of our pyramid are descriptive diagnoses, whereas the higher 2 levels are explanatory.

Presently, most psychiatric diagnoses are syndromic but we are moving to higher levels of understanding. That is good news for patients with treatment resistant psychiatric illnesses.

is professor in the Department of Psychiatry and Behavioral Sciences at the Kansas University School of Medicine-Wichita. Over his 42-year academic medical career he has worked with more than 140 pharmaceutical, biotechnology, device, and diagnostics companies to bring their products to the market. He has been a principal investigator at the site level on all antipsychotic and antidepressants medications approved in the United States over a 25-year period of time. He has received grants/research support from or has served as a consultant, on the advisory board, or on the speaker’s bureau for Alkermes, BioXcel, Eisai, Janssen, Lyndard, Otsuka, Sunovion, and Usona Institute. All clinical trial and study contracts were with and payments made to The University of Kansas Medical Center Research Institute, a research institute affiliated with The University of Kansas School of Medicine-Wichita.

1. Preskorn SH. Patients don’t fail treatments, treatments fail patients. 

The overlap of DSM-IV syndromes: potential implications for the practice of polypsychopharmacology, psychiatric drug development and the human genome project.

Psychopharmacology and psychotherapy: what’s the connection.

Neuroscience basis of clinical depression: implications for future antidepressant drug development.

Put treatment resistance in perspective with Sheldon H. Preskorn, MD.

The Current State of the Art and the Not Too Distant Future

worked with experts from multiple areas in psychiatry to bring you discussions of important topics, such as identifying and treating victims of human trafficking; diagnosing and managing fibromyalgia; and ethically evaluating dangerousness in individuals with personality disorders. Here are some highlights from our selection of this year’s Continuing Medication Education (CME) articles:

Psilocybin Revisited: The Science Behind the Drug and Its Surprising Therapeutic Potential

Psilocybin and psilocin are the main psychedelic agents of the psychoactive mushroom genus Psilocybe.

 Historical and cultural use of these psychoactive mushrooms dates back 3000 years in Mexico and the Southwestern regional areas of the present-day United States. Scientifically, psilocybin was isolated and identified in 1958, synthesized in 1959, and used in various experimental research studies in the early 1960s. During that time, psilocybin and other psychedelic agents such as lysergic acid diethylamide (LSD) generated considerable controversy. Outside of recreational use, could they be used safely as therapeutic interventions? 

Fibromyalgia: What It Is and How to Treat It

Fibromyalgia (FM) is one of the most controversial diagnoses in the field of pain management. Some experts believe that it does not exist and actually represents an accidental or purposeful misdiagnosis of other conditions, while others believe that it is badly underdiagnosed.

 The truth likely falls somewhere between these 2 extremes. FM is a real syndrome, but it is also perhaps overdiagnosed, both because many physicians are unaware of the actual diagnostic criteria, and because there may be a desire to avoid diagnosing patients with other conditions that could explain the symptoms of FM—most notably mental disorders. 

Psychiatric Evaluation of the Peripartum Patient

The peripartum period is not necessarily a time of emotional well-being,

 highlighted by the fact that about 1 in 13 women develop new-onset major depressive disorder (MDD) while pregnant.

 (The term “peripartum” in this article refers to pregnant women and women who are up to 1 year postpartum.) In the postpartum period, 1 in 7 women will develop MDD and are at high risk for psychiatric hospitalization.

 Thus, comprehensive psychiatric evaluation of the peripartum patient is an essential skill. The mainstay of assessment remains the clinical interview; as such, careful and systematic psychiatric evaluation during these periods is crucial for diagnosis, risk assessment, and treatment. The general psychiatric evaluation, however, must be expanded and tailored to the needs of the peripartum patient. 

Psychiatrists’ Response to Human Trafficking

Human trafficking is a public health issue that involves exploiting individuals for forced sex or labor. Traffickers perpetuate the cycle of exploitation by utilizing methods such as emotional, economic, or physical abuse; isolation; and threats. Physical, mental, legal, and social sequelae of human trafficking can persist for years after individuals survive their trafficking situations. Individuals with a preexisting history of psychiatric illnesses, including substance use disorders, are especially vulnerable to being trafficked. 

Here is a full list of our CMEs from 2021:

Microglial Involvement With Psychiatric Diseases

Neuropsychiatric Symptoms of Multiple Sclerosis

Opportunities in Managing Treatment-Resistant Depression and Tardive Dyskinesia

Psychological and Cognitive Insight: How to Tell Them Apart and Assess for Each

Different Strokes: How to Spot and Treat Poststroke Depression

Transgenerational Transmission of Resilience After Catastrophic Trauma

Prognostic Considerations in Anti-NMDA Receptor Encephalopathy With Psychiatric Manifestations

Cognitive/Neuropsychological Functioning and Suicidal Behavior: A Review of Research and Implications for Clinical Practice

Be sure to stay up-to-date by subscribing to the 

Do you have a comment on any of these or other articles? Have a good idea for an article and want to write? Interested in sharing your perspectives? Write to us at 

Psychiatric Times featured a wide variety of psychiatric issues in this year’s CMEs.

CMEs 2021: A Year in Review

The US Food and Drug Administration (FDA) has approved Caplyta (lumateperone) for the treatment of 

Caplyta, an atypical antipsychotic from biopharmaceutical company Intra-Cellular Therapies, is the only drug approved by the FDA for the treatment of depressive episodes stemming from bipolar I or bipolar II disorder in adults as monotherapy or adjunctive therapy with either valproate or lithium. The drug has shown a consistently favorable profile on weight, extrapyramidal symptoms, and cardiometabolic parameters, according to Sharon Mates, PhD, chairman and CEO of Intra-Cellular Therapies.

The drug was previously approved by the FDA for the treatment of schizophrenia in adults in 2019

 following favorable safety and tolerability as well as demonstrated efficiency among patients with schizophrenia in prior studies. With this expansion of indications, Intra-Cellular Therapies announced that plans to launch its Caplyta treatment for bipolar depression will begin immediately.

This approval is important for individuals living with bipolar depression and their providers, given the limited treatment options for depressive symptoms specifically associated with bipolar disorder. Bipolar depression is the most common and the most significant clinical presentation in individuals with bipolar disorder, which currently affects 11 million adults in the United States.

“The efficacy, and favorable safety and tolerability profile, make Caplyta an important treatment option for the millions of patients living with bipolar I or II depression and represents a major development for these patients. Caplyta is approved for a broad range of adult patients, including those patients with bipolar II depression who have been underserved with limited treatment options,” said Roger McIntyre, MD, FRCPC, professor of psychiatry and pharmacology at the University of Toronto and head of the Mood Disorders Psychopharmacology Unit at the University Health Network, Toronto, Canada, in a press release.

“We are excited to offer Caplyta to the millions of patients living with bipolar depression,” Mates said in a press release. “We thank the patients, health care professionals, and our Intra-Cellular team for all their contributions that led to this approval.”

Intra-Cellular Therapies announces U.S. FDA approval of CAPLYTA (lumateperone) for the treatment of bipolar depression in adults

. News Release. Intra-Cellular Therapies. December 20, 2021. Accessed December 20, 2021.

FDA approves Intra-Cellular Therapies’ novel antipsychotic, CAPLYTA (lumateperone) for the treatment of schizophrenia in adults

. News Release. Intra-Cellular Therapies. December 23, 2019. Accessed December 20, 2021.

Caplyta is now FDA-approved for depressive episodes from bipolar I and II.

FDA Approves New Treatment for Bipolar Depression

In every branch of science, nomenclature plays a vital role in allowing a common language to be employed so that a clear and consistent meaning is applied to any term that is routinely used. Such is the case when describing the mechanism of action of a particular drug at a particular receptor—or so it used to be. The title of this editorial may appear to contain a typographical error, but it does not: It is exactly as I wrote it. As the science behind receptor pharmacology has become increasingly complex, a common term currently used to describe a receptor mechanism of action—partial agonism—has served to confuse rather than clarify the mechanism of many drugs placed in this category.

All drugs—in fact, all molecules—have a specific binding affinity for a specific receptor in a prespecified chemical environment. This is commonly referred to as the drug’s inhibition constant (Ki) at a particular receptor and is usually written as a concentration in nanomoles (nM). The FDA-approved product insert of every drug lists the Ki’s at all relevant receptors in Section 12—Clinical pharmacology, subsection 12.2—Pharmacodynamics. The smaller the Ki at a particular receptor, the tighter the drug binds to that specific receptor.

As an example, drug X has a Ki = 1 nM at the dopamine-2 receptor (D

R) and a Ki = 100 nM at the histamine-1 receptor (H1R). That translates clinically into a mechanism of action whereby drug X is very potent at the D

R, but 100-fold weaker at the H1R. If drug X is an antagonist at these 2 receptors, this predicts with high likelihood that drug X would be a good antipsychotic, but a weak antihistamine. If the antagonist drug Y, on the other hand, has a Ki = 1 nM at the H1R and a Ki = 100 nM at the D

R, drug Y should be a great antihistamine, but a weak antipsychotic.

The Ki gives us an important piece of information, but it does not tell us the complete story about what that drug is actually doing at a particular receptor—only how tightly it is binding. Many psychiatric medications bind to multiple receptors from the same or different neurotransmitter systems. To clarify, Ki’s are determined in vitro, and they can vary from one assay to another due to the properties of each assay (eg, pH, ion concentrations, temperature, and other physical chemistry properties). This explains why we can see a range of Ki’s for the same drug at the same receptor from different studies. Despite these differences, the general properties of a drug at various receptors remains consistent across different assays. (Nonetheless, this situation supports the strong need for developing a Ki database based on exactly the same assay conditions for each drug/receptor studied.) The good news is that following the 2003 sequencing of the human genome, receptors that are utilized to determine the binding affinities of drugs that will be used in humans are now cloned from the human genome. In years past, it was common to use rat, mouse, rabbit, or monkey receptors, which are not predictably analogous, structurally, to the corresponding human receptors.

How Does the Drug Impact Receptor Functioning?

Once we have determined the Ki of a specific drug at a specific receptor in a well-defined and reproducible chemical environment (assay), the next step is understanding how that drug changes the activity of the receptor. In the early days of pharmacology, it was simply a matter of determining if a drug appeared to agonize (activate) the receptor or antagonize (block) the receptor. Through decades of increasingly sophisticated research in many areas of basic science, our current understanding defines a wide spectrum of drug–receptor functional actions. Our current descriptions of drug–receptor activity that may occur when a drug binds to a receptor can be found in the 

Confusion of the Descriptor “Partial Agonism”

Let us focus on 2 of these mechanisms, both of which have been used interchangeably and, as a result, have confused the practicing clinician regarding what is actually going on at the drug–receptor interface in our patients’ brains: partial agonism (PA) and antagonism/partial agonism (AT/PA). When I was receiving my biochemistry training, these descriptors clearly differentiated 2 distinct mechanisms of action of a drug.

A PA would bind to a receptor of an endogenous neurotransmitter (EN) and provide some degree of agonism, but less than a full agonist—it would function the same as the EN. Hence, in the absence of the EN, the PA would provide some degree of receptor stimulation. In the presence of the EN, the PA would synergize with the EN and increase the overall agonism to some degree. If the EN was at 100% occupancy of its receptor, the PA would contribute very little.

An AT/PA drug provides both of these functions simultaneously. Clinically useful AT/PA drugs have binding affinities at the target receptor that are much stronger than the binding affinity of the EN. This combination of AT and simultaneous PA at the EN receptor allows for a predictable pharmacodynamic effect if the AT/PA is dosed to occupy 100% of the target receptor. At full AT, the percent of PA determines the functional activity of the EN receptor. If the AT/PA has 10% PA, it functions as an antagonist. If the AT/PA has 90% PA, it functions as an agonist. Consequently, you could create a series of AT/PA drugs that all share the same potent AT, but their PA would range from 1% to 99%. When dosed to 100% antagonism, the percent PA would determine the functional activity of that receptor. This allows for a predictable effect at the EN receptor.

When both PA and AT/PA are described as PA, as they currently are in the psychiatric literature, the opportunity to understand the clinical effect of the drug is lost, as these mechanisms are not differentiated. Two excellent publications describing the AT/PA activity of buprenorphine

 from 2008 and 2010, respectively, specifically define these drugs as AT/PA in the papers’ titles. Over the past 10 years, for reasons that I do not understand, the term partial agonist has become synonymous with both AT/PA and PA.

Buprenorphine is a commonly prescribed drug that has a predictable effect on an individual who is using opioid(s), based on its activity as an AT/PA at the mu opioid receptor (MOR). Understanding its AT/PA provides an exemplary model of how this combination of receptor effects manifests clinically. PET scans on live human brains have demonstrated that buprenorphine occupies close to 100% of the MORs at doses between 18 mg and 24 mg per day, depending on the patient. Like naltrexone, naloxone, and samidorphan, buprenorphine is a potent antagonist at the MOR, but unlike the other 3, it also has functional simultaneous partial agonism approximately equal to 20 mg of methadone at full MOR occupancy. Being a potent antagonist at the MOR, buprenorphine displaces endorphins and most mu opioid agonists, including morphine, heroin, oxycodone, oxymorphone, hydrocodone, hydromorphone, and methadone. This combined AT and PA is the pharmacological reason buprenorphine is such a successful drug in the treatment of opioid use disorders.

Any seasoned buprenorphine prescriber will tell you that adding 24 mg of buprenorphine to an individual’s regimen when that person has been taking more than 30 mg of methadone for several months will result in immediate severe opioid withdrawal.

 The potent antagonism prevents other mu opioid agonists from synergistically increasing buprenorphine’s agonism at the MOR. Referring to buprenorphine as a PA does not convey the complexity of what is happening at the MOR: potent antagonism that displaces endorphins and most opioid agonists, while simultaneously partially agonizing the MOR with approximately 20-mg equivalents of methadone.

All antipsychotics, both typical (first generation) and atypical (second generation), are pure D

R antagonists except for 3: aripiprazole, brexpiprazole, and cariprazine. These 3 are sometimes called “third generation” due to their shared property of AT/PA at the D

R creates different pharmacological rules than those we apply for the other antipsychotics. Referring to these 3 antipsychotics as 

 creates a great deal of confusion about their mechanism of action as well as how to dose them when cross-titrating from a pure antagonist or when they are used in combination therapy.

R that is pharmacologically relevant to the efficacy of aripiprazole, brexpiprazole, and cariprazine as antipsychotics. These 3 agents are the most potent of all FDA-approved antipsychotics, with subnanomolar Ki’s ranging from 0.3 to 0.49 nM. To effectively treat psychotic symptoms, all 3 antipsychotics are dosed to nearly saturate the D

R, which would lead to severe movement disorders, hyperprolactinemia, cognitive blunting, and dysphoria were it not for their PA. At the doses necessary for these 3 drugs to be effective in treating psychotic symptoms, they approach 100% D

R antagonism, hence displacing most other antipsychotics as well as dopamine from the D

The degree of PA for these drugs at the D

R ranges from approximately 25% to 35%, which is occurring simultaneously with the nearly saturated D

R antagonism. This results in a functional neuronal physiology of 65% to 75% D

R antagonism, which is considered the ideal antagonism to treat psychotic symptoms. Not surprisingly, none of the 3 drugs raise prolactin levels, as none achieve greater than 75% D

R saturation. At low doses, the partial agonism may contribute to their antidepressant properties.

When prescribing medications, a clinician relies on a drug’s defined pharmacokinetic and pharmacodynamic properties, involving numerous factors, to make informed choices as to what medication to use. One of those factors is the mechanism of action occurring at the various drug–receptor interfaces. The casual use of the term 

, rather than more specifically defining a drug’s mechanism as a PA or an AT/PA, can result in unexpected and problematic clinical outcomes.

 is medical director, Brain Health, Exeter, New Hampshire; Editor in Chief, 

; staff psychiatrist, Seacoast Mental Health Center, Exeter; consulting psychiatrist, Exeter Hospital, Exeter; and consulting psychiatrist, Insight Meditation Society, Barre, Massachusetts.

Naloxone reversal of opioid-induced respiratory depression with special emphasis on the partial agonist/antagonist buprenorphine

2. Kiss B, Horváth A, Némethy Z, et al. 

Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist–partial agonist antipsychotic candidate: in vitro and neurochemical profile

High dose antipsychotic polypharmacy and dopamine partial agonists – time to rethink guidelines?

The importance of specifically defining a drug’s mechanism as partial agonism or antagonism/partial agonism for better clinical outcomes.

Is That Drug a Partial Agonist or a Partial Agonist?

Although the ultimate goal of pharmacological treatments is to help the patient, sometimes medications can cause adverse effects. Such is the case with some psychiatric medications that can trigger Torsades de Pointes (TdP), a potentially fatal polymorphic ventricular tachycardia that arises during abnormal ventricular repolarization. Prolongation of the corrected QT interval (QTc) on the 12-lead electrocardiogram (ECG) 

 is a primary marker of TdP risk and a major drug safety benchmark used by the US Food and Drug Administration (FDA). As such, psychiatric clinicians must be aware of the risk factors that increase risk of TdP; in addition, they must feel confident performing individual risk-benefit analyses when prescribing a medication with known risk. An important part of this process is basic proficiency in ECG interpretation, including recognition and measurement of relevant intervals and application of appropriate corrections for heart rate (HR) and QRS duration.

Medications that prolong ventricular repolarization do so through direct blockade of the inward rectifier potassium channel encoded by the human ether-a-go-go related gene.

 This blockade results in slowed efflux of potassium from cardiac myocytes prolonging the duration of the cardiac action potential and the QT interval on the ECG. TdP is typically triggered by early afterdepolarizations, which are ectopic activations of the ventricles arising during the prolonged repolarization phase.

Most cases of TdP occur in the context of multiple risk factors, including use of more than 1 QTc prolonging medication, female sex, older age, bradycardia, personal history of structural or functional heart disease, personal or family history of sudden cardiac death, renal impairment (especially hemodialysis), hepatic impairment, and electrolyte disturbance (eg, hypokalemia, hypomagnesemia, hypocalcemia). Close attention should be given to co-administered medications that may inhibit metabolism of high-risk QTc-prolonging medications.

The cardiac action potential begins with transmission of electrical activity from the sinoatrial node to the atrioventricular (AV) node, corresponding to the PR interval on the ECG. Electrical impulses then travel rapidly from the AV node through the His-Purkinje system, leading to rapid and synchronized ventricular depolarization, represented by the QRS complex. Repolarization of the ventricles occurs during the JT interval, which begins at the J-point (end of the QRS complex) and ends with termination of the T-wave. Notably, the QT interval includes the QRS complex and the JT interval, encompassing both ventricular depolarization and repolarization.

What About Heart Rate Correction of the QT Interval?

It is well recognized that the QT interval is HR dependent. Since the 1920s, the Bazett formula (QTc = QT/RR1/2) has been primarily used to derive the “heart rate–corrected QT interval,” or QTc, in clinical and research settings. Most computerized ECG interpretation software uses the Bazett formula by default. Unfortunately, the Bazett formula is well known to overestimate the QTc during fast HR and underestimate it at lower HR. Recognizing this inadequacy, the FDA transitioned from use of the Bazett formula to the Fridericia formula (QTc = QT/RR1/3) in 2017 for drug monitoring studies.

 The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) recommend use of linear regression formulae such as Hodges, Framingham, or nomogram for HR correction.

 A comprehensive study of more than 6000 participants comparing 5 HR correction formulae demonstrated the most consistent QT correction (ie, HR independent) by Fridericia and Framingham.

 In general, the Fridericia, Hodges, and Framingham QTc formulae (

) have the most consistent data and are found in most online or app-based QTc calculators. Although the QTc is considered abnormal when it is above 450 ms in men and above 460 ms in women, TdP does not typically occur when the QTc is <500 ms. Most practitioners use 500 ms as an informal QTc cutoff.

Ventricular conduction delay from bundle branch block or ventricular pacing manifests as widening of the QRS (QRS ≥ 110 ms) due to slowed, cell-to-cell depolarization of the myocardium rather than rapid conduction through the His-Purkinje system. Widening of the QRS complex artificially prolongs the QT interval without prolonging repolarization.

 Psychiatrists who frequently treat patients with cardiac disease should be familiar with methods to correct the QT interval for a wide QRS. Failure to correct for a wide QRS may result in inappropriate withholding or underdosing of necessary psychotropic medication. Recommendations by the ACC/AHA/HRS suggest use of a bivariate formula using both HR and QRS as variables, or the JTc (upper limits of normal: men = 355 ms, women = 372 ms).

What About Specific Psychoptropic Medications?

Many classes of medications, both psychotropics and commonly used nonpsychotropics, can prolong the QTc and increase the risk of TdP.

 One of the best online registries of QTc-prolonging medications is 

. CredibleMeds® catalogues medications according to 4 main categories: possible risk (evidence for QTc prolongation); conditional risk (evidence for QTc prolongation under certain conditions, such as overdose, or when combined with another drug that inhibits metabolism of the primary drug); known risk (evidence for TdP); and drugs to avoid in congenital long QT. Although CredibleMeds® is a comprehensive registry, the levels of evidence are highly variable, with many designations based only on case report. Psychiatrists must be familiar with the evidence for individual drugs to best inform a clinical decision. In the next sections, we will highlight the key medications that all psychiatrists should know.

. Due to the rare nature of TdP, which can be silently lethal, it is difficult to study TdP as a primary outcome measure. Prolongation of the QTc serves as the closest proxy; however, QTc prolongation is only a marker of risk and not an absolute predictor of TdP. Methadone is among the few medications with TdP as a known outcome and deserves vigilance.

 Guidelines for methadone safety and cardiac risk management have been developed by the Substance Abuse and Mental Health Services Administration

 as well as by a joint effort of the American Pain Society and HRS.

 Neither set of guidelines recommends pretreatment ECG in the absence of other risk factors, but this issue has been controversial. Both sets of guidelines balance vigilant monitoring for cardiac risk with attention to harm-reduction strategies, such that ECG screening does not become a barrier to methadone treatment. Methadone is not recommended in patients with a QTc ≥ 500 ms. For patients with a QTc higher than 450 ms but less than 500 ms, alternatives like buprenorphine should be considered when possible. All modifiable risk factors for TdP should be evaluated and corrected prior to methadone initiation. There is not consensus on the frequency of follow-up ECGs; however, this should depend on the baseline QTc (if performed) and the presence of other risk factors. ECGs should also be performed following dose changes or when total daily dose exceeds 120 mg.

In 2011, the FDA issued a drug safety communication regarding citalopram, noting that it should not be prescribed at doses greater than 40 mg and should not be used at doses greater than 20 mg in those with liver dysfunction or who are 60 years or older. It was further noted that 60-mg dosing was no more efficacious than 40-mg dosing. This guidance was based on a single study that demonstrated an increased QTc of 8.5 ms at 20 mg and 18.5 ms at 60 mg. In 2012, the FDA downgraded their guidance, stating that citalopram was not recommended at doses greater than 40 mg and should be discontinued in anyone with a QTc greater than 500 ms.

Since the FDA recommendations, multiple studies have demonstrated similar resultHowever, studies examining risk of ventricular arrhythmia, sudden cardiac death, and all-cause mortality have shown no difference between citalopram and other selective serotonin reuptake inhibitors (SSRIs). Furthermore, patients on higher doses of citalopram that were reflexively reduced have increased risk of adverse psychiatric outcomes. Ultimately, the QTc prolongation risk with citalopram is statistically significantly higher than that with the other SSRIs, but the actual clinical risk is likely minimal.

 It is reasonable to obtain a pretreatment and steady-state ECG in patients prescribed citalopram who have other risk factors for TdP.

Intravenous (IV) haloperidol may be best known for its reputation to cause TdP; however, few data exist to support this impression. A systematic review of 77 clinical trials and case reports/series by Beach et al13 revealed that most prospective studies did not show a difference in QTc prolongation between IV haloperidol and placebo and no greater QTc prolongation than with other antipsychotics. Because IV haloperidol is used in the general hospital setting, often in the intensive care unit, most studies of IV haloperidol have unavoidable confounders, including severe medical illness (including electrolyte disturbance), older age, underlying cardiac disease, and concurrent use of multiple QTc-prolonging medications. When using IV haloperidol, it is reasonable to check a baseline ECG, consider daily ECG if other risk factors are present, mitigate as many modifiable risk factors as possible, and implement continuous monitoring or alternative agents if the QTc is greater than 500 ms or cumulative dosage of IV haloperidol exceeds 100 mg.

Althoughnearly all antipsychotics have been associated with QTc prolongation, there is significant variability across the medication class. Of the typical antipsychotics, the low-potency phenothiazines, including thioridazine and chlorpromazine, have been most consistently associated with QTc prolongation. Ziprasidone has the most QTc prolongation of the atypical antipsychotics. Of the other atypical antipsychotics, quetiapine is associated with mild-to-moderate QTc prolongation, with mixed data. Olanzapine, risperidone, and clozapine are considered to cause mild prolongation of the QTc. Aripiprazole and lurasidone have the best cardiac safety profile of all antipsychotics.

There are no absolute recommendations for ECG monitoring when prescribing antipsychotics. Depending on the presence of other TdP risk factors and the specific risk associated with the individual antipsychotic, psychiatrists may consider obtaining a baseline and steady-state ECG with vigilance for QTc greater than 500 ms or a QTc increase of 60 ms or more following medication initiation.

Other antidepressants and mood stabilizers. 

In healthy patients with no underlying heart disease, tricyclic antidepressants administered at therapeutic doses likely have little impact on the QTc, with low risk of TdP. However, TdP can occur in cases of overdose or when these drugs are used in patients with underlying cardiac disease, especially ventricular conduction delay or ischemic heart disease.

 Of the other antidepressants, including SSRIs and serotonin-norepinephrine reuptake inhibitors, citalopram carries the most risk of QTc prolongation. Sertraline is the best studied and has the best cardiac safety profile for patients with heart disease. Antiepileptic medications used for mood stabilization have not been shown to prolong the QTc. The few studies of lithium have not demonstrated clinically significant QTc prolongation when serum levels are within the therapeutic range.

 Supratherapeutic lithium levels are associated with modest increases of QTc.

Some of the most common nonpsychotropic medications have significant QTc prolongation and deserve special attention. These include the macrolide antibiotics (eg, azithromycin), antifungals (eg, fluconazole), most antiemetics (eg, ondansetron), furosemide (mediated by fluctuation of potassium), and antiarrhythmics (eg, amiodarone).

 Many of these medications are known cytochrome P450 inhibitorsof other QTc-prolonging medications, and they require vigilance, with consideration for alternatives, when used in combination.

When prescribing medications with known risks of QTc prolongation or TdP, psychiatrists must perform a comprehensive risk-benefit analysis, taking into consideration the QTc, risk factors for TdP, strategies to mitigate cardiac risks when possible, and potential psychiatric adverse outcomes that would arise from not prescribing a medication.

is the program director of the Harvard South Shore (HSS) psychiatry residency training program.

is an interventional cardiologist at Brigham and Women’s Hospital.

hERG potassium channels and cardiac arrhythmia.

2. Lankipalli RS, Zhu T, Guo D, Yan G-X. 

Mechanisms underlying arrhythmogenesis in long QT syndrome.

3. Funk MC, Beach SR, Bostwick JR, et al. 

QTc prolongation and psychotropic medications.

4. Center for Drug Evaluation and Research; Center for Biologics Evaluation and Research. Guidance document: E14 Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs [—] questions and answers (R3) guidance for industry. FDA. June 2017. Accessed September 28, 2021. 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e14-clinical-evaluation-qtqtc-interval-prolongation-and-proarrhythmic-potential-non-antiarrhythmic-1

5. Rautaharju PM, Surawicz B, Gettes LS, et al; American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; American College of Cardiology Foundation; Heart Rhythm Society. 

AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology.

6. Vandenberk B, Vandael E, Robyns T, et al. 

Which QT correction formulae to use for QT monitoring?

QT interval and repolarization time in patients with intraventricular conduction delay.

8. Yankelson L, Hochstadt A, Sadeh B, et al. 

New formula for defining “normal” and “prolonged” QT in patients with bundle branch block.

9. Romero J, Baldinger SH, Goodman-Meza D, et al. 

Drug-induced torsades de pointes in an underserved urban population. methadone: is there therapeutic equipoise?

10. Martin JA, Campbell A, Killip T, et al; Substance Abuse and Mental Health Services Administration. 

QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel.

11. Chou R, Cruciani RA, Fiellin DA, et al; American Pain Society; Heart Rhythm Society. 

Methadone safety: a clinical practice guideline from the American Pain Society and College of Problems of Drug Dependence, in collaboration with the Heart Rhythm Society.

12. Beach SR, Celano CM, Sugrue AM, et al. 

QT prolongation, torsades de pointes, and psychotropic medications: a 5-year update. 

13. Beach SR, Gross AF, Hartney KE, Taylor JB, Rundell JR. 

Intravenous haloperidol: a systematic review of side effects and recommendations for clinical use.

Cardiovascular effects of antidepressant drugs: updated.

15. Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SH. 

QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients.

16. Hsu C-H, Liu P-Y, Chen J-H, Yeh T-L, Tsai H-Y, Lin L-J. 

Electrocardiographic abnormalities as predictors for over-range lithium levels.

17. Drug Interactions Flockhart Table™. Indiana University, School of Medicine, Department of Medicine: Clinical Pharmacology. Accessed September 28, 2021. 

https://drug-interactions.medicine.iu.edu/MainTable.aspx

Some psychiatric medications that can trigger Torsades de Pointes (TdP), a potentially fatal polymorphic ventricular tachycardia that arises during abnormal ventricular repolarization. Are you aware of the risk factors that increase risk of TdP?

The Fundamentals of QTc: Understanding Risks and Preventing Problems

Reviewed by Karen B. Rosenbaum, MD, and Susan Hatters Friedman, MD

 is a novel by Australian author Liane Moriarty,

, which was made into a 2-season HBO series. 

was recently adapted into an 8-episode Hulu miniseries, which premiered on August 18, 2021. Although there are many important plot changes between the novel and the miniseries, the miniseries is very well cast, making Moriarty’s characters come to life. Both the novel and the miniseries deal with 9 people who want to reinvent themselves through an exclusive (and expensive) 10-day “wellness” retreat led by a mysterious woman named Masha, played seemingly effortlessly by Nicole Kidman.

[Spoiler Alert] Masha’s backstory is that she was a ruthless, successful businesswoman who nearly died (the method is different between the novel and the miniseries) and was rescued by a mild-mannered, eager Yao (played by Manny Jacinto from 

, who was then a practicing EMT. She survived and changed her life, building “Tranquillum House,” an idyllic wellness retreat where the 9 perfect strangers meet. The novel is set in Australia, but the miniseries is set in the fictional town of Cabrillo, California, although it was filmed in New South Wales, Australia.

Psychiatric themes include suicide and experimental psychopharmacology. For example, the Marconi family are 3 of the Tranquillum House guests: They are the parents and twin sister of a deceased boy who each blame themselves and each other after the boy—17-year-old Zachary—died by suicide 3 years prior. In the book, Zachary’s mother, Heather Marconi, reveals that she did not pay attention to the side effects on the insert of a new asthma medication Zachary was taking, 1 of which was suicidal ideation. In the show, she only remembers reading this while under the influence of Masha’s LSD. In the book, the sister of another guest, Ben, dies by drug overdose after losing a long battle with addiction.

The miniseries takes many liberties with the plot of the novel, including changing characters’ professions, which ultimately shifts the tone of the story. For example, another character, Carmel, a mother of 4 whose husband left her for another woman, becomes violent in the show, but not in the novel. These plot and character changes do increase the suspense, but they also make the characters more 1-dimensional. The book feels less mysterious, but in both, the person responsible for the wellbeing of 9 people, Masha, has a dark past and a narcissistic side that drives her to do things that are self-serving and not in the best interest of others. In both the miniseries and the novel, when the guests eventually realize that they are being medicated, Masha calmly tells them, “It’s called ‘microdosing,’ and it’s perfectly safe.”

Microdosing usually implies taking very small amounts of a psychedelic such as LSD or psilocybin-containing mushrooms—not necessarily enough to cause an altered state of consciousness, but enough to experience an elevation in mood. Well-respected establishments such as the Depression Evaluation Service at Columbia University

 are currently researching the use of psychedelic medications, and several studies examine the risks and benefits of low-dose psychedelics. For example, in 2020, Lea et al“examined motivations, dosing practices, and perceived benefits and limitations of microdosing.” They found that reported benefits included “cognitive and creative enhancement, reduced depression and anxiety, enhanced self-insight and mindfulness, improved mood and attitude toward life, improved habits and health behaviors, and improved social interactions and interpersonal connections.” Some of the negative effects included that these drugs are still illegal, involve self-administration, bring only short-term benefits, and may result in more frequent “off” days.

One of the many problems with Masha microdosing her guests through smoothies is that there is no consent. The guests are unaware that this is happening, and some of them have possible contraindications to psychoactive medications such as other medical conditions and family histories of addiction. The microdosing also causes frank hallucinations. The Marconi family, for example, all see the deceased Zachary. There are also unpleasant side effects, as seen in a study by Anderson et al where 18% of people described physiological discomfort and 7% described increased anxiety.

In the 8th and final episode, Masha makes an ironic attempt to show some semblance of therapeutic integrity. When the Marconi family confronts Masha, saying she left out vital information indicating that she had ulterior motives for helping them hallucinate Zachary, Masha replies, “It’s not acceptable for a ‘therapist’ to be talking about her own life.”

Despite some interesting character development in terms of some of the backstories of the guests and of Masha and her staff, there are very few likeable characters. Although they are all human in terms of having flaws, weaknesses, and difficulties, it is difficult to relate to them at times. Wellness retreats are gaining in popularity, and the benefits of yoga, meditation, and other alternative medicines are widely known and accepted in our field. However, the experimental practices at the fictional Tranquillum House are off-putting and potentially harmful, and they may potentiate fears around the mental health and wellness communities. There are also frank references in the miniseries to Western psychiatric facilities not being as safe as Masha’s experimental “wellness” facility. It is important as psychiatrists to know what entertainment our patients are consuming so that we can dispel potential myths around mental health and experimental psychopharmacology.

is a clinical and forensic psychiatrist in private practice in New York. She is an assistant clinical professor at New York University Langone Medical Center and on the faculty at Weill Cornell Medical Center. 

 serves as the Phillip Resnick Professor of Forensic Psychiatry at Case Western Reserve University, Cleveland. She is also editor of 

Family Murder: Pathologies of Love and Hate

 (Washington, DC: American Psychiatric Association Publishing, 2019), which was written by the Group for the Advancement of Psychiatry’s Committee on Psychiatry & Law, and was awarded the 2020 Manfred Guttmacher Award by the American Psychiatric Association.

Inside the Tranquillum House from Hulu’s Nine Perfect Strangers

. August 25, 2021. Accessed September 5, 2021.

. Columbia University. 2021. Accessed September 13, 2021. 

Psychedelic microdosing: a Subreddit analysis.

5. Anderson T, Petranker R, Christopher A, et al. 

Psychedelic microdosing benefits and challenges: an empirical codebook

Microdosing at “Tranquillum House,” and its implications for real-world experimental psychopharmacology.

Nine Perfect Strangers

An open-label study of psilocybin therapy for depression in patients with cancer found that 50% of participants achieved remission of depression symptoms within 1 week of receiving COMP360 psilocybin therapy.

Results suggest that psilocybin therapy may prove to be helpful in improving quality of life for patients with cancer. 

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The Fundamentals of QTc: Understanding Risks and Preventing Problems

Nine Perfect Strangers

Study Finds Psilocybin Improves MDD in Patients With Cancer

Traveling the Middle Road Between Skepticism and Scientism

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