Atypical Agents Research Articles

English

Neuroleptic malignant syndrome [NMS], although rare, is a well-documented lifethreatening reaction to antipsychotic medications with mortality rate estimated as being up to 20%. NMS was traditionally attributed to potent dopamine antagonism of typical antipsychotics but cases of NMS have been reported for each of the newer atypical antipsychotics. Aripiprazole is one such atypical agent approved by FDA for treating schizophrenia in 2002 and acute bipolar mania in 2004. Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at 5-HT1A receptor and antagonist activity at 5-HT2A receptor. In comparison to other atypical it posses unique mechanism of action that may limit development of hypodopaminergic state, however there are case reports of aripiprazole induced NMS, akathisia, rhabdomyolysis, parkinsonism and excessive somnolence in children. To add to this literature we report a case of 50 year old woman with multiple risk factors, developed NMS with low dose of aripiprazole. INTRODUCTION: The neuroleptic malignant syndrome (NMS) is an idiopathic, life-threatening reaction to Antipsychotic medication, characterized principally by fever, muscle rigidity, altered consciousness, autonomic instability, laboratory findings such as elevated creatine phosphokinase (CPK), 1 leukocytosis, raised liver enzymes. Serious complications are possible, including renal failure, thromboembolism, respiratory failure from chest wall rigidity, aspiration pneumonia, and arrhythmia2. Different criteria’s are proposed by different researchers for diagnosis of NMS but most commonly used are DSM-IV TR,3 and Levensons,1 criteria. Treatment consists of immediate discontinuation of the antipsychotics as well as D2 blocking agents, and most commonly used pharmacologic interventions are bromocriptine, and dantrolene.4 we report a case of 50 year old lady with multiple risk factors, developed NMS with low dose of single agent, aripiprazole. CASE REPORT: Ms XY 50 yrs old lady initially presented to the hospital in November 2009 and was diagnosed to be suffering from undifferentiated schizophrenia and was treated with olanzapine 5mg/day. Later during the course of illness she exhibited depressive symptoms and fluoxetine 20 mg/day was added which was stopped after 6 months as her depressive symptoms remitted. Olanzapine was discontinued after 2 yrs of treatment as she developed Diabetes Mellitus. Later she was initiated on Trifluoperazine 15mg daily which had to be stopped within two weeks due to severe extra pyramidal symptoms [EPS]. Trihexyphenidyl, 2 mg/day was given for 4 weeks till her EPS subsided completely and tablet aripiprazole 2.5mg/day was started which was slowly increased to 5mg/day over next 4 weeks. Within 4 weeks of starting with aripiprazole she developed EPS and at times she experienced acute dystonia. Trihexyphenidyl 2 mg/day was restarted in view of this but low grade of EPS

Risk of Pneumonia in Elderly Nursing Home Residents Using Typical Versus Atypical Antipsychotics

Antipsychotic medications are extensively used in nursing homes for management of behavioral and psychiatric disorders in the elderly. Prior research suggests that pneumonia is one of the common causes of anti psychotic-related mortality in this population. None of the studies compared typical and atypical antipsychotics with respect to pneumonia. To examine the risk of pneumonia with use of typical versus atypical antipsychotics in dual eligible elderly nursing home residents. The study involved a retrospective cohort design matched on propensity score using Medicare and Medicaid Analytical eXtract data from 4 US states. The study population included all elderly dual eligible (Medicaid and Medicare) nursing home residents (aged ≥65 years) who initiated antipsychotics any time between July 1, 2001, and December 31, 2003. The risk of pneumonia during the 6-month follow-up period was modeled using a Cox proportional model and extended Cox hazard model stratified on matched pairs based on propensity score, using atypical agents as the reference category. Analysis of Medicaid-Medicare data revealed that there were 49,904 new antipsychotic (46,293 atypical and 3611 typical) users in the unmatched cohort and 7218 (3609 atypical and 3609 typical) users in the matched cohort. The unadjusted rate of pneumonia was 8.17% (4.61 events per person year) for atypical users and 5.21% (5.21 events per person year) for typical users. HR 1.17, 95% CI 0.83-1.66; and 50-180 days: HR 1.36, 95% CI 0.87-2.14) suggest that there was no significant difference in the risk of pneumonia among typical and atypical users. The study found no differential risk of pneumonia between typical versus atypical antipsychotic use in dual eligible nursing home residents. Given the differential risk of mortality with typical and atypical antipsychotic use in nursing homes, more research is needed to evaluate other contributory factors of mortality with respect to these 2 antipsychotic classes.

“An inexplicable disease”‐ Prion disease as a ‘choose‐your‐own‐ experiment’ case to introduce students to scientific inquiry

The study objective was to develop and test a case study which simulates scientific inquiry within the limits of a single course period and which can be used in large lecture‐format courses. Students unknowingly take the roles of the initial investigators of the Kuru epidemic of Papua New Guinea in 1957 and work in groups to iteratively conduct simulated investigations, evaluate the results, and form hypotheses regarding the nature of the disease. The activity culminates in a mock‐scientific conference, in which student groups collaborate by sharing findings, mirroring real events which led to the discovery of prion diseases. Learning goals focus on student opinions, attitudes and skills related to the nature of science, causes of disease epidemics, and prions as atypical infectious agents. The activity has been implemented successfully at five schools in seven courses which span five fields: biology, microbiology, genetics, zoology, and biochemistry. We present aggregated data from five courses measuring cognitive and affective learning gains. In addition to positive content learning gains and overwhelmingly positive affective responses from students, we were successful in using a modified CLASS‐BIO survey to measure objective changes in attitudes toward biology as a result of the activity alone. We hope that both the activity and approach can be used broadly by life sciences educators.

What Do We Really Know About the Treatment of Delirium with Antipsychotics? Ten Key Issues for Delirium Pharmacotherapy

Despite the significant burden of delirium among hospitalized adults, no pharmacologic intervention is approved for delirium treatment. Antipsychotic agents are the best studied but there are uncertainties as to how these agents can be optimally applied in everyday practice. We searched Medline and PubMed databases for publications from 1980 to April 2012 to identify studies of delirium treatment with antipsychotic agents. Studies of primary prevention using pharmacotherapy were not included. We identified 28 prospective studies that met our inclusion criteria, of which 15 were comparison studies (11 randomized), 2 of which were placebo-controlled. The quality of comparison studies was assessed using the Jadad scale. The DRS (N = 12) and DRS-R98 (N = 9) were the most commonly used instruments for measuring responsiveness. These studies suggest that around 75% of delirious patients who receive short-term treatment with low-dose antipsychotics experience clinical response. Response rates appear quite consistent across different patient groups and treatment settings. Studies do not suggest significant differences in efficacy for haloperidol versus atypical agents, but report higher rates of extrapyramidal side effects with haloperidol. Comorbid dementia may be associated with reduced response rates but this requires further study. The available evidence does not indicate major differences in response rates between clinical subtypes of delirium. The extent to which therapeutic effects can be explained by alleviation of specific symptoms (e.g. sleep or behavioral disturbances) versus a syndromal effect that encompasses both cognitive and noncognitive symptoms of delirium is not known. Future research needs to explore the relationship between therapeutic effects and changes in pathophysiological markers of delirium. Less than half of reports were rated as reasonable quality evidence on the Jadad scale, highlighting the need for future studies of better quality design, and in particular incorporating placebo-controlled work.

Psychiatric Care in Parkinson’s Disease

Parkinson's disease (PD) is a degenerative and disabling disease in which medical providers focus mainly on ameliorating problems in day-to-day functioning. This review summarizes current knowledge about the efficacy and tolerability of psychopharmacological agents in the treatment of depression, anxiety, psychosis, and insomnia in patients with PD. Recommended or promising nonpharmacological interventions are also reviewed. Studies were identified using computerized searches, with further references obtained from the bibliographies of the reviewed articles. Findings in the research literature provide growing evidence concerning the antidepressant treatment of patients with PD. Psychoeducational interventions for managing depression and anxiety symptoms also appear promising. Music therapy has proven to be particularly effective for patients with PD. Psychosis is common in patients with PD. When psychosis is induced by antiparkinson drugs, a dose reduction can be considered, but it is seldom successful. Patients with PD do not generally tolerate conventional antipsychotic medications, justifying evaluation of newer atypical agents in this population. Cholinesterase inhibitors have also become increasingly important in the treatment of PD in recent years. Finally, insomnia is a very frequent complaint in patients with PD and may also contribute to the development of depression. Patients should be encouraged to improve sleep hygiene and use behavioral interventions. Definitive trials of treatments for sleep disorders in this population are also warranted. Therapeutic approaches to the treatment of PD and its associated psychiatric symptoms must be individualized and may involve a combination of antiparkinson drugs, psychopharmacological treatment, and/or psychotherapeutic interventions.

From an Atypical Wake‐promoting Agent to Potent Histamine‐3 Receptor Inverse Agonists

Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors).

Atypical antipsychotics and diabetic ketoacidosis: a review

Atypical antipsychotics have been linked to weight gain and type 2 diabetes, but are also associated with diabetic ketoacidosis (DKA), which can occur more acutely and in the absence of weight gain. Our aim was to review current case reports of DKA in the context of atypical antipsychotic treatment to better understand (a) the scope of the problem, (b) its relationship to different atypical agents, (c) risk factors, (d) long-term outcome, and (e) putative mechanisms of action. Searches in PubMed/Medline, as well as the University of Toronto's Scholar Portal, were performed for all relevant articles/abstracts in English. Sixty reports, yielding 69 cases, affirm that DKA is a rare but serious risk with almost all atypical antipsychotics; however, liability seems to vary between agents, at least partially mirroring risk of weight gain. Mean age of onset was 36.9years (range 12-80), with 68% of cases occurring in males, and 41% in individuals of African American or African Caribbean descent. Over one third of cases present with either no weight gain or weight loss, and 61% of these require ongoing treatment for glycemic control. Death occurred in 7.25% of cases. While the underlying mechanisms are not well understood, antipsychotic-related DKA can occur soon after treatment onset and in the absence of weight gain. Although rare, clinicians must remain vigilant given its acute onset and potential lethality.

1808 – The use of antipsychotic drugs in elderly patients with dementia

Introduction Delusions, hallucinations, aggression, and agitation affect more than half of patients with dementia. Antipsychotic drugs are used to treat these behaviors and symptoms. They are among the most frequently used psychotropic drugs in this disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the current practice in use of antipsychotics medication in outpatients with dementia. Method We conducted a retrospective cohort study involving patients older than 65 years who began outpatient treatment with antipsychotic drugs following a dementia diagnosis. Results 22 patients were included (16 female, 6 male) with mean age of 78.6 years. All patients consulted for behavioral problems. Most received typical aantipsychotic drugs (72,8%), while 36,4% received atypical antipsychotic drugs. 13 patients (59,1%) were receiving haloperidol. Improvement was observed in 54,5% of patients. The comparisons of haloperidol with risperidone suggest no difference in efficacy for the treatment of global behaviour disturbance. On the other hand, use of haloperidol is, however, associated with a higher incidence of extrapyramidal and other side effects. Conclusion The treatment of elderly patients requires daily careful management and monitoring because of their polypathology, polymedication and of their greater sensitivity to the toxic effects of drugs. Overall, the study findings suggest that there is a need to monitor antipsychotic drug use by elderly patients in light of recent efficacy and safety data on atypical agents.

2742 – A prospective comparative study of risperidone long-acting injection for treatment-resistant schizophrenia with dopamine supersensitivity psychosis

Backgrounds: Although treatment-resistant schizophrenia (TRS) is a highly heterogeneous disorder, an established and efficacious treatment for those patients to date is pharmacotherapy with clozapine. Dopamine supersensitivity psychosis (DSP) is characterized by profound unstable positive symptoms and tardive dyskinesia, and its mechanism is related to up-regulation of dopamine D2 receptors (DRD2) which can be induced by long-term treatment with antipsychotics. Patients with DSP take generally excessive high dosages of neuroleptics and thus meet easily the criteria of TRS. A drug with secure and stable pharmacokinetic, which can keep an appropriate blockade of DRD2, may contribute to amelioration and prevention of the dopamine supersensitivity state. Risperidone long-acting injection (RLAI) is a candidate agent which meets this hypothesis. For 115 patients with TRS, we divided them into two groups; the one is those with a history of DSP and the other is without DSP, and treatment with RLAI was conducted for 12-month duration. This is an observational study which did not control concomitant medications or dosage of RLAI. Clinical symptomatology and medications at baseline did not differ between the two groups. The results from the final analysis for remaining 95 patients revealed that the group with DSP showed greater improvements in the change of BPRS total score than the group without DSP. These results suggested strongly that the dopamine supersensitivity state could be related partly with the etiology of TRS. An atypical agent with long half-life time such as RLAI, can provide beneficial effect for patients with DSP.

Salmonella enteridisSeptic Arthritis: A Report of Two Cases

Introduction. Nontyphoidal salmonellosis causes significant morbidity, is transmitted via fecal-oral route, and is a worldwide cause of gastroenteritis, bacteremia, and local infections. Salmonella is a less common etiologic factor for septic arthritis compared with other gram-negative bacteria. Cases. We present two septic arthritis cases with Salmonella enteridis as a confirmed pathogen and also discuss the predisposing factors and treatment. Discussion. Septic arthritis is an orthopedic emergency. The gold standard treatment of septic arthritis is joint debridement, antibiotic therapy according to the culture results, and physiotherapy, which should start in the early postoperative period to prevent limitation of motion. Salmonella is an atypical agent for septic arthritis. It must be particularly kept in mind as an etiologic factor for the acute arthritis of a patient with sickle cell anemia and systemic lupus erythematosus. Clinicians should be cautious that the white blood cell count in synovial fluid can be under 50.000/mm3 in immune compromised individuals with septic arthritis. The inflammatory response can be deficient, or the microorganism may be atypical. Conclusion. Atypical bacteria such as Salmonella species in immune compromised patients can cause joint infections. Therefore, Salmonella species must always be kept in mind for the differential diagnosis of septic arthritis in a clinically relevant setting.

Erythematous skin macules with isolation of Trichophyton eboreum– infection or colonisation?

Dermatophytosis is among the most common skin diseases. They can be difficult to diagnose and are often mistaken with other diagnoses, for example tinea corporis can be mistaken as nummular eczema, impetigo, psoriasis or discoid lupus erythematosus. Atypical infectious agents are not infrequent. Recently, Trichophyton eboreum was characterised. The fungus was isolated from a moccasin-type tinea pedis in a HIV-positive patient. We report a case of eczema-like erythematous skin macules on the arms and the inguinal region of which, however, T. eboreum was isolated.

Clinical consequences of switching from olanzapine to risperidone and vice versa in outpatients with schizophrenia: 36-month results from the worldwide schizophrenia outpatients health outcomes (W-SOHO) study

BackgroundWith many atypical antipsychotics now available in the market, it has become a common clinical practice to switch between atypical agents as a means of achieving the best clinical outcomes. This study aimed to examine the impact of switching from olanzapine to risperidone and vice versa on clinical status and tolerability outcomes in outpatients with schizophrenia in a naturalistic setting.MethodsW-SOHO was a 3-year observational study that involved over 17,000 outpatients with schizophrenia from 37 countries worldwide. The present post hoc study focused on the subgroup of patients who started taking olanzapine at baseline and subsequently made the first switch to risperidone (n=162) and vice versa (n=136). Clinical status was assessed at the visit when the first switch was made (i.e. before switching) and after switching. Logistic regression models examined the impact of medication switch on tolerability outcomes, and linear regression models assessed the association between medication switch and change in the Clinical Global Impression-Schizophrenia (CGI-SCH) overall score or change in weight. In addition, Kaplan-Meier survival curves and Cox-proportional hazards models were used to analyze the time to medication switch as well as time to relapse (symptom worsening as assessed by the CGI-SCH scale or hospitalization).Results48% and 39% of patients switching to olanzapine and risperidone, respectively, remained on the medication without further switches (p=0.019). Patients switching to olanzapine were significantly less likely to experience relapse (hazard ratio: 3.43, 95% CI: 1.43, 8.26), extrapyramidal symptoms (odds ratio [OR]: 4.02, 95% CI: 1.49, 10.89) and amenorrhea/galactorrhea (OR: 8.99, 95% CI: 2.30, 35.13). No significant difference in weight change was, however, found between the two groups. While the CGI-SCH overall score improved in both groups after switching, there was a significantly greater change in those who switched to olanzapine (difference of 0.29 points, p=0.013).ConclusionOur study showed that patients who switched from risperidone to olanzapine were likely to experience a more favorable treatment course than those who switched from olanzapine to risperidone. Given the nature of observational study design and small sample size, additional studies are warranted.

Use of Atypical Antipsychotics as Mono/Polytherapy with Mood Stabilizers for the Treatment of Bipolar Disorder. An Update

Over the last decade, the class of the atypical antipsychotics has become the gold standard for the treatment of bipolar disorder (BD), at least for its manic/mixed phases. This phenomenon has different explanations: first, the number of compounds with formal approvals for BD is higher in comparison with other mood-stabilizers including lithium and anticonvulsants. Second, the sample size of randomized controlled trials assessing the efficacy and safety of different pharmacological treatments is usually larger for most recently approved compounds (i.e., atypical agents for the treatment of BD). If the role of atypical antipsychotics is well-established in the treatment of BD, doubts still persist about their optimal efficacy as monotherapy vs combination treatment with other mood-stabilizers, in particular. In addition, a possible superiority in terms of efficacy for polytherapy needs to be balanced in relation to tolerability issues. The present article was aimed to review the state of the art in the field reviewing the latest evidence arising from international guidelines recommendations and meta-analyses. Keywords: Bipolar disorder, atypical antipsychotics, monotherapy, combination therapy

A Review of Pharmacoepidemiologic Studies of Antipsychotic Use in Children and Adolescents

In Canada, treatment of children and adolescents with antipsychotics is almost always off label. A single atypical agent, aripiprazole, only recently received regulatory authorization for use in the group aged 15 to 17 years. This regulatory approval was restricted to treatment of schizophrenia. The objective of this review was to summarize pharmacoepidemiologic reports examining the frequency of use of these medications. A literature search was used to identify English-language studies examining the pharmacoepidemiology of antipsychotics in children and adolescents. The results of identified studies were summarized using narrative review methods. In countries where longitudinal data are available, increased antipsychotic use has been consistently observed. Generally, most or all of this increase can be attributed to second-generation antipsychotics (SGAs). Major international differences are evident in the literature. European studies describe lower overall frequencies of use than North American studies (most of which were conducted in the United States). SGAs in children and adolescents are used more often in boys than in girls, and are increasingly used for treatment of attention-deficit hyperactivity disorder (ADHD) and conduct disorder (CD). Determining the most appropriate frequency of SGA use in children and adolescents will ultimately depend on decisive clarification of risks and benefits. The currently available literature highlights large international differences in the frequency of use. These differences may reflect fundamental dissimilarities in the therapeutic stance adopted toward ADHD and CD by physicians practicing in different countries.

Comparative Risk of Cerebrovascular Adverse Events in Community-Dwelling Older Adults using Risperidone, Olanzapine and Quetiapine

Atypical antipsychotic agents have been associated with cerebrovascular adverse events, particularly in elderly dementia patients. However, limited evidence exists regarding comparative cerebrovascular profiles of individual atypical agents, particularly in community settings. The objective of this study was to evaluate the risk of cerebrovascular events associated with use of risperidone, olanzapine and quetiapine in community-dwelling older adults in the US. A propensity score-adjusted retrospective cohort design involving the IMS LifeLink™ Health Plan Claims Database was used for the study. The study population included all older adults (aged ≥50 years) who initiated risperidone, olanzapine or quetiapine anytime during 1 July 2000 to 30 June 2008. Patients were followed until hospitalization or an emergency room visit for a cerebrovascular event, or the end of the study period, whichever occurred earlier. The Cox proportional hazard regression model with time-varying covariates was used to evaluate the risk of cerebrovascular events during the follow-up period, using olanzapine as the reference. The covariates adjusted for in the final model included multiple propensity scores and exposure to other medications that could be associated with the risk of cerebrovascular events. A total of 2,458 cerebrovascular events were identified in the study cohort: 1,081 (21.38%) for risperidone users, 816 (18.75%) for olanzapine users and 561 (21.05%) for quetiapine users. After adjusting for propensity scores and other covariates, the Cox proportional hazard model revealed that use of quetiapine [hazard ratio (HR) 0.88; 95% CI 0.78, 0.99] but not risperidone (HR 1.05; 95% CI 0.95, 1.16) was associated with a decrease in the risk of cerebrovascular adverse events compared with olanzapine. The study suggested that quetiapine use may be associated with a moderately lower risk of cerebrovascular events than olanzapine in older adults. Prescribers should closely monitor the patients treated with atypical agents for the incidence of cerebrovascular adverse events.

A Tail with a Thorn in it: Second-Generation Antipsychotics Hand in Hand with Statins

Schizophrenia is a chronic, severe, and disabling mental disorder characterized by deficits in thought processes, perceptions, and emotional responsiveness. Its prevalence in the USA is estimated at 1.1 % by the American Institute of Mental Health [1]. Left untreated, patients with schizophrenia will suffer from severe and prolonged psychotic episodes, causing them to become more and more removed from reality and from the ability to cope with their social and occupational environment. The introduction of chlorpromazine, the first effective anti-psychotic agent, heralded a new era in psychiatry. For the first time a drug that modified the course of the disease became available [2]. Traditionally, antipsychotic agents have been classified into 2 major groups: first-generation (conventional) agents and second generation (atypical) agents. The atypical agents differ pharmacologically from previous antipsychotic agents in their lower affinity for dopamine D2 receptors and higher affinities for other neuroreceptors, including those for serotonin (5-hydroxytryptamine 1A, 2A, 2C, 3, 6, and 7) and norepinephrine (α1 and α2) [3]. First generation antipsychotic agents cause extrapyramidal symptoms. These are manifested by Parkinsonism (hand tremor, rigidity, and reduced facial expression) and repetitive movements (tardive dyskinesia, dystonias, and akathisia), which add to patients’ morbidity and awkwardness. Second generation antipsychotics, owing to their lower affinity for dopaminergic receptors, cause significantly fewer extrapyramidal symptoms. Because of their more favorable side-effect profile second generation antipsychotics became very popular, even though they were not proven to be more effective than typical antipsychotics in controlling psychotic symptoms [2, 4]. Schizophrenic patients have reduced life expectancies compared with the general population [5–7]. From the earliest reports it became increasingly clear that the higher death rate could not be attributed exclusively to unnatural death causes such as trauma and suicide [8]. Other major causes include cancer and cardiovascular diseases. The greatly increased risk of cardiovascular disease in schizophrenic patients is mainly attributable to a high prevalence of conventional risk factors. Smoking rates among these patients are 3 to 5 times higher than in the general population. Furthermore, schizophrenic smokers take in more nicotine per cigarette than smokers without this disorder [9, 10]. Access to physical health care for people with schizophrenia is hindered by both the structure and the underfunding of publicly supported systems of physical health and behavioral health care. Schizophrenic patients often lack the resources for private medical providers, and coordination between health care and behavioral health care systems is usually poor. Research also suggests that schizophrenic patients frequently face discrimination in accessing R. Durst : E. Leitersdorf (*) Center for Research Prevention and Treatment of Atherosclerosis, Hadassah Hebrew University Medical Center, Jerusalem, Israel e-mail: eranl@hadassah.org.il

Are there different neural mechanisms responsible for three stages of weight gain development in anti-psychotic therapy: Temporally based hypothesis

Weight gain as a result of atypical anti-psychotic treatment is a common issue with different atypical anti-psychotic treatments causing differing magnitudes of weight gain. Although differing amounts of weight gain result from different atypical agents little is known about the temporal course of weight gain in anti-psychotic treatment. Specifically is the time course of weight gain comparable across different agents. Therefore this article reviews the temporal course of weight gain for three common atypical anti-psychotics namely; clozapine, olanzapine and risperidone. It is evident that all three of these agents exhibit similar although at distinct magnitudes temporal courses of weight gain. That is an initial rapid increase from baseline to 3 months (stage 1), a steady increase from 3 months to 18 months (stage 2) and a plateau after this point (stage 3) with continued anti-psychotic treatment. It is postulated that each of these stages of weight gain result from distinct neural mechanisms. The hypothesized neural correlates for each stage of weight gain are reviewed and discussed. The article concludes with recommendations for future research.

Overdose of Atypical Antipsychotics

Historically, treatment for schizophrenia focused on sedation. The advent of the typical antipsychotics resulted in treatment aimed specifically at the underlying disease, but these agents were associated with numerous adverse effects, and were not particularly effective at treatment of the negative symptoms of schizophrenia. As a result, numerous atypical agents have been developed over the past 2 decades, including several agents within the past 5 years. Overdose of antipsychotics remains quite common in Western society. In 2010, poison control centres in the US received nearly 43,000 calls related to atypical antipsychotics alone. Due to underreporting, the true incidence of overdose with atypical antipsychotics is likely much greater. Following overdose of an atypical antipsychotic, the clinical effects observed, such as CNS depression, tachycardia and orthostasis are largely predictable based on the unique receptor binding profile of the agent. This article, which focuses on the atypical antipsychotics commonly used in the treatment of schizophrenia, discusses the features commonly encountered in overdose. Specifically, agents that result in QT prolongation and the corresponding potential for torsades de pointes, as well as unique features encountered with the various medications are discussed. The diagnosis of this overdose is largely based on history. Routine use of drug screens is unlikely to be beneficial. The primary goal of management is aggressive supportive care. Patients with significant CNS depression with associated loss of airway reflexes and respiratory failure need advanced airway management. Hypotension should be treated first with intravenous fluids, with the use of direct acting vasopressors reserved for persistent hypotension. Benzodiazepines should be used for seizures, with barbiturates used for refractory seizures. Intravenous magnesium can be administered for patients with a corrected QT interval exceeding 500 milliseconds.

Quetiapine-Induced Galactorrhea With Normal Prolactin Level in an Adult Female Patient

To the Editor: Quetiapine is an atypical antipsychotic agent with less propensity than other atypical antipsychotics to induce antipsychotic-associated hyperprolactinemia in standard recommended therapeutic dosages,1,2 and when it does induce the condition at all, the rise in serum prolactin level is only transient.3 Accordingly, quetiapine has been recommended as an alternative in patients who develop galactorrhea associated with other antipsychotics.4–6 However, hyperprolactinemia with related side effects may rarely be encountered in a few susceptible individuals.7 We describe a case of quetiapine-induced galactorrhea without an increase in blood prolactin level in an adult female patient. We then discuss the implications of quetiapine with respect to such an adverse effect. Case report. Ms A, a 45-year-old white woman, was diagnosed with DSM-IV-TR bipolar disorder at the age of 23 years and experienced repeated episodes of both depression and mania over the years. Treatment with lithium carbonate and sodium valproate was tried without much success. She recently presented to the psychiatric emergency department with an acute manic episode (DSM-IV-TR). The patient was agitated and refused to sit during the interview. She paced back and forth, talked or mumbled incessantly, and occasionally busted into laughter and cursed during the interview. Around the time of admission, her symptoms comprised irritability, psychomotor agitation, pressured speech, flight of ideas, insomnia, grandiose and aggressive behavior, sexual disinhibition, and lack of insight. She denied any auditory and visual hallucinations. Upon her admission to the hospital, a drug screen was negative. Findings of a head computed tomography scan were within normal limits. Results of other routine investigations including complete blood count, complete metabolic profile, thyroid function tests, liver function tests, and prolactin level were within normal limits. Treatment with quetiapine was initiated for both therapeutic as well as prophylactic purposes; she responded well, and her manic symptoms subsided. She was discharged from the hospital after 1 week. After 2 months of continued treatment, she reported breast enlargement, “milk” discharge from her breast, and bilateral breast pain and amenorrhea. Galactorrhea was confirmed by physical examination. Surprisingly, her serum prolactin level at this stage was again found to be within normal range (13 ng/mL; normal range, 2.80–20 ng/mL) instead of being high. Pregnancy test was negative. Thyroid function tests revealed no abnormalities and excluded hypothyroidism from being the cause of galactorrhea. Physical examination revealed no other abnormality. She neither complained of visual disturbance nor described symptoms suggestive of raised intracranial pressure. A brain scan was not performed as the serum prolactin elevation was within normal limits. Since we assumed quetiapine was one of the possible causes of galactorrhea, quetiapine was stopped, which led to dramatic resolution of symptoms within 72 hours. Ms A, however, took another 2 months to resume her normal menstrual cycle. A PubMed search for the years 1996 to 2011 with the keywords antipsychotics, quetiapine, and galactorrhea was performed; other articles were obtained via a Google Scholar search that included the same time span and keywords. To the best of our knowledge, this is the first case reporting galactorrhea without hyperprolactinemia in the medical literature. However, several studies have shown that quetiapine does not increase prolactin level to the same extent as do other antipsychotic medications. The newly accepted explanation for the prolactin-sparing property of quetiapine and other atypical antipsychotic agents is the poor occupancy of dopamine D2 receptors on lactotrope cells in the anterior pituitary gland compared to striatal dopamine D2 occupancy.8 This contrasts with the property of all conventional antipsychotics and some atypical agents like risperidone in blocking dopamine D2 receptors on prolactin-secreting cells in the pituitary gland, removing the main inhibitory effect on prolactin secretion.9 A study on the incidence of hyperprolactinemia and prolactin-related side effects in children and adolescents treated with antipsychotics showed that there is no significant increase in prolactin level after the long-term use (2 years) of quetiapine.10 In 2006, a 12-week randomized, double-blind study of quetiapine, risperidone, or fluphenazine on sexual functioning in people with schizophrenia showed that, overall, quetiapine was associated with normal prolactin levels.11 Treatment with quetiapine and olanzapine caused prolactin levels to be elevated just temporarily. However, no correlation between prolactin levels and dosage could be found in these subjects under treatment.12 Detailed endocrine-metabolic studies performed on 5 women showed isolated galactorrhea with normal serum prolactin levels.13 To our knowledge, 2 case reports7,14 have been published on subjects who developed hyperprolactinemic galactorrhea with quetiapine. However, no case reports have been published about quetiapine-induced galactorrhea with normal level of prolactin as was seen in our subject. Although quetiapine is considered to be a prolactin-sparing atypical antipsychotic, quetiapine-induced galactorrhea may rarely be encountered as a side effect in susceptible individuals, and therefore physicians should routinely inquire about quetiapine as one of the possible causes of galactorrhea even when the prolactin level is within normal limits.

Risk of Falls and Fractures in Older Adults Using Atypical Antipsychotic Agents: A Propensity Score–Adjusted, Retrospective Cohort Study

BackgroundAtypical antipsychotic agents are extensively prescribed in the elderly to treat various behavioral and psychiatric disorders. Past literature has documented an increased risk of falls and factures with the use of risperidone and olanzapine compared with nonuse. However, none of the studies assessed the comparative safety profiles of atypical agents with respect to falls and fractures. ObjectiveThe goal of this study was to evaluate the risk of falls and fractures associated with the use of risperidone, olanzapine, and quetiapine in community-dwelling adults aged ≥50 years. MethodsThe study involved a propensity score–adjusted approach in new users of risperidone, olanzapine, or quetiapine anytime between July 1, 2000, and June 30, 2008, using data from the IMS LifeLink Health Plan Claims database. Patients were followed up until a hospitalization/emergency department visit for fall/fracture or the end of the study period, whichever occurred earlier. The Cox proportional hazards regression model was used to evaluate the comparative risk of falls/fractures. The covariates in the final model included propensity scores and their interaction terms. ResultsThere were 12,145 new users of atypical agents in the study population (5083 risperidone, 4377 olanzapine, and 2685 quetiapine). A total of 417 cases of falls/fractures with at least 1 hospitalization/ emergency department visit after the use of the antipsychotic agents were identified. The number of falls for risperidone, olanzapine, and quetiapine were 179 (3.56%), 123 (2.84%), and 115 (4.34%), respectively. After adjusting for propensity scores, the Cox proportional hazards model showed that there was no statistically significant difference with use of risperidone (hazard ratio = 1.10 [95% CI, 0.86–1.39]) or quetiapine (hazard ratio = 1.12 [95% CI, 0.86–1.46]) compared with olanzapine (reference group) in the risk of falls or fractures. ConclusionsThe study found no significant difference across the individual atypical agents in the risk of falls/fractures in community-dwelling older adults. Future studies are required to evaluate the overall safety profiles of the antipsychotic agents in this population.