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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.)

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.)

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.

This column is the second in a series exploring lessons for psychiatric drug development that can be learned from the development of 6 central nervous system drugs with novel mechanisms of action over the past 25 years. Part 1 presented a brief overview of the neuroscience that supported the development of each of these drugs, including the rationale for selecting their targets and indications. This column reviews specific principles involved in the development of these 6 drugs that have important implications for the future of psychiatric drug development. These include focusing on efficacy for a specific symptom or behavior rather than a broad syndrome, choosing a target in the brain with a specific behavioral output that is conserved from lower mammalian to human brains, and measuring outcomes based on behavioral phenomena that can be readily measured in an unambiguous parametric way. It is hoped that the Research Domain Criteria initiative of the National Institute of Health will promote research advances consistent with this model.

The package insert, which is jointly authored by the U.S. Food and Drug Administration and the manufacturer of the drug, is a summary of all of the preclinical and clinical data accumulated during the successful development of a new drug. Despite the role of the package insert in the safe practice of medicine, prescribers often minimize, overlook, or misunderstand its importance, suggesting a gap in their training. An anonymous, three-question survey was administered to third year medical students (N=34) from two medical schools to assess how well they had been educated about the evidence-based origin, purpose, and implications of the package insert. The results indicate a deficiency in their medical education, and the authors contrast the student responses with the facts. These results underscore the need to revise medical school curricula to provide future prescribers with more education about the importance of the package insert and the relationship between pharmaceutical companies, the U.S. Food and Drug Administration, and prescribers.

This column discusses declining differences in response rates between sequentially introduced selective serotonin reuptake inhibitors (SSRI) and placebo. Although discussions of this phenomenon in the literature have largely focused on increasing placebo response rates, the author proposes that another factor may be responsible. That factor is an order effect, meaning that response rates have been declining as a function of the number of SSRIs on the market when the next SSRI is in development. The rationale is that the pool of potential clinical trial participants likely to respond to a drug with this mechanism of action (MOA) becomes progressively smaller with the introduction of each new agent with the same MOA, because many patients will already have been treat- ed and responded to an earlier member of the class. This phenomenon is not limited to the SSRIs but generalizes to any class of treatments that shares the same MOA.

This column is the third in a series that began in January, 2009 on the improved understanding of and ability to treat patients with major depression. This column focuses on options for the patient who has not benefitted from one or more adequate trials of currently available antidepressants. It begins with a summary of the results of the switching and augmentation strategies studied in the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, funded by the National Institute of Mental Health (NIMH). The column then discusses options not included in the STAR*D study, including aripiprazole, which is now the first medication approved by the U.S. Food and Drug Administration (FDA) as adjunctive therapy for the treatment of patients with clinical depression, and vagus nerve stimulation, delivered by the first implantable device approved by the FDA for the treatment of patients with treatment-resistant depression (TRD). The goal of this column to summarize the data supporting various options for the busy clinician who treats such patients.

Pharmacogenomics is a hybrid field of experimental science at the intersection of human disease genetics and clinical pharmacology sharing applications of the new genomic technologies. But this hybrid field is not yet stable or fully integrated, nor is science policy in pharmacogenomics fully equipped to resolve the challenges of this emerging hybrid field. The disciplines of human disease genetics and clinical pharmacology contain significant differences in their scientific practices. Whereas clinical pharmacology originates as an experimental science, human disease genetics is primarily observational in nature. The result is a significant asymmetry in scientific method that can differentially impact the degree to which gene-environment interactions are discerned and, by extension, the study sample size required in each discipline. Because the number of subjects enrolled in observational genetic studies of diseases is characteristically viewed as an important criterion of scientific validity and reliability, failure to recognize discipline-specific requirements for sample size may lead to inappropriate dismissal or silencing of meritorious, although smaller-scale, craft-based pharmacogenomic investigations using an experimental study design. Importantly, the recognition that pharmacogenomics is an experimental science creates an avenue for systematic policy response to the ethical imperative to prospectively pursue genetically customized therapies before regulatory approval of pharmaceuticals. To this end, we discuss the critical role of interdisciplinary engagement between medical sciences, policy, and social science. We emphasize the need for development of shared standards across scientific, methodologic, and socioethical epistemologic divides in the hybrid field of pharmacogenomics to best serve the interests of public health.

Biological interactions are stereoselective; thus the interactions of drugs with corresponding biological targets must also be stereoselective. However, many drugs used today are racemic mixtures. For example, approximately 25% or 1 in 4 marketed drugs are mixtures of agents (racemates) rather than single chemical entities (enantiomers). One of these enantiomers can be inactive or even counterproductive to the therapeutic use of the drug: either by reducing the efficacy of the active enantiomer or by causing unnecessary tolerability problems or even toxicity through differential pharmacodynamics. The presence of a therapeutically inactive or counterproductive enantiomer can also complicate the pharmacokinetics of the active enantiomer and the interpretation of the therapeutic drug monitoring (e.g., plasma levels) if the assay is not capable of separately quantitating the two enantiomers. This article reviews the history of stereoisomers and the relevant pharmacological principles, then discusses recent changes in rules governing drug approval and the potential advantages to the patient and the manufacturer of developing single enantiomers.

DDIs have important implications for managed care. They can adversely impact patient outcomes and can also have serious cost implications. The problem posed by unintended and adverse DDIs will continue to grow in importance as the complexity and uniqueness of medication regimens escalate in an aging population using increasingly sophisticated and varied pharmacological agents. In this paper, antidepressants and SSRIs in particular were used to illustrate these important points.

Major depression is a serious, potentially life-threatening illness that can cause significant pain and suffering. It afflicts up to 50% of patients who are seen in the primary care setting. However, it is a remarkably treatable disorder, once it is recognized. The mainstay of treatment is education about the illness, brief supportive counseling, and antidepressant medication. This monograph is a synopsis of a book, Outpatient Management of the Depressed Patient, recently published on this subject. We focus on how to diagnose and treat major depression in the primary care setting, in which the vast majority of patients with this condition are seen. We review the condition itself, how to establish the diagnosis, what education and brief supportive counseling are needed and how to provide them, how to select an antidepressant, and how to use the drug to induce and maintain remission.

To assess mental health-related stigma in an emerging Latino immigrant community and explore demographic characteristics associated with stigma. We surveyed 367 Spanish-speaking Latino adults recruited at community-based venues in Baltimore, Maryland. The survey included sociodemographic questions, the Depression Knowledge Measure, Personal Stigma Scale, and the Stigma Concerns about Mental Health Care (SCMHC) assessment. Multiple regression models examining associations between personal stigma and stigma concerns about mental health care, respectively, were constructed using variables that were statistically significant in bivariate analyses. Being male, having less than high school education, reporting high importance of religion, and having lower depression knowledge contributed to higher personal stigma. When controlling for other variables, only depression knowledge contributed unique variance to the prediction of higher SCMHC. Efforts to improve access to and quality of mental health care must be paralleled by ongoing efforts to reduce depression stigma within emergent immigrant Latino communities. [ABSTRACT FROM AUTHOR]

Background: The β‐blockers and antidepressants are two of the most commonly prescribed drug classes in the United States. Several antidepressants are potent inhibitors of cytochrome P450 2D6 liver enzymes (CYP2D6) and can increase the plasma concentrations of certain β‐blockers when administered concomitantly, potentially leading to serious medical consequences such as hypotension, bradycardia, and falls. Objective: The primary objective of this investigation was to determine whether initiating an antidepressant in patients receiving β‐blockers increased the risk of hemodynamic adverse events. Our primary outcome was time to hospital admissions or emergency department (ED) visits for an International Classification of Diseases‐9 diagnosis suggestive of excessive β‐blockade. Methods: We conducted a survival analysis for adults continuously enrolled in the California Medicaid system (Medi‐Cal) between 2004 and 2012. Eligible patients were required to be receiving β‐blocker medications that are primarily CYP2D6 substrates (e.g., metoprolol, propranolol, or carvedilol). Univariate and multivariable analyses were performed for patients who concurrently received antidepressants with β‐blockers. An additional multivariable analysis analyzed the association of this combination upon hospitalizations or ED visits for all causes. Results: A total of 21,292 beneficiaries met the inclusion criteria, and 4.3% of patients required hospitalization or ED visits within 30 days of co‐medication. In multivariable analysis, patients receiving antidepressants with moderate to strong CYP2D6 inhibitory potential (fluoxetine, paroxetine, duloxetine, or bupropion) had a greater risk for hospitalization or ED visits for hemodynamic events than those initiated on antidepressants with weak CYP2D6 inhibition for 30 days or less when each was compared with patients receiving no antidepressants (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.03–2.81; p=0.04 vs HR 1.24; 95% CI 0.82–1.88; p=0.30). Other demographic variables associated with increased morbidity included advanced age, male sex, higher β‐blocker doses, and African American race or Hispanic ethnicity. Conclusions: Results of this analysis suggest that initiation of certain antidepressants was associated with an increased risk for serious medical sequelae among patients concurrently receiving β‐blockers. Greater risk was observed with antidepressants that potently inhibit the CYP2D6 enzyme, implying that increased morbidity may be mediated by a metabolic drug interaction. [ABSTRACT FROM AUTHOR]

The article reviews the progress that has been made in understanding COVID-19 and the possible pathways for moving forward. Topics discussed include the natural history of the COVID-19 illness, epidemiological approaches to mitigate the transmission of COVID-19 such as good hygiene practices, social distancing, and quarantine, and the risk factors for the seriousness of the illness.

Background. Sleep is one of the most essential processes required to maintain a healthy human life, and patients experiencing psychiatric illness often experience an inability to sleep. The aim of this study is to test the hypothesis that antidepressant compounds with strong binding affinities for the serotonin 5-HT2C receptor, histamine H1 receptors, or norepinephrine transporter (NET) will be associated with the highest odds of somnolence. Methods. Post-marketing cases of patient adverse drug reactions were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) during the reporting window of January 2004 to September 2019. Disproportionality analyses of antidepressants reporting somnolence were calculated using the case/non-case method. The reporting odds-ratios (ROR) and corresponding 95% confidence interval (95% CI) were computed and all computations and graphing conducted in R. Results. There were a total of 69,196 reported cases of somnolence out of a total of 7,366,864 cases reported from January 2004 to September 2019. Among the 30 antidepressants assessed, amoxapine (n=16) reporting odds-ratio (ROR) = 7.1 (95% confidence interval [CI] [4.3-11.7]), atomoxetine (n = 1,079) ROR = 6.6 (95% CI [6.2-7.1]), a compound generally approved for attention deficit hyperactivity disorder (ADHD), and maprotiline (n = 18) ROR = 6.3 (95% CI, 3.9-10.1) were the top three compounds ranked with the highest reporting odds of somnolence. In contrast, vortioxetine (n=52) ROR = 1.3 (95% CI [1.0-1.8]), milnacipran (n=58) ROR = 2.1 (95% CI [1.7-2.8]), and bupropion (n=1,048) ROR=2.2 (95% CI [2.1-2.4]) are least significantly associated with somnolence. Moreover, levomilnacipran (n=1) ROR = 0.4 (95% CI [0.1-2.9]) was not associated with somnolence. Conclusion. Among the thirty tested antidepressants, consistent with the original hypothesis, amoxepine has strongest 5-HT2C receptor binding affinity and has the highest reporting odds of somnolence. Atomoxetine, ranked second in reporting odds of somnolence overall, binds to the NET with with the strongest binding affinity among the thirty compounds. Mirtazapine, a tetracyclic antidepressant, was ranked 11th in reporting odds of somnolence and had the strongest H1 receptor binding affinity. This study provides an informative ranking of somnolence among thirty antidepressant compounds with an already wide array of clinical indications as well as provides insight into potential drug repurposing in psychopharmacology. [ABSTRACT FROM AUTHOR]

Study Objective: To compare the risk of antihypertensive treatment intensification (TI) and major adverse cardiovascular events (MACE) with the initiation of serotonin norepinephrine reuptake inhibitors compared to selective serotonin reuptake inhibitors (SSRIs) in patients with stable hypertension and depression., Design: Retrospective cohort study., Data Source: IBM MarketScan® commercial claims database and Medicare Supplemental claims database from 2007 to 2019., Patients: Patients aged 18 years or older with stable treated hypertension and depression who newly initiate either serotonin norepinephrine reuptake inhibitors or SSRIs., Intervention: Serotonin norepinephrine reuptake inhibitors versus SSRIs., Measurements and Main Results: The primary outcomes were: (1) TI (first occurrence of antihypertensive regimen augmentation or dose escalation); (2) MACE (first occurrence of stroke or acute myocardial infarction). Baseline risk between the two groups was balanced via 1:1 propensity score (PS) matching. A Cox proportional hazard regression model was used to estimate adjusted hazard ratio (aHR) and 95% confidence intervals (95% CI). After 1:1 PS matching, we included 19,160 patients in the study cohort (mean age: 52 years, 62% females) of which 9580 initiated serotonin norepinephrine reuptake inhibitors and 9580 initiated SSRIs. Patients who initiated serotonin norepinephrine reuptake inhibitors had 15 MACE events (incidence rate per 1000 person-years [IR], 3.9) and 1675 TI events (IR, 540.2), compared with 17 MACE events (IR, 4.0) and 1774 TI events (IR, 518.5) in the SSRI group. The risk of TI (aHR: 1.01, [95% CI: 0.94, 1.08]) and MACE (aHR: 0.98, [95% CI: 0.49, 1.96]) did not differ among patients initiated serotonin norepinephrine reuptake inhibitors versus SSRIs., Conclusions: Among patients with stable hypertension and depression, initiation of serotonin norepinephrine reuptake inhibitors had a similar risk of antihypertensive TI and MACE compared to initiation of SSRIs. Future study with a larger sample size is needed to confirm our findings., (© 2022 Pharmacotherapy Publications, Inc.)

The article discusses the clinical applications and goals of the Research Domain Criteria (RDoC) program for mental disorders. Topics covered include the reason behind the low response rate to psychiatric drugs, the challenge posed by heterogeneity in specifying target engagement and relating target engagement to outcomes and the goal of developing a clinical research framework based upon dimensions of neurobiological measures.

Background: The higher prevalence and cost of depression for women compared with men and the possible gender differences in treatment response demand the inclusion of women in clinical trials of depression treatments. The 1993 National Institutes of Health (NIH) Revitalization Act set a new standard, requiring investigators to consider the inclusion of women and analyze outcomes by gender, yet compliance with these standards in depression research has not been examined systematically. The purpose of this study is to examine the inclusion of women and gender-specific analyses in recent randomized clinical trials (RCTs) for depression. Methods: RCTs were identified through a MEDLINE search for trials published between January 1 and December 31, 2007, and a Clinicaltrials.gov search of self-identified interventional studies to treat depression. Results: Of the 150 RCTs for depression published in 2007, 15% did not report the gender composition of their sample, 50% of studies did not analyze outcomes by gender, and 12% controlled for gender but did not analyze for gender differences. Of the 768 trials reviewed on Clinicaltrials.gov, 89% reported recruiting male and female participants, yet <1% reported an intention to analyze results by gender. Conclusions: Many recent studies of depression treatments include women but do not examine outcomes by gender. Understanding how women differ from men in response to treatment is critical for enhancing treatment efficacy for the greatest number of adults with depression. [ABSTRACT FROM AUTHOR]

The potential for cytochrome P450 (CYP) 2D6 substrates to interact with desvenlafaxine (administered as desvenlafaxine succinate) and paroxetine was evaluated. In an open-label, crossover study, 20 healthy volunteers (aged 21-50) were randomized to 2 series of 9 days each of desvenlafaxine (100 mg/d) or paroxetine (20 mg/d), separated by a 5-day washout. The CYP2D6 substrate desipramine (50 mg) was administered alone on day 1 and coadministered on day 6 of dosing with either desvenlafaxine or paroxetine. CYP2D6 genotype was determined at baseline. Based on least squares geometric mean ratios between reference (desipramine alone) and test treatments, desvenlafaxine produced minor increases in desipramine area under the plasma concentration versus time curve (AUC; 36%) and peak plasma concentration (C[submax]; 30%) (vs paroxetine: 419%, 90%, respectively; both P < .001). Desvenlafaxine produced little change in 2- hydroxydesipramine AUC (16% increase) and C[submax] (0%) versus paroxetine (18% and 82% decreases, respectively; P = .008, P < .001, respectively), indicating that desvenlafaxine, especially at the recommended therapeutic dose of 50 mg/d for major depressive disorder in the United States, has little potential to interact with CYP2D6 substrates. [ABSTRACT FROM AUTHOR]

Objective: This secondary data analysis from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study compared clinical characteristics and outcome after citalopram treatment for Hispanic outpatients whose language preference was English (N=121) or Spanish (N=74). Methods: Data for Hispanic outpatients with nonpsychotic major depression were gathered from two STAR*D regional centers. Participants received citalopram for up to 14 weeks, with dosage adjustments based on routine clinical assessments. Efforts were made to achieve re- mission with a measurement-based care approach, with adjustments symptoms and side effects. Results: Spanish speakers were older, were more likely to be women, were less educated, had lower income, had more medical burden, and were more likely than English speakers to be seen in primary care rather than in psychiatric clinics. Compared with Spanish speakers, English speakers had more previous suicide attempts and more family history of mood disorders. The groups did not differ in a clinically meaningful way in severity of depression. Before adjustment for baseline differences, Spanish-speaking participants had lower rates of and slower times to remission and response compared with English speakers. After adjustment for baseline variables, these differences were no longer significant. Relapse rates did not differ between groups. Conclusions: Compared with English-speaking Hispanic patients, Spanish-speaking Hispanic patients may have a less robust response to antidepressants. The reasons for this are not clear but may include more disadvantaged social status. The degree to which these results can be generalized to other Hispanic populations or to other non-English-speaking groups remains to be seen. [ABSTRACT FROM AUTHOR]

The article presents information on a study on the efficacy of antidepressants for child and adolescent depression (CAD). According to the article, selective serotonin reuptake inhibitors have become the top-selling drug category since being introduced in the U.S. in 1989. The study concluded that limitations, patients and physicians should demand stronger evidence for the efficacy of antidepressants for CAD.

Choice-based conjoint analysis was used to construct and analyze multiple panels of drug products from which a sample of Midwestern physicians were asked to choose. The panels were varied on the drug attributes of brand name, efficacy, frequency of administration, side effects, and patient out-of-pocket expense based on prescription benefit program reimbursement. An acute medication (antibiotic in the treatment of community-acquired pneumonia) and a chronic medication (antidepressant) were simulated for physicians. For both types of agents, patient out-of-pocket expense was the most important attribute, followed by slightly different arrangements of frequency of administration, effectiveness, and side effects, which were statistically significant. [ABSTRACT FROM AUTHOR]

Assesses the efficacy and safety of risperidone on the treatment of acute mania in the U.S. Use of antipsychotics in controlling manic symptoms; Reduction of mania following administration of risperidone with mood stabilizer; Characterization of the hyperaroused state in mania.

Examines the functional neuroanatomy of the placebo effect in controlled clinical trials in the U.S. Measurement of changes in brain glucose metabolism; Effects on the administration of placebo; Association with regional metabolic increases.

Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend... [ABSTRACT FROM AUTHOR]

Objective: This paper reports results stemming from a retrospective inquiry designed to determine the prescribing pattern of tricyclic antidepressants (TCAs) relative to selective serotonin reuptake inhibitors (SSRIs), and the subsequent effect on regimen adherence among African American (Black) and White beneficiaries enrolled in the state of South Carolina Medicaid programme. Patients and Methods: Adjudicated patient-level paid-claims data for the time-frame 1 January 1990 to 31 December 1994 were abstracted resulting in a statewide cohort of 8596 ambulatory beneficiaries, 18 to 64 years of age, without receipt of antidepressant pharmacotherapy in the 1-year time-frame prior to initiating a regimen of either a TCA or SSRI, and remaining Medicaid-eligible for 1 year thereafter. Results: Black race [odds ratio (OR) = 1.56, 95% confidence interval (CI) = 1.43 to 1.70], age 40 to 64 years (OR = 1.15, 95% CI = 1.06 to 1.26), and male gender (OR = 1.27, 95% CI = 1.14 to 1.41) were significant predictors of initiating antidepressant pharmacotherapy with a TCA. Relative to Whites, Blacks were found to be less likely to have obtained at least a 3-month (≥90 days) supply of a TCA (22.1 vs 31.7%) or an SSRI (30.7 vs 36.1%), or to have obtained a 6-month (≥180 days) supply of a TCA (6.4 vs 10.9%) or an SSRI (8.1 vs 13.2%). Conclusion: Further prospective research is required to discern the reasons for observed differences in prescribing and adherence patterns for antidepressant pharmacotherapy by age, gender and race, and to foster the development of educational programming designed to ensure clinically rational and equitable access to pharmacotherapeutic innovation. [ABSTRACT FROM AUTHOR]

Assesses the anterior cingulate and hippocampal deficits of depressed geriatric patients in Mountain View, California. Use of positron emission tomography in patient examinations; Correlation between memory deficits and hippocampal activity.

Reports that the U.S. Food and Drug Administration has requested valproate manufacturer Abbott Laboratories to add warning concerning the risk of pancreatitis to its labeling. Indications of valproate; Safety and effectiveness of the drug; Side effects of the drug. INSETS: The FDA based the label change recommendation on its review of...;Valproate: Revised Black Box Warning.

Focuses on mirtazapine, an antidepressant drug released in the United States. Pharmacological background of the drug; Efficacy of the drug; Side effects of the drug.