Contrave, Lybalvi, Auvelity, and Cobenfy: What Do They Have in Common?

This column reviews 4 psychiatric combination products: Contrave (bupropion + naltrexone), Lybalvi (olanzapine + samidorphan), Auvelity (dextromethorphan + bupropion), and Cobenfy (xanomeline + trospium). All have been approved in the last 11 years. These medications are all based on planned and therapeutic drug interactions involving pharmacokinetics and/or pharmacodynamics.

An examination of symptoms, function and quality of life as conjoint clinical outcome domains for treatment-resistant depression.

Objective: The treatment of depression aims to improve depressive symptoms, daily function and quality of life (QoL). These exploratory analyses of a database of convenience from the RECOVER trial evaluated how a "tripartite" metric based on these 3 outcome domains might perform in treatment-resistant depression (TRD).

Methods: Outcome domains included depressive symptoms (MADRS, QIDS-C, QIDS-SR), function (WPAI item-6) and QoL (Mini-Q-LES-Q) obtained at months 3, 6, 9 and 12 in outpatients with markedly TRD in the double-blind RECOVER trial that compared sham to active adjunctive vagus nerve stimulation (VNS).

How the Use of Generic Names for Drugs Can Help Patients Avoid Untoward Adverse Effects.

This column presents the case example of a patient who was prescribed 3 different brand name drugs, all of which contain bupropion, which has a dose-dependent seizure risk. This case illustrates how such prescribing can result in a patient exceeding the recommended maximum daily dose of bupropion and having a seizure. This column also explains why prescribers should advise their patients to get their prescriptions filled by the same pharmacy or pharmacy chain.

From the Washington University (or Feighner) Psychiatric Diagnostic Criteria to DSM-III and Subsequent Versions: A Personal Perspective.

The goal of this column is to give an autobiographical perspective on what I saw and learned as a trainee about the origins and the people behind the development of criteria-based psychiatric diagnosis. These individuals' own words are used to explain their rationale and goals. I further explain the transition from the Washington University (or Feighner) criteria to the Research Diagnostic Criteria to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III).

How Quickly Multiple Medication Use Can Start: A Medication for Every Complaint on the First Visit Compromising the Ability to Determine Cause and Effect.

This article presents a case demonstrating that multiple medication use can begin on the first outpatient visit if the prescriber makes multiple psychiatric diagnoses and then feels the need to treat each diagnosis with a different central nervous system active medication labeled for each indication. This approach poses potential problems. First, a single drug or perhaps 2 drugs, in this case, may have been sufficient as initial and perhaps final treatment.

Efficiency and Completeness in Outpatient Visits Using the Scientific Method and Analog Scales.

The relationship between the scientific method and clinical practice was discussed in an earlier column. Another column described the application of analog scales to clinical practice. This column will discuss how the combination of these 2 strategies can be used to increase the efficiency and completeness of outpatient psychiatric management.

A False-positive Diagnosis of a Lethal Serotonin Syndrome Based on Postmortem Whole-blood Levels of Sertraline: How Forensic Detective Work Uses Medical Knowledge and Clinical Pharmacology to Solve Cases.

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.

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.

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.

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.

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.

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.

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 5HT serotonin receptor agonist for the treatment of obesity with limited off-target effects at the 5HT and 5HT receptors.

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.

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.

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.

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.

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

Determine if sublingual dexmedetomidine, a selective α adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or schizoaffective disorder. This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults diagnosed with schizophrenia or schizoaffective disorder per the , Fifth Edition () criteria. The study was conducted at 15 US sites between January 23, 2020, and May 8, 2020.

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.

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. 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 ) 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.