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This column is the third in a 3-part series describing cases in which general medical knowledge, including psychiatric and clinical pharmacology, was instrumental in determining whether dereliction was the direct cause of damages in a malpractice suit. This case illustrates how not taking into account the following variables can result in a false-positive diagnosis of a lethal serotonin syndrome: (a) the time course of treatment, (b) the time course of symptoms, (c) the difference between antemortem plasma and postmortem whole-blood levels of highly protein bound and highly lipophilic drugs. The case also illustrates how taking those 3 variables into account led to the conclusion that there was no dereliction in the care of the patient that was the direct cause of his death, and hence, there was no medical malpractice., Competing Interests: Over his 45-year career, S.H.P. has worked with over 145 pharmaceutical and biotech companies in the United States and throughout the world. Over the past year, 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, and Janssen. There were no clinical trial and study contracts during the 2 years preceding this paper, but any would have been with and payments made to the Kansas University Medical Center Research Institute, a research institute affiliated with the Kansas University School of Medicine-Wichita. The remaining author declares no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This column is the second of a 3-part series describing cases where general medical knowledge, including psychiatric and clinical pharmacology, were instrumental in determining dereliction and direct cause in a malpractice suit. This case summarizes how lamotrigine can cause dangerous consequences if its pharmacology is not properly understood. The case also illustrates how the 4 Ds of a forensic malpractice suit were met in this case. First, there was duty on the part of the prescriber which, if followed, would have prevented or minimized the damages experienced by the patient. Dereliction in the performance of a patient-physician treatment contract was a direct cause of the development of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in this patient. An immune-mediated reaction to lamotrigine or one of its metabolites has been extensively reported in the literature, with the risk of this reaction increasing at higher doses and with more rapid titration, fulfilling the elements of direct cause. Dereliction implies a deviation from the standard of care. On the basis of the clinical information from the package insert, more likely than not a deviation from the standard of care occurred in this case when lamotrigine was titrated faster than recommended by the package insert., Competing Interests: Over his 45-year career, S.H.P. has worked with over 145 pharmaceutical and biotech companies in the United States and throughout the world. Over the past year, 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, and Janssen. There were no clinical trial and study contracts during the 2 years preceding this paper, but any would have been with and payments made to the Kansas University Medical Center Research Institute, a research institute affiliated with Kansas University School of Medicine-Wichita. D.D.M. declares no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This column is the first of a 3-part series illustrating the importance of medical knowledge, including clinical pharmacology, in a forensic context. This first case involved an 18-year-old high school student who suffered an anoxic brain injury and remained in a state of permanent decorticate posture, unresponsive except for grunts and primitive movements until he died several years later. Our investigation began by ruling out plausible causes that were suggested by the defense in the malpractice suit. Once those possibilities were eliminated, the focus was on what accounted for the damage to the patient using general medical knowledge and clinical pharmacology. The 4 Ds of forensic psychiatry (duty, damages, dereliction, and direct cause) are the 4 elements that the plaintiff is required to prove in civil court to prevail in a malpractice suit and are applied to this case with a special focus on dereliction and direct cause. This catastrophic outcome was due to 3 factors. First, the patient had physiologically significant dehydration to the point that he had developed a reflex tachycardia to maintain his blood pressure. Second, the patient had been switched from extended to immediate-release quetiapine, resulting in a doubling of the peak concentration of the drug, which produced higher occupancy of alpha-1 adrenergic, histamine-1, and dopamine-2 receptors, causing a further drop in his blood pressure as well as increased sedation and impairment of his gag reflex. These effects occurred quickly because of the faster absorption of the IR formulation of the drug. Third, the patient had gone to sleep in a reclining chair so that his brain was above his heart and his lower extremities were below his heart, resulting in an increased "steal" of cardiac output going to his brain. These 3 factors together led the patient to aspirate and suffer a hypoxic brain injury after an episode of vomitus. This column explains the process by which the cause of this sad outcome was determined, how it was related to a dereliction of duty to the patient, and how other proposed causes were ruled out., Competing Interests: Over his 45-year career, S.H.P. has worked with over 145 pharmaceutical and biotech companies in the United States and throughout the world. Over the past year, 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, and Janssen. All clinical trial and study contracts were with and payments made to the Kansas University Medical Center Research Institute, a research institute affiliated with Kansas University School of Medicine-Wichita. The remaining author declares no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This column focuses on the status of intravenous racemic ketamine for the treatment of patients suffering from a form of major depressive disorder that does not respond to trials of currently available biogenic amine antidepressants. To provide context, the column reviews the 3 pivotal elements of the usual Food and Drug Administration (FDA) drug approval process: (1) the unmet medical need (ie, the indication) for which the drug is being developed, (2) the efficacy of the drug for that condition, and (3) the safety/tolerability of the drug. This column is based on the author's 45-year history of drug development work and is not a statement of the FDA. There are typically 3 phases in the drug development process: (1) studies done in normal volunteers, (2) typically small-scale proof of concept studies, and (3) large-scale registration trials. This third phase is critical in determining the efficacy, safety, and tolerability of the drug in a manner that most closely follows the clinical use of the drug. This column focuses specifically on whether generally small-scale studies done in academic centers are sufficient for drug approval, and it briefly reviews lithium and clozapine as examples of psychiatric medications that had such academic research in the literature, as well as clinical use in other countries. Those data supported the unique value of these medications in patients with bipolar disorder and treatment-resistant schizophrenia (ie, the unmet medical need), respectively, and the findings led American psychiatrists to advocate for FDA approval of these medications. Their efforts led to the needed registration trials for FDA approval of these medications. This column reviews the key features of registration trials and the reason that they are critical for FDA approval, and it discusses 2 special considerations related to the intravenous administration of racemic ketamine. First, racemic ketamine is not esketamine but, instead, it contains R-ketamine in addition to S-ketamine (ie, esketamine). The second consideration is that differences between intravenous and intranasal administration may affect the safety of the drug. While safety concerns were specifically addressed in the registration trials for esketamine, comparable research remains to be done for intravenous racemic ketamine. Understanding how the FDA's drug approval process works is important for prescribers, their patients, and the public., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This column presents a way of conceptualizing the clinical practice of medicine including psychiatry within the framework of the scientific method. The goal is to aid practicing clinicians as well as trainees. This conceptual framework will improve the care of patients as it applies a discipline relative to giving time-limited trials of the various treatments available and then an assessment of whether the treatment worked adequately or not and what to do in the latter case. In this way, this approach should decrease the risk of excessive multiple medication use to treat a specific patient. Incorporating this conceptual framework early in the training of mental health care prescribers would be desirable., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Clomipramine (CIMI) is an effective treatment for obsessive-compulsive disorder in patients who have failed to respond to trials of selective serotonin transport inhibitors (eg, sertraline). The case presented here illustrates how knowledge of the pharmacodynamics and pharmacokinetics of CIMI in a specific patient can be used to personalize treatment to optimize the likelihood of efficacy (ie, maximum benefit to risk ratio). The approach described in this column considered: (1) the patient's diminished ability to clear CIMI and its major metabolite, desmethlyclomipramine due to a genetic deficiency in cytochrome P450 2D6 enzyme activity, and (2) the patient's ability to extensively convert CIMI to desmethlyclomipramine. That conversion impairs the ability to inhibit the serotonin transporter, the mechanism that is most likely responsible for the efficacy of CIMI in obsessive-compulsive disorder., Competing Interests: Over his 45-year career, S.H.P. has worked with over 145 pharmaceutical and biotech companies in the United States and throughout the world. Over the past year, 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, Janssen. All clinical trial and study contracts were with and payments made to the Kansas University Medical Center Research Institute, a research institute affiliated with Kansas University School of Medicine-Wichita. R.R. declares no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Eight different cases are presented in this column, along with the lessons and principles that can be learned from each. The lessons and principles are general in nature and hence they are applicable to patients that readers will likely encounter., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This column reviews the neurobiology of the sleep-wake cycle as it is currently known, the 7 classes of currently available sleep-enhancing medications, and how their mechanisms of action relate to the neurobiology of sleep. Clinicians can use this information to select medications for their patients, which is particularly important because some patients respond to some of these medications but not others, or tolerate some but not others. This knowledge can also help the clinician switch among classes when a medication that was initially efficacious begins to fail a patient. It can also prevent the clinician from cycling through all of the members of a single medication class. Such a strategy is unlikely to be helpful for a patient except in the situation in which pharmacokinetic differences among members of the medication class result in some agents in that class being helpful for a patient who has either a delayed onset of action or undesirable carry-over effects with other agents in that class. An understanding of the classes of sleep-enhancing medications highlights the importance of knowing the neurobiology that underlies a psychiatric illness. The activity of a number of neurobiological circuits, such as the one reviewed in this column, has now been well established, while work to understand others is still at a much earlier stage. Psychiatrists who gain an understanding of such circuits will be better able to provide effective care for their patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This column provides some criteria for evaluating whether a case series or case report may warrant publication. It will emphasize the value of having biomarker data in addition to clinical data to enhance the potential validation of the report and provide ways to test the findings in randomized, controlled clinical trials (RCTs). The potential validity of the case series or report is also high if the outcome is something that would not normally be expected such as, by way of example but not limited to, sudden death or malignant hypertension in someone who had always been normotensive. Examples illustrating how case series/case reports have changed the course of clinical practice or regulatory rules governing drug approval by the US Food and Drug Administration are presented, as well as examples of how those reports have been validated by more rigorous studies including RCTs. The column also includes a discussion of situations in which case series/case reports might have an endpoint (eg, sudden death) that would not be ethical to investigate in an RCT, as well as how biomarkers have been used in such instances to avoid serious untoward outcomes for a participant while still testing the hypothesis., Competing Interests: Over his 45-year career, S.H.P. has worked with over 145 pharmaceutical and biotech companies in the United States and throughout the world. Over the past year, 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, Janssen, Otsuka, Relmada, and Usona Institute. All clinical trial and study contracts were with and payments made to the Kansas University Medical Center Research Institute, a research institute affiliated with Kansas University School of Medicine-Wichita. A.G.A. declares no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This column is the second in a 2-part series presenting the comparative pharmacology of the 3 Food and Drug Administration-approved dual orexin receptor antagonists, daridorexant, lemborexant, and suvorexant. Both of the columns in this series emphasize the pharmacokinetics of these drugs as they are relevant to their use as sleep medications. Although other classes of sleep medications are not discussed, the same pharmacokinetic principles also apply to them in terms of endeavoring to match the pharmacokinetics of an agent to the individual's usual sleep cycle. This second column in the series focuses on the metabolism of each of the 3 drugs by the cytochrome P450 enzyme CYP3A, guidance for using these agents in combination with drugs that are CYP3A inhibitors or inducers, and how to adjust dosing in patients with comorbid conditions such as hepatic or renal impairment., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Based extensively on tables and figures, this chapter reviews drug development in psychiatry with an emphasis on antidepressants from the 1950s to the present and then looks forward to the future. It begins with the chance discovery drugs and then moves to through their rational refinement using structure activity relationships to narrow the pharmacological actions of the drugs to those mediating their antidepressant effects and eliminating the effects on targets that mediate adverse effects. This approach yielded newer antidepressants which compared to older antidepressants are safer and better tolerated but nevertheless do still not treat the approximately 40% of patients with major depression (MD) which is unresponsive to biogenic amine mechanisms of action. This form of MD is commonly referred to as treatment resistant depression. Esketamine is an antidepressant which has a novel mechanism of action: blockade of the glutamate NMDA receptor. These studies coupled with earlier studies with other NMDA drugs suggest approximately 60% of patient with TRD are rapidly and robustly responsive to this mechanism of action. Thus, there appears to be three forms of MD based on pharmacological responsiveness: (a) 60% responsive to biogenic amine mechanisms of action, (b) 24% (i.e., 40 × 60%) responsive to NMDA but not to biogenic amine mechanisms of action, and (c) 16% (i.e., 40-24%) not responsive to either of these mechanisms of action. Scientific investigation of these three groups may yield important information about the pathophysiology and/or pathoetiology of these different forms of MD. This information coupled with studies into the neurobiology (e.g., imaging studies, connectomes to name a few approaches being used) and genetics of MD should provide the fundamental knowledge which will permit a rational search for and discovery of newer antidepressant drugs and other somatic and psychotherapeutic approaches to the treatment of patients with different forms of MD based on pathophysiology and pathoetiology. Examples are given of how such discovery and development have occurred in other areas of medicine and even in central nervous system (CNS) space including six novel mechanisms of action CNS drugs which have been successfully developed and marketed over the last 25 years., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The development of medications used to treat psychiatric conditions has largely proceeded through serendipity, where a potential drug to treat mental illness is identified by chance. This approach is based on a limited understanding of the underlying pathophysiology of mental illness and brain disorders. Identification of novel neurotransmitter systems has allowed for new molecular-based approaches for drug development that identify specific receptor targets to treat a specific symptom. An example of this approach includes the development of suvorexant, which is a dual orexin receptor antagonist FDA approved in 2014 for the treatment of insomnia. This chapter will discuss challenges in psychiatric drug development; the importance of identifying discrete neurotransmitter systems that target a specific symptom, not a syndrome; the orexin pathway and targets within this pathway that can be used to modulate sleep; and a high-throughput approach to streamlining drug development., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Six lessons can be learned from the pivotal registration trials for sublingual dexmedetomidine (SLD) for the treatment of agitation in individuals with bipolar disorder or schizophrenia: (1) Knowing the function of a well-defined circuit in the brain, such as the locus coeruleus (LC), facilitates the development of central nervous system drugs. (2) Agitation can be conceptualized both clinically and physiologically. From both perspectives, agitation can present and escalate along a spectrum from mild, characterized as mainly hyperaroused (possibly only a subjective experience with no observable manifestations in its mildest form), to moderate to severe. In the severe state, the patient poses a potential danger to self and others. The level of agitation a patient is experiencing can determine the most appropriate treatment. Behavioral techniques may be sufficient for the mild state. As agitation progresses beyond mild severity, medication intervention becomes needed. SLD can be effective when agitation is moderate or even more severe. At this stage, patients can recognize and be distressed by their symptoms and participate in treatment. When agitation has escalated to such a severe state that patients can no longer participate in treatment, then intramuscular or intravenous medication may be needed. In quite severe cases, physical restraint as well as medication may be required. The Positive and Negative Syndrome Scale-Excited Component (PANSS-EC or PEC), a subscale of the PANSS, is a helpful instrument to assess where an individual is along the agitation spectrum. The PEC has been used in studies of pharmacological treatments for agitation, and it is accepted by the US Food and Drug Administration as the primary rating instrument in pivotal efficacy studies of treatments for agitation. (3) Where the patient is on the agitation spectrum is a function of the activity of the LC, which can be one factor in determining the SLD dose that will optimize the patient's clinical outcome. Clinical outcome is optimized when complete resolution of agitation is rapidly achieved, and adverse effects either do not occur or are not clinically meaningful. The adverse effects of greatest interest with SLD are decreases in resting systolic and diastolic blood pressures, reductions in these blood pressures under orthostatic stress, and lower resting heart rate. (4) To ensure safety, the subjects in 2 healthy volunteer studies were not administered doses equivalent to those used to treat agitated patients. The highest dose which a healthy volunteer tolerated in those studies was 40 µg. Agitated patients were treated with 120 and 180 µg doses. Thus the difference in doses was 3- to 4.5-fold. Agitated patients could also receive 2 additional half doses with an interval of 2 hours between the first and second administrations. For context, there are other examples of situations in which the dose of a drug that is well tolerated by healthy volunteers is lower than the dose that is well tolerated by patients. For example, it has long been accepted that patients with an acute relapse of schizophrenia can tolerate and need higher doses of D2 antagonists for efficacy than healthy volunteers can tolerate who will generally experience substantial sedation if given what is a clinically effective dose in such patients. (5) Agitation is a state phenomenon that may not recur when it is effectively treated, so that the treatment effect can persist for 24 hours despite the plasma half-life of the drug being 2 to 3 hours. (6) Given the established function of the LC, the fact that the dose response and the time curve of the effect are virtually identical in agitated individuals with bipolar disorder or schizophrenia supports the conclusion that the drug is not treating the syndromic diagnoses of bipolar disorder and schizophrenia but rather the state of being agitated because of overactivity of the LC. These 6 lessons are consistent with the discussions in numerous earlier columns in this series and are critical for both the practice of clinical psychopharmacology and psychiatric drug development., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This column reviews >50 years of research on the functions subsumed by the locus coeruleus (LC) (also called the central adrenergic system). A major role of the LC is monitoring acid-base balance in the brain and responding by regulating blood-brain permeability to water and other small molecules and cerebral blood flow. The LC, through its downward projections, also regulates and coordinates respiratory and cardiac functions. Through its effect regionally or more globally depending on the stimulus and its magnitude, the LC can regulate the extracellular space in the brain, which in turn can alter ionic concentrations and thus the sensitivity of neurons to signaling. As a result of these far-reaching effects, the LC has been implicated in brain functions ranging from sleep and wakefulness to psychiatric conditions such as hyperarousal/hypervigilance, fear, agitation, anxiety, and panic attacks. This understanding of the brain functions subsumed by the LC has, in turn, led to the most recent development in the use of dexmedetomidine, an alpha-2 adrenergic agonist, to treat agitation in patients with bipolar disorder. This column also illustrates a theme discussed in a series of previous columns concerning the successful development of novel psychiatric/central nervous system drugs on the basis of an understanding of relatively simple circuits or mechanisms that underlie pathologic behavior., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This column presents a real-life case of a patient who developed severe and prolonged Parkinsonism secondary to the loading dose strategy recommended in the prescribing information (package insert) for paliperidone palmitate (Invega Sustenna). This column presents 2 major points. First, the case illustrates what the practitioner must do before following the general guidelines for a loading dose approach to the administration of paliperidone palmitate as outlined in the package insert to decrease the likelihood of a serious and potentially fatal consequence. Second, the case illustrates how therapeutic drug monitoring can be useful in assessing and managing patients who develop an untoward reaction. In this case, therapeutic drug monitoring was done using serum prolactin levels because the available laboratory could not measure the level of the drug itself in plasma, and the case highlights some limitations to keep in mind when using plasma prolactin levels to do such monitoring. To put this case in context, a review of the literature was conducted which identified 3 related cases. The author also refers readers to previous articles on therapeutic drug monitoring and pharmacokinetic considerations that arise when using depot (long-acting injectable) antipsychotics., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Novel central nervous system (CNS)-based therapies have been difficult to produce due to the complexity of the brain, limited knowledge of CNS-based disease development and associated pathways, difficulty in penetrating the blood brain barrier, and a lack of reliable biomarkers of disease. Reverse engineering in drug development allows the utilization of new knowledge of disease pathways and the use of innovative technology to develop medications with enhanced efficacy and reduced toxicities. Lorcaserin was developed as a specific 5HT 2C serotonin receptor agonist for the treatment of obesity with limited off-target effects at the 5HT 2A and 5HT 2B receptors. This receptor specificity limited the hallucinogenic and cardiovascular side effects noted with other serotonin receptor agonists. Reverse engineering approaches to drug development reduce the cost of producing new medications, identify specific populations of patients that will derive the most benefit from therapy, and produce novel therapies with greater efficacy and limited toxicity., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

This first column in a 2-part series focuses on the pharmacokinetics of the 3 Food and Drug Administration-approved dual orexin receptor antagonists, daridorexant, lemborexant, and suvorexant, specifically as they relate to their use as sleep medications. Although other classes of sleep medications are not discussed, the same pharmacokinetic principles also apply to them., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This article presents the case of a Vietnamese-American medical student who had 2 distinct identities which were not due to a pathologic process but rather were the result of learning. This case illustrates the complexity of brain function which is fundamental to psychiatry., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Major depressive disorder (MDD) is a descriptive, syndromic diagnosis which will likely be discovered to be more than a single disorder when understood from a pathobiological or pathoetiological perspective. To date, attempts to divide this disorder into more homogenous phenotypes on the basis of signs and symptoms have not yielded more information on the pathobiological or pathoetiological factors that can cause a major depressive episode. This column proposes a new way of dividing MDD into 3 subtypes based on responsiveness to pharmacological treatments that are pharmacologically quite different from each other: type 1, which is responsive to treatment with biogenic amine antidepressants; type 2, which is not responsive to treatment with biogenic amine antidepressants but is responsive to antidepressants that work on the glutamine neurotransmitter system via the N-methyl-D-aspartate receptor; and type 3, which is not responsive to either of these 2 types of antidepressants. The goal of this formulation is to develop biologically meaningful subtypes that can be further studied to understand the pathobiology underlying these 3 types of MDD with the goal of developing newer treatments and earlier ways of diagnosing these conditions., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In response to a question posed by a valued colleague, this column will discuss 4 fundamental pharmacokinetic concepts: (1) What does the term clearance encompass? (2) What do the terms first order and second order pharmacokinetics mean? (3) What does the term nonlinear pharmacokinetics mean and is it just a synonym for zero order pharmacokinetics? (4) What is the clinical relevance, if any, of these concepts and why? In addition, this column cites several earlier columns that are relevant to aspects of each of the answers. Thus, readers interested in more details can refer to these earlier publications that include case examples and figures that further illustrate various points. In considering the clinical relevance of these pharmacokinetic concepts, this column discusses relative binding affinity for targets and the concept of selective versus nonselective drugs, which are foundational cornerstones for understanding and optimally using currently available psychopharmaceutical agents., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In June, 2022, the United States Department of Veterans Affairs (VA) announced an initiative to reduce death due to suicide in US Veterans. This column is based on a proposal written for that initiative, as well as on an earlier psychopharmacology column in this journal that reviewed the statistics and the genetics of suicide, and the US medicolegal death investigation system. This system is composed of 3137 county coroner or medical examiner offices across the country that are responsible under state and local law for investigating deaths that are not explained by natural causes and are suspicious and/or unattended. Thus, this system gathers data concerning all deaths due to suicide. Currently this death investigation system costs US taxpayers ∼$660 million per year, and it has determined that ∼45,000 Americans die from suicide each year. In the conduct of these investigations, a large amount of data is collected, including biological samples. While the demographic data are reported to the Centers for Disease Control (CDC), little-if anything-is done with the collected biological material beyond its use in determining the cause of death of the individual. The earlier column on this topic advocated for the establishment of a central database to retain and utilize this information to further understand the biopsychosocial causes of suicide, with the goal of preventing suicides. This column describes a proposal submitted to the VA system for how such a system could initially be piloted in a small group of VA medical centers and then expanded to the entire system. This initial effort could then, in turn, serve as a model for expanding such data gathering to the entire US medicolegal death investigation system., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Therapeutic drug monitoring (TDM) results are a biological measure of the ability of the patient to clear a drug as long as the patient is adhering to the prescribed dosage. If the patient is not adherent, then TDM can provide evidence of such nonadherence. To properly interpret TDM results, several variables must be considered. First and foremost is the dose the patient is supposed to be taking. The second variable is whether the patient should have achieved a steady-state condition, which means that the amount of drug the patient is taking in a day is equal to the amount the patient is eliminating in the same day so that the level will not change unless changes occur in either the dosing rate or the ability of the patient to clear the drug. For drugs with a half-life of 24 hours, steady state typically occurs when the patient has been taking the same dose for 5 to 7 days (ie, 5 x the half-life). The third variable is the time between when the last dose was taken and the sample was obtained. Ideally, for most drugs, that desired interval is 10 to 12 hours after the last dose was taken assuming the patient is taking the dose daily as different rules apply for depot medications. There are 2 reasons for this stipulation. First, this interval will best reflect the average concentration that the patient achieves over the daily dosing interval on that drug. Second, for most orally administered drugs, the value that is obtained 10 to 12 hours after the last dose will not be influenced by differences in the absorption of the drug. In contrast, if the sample is obtained during the absorption phase, the plasma concentration can be both much higher and less predictable than is the case when absorption is complete. Therefore, these 3 variables must be included when recording TDM results in the chart. As explained in this column, the TDM result without this information is not optimally interpretable. Parenthetically, TDM results do not need to be repeated (unless specific concerns arise as explained in this column), because these results are a measure of the ability of the patient to clear the drug. For depot medications (eg, antipsychotics), the results should be obtained at the end of the dosing cycle just before the administration of the drug and after the patient has ideally received 4 to 5 injections at equal intervals (eg, monthly) to be near steady-state. Parenthetically, TDM at the appropriate fixed interval (usually monthly) with depot medications is much less sensitive to timing issues than TDM of orally administered drugs. This column explains the rationale for obtaining TDM results, principally focusing on orally administered drugs and how to optimally chart and disseminate these results., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Genetic tests, unlike most other laboratory tests, are trait rather than state tests. That means the results almost always stay the same. Exceptions to this rule are discussed in this column. Trait tests require documentation in such a way that they are not buried in the chart and forgotten, as usually happens with state (or point-in-time tests) such as serum potassium levels. Genetic test results and their implications should be explained to the patient in as much detail as possible and also shared and discussed with all health care providers treating the patient. This column explains the rationale for and the means to accomplish the goals of optimally charting and disseminating the results of such tests., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

This column reviews the development of intranasal esketamine with particular emphasis on the consistency of the clinical trial results. In the process, it illustrates methodological issues important in the approval process by an agency such as the United States Food and Drug Administration. Topics covered include the importance of study design, the nature of the comparator, and the prespecified statistical analysis plan. The column also discusses what is considered a positive versus a supportive study and the differences between phase 2 and phase 3 studies and the rationale for including both in the development process. While this information is particularly germane to intranasal esketamine, it also serves as a more general example of the drug development and approval process., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

QTc stands for heart-rate corrected QT interval on the electrocardiogram and is a measure of the efficiency of repolarization of the left ventricle. Excessive prolongation, generally considered to be >500 ms, can result in a potentially fatal ventricular arrhythmia known as torsade de pointes. Some psychiatric medications can cause this arrhythmia and, therefore, this issue is important to all prescribers of psychiatric medications. It is also important to keep in mind that there are multiple algorithms used to calculate the QTc. The Bazett's algorithm, one of the most commonly used algorithms on electrocardiogram machines, can produce an artificially prolonged QTc; however, the use of this algorithm is not generally identified on the printout from the electrocardiogram machine, which can cause unnecessary concern and delay treatment of patients. For these reasons, this article explains the basic concepts of the QT interval and QTc interval and discusses why it is important for psychiatrists and other prescribers to know this information. A case report is then used to illustrate the clinical application of this knowledge so that effective treatment is not unnecessarily delayed., Competing Interests: Over his 40-year career, S.H.P. has worked with over 140 pharmaceutical and biotech companies in the United States and throughout the world. Over the past year, 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, National Institute of Mental Health, Novaritis, Otsuka, Sunovion, and Usona Institute. All clinical trial and study contracts were with and payments made to the Kansas University Medical Center Research Institute, a research institute affiliated with Kansas University School of Medicine-Wichita. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

This article explains how the mortality rate of an illness such as Coronavirus Disease 2019 (COVID-19) is calculated as well as how the definition of what is a "case" has changed from the earliest days of the pandemic to now. Many factors were not known about The Sudden Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) which causes COVID-19 at the beginning of the pandemic because it is a novel human pathogen. One key factor that was not known in the earliest days of the pandemic was that many patients are either asymptomatic or have symptoms so mild that they may not seek medical attention and hence these patients would not be identified as a "case" if that term is defined as being sufficiently symptomatic to be seeking medical attention. Cases in the earliest days of the pandemic were defined as based on having symptoms (eg, fever, cough, respiratory distress) after ruling out other possible causes. Cases now are defined by tests confirming that the person is shedding the SARS-CoV-2 (ie, a laboratory vs. a symptomatic diagnosis). The mortality rate of this virus dropped as a function of this change. On the basis of the results of an unintended, naturalistic experiment on an expeditionary cruise in March of 2020, there was more than a 5-fold drop in the calculated mortality rate due to this definitional change in what constituted a case. This column explains this issue and discusses its implications for effectively dealing with the SARS-CoV-2 (or COVID-19) pandemic.

This column first reviews 2 key equations that are central to clinical pharmacology. Clinicians can use the first equation to predict the effect of a specific dose of a specific drug in specific circumstances on the basis of 3 variables: (1) the drug's pharmacodynamics, (2) the drug's pharmacokinetics, and (3) biological variance in the individual patient. Clinicians can use the second equation to determine the concentration of a drug that a patient will achieve on a given dose depending on the patient's ability to clear the drug from the body. These 2 equations allow prescribers to predict whether the dose of a drug a patient is receiving is likely to achieve the desired clinical response (not so low that it is clinically ineffective or so high that it causes adverse effects that interfere with the patient's ability to tolerate or benefit from the treatment). The author then describes 2 tools clinicians can use to determine a patient's ability to clear a drug from the body, and thus calculate the concentration of the drug using Equation 2. These tools are: (1) estimation of creatinine clearance and (2) therapeutic drug monitoring.

This column is the ninth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmaco-dynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. The sixth column discussed key pharmacodynamic interactions involving ethanol, opioids, and monoamine oxidase inhibitors. The seventh and eighth columns presented the concept of relative receptor binding and included tables summarizing the relative receptor binding affinity of currently available antipsychotics and antidepressants, respectively. This ninth and final column in this series discusses pharmacokinetic DDIs with a focus on psychiatric medications and contains 3 tables. The first table is an abbreviated version of a table available online showing which drugs are substrates for which cytochrome P450 (CYP) enzymes and which drugs are inhibitors or inducers of specific CYP enzymes. The abbreviated version of the table presented in this column focuses on psychiatric medications. This table and the larger website version can allow prescribers to anticipate which drug combinations may pose the risk of a CYP enzyme-mediated DDI. The second table summarizes which antidepressants inhibit specific CYP enzymes and which antidepressants do not or are unlikely to inhibit specific CYP enzymes. The third table presents psychiatric medications whose clearance is not principally dependent on CYP enzyme-mediated oxidative metabolism as a necessary step in their clearance from the body. The latter 2 tables inform prescribers as to which drugs they may prefer to use to avoid CYP enzyme-mediated DDIs. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use ≥2 drugs in combination to optimally treat a patient.

This column is the eighth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmacodynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. The sixth column discussed key pharmacodynamic interactions involving ethanol, opioids, and monoamine oxidase inhibitors. That column focused particularly on hypertensive crises and serotonin syndrome with monoamine oxidase inhibitors and also DDIs involving psychiatric medications with adverse effects on the cardiovascular system and on the central nervous system. The seventh column presented the concept of relative receptor binding and included a table summarizing the relative receptor binding affinity of antipsychotics including all of the newer agents as well as some of the older agents such as haloperidol. This eighth column in this series presents a parallel table to the one in the seventh column summarizing the relative receptor binding affinity of currently available antidepressants. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use ≥2 drugs in combination to optimally treat a patient.

This column is the seventh in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmacodynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. The sixth column discussed key pharmacodynamic interactions involving ethanol, opioids, and monoamine oxidase inhibitors. That column focused particularly on hypertensive crises and serotonin syndrome with monoamine oxidase inhibitors and also DDIs involving psychiatric medications with adverse effects on the cardiovascular system and on the central nervous system. This seventh column in this series presents the concept of relative receptor binding and includes a table summarizing the relative receptor binding affinity of commonly used antipsychotic medications, including all of the newer agents as well as some of the older agents such as haloperidol. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use ≥2 drugs in combination to optimally treat a patient.

Objective: Determine if sublingual dexmedetomidine, a selective α 2 adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or schizoaffective disorder., Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults diagnosed with schizophrenia or schizoaffective disorder per the Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition ( DSM-5 ) criteria. The study was conducted at 15 US sites between January 23, 2020, and May 8, 2020. Participants were randomized to sublingual dexmedetomidine 180 μg, 120 μg, or matching placebo. The primary efficacy endpoint was mean change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC) total score at 2 hours postdose., Results: Altogether, 380 participants (mean age 45.6 years, 63.4% identifying as male, 77.9% identifying as Black or African American) were randomized; 380 (100%) self-administered study medication, and 372 (97.9%) completed the study. The mean PEC total score at baseline (17.6) indicated mild to moderate agitation. At 2 hours postdose, the least squares mean changes (SE) from baseline were -10.3 (0.4) for sublingual dexmedetomidine 180 μg, -8.5 (0.4) for 120 μg, and -4.8 (0.4) for placebo. Least squares mean differences (97.5% confidence intervals) in the sublingual dexmedetomidine groups were -5.5 (-6.7 to -4.3) for 180 μg and -3.7 (-4.9 to -2.5) for 120 μg (both P  < .001 vs placebo). The most commonly encountered adverse events with dexmedetomidine (incidence ≥ 5% and ≥ 2× rate observed with placebo) were somnolence, dry mouth, and hypotension for the 120 μg dose, and somnolence, dizziness, orthostatic hypotension, and oral hypoesthesia for the 180 μg dose., Conclusions: Treatment with sublingual dexmedetomidine 180 μg or 120 μg was more efficacious than placebo in reducing acute agitation associated with schizophrenia as measured by PEC scores at 2 hours postdose., Trial Registration: ClinicalTrials.gov identifier: NCT04268303., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Objective: To describe the tolerability of esketamine nasal spray based on the adverse event profile observed during treatment sessions occurring early and later over the course of treatment., Methods: In 2 long-term, phase 3 studies (NCT02493868, October 1, 2015-February 16, 2018; NCT02497287, September 30, 2015-October 28, 2017), patients with treatment-resistant major depressive disorder (per DSM-5 ) and nonresponse to ≥ 2 oral antidepressants received esketamine nasal spray (56 or 84 mg) twice weekly during a 4-week induction phase, weekly for weeks 5-8, and weekly or every 2 weeks thereafter as maintenance treatment, in conjunction with a new oral antidepressant. A post hoc analysis using descriptive statistics evaluated occurrence (incidence, frequency, severity) and recurrence (incidence and severity) of events of specific interest., Results: In patients treated with esketamine nasal spray plus a newly initiated oral antidepressant (n = 928), spontaneously reported adverse events of dizziness, nausea, sedation, vertigo, and increased blood pressure were more likely to recur after the first week of treatment if they occurred more frequently (twice > once > none) during the first week. The same pattern was observed when these events were assessed by structured instruments. Incidences of dizziness, dissociation, increased blood pressure, nausea, vertigo, and sedation were highest in week 1 of treatment (20.6%, 16.7%, 4.3%, 14.0%, 12.1%, and 3.8%, respectively) and decreased thereafter. Initial occurrences and subsequent recurrences of events were mostly mild or moderate in severity., Conclusions: Adverse events during treatment with esketamine nasal spray plus an oral antidepressant generally become less frequent with ongoing treatment, and the majority are mild or moderate in severity., Trial Registration: ClinicalTrials.gov identifiers: NCT02493868; NCT02497287., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

This column is the sixth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmacodynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. This sixth column in the series discusses some key issues related to pharmacodynamic interactions involving commonly used psychiatric medications. The column first discusses 3 types of pharmacological agents that deserve special mention because of the widespread types of pharmacodynamic DDIs they can have with psychiatric and other medications: ethanol, opioids, and monoamine oxidase inhibitors, with a special focus on hypertensive crises and serotonin syndrome with monoamine oxidase inhibitors. The column also discusses DDIs in terms of effects on the cardiovascular system, including QTc prolongation, blood pressure and heart rate regulation, increased risk of bleeding and abnormal bleeding, and valvular heart disease, and on the central nervous system, including increased sedation, respiratory depression, body temperature regulation, and tardive dyskinesia. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use more than 1 drug in combination to optimally treat a patient.

This column is the fifth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. In the preceding column, a classificatory system based on mechanism of action was presented and a table was provided outlining the primary, known mechanism(s) of action of all commonly used psychiatric medications. This column presents a parallel table summarizing major types of pharmacodynamic DDIs based on mechanism of action. Clinicians can use these 2 tables to predict pharmacodynamically mediated DDIs. As discussed in the third column in this series, a classification scheme for drugs based on what enzymes, if any, are responsible for their biotransformation as a necessary step in their eventual elimination and whether a drug is an inhibitor or inducer of those enzymes can be used to predict pharmacokinetic DDIs mediated by cytochrome P450 enzymes, just as the mechanism-based classification system presented in this and the fourth column in this series can be used to predict pharmacodynamic-based DDIs. The ultimate intent of this series is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use >1 drug in combination to optimally treat a patient.

This column is the fourth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. This column discusses how drugs with multiple mechanisms of action have the potential to interact pharmacodynamically by the mechanism(s) mediating their therapeutic indication and for some drugs by other mechanisms (ie, drugs with multiple mechanisms of action). In this and the next column in this series, we present a classificatory system in the form of 2 tables that prescribers can use to predict the action of a neuropsychiatric drug when used alone as well as DDIs that can occur when it is used in combination with other drugs. The table in this column presents neuropsychiatric medications classified according to their mechanism(s) of action. The next column in this series will present a parallel table summarizing major types of pharmacodynamic DDIs based on mechanism of action and discuss strategies for minimizing adverse outcomes from such unintended DDIs. The authors recommend that health care providers' knowledge of the drugs they frequently prescribe include both their generic and brand names (to avoid confusion leading to dispensing the wrong drugs), routinely used doses, pharmacokinetics including half-lives, pharmacodynamics including mechanism(s) of action and binding profile for specific receptor(s) (not specifically discussed here but available in other columns by the first author), adverse effect profiles, potential DDIs, and the evolving research literature on these agents.

This column is the third in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first column in this series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs and how to recognize such DDIs, and strategies for avoiding them. The second column in the series further discussed strategies for avoiding and/or minimizing adverse outcomes from DDIs. This third column deals with pharmacokinetic considerations concerning DDIs in psychiatric practice. Specifically, this column discusses the 2 major types of pharmacokinetically mediated DDIs: those mediated by cytochrome P450 (CYP) enzymes and those mediated by transport proteins. The role of each of these regulatory proteins in the pharmacokinetics of drugs is reviewed as well as how genetically determined variation in the functional activity of these regulatory proteins can alter the accumulation of a drug in the body (ie, via CYP enzymes) and in specific compartments of the body (ie, via transport proteins), either increasing or decreasing their accumulation leading to either reduced efficacy or increased toxicity. This column further explains how coprescribed drugs can also affect the functional integrity of these regulatory proteins and lead to differences from usual in the accumulation of drugs dependent on the activity of these CYP enzymes and drug transporters. This phenomenon is known as phenoconversion in which a patient can functionally change from his or her genetic status, for example, having extensive or normal metabolism, to having poor or slow metabolism and hence greater accumulation than would be expected based on the patient's genotype.

Importance: Acute agitation is common in patients with bipolar disorder and requires urgent management to relieve distress and to prevent escalation to aggressive behavior., Objective: To evaluate the effect of orally absorbed, sublingual dexmedetomidine, a selective α2A-adrenergic receptor agonist on symptoms of acute agitation in patients with bipolar disorder., Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted in 15 sites in the US with enrollment between February 24, 2020, and April 27, 2020, and final follow-up on May 21, 2020. A total of 380 adults with bipolar I or II disorder were randomized and 362 completed the study., Interventions: Participants were randomized to 3 groups: sublingual dexmedetomidine 180 μg (n = 127), sublingual dexmedetomidine 120 μg (n = 127), or placebo (n = 126)., Main Outcomes and Measures: The primary efficacy end point was the mean change from baseline at 2 hours for the Positive and Negative Syndrome Scale-Excited Component (PEC) total score. The range of possible total scores is 5 (absence of agitation) to 35 (extremely severe). The secondary end point was the earliest time of a statistically significant change in PEC total score from baseline for the drug vs placebo. On the primary efficacy end point, to account for multiplicity associated with comparing 2 sublingual dexmedetomidine doses with placebo, the 2-sided significance level for each dose vs placebo was set at .025., Results: Of 380 patients randomized (mean age, 45.6 years; 54.8% women; and 56.1% Black individuals), 378 (99.5%) self-administered the study medication and completed the study. Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.0. Two hours after taking the medication, the mean changes from baseline in PEC total score were -10.4 for sublingual dexmedetomidine 180 μg, -9.0 for sublingual dexmedetomidine 120 μg, and -4.9 for placebo. Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were -5.4 (97.5% CI, -6.6 to -4.2) for 180 μg and -4.1 (97.5% CI, -5.3 to -2.9) for 120 μg (both doses P < .001 vs placebo). Treatment effects began 20 minutes after taking the medication among patients in the sublingual dexmedetomidine groups (least-square mean difference for 180 μg, -1.1 [97.5% CI, -2.0 to -0.2]; P = .007; for 120 μg, -1.0 [97.5% CI, -1.9 to -0.1]; P = .009). Adverse events occurred in 35.7% of patients taking 180 μg of dexmedetomidine, 34.9% taking 120 μg, and 17.5% taking placebo. The most common adverse events (≥5%) in the respective 180 μg, 120 μg, and placebo groups were somnolence (21.4% and 20.6% vs 4.8%); dry mouth (4.8% and 7.1% vs 0.8%); hypotension (6.3% and 4.8% vs 0%); and dizziness (5.6% and 5.6% vs 0.8%)., Conclusions and Relevance: Among patients with mild to moderate agitation associated with bipolar disorder, treatment with a sublingual film formulation of dexmedetomidine 120 μg or 180 μg, compared with placebo, resulted in significantly greater reduction in the agitation score at 2 hours. Further research is needed to understand the spectrum of patients for whom this treatment would be effective and feasible and to better understand the clinical importance of the observed effect size., Trial Registration: ClinicalTrials.gov Identifier: NCT04276883.

The goal of this column is to provide information to health care professionals about drug-drug interactions (DDIs) and why DDIs are important to consider in those at serious risk of illness with Coronavirus Disease 2019 (COVID-19). Important considerations discussed in this column include the frequency and complexity of multiple medication use, particularly important for the older patient who often has multiple comorbid illnesses. The column covers the following issues: (1) Why patients at high risk for serious illness from COVID-19 are also at high risk for DDIs. (2) Application of results of pharmacoepidemiological studies to the population at risk for serious COVID-19 illness. (3) Mechanisms underlying DDIs, frequency and potential complexity of DDIs, and how DDIs can present clinically. (4) Methods for preventing or mitigating DDIs. (5) An introduction to the University of Liverpool drug interaction checker as a tool to reduce the risk of adverse DDIs while treating patients for COVID-19. Commentary is also provided on issues related to specific psychiatric and nonpsychiatric medications a patient may be taking. A subsequent column will focus on DDIs between psychiatric medications and emerging COVID-19 treatments, as a detailed discussion of that topic is beyond the scope of this column.

The goal of this column is to help mental health care professionals understand coronavirus disease 2019 (COVID-19) so that they can better explain the complexities of the current crisis to their patients. The bottom-line of this column is that, while COVID-19 can infect virtually everyone in the human population, only about 5% are susceptible to severe infection requiring admission to an intensive care unit and/or causing a fatal outcome and this population can be identified on the basis of comorbid medical illness and/or age. These numbers are based on experience in China, the United States, and Europe. Table 1 presents an analysis conducted by the US Centers for Disease Control and Prevention (CDC), which is further supported by several other sources reviewed in the article. The population at risk for severe infection are individuals with comorbid medical illness and those 85 years of age and older. The comorbid medical illnesses identified as risk factors are preexisting respiratory and cardiovascular disease, immunocompromised status, morbid obesity (ie, body mass index ≥40), diabetes mellitus, and possibly significant kidney or liver impairment. Parenthetically, news reports and the literature sometimes cite age 60 years and older as a risk factor but age between 60 and 85 years is likely a surrogate for having 1 or more of these comorbid medical conditions. While 5% may initially seem like a small number, it nevertheless potentially represents 16.5 million people, given the United States population of 330 million. That is a tremendous number of people requiring intensive care unit admission and/or potentially dying, and individuals in this population have overwhelmed the US health care system in some hotspots. For this reason, this column suggests taking this at-risk population into account in mitigation strategies when attempting to open the US economy. The column addresses the following questions: (1) What are the 3 aspects of the race to minimize the damage caused by COVID-19? (2) What data are currently available to help guide decisions to be made? (3) What strategies have been employed to date and how successful have they been? and (4) Might risk stratification of exposure be a viable strategy to minimize the damage caused by the virus? The race to minimize the damage caused by COVID-19 requires that we obtain knowledge about the disease and its treatment or prevention, how to best safeguard public health and avoid overwhelming the health care system, and how to minimize the societal damage caused by substantial disruption of the economy. Data gathered over the past 4 months since the COVID-19 virus emerged as a human pathogen have provided guidance for our decisions going forward. The most widely adopted strategies for dealing with the COVID-19 pandemic to date have involved the epidemiological approach of encouraging good hygiene practices and social distancing, including orders to "shelter in place," quarantine of high-risk individuals, and isolation of infected individuals. The goal of this epidemiological approach has been to "flatten the curve" by reducing the height of the peak of the infection to avoid overwhelming the health care system and society in general, while buying time to learn more about the disease and find more effective ways to deal with it. However, now that more is known about COVID-19 and the portion of the population that is most at risk for serious adverse outcomes including death, it may be possible to move from a shelter-in-place approach for the entire population to focus on those at most risk and thus facilitate a gradual and rational phased reduction of social restrictions to reopen the economy. Such a graduated opening would be based on regions of countries meeting specific criteria in terms of being able to contain the virus, coupled with vigorous monitoring to look for outbreaks, followed by case monitoring, isolation of infected individuals and quarantine of exposed individuals, and increased use of testing for active disease as well as for immunity. Taking the data on high-risk individuals into account would allow for a gradual lifting of restrictions on the majority of the population while maintaining more stringent safeguards to protect the vulnerable portion of the population. Nevertheless, the entire population would need to continue to practice good hygiene and social distancing while simultaneously-and perhaps even more vigorously-focusing on sheltering the vulnerable population until adequate community immunity has been achieved to prevent the spread of the virus, whether that is accomplished through natural exposure alone or with the addition of safe and effective vaccine(s) which may not be available for a year. Continued widespread testing for antibodies will help determine how far or close this country is-and other countries are-from developing effective community immunity.

The goal of this column is to inform mental health care professionals about the evolving way the diagnosis of Coronavirus Disease 2019 (COVID-19) is being made, with emphasis on tests to assist in making the diagnosis and to determine the presence of antibodies to the virus. This column also provides some general information about the disease, its relative risks, and efforts to develop effective treatments. Links to credible websites that are being continuously updated are also provided for readers who want more information and to stay current with ongoing developments.

Delirium is a heterogeneous syndrome primarily characterized by fluctuations in attention and awareness. Sleep-wake disturbances are a common and significant feature of delirium and can manifest as circadian rhythm inversion, sleep fragmentation, and reduced rapid eye movement (REM) and slow-wave sleep. Some literature suggests that the relationship between sleep disruption and delirium is reciprocal wherein the two reinforce one another and may share an underlying etiology. As there are no FDA-approved medications for delirium or delirium-related sleep disturbances, management is primarily focused on addressing underlying medical concerns and promoting physiologic circadian patterns with non-pharmacological behavioral interventions. In practice, however, medications are often used, albeit with limited evidence to support their use. This literature review explores the pharmacology and pharmacokinetics of several medications with literature investigating their use in delirium: melatonin, ramelteon, dual orexin receptor antagonists (DORAs), and dexmedetomidine. Current evidence suggests a possible benefit of ramelteon or melatonin, dexmedetomidine for patients in the ICU setting, and DORAs as therapeutic options for the re-regulation of sleep-wake cycle disruption in delirium. We discuss pertinent pharmacokinetic and pharmacodynamic factors that may influence clinical decision-making regarding these interventions., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Based extensively on tables and figures, this chapter reviews drug development in psychiatry with an emphasis on antidepressants from 1950s to the present and then looks forward to the future. It begins with the chance discovery drugs and then moves to through their rational refinement using structure activity relationships to narrow the pharmacological actions of the drugs to those mediating their antidepressant effects and eliminating the effects on targets that mediate adverse effects. This approach yielded newer antidepressants which compared to older antidepressants are safer and better tolerated but nevertheless do still not treat the approximately 40% of patients with major depression (MD) which is unresponsive to biogenic amine mechanisms of action. This form of MD is commonly referred to as treatment resistant depression. Esketamine is an investigational antidepressant which has a novel mechanism of action: blockade of the glutamate NMDA receptor. Positive trials reported this year for esketamine make it likely this drug will be approved next year in the USA. These studies coupled with earlier studies with other NMDA drugs suggest approximately 60% of patient with TRD are rapidly and robustly responsive to this mechanism of action. Thus, there appears to be three forms of MD based on pharmacological responsiveness: (a) 60% responsive to biogenic amine mechanisms of action, (b) 24% (i.e., 40 × 60%) responsive to NMDA but not to biogenic amine mechanisms of action, and (c) 16% (i.e., 40 - 24%) not responsive to either of these mechanisms of action. Scientific investigation of these three groups may yield important information about the pathophysiology and/or pathoetiology of these different forms of MD. This information coupled with studies into the neurobiology (e.g., imaging studies, connectomes to name a few approaches being used) and genetics of MD should provide the fundamental knowledge which will permit a rational search for and discovery of newer antidepressant drugs and other somatic and psychotherapeutic approaches to the treatment of patients with different forms of MD based on pathophysiology and pathoetiology. Examples are given of how such discovery and development has occurred in other areas of medicine and even in central nervous system (CNS) space including six novel mechanisms of action CNS drugs which have been successfully developed and marketed over the last 25 years.

Several companies offer pharmacogenetic testing for psychiatry on the basis of the claim that the outcome of drug selection is better when guided by such testing than when such testing is not used. This column examines the results of the GeneSight Psychotropic Test which groups various antidepressants and antipsychotics into 3 bins: green ("use as directed"), yellow ("use with caution"), and red ("use with increased caution and more frequent monitoring"). The authors examined how frequently the same drugs appeared in these different bins in 19 patients. They found that of the 22 antidepressants evaluated, 2 were virtually always (>90%) in the green bin: desvenlafaxine and levomilnacipran; and 8 were almost never (≤10.5%) in the green bin: citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, and sertraline. Of the 16 antipsychotics evaluated, they found that 4 were virtually always (>90%) in the green bin: asenapine, lurasidone, paliperidone, and ziprasidone; and 2 were almost never (≤10.5%) in the green bin: chlorpromazine and thioridazine. What was common among those drugs almost always in the green bin versus those almost never in the green bin were newer versus older marketed drugs and those not dependent versus dependent on oxidative metabolism for their clearance. The authors concluded that the results of this pharmacogenetic testing could be predicted on the basis of knowledge of the pharmacology of the drugs, particularly whether their clearance was dependent on oxidative drug metabolism.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized anxiety disorder, and panic disorder. Venlafaxine is metabolized to the active metabolite desvenlafaxine mainly by CYP2D6. Genetic polymorphism of CYP2D6 and coadministration with other medications can significantly affect the pharmacokinetics and/or pharmacodynamics of venlafaxine and its active metabolite. This study aimed to establish the PBPK models of venlafaxine and its active metabolite related to CYP2D6 genetic polymorphism and to predict drug-drug interactions (DDIs) with clarithromycin and paroxetine in different CYP2D6 genotypes. Clinical pharmacogenomic data for venlafaxine and desvenlafaxine were collected to build the PBPK model. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) characteristics of respective compounds were obtained from previously reported data, predicted by the PK-Sim ® software, or optimized to capture the plasma concentration-time profiles. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and plasma concentration-time profiles to the observed data. Predicted plasma concentration-time profiles of venlafaxine and its active metabolite were visually similar to the observed profiles and all predicted AUC and C max values for respective compounds were included in the twofold error range of observed values in non-genotyped populations and different CYP2D6 genotypes. When clarithromycin or clarithromycin plus paroxetine was concomitantly administered, predicted plasma concentration-time profiles of venlafaxine properly captured the observed profiles in two different CYP2D6 genotypes and all predicted DDI ratios for AUC and C max were included within the acceptance range. Consequently, the present model successfully captured the pharmacokinetic alterations of venlafaxine and its active metabolite according to CYP2D6 genetic polymorphism as well as the DDIs between venlafaxine and two CYP inhibitors. The present model can be used to predict the pharmacokinetics of venlafaxine and its active metabolite considering different races, ages, coadministered drugs, and CYP2D6 activity of individuals and it can contribute to individualized pharmacotherapy of venlafaxine., (© 2024. The Pharmaceutical Society of Korea.)

This column is the second in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first column in this series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs and how to recognize such DDIs, and strategies for avoiding them. This second column in the series discusses strategies for minimizing adverse outcomes from such unintended DDIs. Given the huge and rapidly increasing number of available prescription and over-the-counter medications as well as nutritional supplements, the author recommends that all prescribers develop a personal formulary of ∼30 drugs that they use in everyday practice and with which they are intimately familiar. It is recommended that their knowledge of these drugs include both their generic and brand names (to avoid confusion leading to prescription of the wrong drugs), routinely used doses, pharmacokinetics including half-lives, pharmacodynamics including mechanism(s) of action and binding profile for specific receptors, adverse effect profiles, potential DDIs, and the evolving research literature on these agents. The author stresses the value of establishing a therapeutic alliance involving the patient and the people around him or her (eg, prescribers, family members, pharmacists, nurse practitioners, home health professionals, friends when appropriate) to promote the patient's understanding of and adherence to treatment. It is also important to establish a therapeutic goal with a specific time expectation (eg, reduction in depressive symptoms within 4 wk), after which the prescriber should discuss adherence with the patient and significant others, consider a dose adjustment, or discontinue the drug after an adequate therapeutic trial or the development of an adverse effect that outweighs any benefit the drug may be having. The author outlines major principles for avoiding adverse DDIs and includes a table of online resources that provide information concerning different types of DDIs. The column ends with a discussion of limitations of currently available drug alert software programs and information on how and where to report adverse drug reactions.

This column begins a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. As explained in this column, this topic is important for multiple reasons. First, a large percentage of the population is receiving psychiatric medications. Second, these patients are likely to be on multiple medications which means that they are at risk for an adverse DDI. Third, DDIs may occur but not be recognized even though they have significant health care consequences for the patient. Fourth, these consequences can range from a catastrophic outcome to more everyday clinical problems involving a myriad of presentations as enumerated in this column. Also discussed in this column is the fact that all drugs, including psychiatric medications, interact on the basis of their pharmacodynamics and pharmacokinetics rather than their therapeutic use. Therefore, psychiatric medications may interact with medications prescribed for nonpsychiatric reasons as well as with other psychiatric medications. Tables are included that explain reasons for multiple medication use and principles to follow to minimize the risk of adverse DDIs.