Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients.

Atypical antipsychotics induce pre-diabetic symptoms in some but not all patients, characterized most notably by elevated weight. The side effect profiles of the various drugs in the class differ, however, raising the possibility of drug-specific mechanisms for similar side effects. We used physiogenomic analysis, an approach previously employed to study the genetics of drug and diet response, to discover and compare genetic associations with weight profiles observed in patients treated with olanzapine and risperidone as an approach to unraveling contrasting mechanistic features of both drugs. A total of 29 single nucleotide polymorphisms (SNPs) were selected from 13 candidate genes relevant to two potential pharmacological axes of psychotropic-related weight profiles, appetite peptides and peripheral lipid homeostasis. We applied physiogenomic analysis to a cross-section of 67 and 101 patients being treated with olanzapine and risperidone, respectively, and assessed genetic associations with the weight profiles. Weight profiles in patients treated with olanzapine were significantly associated with SNPs in the genes for apolipoprotein E, apolipoprotein A4 and scavenger receptor class B, member 1. Weight profiles in patients treated with risperidone were significantly associated with SNPs in the genes for leptin receptor, neuropeptide Y receptor Y5 and paraoxonase 1. These results are consistent with contrasting mechanisms for the weight profile of patients treated with these drugs. Genes associated with olanzapine weight profiles may be related to peripheral lipid homeostatic axes, whereas those associated with risperidone's may be related to brain appetite peptide regulation. Future physiogenomic studies will include neurotransmitter receptor SNPs and validation in independent samples.

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.

Intravenous iron dextran and erythropoietin use in pediatric hemodialysis patients.

Recombinant human erythropoietin (rHuEPO) is an effective treatment for the anemia of chronic renal failure. However, adequate availability of iron is necessary for an optimal response. We prospectively evaluated the effect of an intravenous iron protocol in a pediatric hemodialysis unit. Patients with either a serum ferritin less than 150 ng/ml or transferrin saturation (TSAT) less than 20% received intravenous iron dextran during ten consecutive dialysis sessions. The administration of rHuEPO was adjusted using a protocol designed to maintain patient hematocrit between 33% and 36%. Thirteen courses of intravenous iron were evaluated. Patients received 4 mg/kg of iron dextran (maximum of 100 mg) during each of ten consecutive dialysis sessions. In 12 cases there was a decrease in rHuEPO use 2 months after completing the course of intravenous iron. The mean rHuEPO dose decreased from 3,784 units to 2,115 units (P<0.005). Based on the criteria of response to intravenous iron, a percentage iron saturation of less than 20% had a high specificity for detecting iron deficiency. All patients who received a course of intravenous iron had a TSAT less than 20%. The measurement of serum ferritin was less useful in our patients.

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 microU/L. A diagnosis of hypothyroidism was subsequently made, treatment with levothyroxine was initiated, and the patient's 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.

Clozapine-associated elevation in serum triglycerides.

OBJECTIVE: This study was conducted to determine serum lipid level changes in patients who received clozapine or haloperidol. METHOD: Medical records of 222 inpatients treated with clozapine or haloperidol were reviewed. Age, weight, gender, daily antipsychotic dose, total cholesterol level, serum triglyceride level, and concurrent medications were recorded. RESULTS: Clozapine-treated men had significantly higher follow-up serum triglyceride concentrations over baseline than did haloperidol-treated men. Female patients experienced serum triglyceride level elevations regardless of antipsychotic treatment. Changes in total cholesterol levels were not significantly different between treatment groups. CONCLUSIONS: An increase in serum triglyceride levels occurred in clozapine-treated patients; screening for serum triglyceride elevations may be warranted before treatment with clozapine.

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 serotonin's 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 Parkinson's 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 Parkinson's 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.

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 patient's 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 paroxetine's 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 paroxetine's promise for longer treatment periods (i.e., > or = 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 agent's place in the long-term treatment of major depression.

Does fluoxetine exacerbate Parkinson's disease?

BACKGROUND: Because fluoxetine may be associated with an induction or exacerbation of parkinsonism, caution has been suggested when considering fluoxetine as an antidepressant for patients with Parkinson's disease. METHOD: We retrospectively reviewed the medical records of 23 outpatients with Parkinson's disease who were receiving or had received fluoxetine. One author evaluated all patients using the Northwestern University Disability Scale for scoring parkinsonism. Rather than employing a formal depression scale, we assessed depression globally. Concurrent medications were permitted. RESULTS: Twenty of the 23 patients experienced no worsening of parkinsonism while being treated with up to 40 mg of fluoxetine per day. The other 3 patients' parkinsonism worsened to a mild degree: a 74-year-old man experienced an increase in akinesia, tremor, and rigidity; a 77-year-old man experienced a slight worsening in tremor and rigidity; and a 56-year-old man experienced a decline in gait and akinesia. It was unclear if these declines, which were neither acute nor severe, were due to fluoxetine treatment or the progression of the disease. Signs of parkinsonism in 2 patients appeared to improve during fluoxetine treatment. CONCLUSION: Fluoxetine, in doses up to 40 mg/day, does not appear to be associated with exacerbations of parkinsonian signs and symptoms in outpatients with Parkinson's disease. Further investigation of fluoxetine for the treatment of depression in patients with Parkinson's disease is warranted.