Back to table of contents Previous article Next article Book ForumFull AccessYale Textbook of Public PsychiatryThomas E. Smith, M.D.Thomas E. SmithSearch for more papers by this author, M.D.Published Online:1 Sep 2017https://doi.org/10.1176/appi.ajp.2017.17040431AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail edited by Selby C. Jacobs, M.D., and Jeanne L. Steiner, D.O. New York, Oxford University Press, 2016, 312 pp., $125.00 (hardcover).In psychiatry’s diverse and colorful family of subspecialties, public psychiatry has always been the “plain Jane” cousin who shows up at all the reunions but keeps quiet and off to the side. It’s neither the flashy young neurobiologist nor the sophisticated depression specialist, and it has certainly never resembled the refined, matronly psychoanalyst. Indeed, public psychiatry seems to have been content with its place in the background. But with widespread health care reform taking hold with its emphasis on person-centered care and attention to meaningful outcomes, public psychiatry’s time in the shadows may be ending. One gets that sense when reading the recently published Yale Textbook of Public Psychiatry. Editors Selby Jacobs and Jeanne Steiner collaborated with their department colleagues to publish a text that creates a coherent narrative for public psychiatry by weaving together history, the current landscape, training priorities, and key best practices and competencies. The Yale group’s profile is impressive, as each chapter is coauthored by a faculty member with a national or international reputation in the area. This is a text worth reading.The text features four sections. Part I describes the public psychiatry service system by outlining the discipline’s origins in community and public health initiatives from the last century. A highlight is chapter 3, “Recovery and Recovery-Oriented Practice,” which relates the evolution of the recovery movement and provides a succinct review of person-centered concepts, recovery-oriented services, and the nature and impact of peer services. Part II is anchored in the present and rightfully asserts that today’s public psychiatrists must be competent to provide integrated (general medical and behavioral health) care, to apply a public health perspective to understand diseases and modifying factors at the population level, and to serve the ever-increasing number of patients with serious mental illness who are also involved in civil and criminal justice systems. This section lays out the foundation of the public psychiatrist’s current clinical identity.Part III drills down into core clinical skills, focusing on children and young adults, hospital and outpatient service settings, and the importance of outreach and engagement strategies. Chapters throughout the text are similarly structured to provide history and context leading to a description of current best practices and required clinical competencies. For example, a chapter on services for children and adolescents includes a brief review of psychoanalytic theory and practice for children beginning with Sigmund Freud and tracing the evolution of Anna Freud’s clinic, which currently provides services in London’s publicly funded care system. Chapter 10, “Early Intervention and Prevention for Psychotic Disorders,” begins in Melbourne, where the first Early Psychosis Prevention and Intervention Centre was established in 1992. This background provides context that is interesting and greatly enhances the reader’s understanding of the material.Consecutive chapters describe the shift from inpatient to outpatient care for individuals with serious mental illness that has taken place over the past half-century. A thorough review of state hospital inpatient care is necessary given that public psychiatry’s early identity was forged in large state asylums. Subsequent chapters trace the shift to outpatient care and describe the comprehensive array of community-based services that are the backbone of today’s public psychiatry. Chapter 13, “Clinical Competence in Outreach and for Special Populations,” stands out for its description of key outreach strategies used by public psychiatrists to ensure that high-need, high-risk patients are effectively engaged and served. This chapter also details unique needs and challenges encountered when working with patients with traumatic brain injuries; with those with co-occurring substance use disorders; and with the elderly, homeless, and the lesbian, gay, bisexual, and transgender populations.The final section of the text takes a step back and examines public psychiatry’s administrative structure with chapters devoted to workforce issues, training needs and priorities, and future challenges. Public psychiatrists’ roles as medical and clinical directors, teachers, and practitioners are defined, emphasizing the many leadership opportunities and potential for public psychiatrists to meaningfully affect clinical- and system-level policies. The final chapter outlines key future challenges in the field, including the increasing focus on risk and quality management, practitioner accountability, and our nation’s continuing and often chaotic approach to reforming the organization of and funding for health care. Indeed, a section heading near the end of the final chapter is “The Road Ahead is Unclear.” This brings the story full circle, ending with the acknowledgment made in the text’s introductory chapters that public psychiatry’s foundation always has and always will be anchored in the unsteady realm of social and safety-net services for the truly disadvantaged.But the story is well told. One comes away feeling that public psychiatry has grown in stature and deserves greater recognition in psychiatry’s broad family of subspecialties, no longer the shrinking violet. The editors are commended for recognizing the breadth of talent and experience at Yale and for organizing a succinct and informative text that is very much worth reading.Dr. Smith is Associate Medical Director, New York State Office of Mental Health, Albany; and Special Lecturer, Department of Psychiatry, Columbia University Medical Center, New York.The author reports no financial relationships with commercial interests. FiguresReferencesCited byDetailsCited byNone Volume 174Issue 9 September 01, 2017Pages 906-907 Metrics KeywordsOther Psychological IssuesAdministrationPublic PsychiatryHealth Care ReformPDF download History Accepted 1 April 2017 Published online 1 September 2017 Published in print 1 September 2017

Introduction: Maintenance of antipsychotic drugs (APD) is critical in the management of patients with serious mental illness in preventing relapse. Although older patients have better adherence rates compared to younger patients, lack of adherence remains a concern. The objective of the study is to assess factors associated with potential non-adherence of prescribed antipsychotic medications in older patients.

This study aimed to identify potential nonadherence among pediatric, adolescent, and young adult patients prescribed attention-deficit/hyperactivity disorder (ADHD) stimulant medications and assess the differences in illicit substance and/or nonprescribed medication use in patients testing positive versus negative for the ADHD medication.

Persecutory delusions are a clinically important symptom in schizophrenia associated with social avoidance and increased violence. Few studies have investigated the neurobiology of persecutory delusions, which is a prerequisite for developing novel treatments. The aim of this two-paradigm functional magnetic resonance imaging (fMRI) study is to characterize social “real world” and linguistic threat brain activations linked to persecutory delusions in schizophrenia (n=26) using instructed-fear/safety and emotional word paradigms. Instructed-fear/safety activations correlated to persecutory delusion severity demonstrated significant increased lateral orbitofrontal cortex and visual association cortex activations for the instructed-fear vs. safety and instructed-fear vs. baseline contrasts; decreased lateral orbitofrontal cortex and ventral occipital-temporal cortex activations were observed for the instructed-safety stimuli vs. baseline contrast. The salience network also showed divergent fear and safety cued activations correlated to persecutory delusions. Emotional word paradigm analyses showed positive correlations between persecutory delusion severity and left-lateralized linguistic and hippocampal–parahippocampal activations for the threat vs. neutral word contrast. Visual word form area activations correlated positively with persecutory delusions for both threat and neutral word vs. baseline contrasts. This study links persecutory delusions to enhanced neural processing of threatening stimuli and decreased processing of safety cues, and helps elucidate systems-level activations associated with persecutory delusions in schizophrenia.

A flexible synthesis of the C1-C12 fragment of Tedanolide C has been accomplished in eight steps from 2-methyl-2,4-pentadienal. Asymmetric hydroformylation of a 1,3-diene allows for the late-stage generation of either C10 epimer with complete catalyst control. Diastereoselective addition of an isobutyryl β-ketoester dianion to an α,β-disubstituted chiral aldehyde sets the C5 stereochemistry while installing the geminal dimethyl unit. Differential protection of a syn-1,3-diol is performed as a highly efficient single-pot operation.

Back to table of contents Previous article Next article PerspectivesFull AccessSuccessful Rechallenge With Clozapine After EosinophiliaCatherine E. Roberts, M.D., Lindsey Young Mortenson, M.D., David B. Merrill, M.D., Neala Rafizadeh, M.D., Thomas E. Smith, M.D., and Jeffrey A. Lieberman, M.D.Catherine E. RobertsFrom the Department of Psychiatry, Columbia University, New York.Search for more papers by this author, M.D., Lindsey Young MortensonFrom the Department of Psychiatry, Columbia University, New York.Search for more papers by this author, M.D., David B. MerrillFrom the Department of Psychiatry, Columbia University, New York.Search for more papers by this author, M.D., Neala RafizadehFrom the Department of Psychiatry, Columbia University, New York.Search for more papers by this author, M.D., Thomas E. SmithFrom the Department of Psychiatry, Columbia University, New York.Search for more papers by this author, M.D., and Jeffrey A. LiebermanFrom the Department of Psychiatry, Columbia University, New York.Search for more papers by this author, M.D.Published Online:1 Nov 2011https://doi.org/10.1176/appi.ajp.2010.10040519AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Case Presentation“Mr. B” was a 27-year-old, single, unemployed man who lived with and was financially supported by his mother. He had an 8-year history of treatment-resistant chronic paranoid schizophrenia. He had two previous psychiatric hospitalizations and no history of violence, substance abuse, or suicide attempts.Mr. B was born to married parents. His parents divorced when he was in grade school, after which he continued to live with his mother and older sister and successfully completed high school at age 19. He was noted to be quiet and somewhat withdrawn, but he functioned well, got good grades, had friends, and developed several hobbies.A few weeks before his high school graduation, Mr. B's mother noticed that he was more withdrawn and irritable, and she suspected that he was talking to himself. These symptoms worsened over several weeks, and Mr. B was hospitalized. During this first hospitalization, Mr. B was diagnosed with schizophrenia. He was treated with risperidone, which was not effective, and then with olanzapine. Although olanzapine controlled his positive symptoms relatively well, he never returned to his baseline functionality, and he continued to have intermittent auditory hallucinations and functional impairment, spending the next several years at home, taking classes and developing his hobbies.One year before his admission to our hospital, Mr. B was hospitalized for a second time after he was switched from olanzapine to aripiprazole because of oversedation. Soon after this medication change, Mr. B became increasingly psychotic, with distressing auditory hallucinations and paranoia that ultimately prompted him to ask a friend to kill him. Despite treatment with concurrent high dosages of olanzapine and haloperidol during this second hospitalization, Mr. B's positive and negative symptoms progressed, and a trial of clozapine was started. He experienced notable improvement after several days on clozapine, with decreased auditory hallucinations, a greater ability to socialize, and a brighter, more engaged affect. Mr. B developed tachycardia, with a heart rate in the low 100s, and propranolol was started. Approximately 2 weeks after initiation of clozapine, Mr. B became febrile. At the time, his clozapine dosage was 100 mg/day. Clozapine was stopped and a fever workup was performed. No further evidence of acute inflammation was found, and multiple blood draws revealed normal total WBC and absolute neutrophil counts. Mr. B's psychotic symptoms worsened, and his clozapine dosage was titrated back to 100 mg/day after he had been afebrile for a few days.Mr. B again developed tachycardia, which was treated this time with atenolol. His positive and negative symptoms also improved, but 1 week later he developed eosinophilia, with a count of 2.7×109/liter, 23% of the total WBC count. Eosinophilia persisted 2 days later, with the count at 2.8×109/liter, 27% of the total WBC count. Clozapine was again stopped, and a cardiac workup was performed, including cardiac enzymes, an ECG, and an echocardiogram, none of which showed evidence of myocarditis. At this point, the treating psychiatrist and consulting cardiologist recommended that Mr. B not be treated with clozapine again because of the risk of an acute inflammatory syndrome.After discontinuation of clozapine, Mr. B's psychotic symptoms again worsened, and he was treated with relatively high dosages of haloperidol (15 mg/day), olanzapine (20 mg/day), and aripiprazole (20 mg/day). This combination improved his symptoms enough to allow him to be discharged. Over the next several months, Mr. B experienced intermittent and nondistressing auditory hallucinations. Haloperidol was eventually discontinued, and the dosage of aripiprazole was decreased. Mr. B was maintained on olanzapine (20 mg/day) and aripiprazole (2.5 mg/day), and he attended cognitive rehabilitation at a clinic for patients with psychotic disorders 3 days a week and saw a therapist once a week. He continued to be isolative and asocial, however, and was markedly impaired functionally, spending most of his time at home.Given his persistent symptoms, functional impairment, and prior positive response to clozapine, Mr. B, his mother, and his psychiatrist decided to consider a clozapine rechallenge. A few days before the rechallenge, Mr. B abruptly stopped taking all of his medications and became more acutely psychotic. He became increasingly preoccupied with the idea that he had done something terrible, spoke of the need to go to a foreign country to escape his auditory hallucinations, and said he “[had] to die” because he had “ruined the world with [his] thoughts.” One day before admission, he asked his mother if drinking detergent would kill him, and then asked her for poison, prompting her to bring him to the emergency department.On assessment in the emergency department, Mr. B's laboratory values were within normal limits, including liver function tests, a basic metabolic panel, and levels of amylase, lipase, thyroid-stimulating hormone, and blood alcohol, and his WBC count was 6.9×109/liter with 0% eosinophils. Urine toxicology results and a baseline ECG were normal. Mr. B was admitted to our psychiatric unit on an involuntary basis.At the time of admission, Mr. B was disheveled, with extremely poor eye contact and a flat affect. During interviews he was guarded and his responses were curt. Although he denied having auditory hallucinations, he was frequently seen talking or laughing to himself. He endorsed recent suicidal ideation but declined to elaborate, saying it was “hard to talk about.” Because of Mr. B's deteriorating condition and several failed antipsychotic medication trials, the decision was made to rechallenge with clozapine using a slow dose titration and close monitoring of blood parameters. Mr. B's mother, who was his health care proxy, was involved in extensive discussions about the risks of clozapine, and Mr. B agreed to the trial.When clozapine treatment was initiated, Mr. B's previous dosages of olanzapine (20 mg/day) and aripiprazole (2.5 mg/day) were initially continued for antipsychotic coverage. After 3 days of treatment with clozapine, aripiprazole was discontinued in order to minimize the risks of antipsychotic polypharmacy, and an olanzapine taper was started. Because of Mr. B's history of clozapine-induced eosinophilia, near-daily laboratory studies—including CBC with differential, basic metabolic panel, serum troponin level, liver function tests, amylase level, and lipase level—were performed to track his eosinophil count and monitor for signs of associated inflammation.Figure 1 illustrates the course of Mr. B's clozapine dosage and eosinophil counts throughout the clozapine trial and beyond. On day 6 of the hospitalization, Mr. B's eosinophil count increased from 0% of the total WBC count to 6% (the upper limit of normal). Mr. B remained guarded and internally preoccupied, but he reported no distress and his other laboratory values were normal. Over the next 2 weeks, clozapine was titrated slowly (typically increased by 25 mg every few days, but at times more slowly), olanzapine was gradually decreased to 10 mg/day, and Mr. B's positive and negative symptoms improved. The voices were less bothersome, and Mr. B was more spontaneously conversant, made better eye contact, and voluntarily interacted more with the staff and patients. He also began exercising and playing the piano in the unit's lounge.FIGURE 1. Changes in Absolute Eosinophil Count After Initiation of Clozapine RechallengeDuring the first 2 weeks of clozapine treatment, Mr. B's eosinophils increased gradually to 1.1×109/liter, 13% of the total WBC count. Lipase levels were transiently elevated, increasing over 2 days to 115 U/liter before returning to normal. At this time, even though Mr. B was physically asymptomatic and had not developed tachycardia or fever as he had during two previous trials with clozapine, we decided to hold his clozapine dose at 75 mg/day until consultations were obtained from the allergy and hematology services.The consulting services gave conflicting recommendations. The allergy consultation service recommended stopping clozapine out of concern that the eosinophilia might reflect a “chronic inflammatory state” with a high likelihood of end organ damage (e.g., pulmonary fibrosis, renal insufficiency, diabetes, or myocarditis) if it persisted. However, a second consultant from the allergy department felt that continuing treatment with clozapine would be safe as long as the total number of eosinophils did not rise above 1.5×109/liter, the cutoff for a diagnosis of idiopathic eosinophilia, a condition not believed to lead to end organ damage (1). The recommendation of the hematology service was to continue clozapine treatment with close monitoring of the patient's erythrocyte sedimentation rate (ESR) and C-reactive protein level, even with the current level of eosinophilia, since the patient was not showing signs of end organ involvement.Before deciding whether to continue the clozapine titration, we reviewed published treatment recommendations for idiopathic eosinophilia, defined as a total eosinophil count >1.5×109/liter for more than 6 months without an identifiable cause. In idiopathic eosinophilia, the standard of care is to monitor periodically for signs of end organ involvement with testing, including ECG, echocardiogram, serum troponin levels, and pulmonary function tests (2, 3). These considerations were discussed with the patient and his mother, who agreed with the treatment team that the known benefits of clozapine to the patient (i.e., his previous and current clinical improvement, including remission of command auditory hallucinations to kill himself) outweighed the potential risks (e.g., end organ damage) as long as close monitoring was continued. Mr. B was therefore continued on clozapine with frequent blood testing that included ESR and C-reactive protein level. We agreed to reevaluate this decision if Mr. B's total eosinophil count rose above 1.5×109/liter. Mr. B's cardiac and pulmonary functioning was assessed. An echocardiogram showed no change in cardiac function from 2 weeks before admission. Pulmonary function tests were consistent with poor patient effort but did not otherwise suggest compromised lung function.Although there are no standard recommendations in the literature for monitoring renal or pancreatic function in patients with idiopathic eosinophilia, we monitored Mr. B's creatinine, BUN, amylase, and lipase levels closely. Throughout the clozapine titration, these levels were always within normal limits. Mr. B's lipase was elevated on four nonconsecutive days near the beginning of the titration but then normalized and remained within normal limits.Mr. B's eosinophilia reached a peak of 1.2×109/liter (16% of the total WBC count) at a clozapine dosage of 150 mg/day approximately 1 week later. Although Mr. B continued to show no signs of end organ inflammation, the clozapine titration was slowed several times because of increased eosinophilia. Early in the course of treatment, it appeared that the degree of eosinophilia varied with the clozapine dosage (Figure 1). After 4 weeks, however, this relationship was less apparent. At the end of week 6 of hospitalization, Mr. B was discharged home on clozapine (150 mg/day), olanzapine (10 mg/day), and fluoxetine (20 mg/day) (the latter had been added for depressive symptoms during his hospitalization). His eosinophil count was 3.4×108/liter (5% of the total WBC count), and all other laboratory values were within normal limits. A follow-up echocardiogram showed no significant change. Mr. B was no longer suicidal, his auditory hallucinations were significantly improved, his mood and affect were brighter, and he continued to be more spontaneously conversant and to make better eye contact. He stated that he was especially pleased that he had been able to make friends while in the hospital. He was discharged with close follow-up, including cognitive rehabilitation, outpatient psychiatric appointments, and routine blood draws and repeat ECG, echocardiogram, and pulmonary function tests at 6-month intervals should the eosinophilia persist.Mr. B's peripheral eosinophil levels decreased around the time of his discharge and remained within normal limits over the next year of clozapine treatment. The dosage was gradually raised as high as 400 mg/day but was then lowered to 300 mg/day because of persistent nocturnal enuresis. At the 1-year point, Mr. B was still taking clozapine and was not taking any other antipsychotic medications. He continued to show good symptom control and functional improvement.DiscussionIt is well established that the antipsychotic medication clozapine can cause blood dyscrasias, the most concerning of which is agranulocytosis (4). Clozapine-induced eosinophilia has also been reported, often in association with organ-specific inflammatory processes, with myocarditis being the most cited example (5–16). When there is evidence of organ-specific inflammation, clozapine is normally discontinued to prevent end organ damage (5–10, 12, 13, 15, 17). Less commonly reported are cases of clozapine-induced eosinophilia in which there is no evidence of specific organ inflammation (18–21). In these instances, it is less clear whether or not clozapine should be discontinued.Since the discovery of agranulocytosis as a potentially fatal side effect of clozapine, close attention has been paid to all blood dyscrasias associated with the drug, including eosinophilia. Shortly after clozapine's introduction in the United States in 1989, Stricker and Tielens (18) reported the first case of clozapine-associated eosinophilia. In that case, clozapine was discontinued, although there were no signs of associated organ inflammation. Over the next few years, other reports were published describing “benign eosinophilia,” in which peripheral eosinophilia was noted shortly after clozapine administration, without other evidence of disease or inflammatory processes. Tiihonen and Paanila (19) reported the case of a 38-year-old woman who developed an eosinophil count of 1.5×109/liter without somatic symptoms. Banov et al. (20) described a retrospective study in which none of 17 patients who developed eosinophilia while taking clozapine had somatic complaints or an identifiable disease process to explain the eosinophilia. Schuepbach et al. (21) described two patients with elevated eosinophil counts without medical complaint. These reports concluded that eosinophilia was not necessarily a marker for medical illness, and no recommendations were made regarding discontinuation of clozapine treatment in the presence of eosinophilia without associated somatic symptoms. Banov et al. (20) and Hummer et al. (22) hypothesized that eosinophilia may be a herald sign for the development of neutropenia, but this hypothesis has not been borne out (23).By the late 1990s, however, many cases of clozapine-associated inflammatory conditions had been described. Several cases of pancreatitis were reported (5–7), as well as hepatitis (8–10), colitis (11, 12, 16), and nephritis (13). Peripheral eosinophilia was reported in all of these cases, and when biopsies were performed, there was also evidence of tissue eosinophilic infiltrates (12–14, 16). Most worrisome were cases of myocarditis (14, 15). Kilian et al. (14) studied 8,000 patients started on clozapine in Australia over a 5-year period and documented a 1,000- to 2,000-fold increase in the rate of potentially fatal myocarditis following initiation of clozapine treatment. Subsequent studies placed the incidence of clozapine-induced myocarditis between 0.015% (24) and more than 3% (25), depending on the population under study and the diagnostic criteria used for myocarditis. In most cases where autopsy results were available, cardiac eosinophilic infiltrates were noted, suggesting an acute drug reaction. Several other reports of clozapine-induced myocarditis have been published (15, 26), and eosinophilia is now believed to be an important marker for potentially serious inflammatory conditions in patients treated with clozapine.The pathophysiology of drug-induced blood dyscrasias is unclear. In recent years, several hypotheses for the development of drug-induced neutropenia and agranulocytosis have been posited (27, 28). Two potential explanations of clozapine-induced neutropenia involve reactive oxygen species. When clozapine is oxidized, a reactive nitrenium ion is produced. This ion reacts with sulfydryl groups in the glutathione cycle and may deplete the ATP supply of neutrophils, leading to apoptosis and eventual neutropenia (27). It may also be the case that when nitrenium ions react with sulfydryl groups, haptens are formed, inducing antibodies against neutrophils. An alternative, although not mutually exclusive, hypothesis is that the reactive metabolites formed when clozapine is oxidized affect the bone marrow stroma itself, limiting or prohibiting the maturation of progenitor cells, thereby leading to agranulocytosis (27). In addition to the haptenation-induced autoantibodies discussed above, other immunological explanations for drug-induced agranulocytosis have been proposed. For example, antibodies may form immune complexes with the drug, targeting membrane glycoproteins and leading to neutrophil destruction (27, 28). Several genetic hypotheses for drug-induced agranulocytosis have also been considered (27, 28). Single-nucleotide polymorphisms in genes that control drug metabolism may result in unusually high blood and tissue levels of the drug in some individuals, although this would not, in itself, account for the idiosyncratic nature of agranulocytosis (27). Single-nucleotide polymorphisms in genes encoding human leukocyte antigens have also been implicated in the development of drug-induced agranulocytosis (27).The pathophysiology of clozapine-induced eosinophilia is similarly unclear, but it may also result from immunological processes. It has been suggested that a type I hypersensitivity reaction is involved, a hypothesis supported in some cases by an elevation of IgE levels (29), angioedema, and rash (9). Some investigators have hypothesized that clozapine may stimulate T-lymphocytes, with a subsequent increase in interleukin-5, which promotes the production of eosinophils (21).Although immunological processes may underlie both clozapine-induced neutropenia/agranulocytosis and eosinophilia, they appear to have distinct pathophysiologies, as suggested by their different recurrence propensities. Patients who have discontinued clozapine as a result of confirmed agranulocytosis tend to experience a rapid and severe recurrence of neutropenia on clozapine rechallenge, which does not appear to be the case for many patients who develop eosinophilia when treated with clozapine. We found reports of eight such patients who were rechallenged with clozapine (5, 6, 11, 17–19, 21), and only two of them developed eosinophilia with signs of end organ damage (5, 6). In several cases in which “benign” eosinophilia (i.e., unaccompanied by other evidence of disease or inflammation) occurred, treatment with clozapine was continued (19–21). At least one of these cases was similar to ours: a patient developed “benign” eosinophilia that recurred, to a lesser extent, on rechallenge and then normalized (21). This resolution of eosinophilia despite ongoing clozapine treatment argues against a sustained immunologically mediated reaction. Rather, it suggests the possibility of an acute allergic reaction, as reflected by the “on/off” phenomenon noted in several other case reports (5, 6, 18, 21, 29).Unlike clozapine-induced neutropenia, there are no standardized monitoring recommendations for eosinophilia that occurs in the context of clozapine treatment, and there is debate in the literature over how to manage it. In almost all case reports with clear evidence of end organ involvement (e.g., pancreatitis, hepatitis, nephritis, myocarditis), clozapine treatment was stopped (5–9, 12, 13, 15, 17). Despite the fact that in the majority of these cases, eosinophil counts and abnormal enzyme levels returned to normal, most patients were not rechallenged with clozapine (7–9, 12, 13, 15). Several well-tolerated rechallenge attempts (11, 17–19, 21) and cases of successful clozapine continuation despite eosinophilia (11, 19–21) suggest that when eosinophilia develops without signs or symptoms of organ involvement, it may be safe to continue clozapine treatment or to rechallenge if clozapine was stopped. We recommend that when a patient develops eosinophilia and signs or symptoms of organ inflammation, strong consideration be given to discontinuing clozapine. However, when such signs or symptoms are absent, the optimal course of action is less clear, and cases should be evaluated on an individual basis. If a patient has not responded to other antipsychotic treatment, it may be justified to continue or restart clozapine. The risks and benefits must be carefully considered. Our patient never developed evidence of significant organ involvement, and we decided to continue treatment with clozapine, as the clinical benefits he experienced were believed to outweigh the risks.ConclusionsFor many patients with refractory psychotic symptoms, clozapine remains the best therapeutic option. It is our recommendation that if eosinophilia develops without signs of end organ damage or inflammation, clozapine continuation or rechallenge with careful monitoring may be considered. The patient, family, and appropriate medical consultants should be involved in the decision-making process.From the Department of Psychiatry, Columbia University, New York.Address correspondence to Dr. Lieberman (jlieberman@columbia.edu).Received April 8, 2010; revision received Dec. 10, 2010; accepted Dec. 20, 2010.Dr. Lieberman has received grant support from Allon, GlaxoSmithKline, Merck, Novartis, Pfizer, Sepracor, and Targacept; has served (without financial compensation) on the advisory boards of Bioline, GlaxoSmithKline, Intracellular Therapies, Eli Lilly, Pierre Fabre, and Psychogenics; and holds a patent from Repligen. The other authors report no financial relationships with commercial interests.References1. Tefferi A: Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment. Mayo Clin Proc 2005; 80:75–83Crossref, Medline, Google Scholar2. Tefferi A: Modern diagnosis and treatment of primary eosinophilia. 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J Clin Psychiatry 1998; 59:195–197Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited bySecond to none: rationale, timing, and clinical management of clozapine use in schizophrenia25 March 2023 | Therapeutic Advances in Psychopharmacology, Vol. 13Clozapine-induced eosinophilia: A case report31 August 2023 | SAGE Open Medical Case Reports, Vol. 11Clozapine-Induced Fever and Plasma Cytokine Changes in a Patient With Schizophrenia10 October 2022 | Clinical Neuropharmacology, Vol. 45, No. 6Exceptionally High Clozapine-Associated Eosinophilia9 February 2021 | Journal of Clinical Psychopharmacology, Vol. 41, No. 2Eosinophilic pneumonia during treatment with clozapine: reports from a retrospective case series8 April 2020 | International Clinical Psychopharmacology, Vol. 35, No. 5ClozapineRechallenge Following Clozapine-Associated Eosinophilia22 July 2019 | Journal of Clinical Psychopharmacology, Vol. 39, No. 5Zero Eosinophil Count as a Predictor of Clozapine-Associated Late-Onset AgranulocytosisJournal of Clinical Psychopharmacology, Vol. 38, No. 5Clozapine Rechallenge After Major Adverse Effects: Clinical Guidelines Based on 259 CasesAmerican Journal of Therapeutics, Vol. 25, No. 2Annals of General Psychiatry, Vol. 16, No. 1Successful rechallenge with clozapine after treatment associated eosinophilia10 July 2016 | Australasian Psychiatry, Vol. 24, No. 4Simple Pulmonary Eosinophilia Associated With Clozapine TreatmentJournal of Clinical Psychopharmacology, Vol. 35, No. 1International Journal of Clinical Pharmacy, Vol. 37, No. 6Clozapine induced eosinophilia: An often neglected important adverse effectIndian Journal of Psychiatry, Vol. 57, No. 4, Vol. 35Jornal Brasileiro de Psiquiatria, Vol. 62, No. 3 Volume 168Issue 11 November 2011Pages 1147-1151 Metrics PDF download History Received 8 April 2010 Revised 10 December 2010 Accepted 20 December 2010 Published online 1 November 2011 Published in print 1 November 2011

INTRODUCTIONOne in a hundred people will develop schizophrenia; about 75% of people have relapses and continued disability, and a third fail to respond to standard treatment. Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (demotivation, self-neglect, and reduced emotion) have not been consistently improved by any treatment.METHODS AND OUTCOMESWe conducted a systematic review and aimed to answer the following clinical questions: Which interventions reduce relapse; and improve adherence rates? Which interventions are effective in people resistant to standard antipsychotic drugs? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).RESULTSWe found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.CONCLUSIONSIn this systematic review we present information relating to the effectiveness and safety of the following interventions: behavioural therapy, clozapine, cognitive behavioural therapy (CBT), compliance therapy, continuation of antipsychotic drugs (reduce relapse rates), first-generation antipsychotic drugs in treatment-resistant people, multiple-session family interventions, psychoeducational interventions, second-generation antipsychotic drugs in treatment-resistant people, and social-skills training.

Hennoxazole A is a sponge metabolite with antiviral and analgesic activity. A key feature of the synthesis shown below (the fourth reported to date) is the late-stage metalation-alkylation of the methyloxazole L, a step for which choice of base is important.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAcylation, Diastereoselective Alkylation, and Cleavage of an Oxazolidinone Chiral AuxiliaryThomas E. Smith , David P. Richardson , George A. Truran , Katherine Belecki , and Megumi Onishi View Author Information Department of Chemistry, Williams College, Williamstown, MA 01267Cite this: J. Chem. Educ. 2008, 85, 5, 695Publication Date (Web):May 1, 2008Publication History Received3 August 2009Published online1 May 2008Published inissue 1 May 2008https://pubs.acs.org/doi/10.1021/ed085p695https://doi.org/10.1021/ed085p695research-articleACS PublicationsRequest reuse permissionsArticle Views2709Altmetric-Citations16LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alcohols,Enolates,Organic reactions,Organic synthesis,Post-translational modification Get e-Alerts

An enantioselective, convergent total synthesis of the antiviral marine natural product (-)-hennoxazole A is completed in 14 steps (longest linear sequence) from commercially available 4-methyloxazole-2-carboxylic acid. Synthesis of the C(1)-C(15) pyran/bisoxazole fragment takes advantage of an aldol-like coupling between a dimethyl acetal and an N-acetylthiazolidinethione for the direct, stereoselective installation of the C(8)-methoxy-bearing stereocenter. A one-pot acetoacetate acylation/decarboxylation/cyclodehydration of another elaborate thiazolidinethione allows for rapid assembly of the pyran-based ring system. Synthesis of the C(15)-C(25) skipped triene side chain fragment makes use of a [2,3]-Wittig-Still rearrangement for efficient installation of the trisubstituted Z-double bond. Key late-stage coupling of the two fragments is effected by deprotonation of the methyl group on the bisoxazole system using lithium diethylamide, followed by alkylation with an allylic bromide side chain segment to form the C(15)-C(16) bond.

[421-83-0] CClF3O2S (MW 168.53) InChI = 1S/CClF3O2S/c2-8(6,7)1(3,4)5 InChIKey = GRGCWBWNLSTIEN-UHFFFAOYSA-N (trifluoromethylsulfonation agent;1 chlorinating agent;2 metal-catalyzed chlorotrifluoromethylation of alkenes3) Alternate Name: triflyl chloride. Physical Data: bp 29–32 °C, d 1.583 g cm−3. Solubility: sol CH2Cl2, THF, dioxane. Form Supplied in: colorless liquid, 99 +%. Analysis of Reagent Purity: IR: 1424, 1306, 1237, 1115, 771, 611, 565, 532, 404 cm−1.4 Preparative Methods: dried Zinc Trifluoromethanesulfonate is heated with PCl5·2ZnCl at 260 °C. Fractional distillation of the volatile products gives TfCl (94% yield).5 Handling, Storage, and Precautions: moisture sensitive; store under N2 in the cold. This toxic reagent is corrosive and is a lachrymator. It should only be handled in a fume hood.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewCompendium of Organic Synthetic Methods, Volume 11 By Michael B. Smith (University of Connecticut). John Wiley & Sons, Inc., Hoboken, NJ. 2003. xx + 795 pp. 6 × 9 in. $115.00. ISBN 0-471-25965-9.Thomas E. SmithView Author Information Williams College Williamstown, Massachusetts 01267Cite this: J. Nat. Prod. 2004, 67, 5, 926Publication Date (Web):March 18, 2004Publication History Published online18 March 2004Published inissue 1 May 2004https://pubs.acs.org/doi/10.1021/np030729whttps://doi.org/10.1021/np030729wbook-reviewACS PublicationsCopyright © 2004 American Chemical Society and American Society of PharmacognosyRequest reuse permissionsArticle Views46Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alcohols,Aldehydes,Chemical reactions,Substrates Get e-Alerts

This article describes a systematic and integral method of incorporating self-help books into psychotherapy as a collaborative function. We address the distinctions between self-help and bibliotherapy, consider bibliotherapy as adjunctive or integrative to psychotherapy, and outline the multiple uses of bibliotherapy for clinical purposes. How to apply self-help books in psychotherapy and ways to select books are illustrated by a case example. Indications and contraindications for bibliotherapy in therapy are outlined.

Development of a successful synthetic route to the racemic monoterpene 7R-paeonimetaboline-I is reported; extension of this methodology in an approach to synthesis of racemic paeoniflorigenone is also summarized. © 1997 Elsevier Science Ltd. As a result of their intriguing chemical structures and their occurrence in a wide variety of traditional Chinese and Japanese herbal medicines, the monoterpenes in the paeoniflorigenone family recently have been active targets for total synthesis. Prompted by the known use of root extracts of the paeony species Paeonia Albiflora PALLAS var. trichocarpa BUNGE as an analgesic salve x and for the treatment of a variety of other painful afflictions, 2 Japanese researchers have isolated the novel tricyclic monoterpene paeoniflorigenone, 1, 3 and the structurally-similar bicyclic paeonilactones-A (2), -B (3), and C (4). 4 Related in structure to 1, the metabolite 7Rpaeonimetaboline-I (5) has been isolated from bacterial digestion extracts of paeony roots. 5 Study of the pharmacological activity of these materials has shown that 1 causes a blocking effect on the neuromuscular

Introduction. This study examined the relationships between symptoms, cognitive functioning, and social skill deficits in schizophrenia. Few studies have incorporated measures of cognitive functioning and symptoms in predictive models for social problem solving. Method. For our study, 44 participants were recruited from consecutive outpatient admissions. Neuropsychological tests were given to assess cognitive function, and social problem solving was assessed using structured vignettes designed to evoke the participant's ability to generate, evaluate, and apply solutions to social problems. A sequential model-fitting method of analysis was used to incorporate social problem solving, symptom presentation, and cognitive impairment into linear regression models. Predictor variables were drawn from demographic, cognitive, and symptom domains. Because this method of analysis was exploratory and not intended as hierarchical modelling, no a priori hypotheses were proposed. Results. Participants with higher scores on tests of cognitive flexibility were better able to generate accurate, appropriate, and relevant responses to the social problem-solving vignettes. Conclusions. The results suggest that cognitive flexibility is a potentially important mediating factor in social problem-solving competence. While other factors are related to social problem-solving skill, this study supports the importance of cognition and understanding how it relates to the complex and multifaceted nature of social functioning.