Life-threatening Rash Due to Lamotrigine and a Failure to Understand Its Pharmacology: How Forensic Detective Work Uses Medical Knowledge and Clinical Pharmacology to Solve Cases.

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.

Cerebral Anoxia in an 18-year-old Patient Being Treated for Major Depressive Disorder: How Forensic Detective Work Uses Medical Knowledge Including Clinical Pharmacology to Solve Cases.

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.

How the Food and Drug Administration Drug Approval Process Relates to the Potential Approval of Intravenous Racemic Ketamine for Treatment-resistant Major Depression.

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.

The Essential Parallels Between Clinical Practice and the Scientific Method.

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.

Personalized Medicine in the Treatment of a Patient With Obsessive-Compulsive Disorder With Clomipramine.

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.

Eight Clinical Cases and the Lessons They Taught.

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.

Seven Mechanistically Different Classes of Medications Can Be Used to Treat Insomnia and Related Sleep Disorders.

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.

Can the Publication of Case Series or Case Reports Lead to a Change in Clinical Practice?

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.

Drug Development in Psychiatry: The Long and Winding Road from Chance Discovery to Rational Development.

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.

Discovery of New Transmitter Systems and Hence New Drug Targets.

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.

Reverse Engineering Drugs: Lorcaserin as an Example.

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 5HT2C serotonin receptor agonist for the treatment of obesity with limited off-target effects at the 5HT2A and 5HT2B 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.

Comparative Pharmacology of the 3 Marketed Dual Orexin Antagonists-Daridorexant, Lemborexant, and Suvorexant-Part 2. Principal Drug Metabolizing Enzyme, Drug-Drug Interactions, and Effects of Liver and Renal Impairment on Metabolism.

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.

Comparative Pharmacology of the 3 Marketed Dual Orexin Antagonists-Daridorexant, Lemborexant, and Suvorexant: Part 1: Pharmacokinetic Profiles.

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.

Sublingual Dexmedetomidine for the Treatment of Acute Agitation in Adults With Schizophrenia or Schizoaffective Disorder: A Randomized Placebo-Controlled Trial.

Objective: Determine if sublingual dexmedetomidine, a selective α2 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.

Longitudinal Course of Adverse Events With Esketamine Nasal Spray: A Post Hoc Analysis of Pooled Data From Phase 3 Trials in Patients With Treatment-Resistant Depression.

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.

Building a Comprehensive Biopsychosocial Database to Identify Underlying Causes of Suicide and Improve Suicide Prevention.

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.

Treatment of Agitation in Individuals With Bipolar Disorder or Schizophrenia: Lessons Learned for Clinical Psychiatry and Psychiatric Drug Development.

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.

How an Understanding of the Function of the Locus Coeruleus Led to Use of Dexmedetomidine to Treat Agitation in Bipolar Disorder: Example of Rational Development of Psychiatric Medications.

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.