Jessica L. Gören

Quetiapine, an Atypical Antipsychotic

The discovery of antipsychotic agents in the 1950s revolutionized the treatment of schizophrenia. A large body of evidence supports the dopamine D2 receptor antagonists efficacy in the treatment of psychotic symptoms. However, the advent of newer agents seems to point to a more complex interaction of neurotransmission in the pathophysiology of schizophrenia. In fact, a defining characteristic of atypical agents is a higher ratio of serotonin (5HT2) receptor blockade to D2 receptor blockade. Clozapine was the first atypical agent to be introduced; it was followed by risperidone, olanzapine, and now quetiapine, which is a dibenzothiazepine derivative structurally related to clozapine and olanzapine.

Bioavailability and Lack of Toxicity of S‐Adenosyl‐l‐Methionine (SAMe) in Humans

Study Objective. To determine if S‐adenosyl‐l‐methionine (SAMe), a widely used dietary supplement with antidepressant properties, is significantly bioavailable, and whether toxic methylated compounds are produced with oral SAMe administration in humans. Serum homocysteine levels were also measured since alterations in these levels have been theorized in association with SAMe.

When Is Antipsychotic Polypharmacy Supported by Research Evidence? Implications for QI

BACKGROUND Concurrent use of multiple standing antipsychotics (antipsychotic polypharmacy) is increasingly common among both inpatients and outpatients. Although this has often been cited as a potential quality-of-care problem, reviews of research evidence on antipsychotic polypharmacy have not distinguished between appropriate versus inappropriate use. METHODS A MEDLINE search from 1966 to December 2007 was completed to identify studies comparing changes in symptoms, functioning, and/or side effects between patients treated with multiple antipsychotics and patients treated with a single antipsychotic. The studies were reviewed in two groups on the basis of whether prescribing was concordant with guideline recommendations for multiple-antipsychotic use. RESULTS A review of the literature, including three randomized controlled trials, found no support for the use of antipsychotic polypharmacy in patients without an established history of treatment resistance to multiple trials of monotherapy. In patients with a history of treatment resistance to multiple monotherapy trials, limited data support antipsychotic polypharmacy, but positive outcomes were primarily found in studies of clozapine augmented with a second-generation antipsychotic. DISCUSSION Research evidence is consistent with the goal of avoiding antipsychotic polypharmacy in patients who lack guideline-recommended indications for its use. The Joint Commission is implementing a core measure set for Hospital-Based Inpatient Psychiatric Services. Two of the measures address antipsychotic polypharmacy. The first measure assesses the overall rate. The second measure determines whether clinically appropriate justification has been documented supporting the use of more than one antipsychotic medication.

Antipsychotic Prescribing Pathways, Polypharmacy, and Clozapine Use in Treatment of Schizophrenia

OBJECTIVE To ensure optimal care for patients with schizophrenia, antipsychotic medications must be appropriately prescribed and used. Therefore, the primary objectives of this study were to identify and describe pathways for antipsychotic prescribing, assess the consistency of observed pathways with treatment guidelines, and describe variability across facilities. METHODS Data from Veterans Affairs administrative data sets from fiscal year (FY) 2003 to FY 2007 were gathered for analysis in this retrospective cohort study of antipsychotic prescribing pathways among 13 facilities across two regional networks. Patients with a new episode of care for schizophrenia or schizoaffective disorder in FY 2005 were identified, and antipsychotic prescribing history was obtained for two years before and after the index diagnosis. Demographic characteristics and distribution of comorbidities were assessed. Median medical center rates of polypharmacy were calculated and compared with Fishers exact test. RESULTS Of 1,923 patients with a new episode of schizophrenia care, 1,003 (52%) had complete data on prescribing pathways. A majority (74%) of patients were prescribed antipsychotic monotherapy, and 19% received antipsychotic polypharmacy. Of patients receiving antipsychotic polypharmacy, 65% began polypharmacy within 90 days of starting any antipsychotic treatment. There was a fourfold difference in polypharmacy across facilities. Antipsychotic polypharmacy was not associated with geographic location or medical center patient volume. Clozapine utilization was low (0%-2%). CONCLUSIONS Retrospective examination of longitudinal prescribing patterns identified multiple antipsychotic prescribing pathways. Although most patients received guideline-concordant care, antipsychotic polypharmacy was commonly used as initial treatment, and there was substantial variability among facilities. Study findings suggest the utility of secondary data to assess treatment adaptation or switching for practical clinical trials.

S-adenosyl-l-methionine: effects on brain bioenergetic status and transverse relaxation time in healthy subjects

BACKGROUND S-adenosyl-L-methionine is an effective treatment for clinical depression, although the mechanism underlying this effect is unclear. Presently, in vivo phosphorus magnetic resonance spectroscopy (31P MRS) and brain transverse relaxometry were employed to test if S-adenosyl-L-methionine supplementation alters brain bioenergetics and/or transverse relaxation time (T2RT) in a nondepressed cohort. If these magnetic resonance techniques are sensitive to S-adenosyl-L-methionine induced alterations in neurochemical processes, these methods may be used in cases of clinical depression to elucidate the mechanism underlying the antidepressant effect of S-adenosyl-L-methionine. METHODS Twelve subjects self-administered 1600 mg of oral S-adenosyl-L-methionine daily. Phosphorus spectra and transverse relaxation time were acquired at baseline and after treatment using a 1.5 Tesla scanner. RESULTS Phosphocreatine levels were significantly higher after treatment, whereas beta nucleoside triphosphate levels, predominantly adenosine triphosphate in brain, were significantly lower after treatment. A surprising gender difference in T2RT emerged after supplementation, with women exhibiting significantly lower T2RT than men. CONCLUSIONS Alterations in phosphocreatine and beta nucleoside triphosphate are consistent with the report that S-adenosyl-L-methionine is involved in the production of creatine, which in turn is phosphorylated to phosphocreatine using adenosine triphosphate. These findings suggest that S-adenosyl-L-methionine alters parameters associated with cerebral bioenergetic status and that some effects of S-adenosyl-L-methionine (T2RT) occur in a gender-specific manner.

Infection and Inflammation Leading to Clozapine Toxicity and Intensive Care A Case Series

Objective: To describe 3 cases of clozapine toxicity associated with infectious and/or inflammatory processes. Case Summaries: Three patients stable on clozapine therapy prior to a medical hospital admission developed clozapine toxicity. It was suspected that an acute infectious and/or inflammatory process in each patient was related to abrupt mental status changes, onset of sialorrhea, myoclonus, and/or need for ventilatory support. Investigations of altered mental status did not reveal alternative causes and presentations were not consistent with neuroleptic malignant syndrome, other acute neurologic complications, or psychiatric decompensation. All patients improved after clozapine dose reductions allowing for transfer from intensive care units. Using the Naranjo ADR Probability Scale for each case, a probable relation between clozapine toxicity and the infectious and/or inflammatory process was determined. Discussion: Clozapine toxicity may manifest with multiple symptoms, including sedation, sialorrhea, and hypotension. In addition to overdose and drug interactions; infection and/or inflammation may precipitate clozapine toxicity. This may be related to cytokine-mediated inhibition of cytochrome P450 1A2. The likelihood of toxicity via this mechanism has not been well characterized, thus careful monitoring is required for medically ill patients receiving clozapine. Clozapine is extensively bound to the acute phase reactant, α-1 acid glycoprotein, which may unpredictably protect against clinical toxicity. C-reactive protein has also been investigated to relate clozapine toxicity to infection and/or inflammation. Conclusion: Clozapine toxicity developed in 3 patients admitted to a medical setting suspected to be related to infection and/or inflammation. Clinicians should be aware of this potential adverse drug event with clozapine.

Mania with Bupropion: A Dose-Related Phenomenon?

OBJECTIVE: To report a case in which bipolar depression was resistant to usual therapies, requiring dosages of bupropion >450 mg/d and to review the literature on mania associated with bupropion and propose a potential theory of a dose-related threshold associated with bupropion and mania. CASE SUMMARY: A 44-year-old white man with a 25-year history of bipolar affective disorder presented with depression resistant to usual therapies. Bupropion therapy was initiated and the dosage was titrated to 600 mg/d. After exceeding the maximum recommended daily dose (450 mg/d), he experienced a manic episode attrib uted to high-dose bupropion. DISCUSSION: Due to increased risk of seizures, current prescribing guidelines state that the total daily dose of bupropion is not to exceed 450 mg/d. Since bupropion is the agent least likely to cause a manic switch in bipolar disorder, this agent seemed a logical choice to treat the patients depression. Due to a lack of response, the bupropion dosage was titrated to a maximum of 600 mg/d. Since the patient did not switch into mania until the dosage exceeded 450 mg/d, we speculate that this adverse reaction is a dose-related phenomenon. Scientific literature supports this theory. CONCLUSIONS: A switch into mania is a potential risk associated with antidepressant drug use in bipolar affective disorder. Bupropion is believed to be associated with a decreased risk compared with other antidepressant therapies. However, our case report as well as others support the theory that this decreased risk may be due to dosages not exceeding the recommended daily dose (450 mg/d). Doses of bupropion >450 mg/d should be used with caution in depressed patients with bipolar affective disorder.

Levetiracetam, Seizures, and Suicidality

Danny is a 28-year-old, white male with a history of depression, anxiety and panic attacks, childhood abuse, and multiple medical problems. As a newborn he was treated with ventriculo-peritoneal shunting for hydrocephalus. As a result, he suffers from persistent seizures, an unspecified mild cognitive impairment, and a noticeable stutter. Danny grew up outside of Boston, where he lived with his mother, father, and two sisters. His parents underwent a difficult divorce when he was 14 years old, but he remains close to his family. Apart from alcohol abuse in his father, there is no family history of psychiatric illness. Danny earned Bs and Cs in high school, eventually attending vocational school for printing and graphic design. He has had consistent difficulties in maintaining stable employment and has shifted among various jobs, including retail store manager, martial arts instructor, chef, and postal service worker. Although he receives Social Security disability for epilepsy and

Pharmacologic Management of Bipolar Disorder in a Medicare Advantage Population

OBJECTIVE The purpose of this study was to examine patterns of pharmacotherapy for beneficiaries in a high-risk Medicare Advantage program who were diagnosed with bipolar disorder. METHODS This was a cross-sectional study of 2338 Medicare Advantage beneficiaries diagnosed with bipolar disorder. Pharmacotherapy treatment was assessed via receipt of (1) a mood stabilizer or antipsychotic or both (i.e., guideline concordant bipolar care) and (2) unopposed antidepressant (i.e., without prescription of a mood stabilizer or an antipsychotic). Logistic regression was used to examine correlates of bipolar disorder care. RESULTS Among those younger than 65 years of age (n = 1395), 54% received guideline concordant therapy and 29% received unopposed antidepressant therapy. Among those 65 years and older (n = 943), 40% received guideline concordant therapy and 33% received unopposed antidepressant therapy. CONCLUSION Overall, about half of beneficiaries in this Medicare Advantage plan received guideline concordant pharmacotherapy for bipolar disorder, while approximately one-third received an unopposed antidepressant prescription. Antipsychotic medications accounted for most of the monotherapy observed. This study identifies opportunities for further improvements in the pharmacotherapy of bipolar disorder in high-risk Medicare patients.

Drug Interactions and Polypharmacy

Over the past 20 years the number of psychotropic medications has increased dramatically. As a result, the use of psychotropic polypharmacy has rapidly expanded. One outcome of psychotropic polypharmacy has been an increase in the number of drug interactions that occur in routine clinical practice. Although drug interactions resulting in death are rare, the effects of drug interactions are often misinterpreted as drug inefficacy or toxicity. Therefore an understanding of pharmacodynamic and pharmacokinetic drug interactions is essential when using polypharmacy. This chapter reviews the mechanisms of drug interactions, describes the most commonly seen drug interactions and offers suggestions for addressing drug interactions in clinical practice. Given polypharmacy is common in psychiatry; clinicians must routinely assess which medication combinations are safe to prescribe, require dose adjustments and are best avoided. Future research should focus on the role of genetics and interventions to decrease adverse drug reactions related to drug interactions.