Charles F. Caley

New onset diabetes and atypical antipsychotics

As a class, the atypical antipsychotics are the first line treatment choice for the psychopharmacologic management of psychotic disorders. Emerging evidence currently suggests that at least two of the atypical antipsychotics, clozapine and olanzapine, and possibly quetiapine may be associated with the risk of new onset diabetes or serum glucose dyscontrol. Computerized Medline and Current Contents searches from years 1966 through June 2000 were undertaken to retrieve all pertinent studies and case reports of typical and atypical antipsychotics and glucose-insulin problems. Historically, both schizophrenia and the older antipsychotics medications have been reported to be associated with a similar risk for causing disruptions in serum glucose control. Additionally, diabetes has well recognized associations with a number of medical disorders such as cardiovascular disease; it is therefore worthy of attention. Hypothesized mechanisms for antipsychotic induced diabetes ranges from the antagonism of several neurotransmitter receptors to insulin resistance. A total of thirty-five cases of induced or exacerbated diabetes are presently available in the published literature; the vast majority of cases implicate clozapine (n=20) and olanzapine (n=15). In multiple cases, diabetic ketoacidosis has been the presenting symptom; daily atypical antipsychotic doses have been within acceptable ranges and were not considered to be excessive.

Extrapyramidal Reactions and the Selective Serotonin-Reuptake Inhibitors

OBJECTIVE: To review the known published reports of extrapyramidal reactions (EPRs) associated with the use of selective serotonin-reuptake inhibitors (SSRIs). DATA SOURCES: Information was selected from a MEDLINE search (January 1990 to January 1996) of English-language medical literature. Manual searches of pertinent journal article bibliographies were also performed. DATA EXTRACTION: Appropriate information from all reports obtained was included, with specific attention directed toward patient age, gender, primary psychiatric diagnosis, total daily SSRI dosage, dosage escalation strategy, and concurrent psychotropic medications. DATA SYNTHESIS: Reports of EPRs associated with SSRI use have been accumulating in the medical literature for several years. More commonly associated with high-potency antipsychotics, EPRs can have an adverse impact on medication compliance and hospital readmissions. The proposed hypothesis for EPRs occurring with SSRI use involves serotonins inhibitory actions on extrapyramidal dopamine activity. Other possible contributing factors include pharmacokinetic interactions or drug—disease interactions. EPRs may include dystonias, dyskinesias, akathisia, parkinsonism, exacerbations of Parkinsons disease, and possibly the neuroleptic malignant syndrome. The majority of SSRI-related reactions appear to occur within the first month of treatment. Information from available case reports does not strongly support any consistent risk factor, although some worth considering may include total SSRI daily dose, rapid dose escalation strategies, increased age, female gender, concurrent psychotropics known to also precipitate EPRs, and concurrent disease states such as Parkinsons disease. Since SSRI-related EPRs have occurred in different situations with different possible contributing factors, clinical pharmacy practitioners and other healthcare providers should remain aware of these reactions and carefully consider educating and monitoring their patients accordingly. CONCLUSIONS: The use of SSRIs may be associated with the development of EPRs; therefore, appropriate monitoring should be considered for patients so that optimal pharmaceutical care may be provided.

Ziprasidone: The Fifth Atypical Antipsychotic

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of ziprasidone as a treatment for schizophrenia. DATA SOURCES: Information was selected from a MEDLINE search (July 2000–October 2001) of English-language medical literature using ziprasidone as the search term. Manual searches of pertinent journal article references, request for medical information from Pfizer, and access of the Web site of the Food and Drug Administration were also performed. STUDY SELECTION: All available published information regarding the pertinent characteristics of ziprasidone were considered for selection. DATA EXTRACTION: Pharmacology and pharmacokinetic studies were selected to provide a comprehensive description of these characteristics. Clinical investigations were evaluated for design, sample size, diagnosis, duration, and outcome. Data from all investigations were selected by 1 author and reviewed by both authors. DATA SYNTHESIS: Ziprasidone is a benzisothiazolyl piperazine—type atypical antipsychotic that shares the serotonin2A/dopamine2 (5-HT2A/D2) profile of the available atypical antipsychotics. Ziprasidone has demonstrated in vitro activity as a 5-HT1A receptor agonist and as a very weak inhibitor of serotonin and norepinephrine reuptake. These data do not support ziprasidone as being a clinically meaningful inhibitor of serotonin/norepinephrine reuptake. Oral bioavailability of ziprasidone taken with food is approximately 60%, half-life is approximately 6–7 hours, and protein binding is extensive at >99%. Twelve metabolites have been identified, yet only 4 of these are considered to be primary metabolites. Metabolism of ziprasidone by aldehyde oxidase produces its only metabolite with potential pharmacologic activity; CYP3A4 also contributes to the metabolism of ziprasidone. Clinical studies support ziprasidone as efficacious for the treatment of patients with acute exacerbations of schizophrenia or schizoaffective disorder. Daily doses permitted in these clinical trials ranged from 40 to 160 mg, but only doses between 120 and 160 mg/d have been superior to placebo. Future research efforts should be directed toward refractory schizophrenia, cognitive impairment in schizophrenia, affective and anxiety symptoms associated with schizoaffective disorder, and bipolar disorder. Adverse effect characteristics of ziprasidone commonly include headache, nausea, and somnolence; infrequent effects include extrapyramidal symptoms and weight gain. Ziprasidone has been reported to cause an average QTc prolongation of approximately 20 msec; there have only been 2 patients (0.06%) reported by the manufacturer to have a measured QTc interval >500 msec. CONCLUSIONS: Ziprasidone is a safe and efficacious atypical antipsychotic for the acute management of schizophrenia. Efficacy data and most safety data for ziprasidone support its use as a first-line treatment for schizophrenia; however, its potential effects on ventricular repolarization relegate it to second-line status in patients with comorbid cardiovascular risks.

Sulpiride: an Antipsychotic with Selective Dopaminergic Antagonist Properties

Objective: To review the pharmacology, pharmacokinetics, clinical investigations, and adverse effects of sulpiride as a treatment for schizophrenia. Data Sources: Information was selected from a MEDLINE search of English-language medical literature using “sulpiride” as the search term. Manual searches of pertinent journal article bibliographies also were performed. Study Selection: Clinical investigations with a blind, controlled, randomized design and treatment durations of at least 6 weeks were preferred. Formal assessment of a patients schizophrenia was required. One clinical investigation using a 4-week treatment duration and 1 open investigation were included for purposes of adverse reaction assessment. Data Extraction: Clinical investigations were evaluated for design, sample size, diagnosis, duration, and outcome. Data from all investigations were selected by 1 author and reviewed by both authors. Data Synthesis: Sulpiride is a substituted benzamide with selective dopaminergic blocking activity. Early pharmacology reports hypothesized that sulpiride was selective for dopamine (D)2 receptors only, but sulpiride also blocks D3 and D4 receptors. Sulpiride does not block D1, adrenergic, cholinergic, gamma-aminobutyric acid–ergic, histaminergic, or serotonergic receptors to an appreciable extent. The oral bioavailability of sulpiride is poor, with estimates approximating 35%. Sulpiride does not appear to have an extensive first-pass metabolism, nor is it extensively protein-bound. There have been no identified active metabolites, and elimination appears to depend primarily on the kidneys. Clinical studies support sulpiride as being equally effective as active controls in the acute treatment of patients with schizophrenia. Daily doses permitted in these clinical investigations ranged from 100 to 3200 mg. Further investigation is required to determine the usefulness of sulpiride as a chronic treatment of schizophrenia and its effectiveness in treating the negative symptoms of schizophrenia. Sulpiride may cause extrapyramidal effects, autonomic effects, tardive dyskinesia, and the neuroleptic malignant syndrome. The incidence of these adverse reactions has not been established. Conclusions: Sulpiride is a safe and effective pharmacotherapeutic treatment for the acute management of schizophrenia. A unique pharmacology does not appear to provide sulpiride with a greater effectiveness than the standard antipsychotics, but may provide it with minor safety advantages.

Paroxetine: A Selective Serotonin Reuptake Inhibiting Antidepressant

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical investigations, adverse effects, and dosing strategies of paroxetine as a treatment of major depression. DATA SOURCES: Specific paroxetine information was selected from a MEDLINE search using paroxetine as the search term. Other sources included manual searches of pertinent journal article references, meeting abstracts, and the manufacturer. STUDY SELECTION: Clinical investigations with a blind, controlled (placebo and/or active), randomized design were selected. With the exception of treatment-resistant depression, no short-term, open investigations were selected. DATA EXTRACTION: Clinical investigations were evaluated for design, sample size, diagnosis, duration, definition of response, and outcome. Data from all investigations were selected by one author and reviewed by both authors. DATA SYNTHESIS: Paroxetine is a selective serotonin reuptake inhibitor (SSRI) recently approved for the treatment of major depression. It is a potent and selective inhibitor of serotonin reuptake and has weak or no activity on the other monoamines; it is also weakly anticholinergic. Although pharmacokinetic parameters are variable, paroxetine is generally well absorbed, highly protein bound, hepatically cleared, and has no active metabolites. Clinical investigations support paroxetines effectiveness as an antidepressant in an outpatient population with moderately severe depression. Its effectiveness is superior to that of placebo and is comparable to that of active controls. The majority of investigations have been six weeks in duration. Additional data are required to support paroxetines promise for longer treatment periods (i.e., ≥1 y), in the elderly, and for treatment-resistant depression. Adverse effects appear to be similar to those caused by the other SSRIs; some of the most common are nausea, diarrhea, insomnia, dry mouth, and nervousness. Significant drug interactions may occur with the monoamine oxidase inhibitors, phenobarbital, and phenytoin. CONCLUSIONS: Paroxetine is safe and effective for treatment of outpatients with moderately severe depression. Further clinical data and experience are necessary to determine this agents place in the long-term treatment of major depression.

Possible Hypothyroidism Associated with Quetiapine

OBJECTIVE: To report a case of hypothyroidism occurring after the addition of quetiapine to an existing drug regimen. CASE SUMMARY: A 46-year-old African-American woman diagnosed with schizoaffective disorder, bipolar type, and a four-year history of successfully treated hyperthyroidism, was suboptimally responsive to olanzapine treatment. Transition from olanzapine to quetiapine was initiated and, approximately two months after adding quetiapine to a standing pharmacotherapeutic regimen, the patient developed an elevated thyroid-stimulating hormone (TSH) concentration of 8.45 μU/L. A diagnosis of hypothyroidism was subsequently made, treatment with levothyroxine was initiated, and the patients thyroid function became stable. DISCUSSION: Drug-induced hypothyroidism is known to occur with several medications. Quetiapine is an atypical antipsychotic with the potential to decrease thyroid hormone concentrations in some patients; this effect may be dose related. Despite this known adverse effect, the manufacturer of quetiapine reports that elevated TSH concentrations and subsequent treatment with thyroid hormone supplementation have occurred only rarely. We report the development of hypothyroidism in a patient who had previously received successful radioactive iodine treatment for hyperthyroidism in 1994, but who had no detected thyroid abnormalities until treatment with quetiapine was started four years later. CONCLUSIONS: Patients with compromised thyroid function who receive treatment with quetiapine may develop hypothyroidism. Appropriate care for these patients may include an increased awareness of possible hypothyroidism and consideration of thyroid function monitoring.

Possible Case of Mania Associated with Ma-Huang

Several commercially available weight‐loss supplements contain ma‐huang, an herb derived from Ephedra sinica. Previous reports have raised awareness that ma‐huang supplements may precipitate symptoms consistent with mania in susceptible individuals. A 21‐year‐old woman required psychiatric hospitalization as a result of acute manic symptoms with psychosis. The emergence of her symptoms coincided with her use of two supplements containing ma‐huang. Consumers need to be educated about the potential adverse psychiatric effects of ma‐huang in order to make well‐informed decisions before using such supplements. A preexisting psychiatric disorder may also increase susceptibility to these adverse effects.

Extrapyramidal Reactions Associated With Serotonergic Antidepressants

Objective: Extrapyramidal reactions (EPRs) associated with serotonergic antidepressant treatments have been reported since 1958. These reactions can be distressing for patients and complicate treatment. Our objective was to complete a follow-up review of published EPR cases reported for serotonergic antidepressants. Data Sources: Published cases between January 1998 and May 2015 were collected through a medical literature search. Citation reference lists were also searched manually. Study Selection and Data Extraction: Identified cases were reviewed for patient age, gender, psychiatric diagnosis, dosage, time to reaction onset, concurrent medications, and EPR description. Cases were excluded when there was not a clear description, if descriptions were not consistent with accepted definitions, or if the written English was poor. We included cases of akathisia, dystonia, dyskinesia, parkinsonism, or mixed EPRs. Authors scored each case using the Naranjo adverse drug reaction probability scale. Data Synthesis: We identified 86 published reports involving 91 patients; selective serotonin reuptake inhibitors were implicated in 80.2% of cases. All EPR types were reported: 17 akathisia cases, 18 dyskinesia cases, 27 dystonia cases, 19 parkinsonism cases, and 10 mixed EPR cases. EPRs typically occurred within 30 days of either treatment initiation or dose increase. Age, gender, antidepressant dosing, or concurrent antipsychotic treatment did not appear to broadly contribute to EPR risk. Naranjo scores ranged from 2 to 8. Conclusions: Case reports associating serotonergic antidepressants with EPRs continue to be published. Practitioners are advised that monitoring for such is important. Rigorous research efforts are needed to better understand the clinical risk factors for these adverse drug reactions.

Interpreting and Applying CYP450 Genomic Test Results to Psychotropic Medications

The promises of personalized medicine have health care professionals and the public at large in great anticipation of the idea that understanding a patient’s genetic composition will provide clear answers to their treatment needs. For many practitioners in mental health care, there has been a question about whether or not CYP450 genetic polymorphisms can reliably inform psychotropic treatment response and tolerability. Unfortunately, the published evidence addressing this issue is mixed with only some researchers finding a positive correlation between a patient’s inherited metabolizer status and either response or tolerability to a specific medication or a therapeutic class of medications. Despite this mixed evidence, clinical practitioners have started genotyping CYP450 enzymes for some of their patients with the hope that these data may shed some light on difficult treatment decisions. This review will focus on the metabolism of psychotropics and important aspects of understanding the genomics of the cytochrome P450 enzymes 2C9, 2C19, and 2D6. Additionally this review will illustrate sample laboratory reports from 4 different laboratories which test for CYP450 genomics and then finally provide 3 different case scenarios which illustrate a process that pharmacists can use when applying genomic laboratory data to patient care.

The Role of a Psychiatric Pharmacist in College Health

Abstract Published evidence indicates there is a growing prevalence of psychiatric illnesses on college campuses, and that approximately one quarter of students may be taking psychotropic medications. But attracting and retaining experienced mental health care professionals to college health settings is a challenging task. The psychiatric pharmacist is one professional resource that can serve as both a clinical and educational consultant for college mental health services. A pilot psychiatric pharmacist service project is described.