INDIANA PHARMACISTS ALLIANCE (IPA) CONTINUING PHARMACY EDUCATION. An Update on the Pharmacologic Management of Schizophrenia

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1 An Update on the Pharmacologic Management of Schizophrenia Authors: Thomas R. Smith, PharmD Assistant Professor of Pharmacy Practice Manchester University College of Pharmacy Mei T. Liu, PharmD Clinical Assistant Professor Earnest Mario School of Pharmacy Rutgers University Megan E. Maroney, PharmD Clinical Assistant Professor Earnest Mario School of Pharmacy Rutgers University ACPE UAN: H01-P 1.5 Contact Hours (.15 CEU s) This is a knowledge-based activity. See end of article for CE details Target Audience: Pharmacists Faculty Disclosure: The faculty has no conflicts of interest to disclose. GOAL: To examine the clinical characteristics of schizophrenia and its current treatment modalities including three recently developed second-generation antipsychotics. OBJECTIVES: 1. List current pharmacotherapy recommendations for treating schizophrenia 2. Identify the advantages and disadvantages of the newer antipsychotics developed for schizophrenia 3. Recognize situations in which long-acting injectable antipsychotics are ideal 4. Recommend the most appropriate therapy given specific patient characteristics. I. INTRODUCTION One of the most complex and heterogeneous psychiatric disorders, schizophrenia remains a clinically relevant and challenging disease despite advances in pharmacologic therapies. It places extreme amounts of burden on patients, caregivers, and society in terms of financial strains, quality of life, and significant morbidities and mortality. An estimated 2-3% of the population suffers from this disease. Those inflicted, on average, die years earlier than the average population. This is most often from cardiovascular diseases due in part from the numerous metabolic and lifestyle risks associated with the disorder, 1

2 as well as suicide and causes associated with poor access to healthcare. 1,2 Schizophrenia presents with a variety of signs and symptoms, which may often differ between patients. The DSM-5 criteria for a diagnosis of schizophrenia calls for two or more symptoms of delusions, hallucinations, disorganized speech (at least one of these previous three symptoms must be present), grossly disorganized or catatonic behavior, and negative symptoms, each occurring for a significant portion during a one-month period. 3 These diagnostic criteria incorporate two symptom clusters of schizophrenia - positive and negative symptoms. Positive symptoms are ones that are the most recognizable in schizophrenia and include delusions, hallucinations, and paranoia. Among negative symptoms are apathy and a lack of self-care; less dramatic symptoms but nonetheless problematic and burdensome to patients, caregivers, and healthcare professionals. A third domain not discussed in the diagnostic criteria encompasses cognitive symptoms which include impairment of memory and cognitive function, leading to negative outcomes such as poor performance at work or school. Often, these symptoms appear insidiously, and thus a diagnosis can be difficult to obtain. Other psychiatric disorders such as major depressive disorder, bipolar disorder, and schizoaffective disorder may present with some similar symptomatology as schizophrenia and must be ruled out to ensure a proper diagnosis. 1,3 The etiology and pathophysiology of schizophrenia are just as complex as its 2 diagnosis and presentation. Genetic factors are believed to be at least partly involved, as those with a relative with schizophrenia are more likely to be diagnosed. 4 Disturbances occurring while in-utero and around the time of birth are also possible explanations for the cause of this disease. Hypoxia, infection, stress, and malnutrition occurring near delivery have been linked to mothers of those with schizophrenia. 5 Social and environmental factors may also be at play since it is known that immigrants, individuals in urban environments, and those exposed to cannabis may be at an elevated risk for developing the illness. 1 Both physical and chemical central nervous system alterations are present in individuals with schizophrenia. Computer axial tomography (CAT) scans and magnetic resonance imaging (MRI) studies have displayed changes in brain volume in schizophrenic patients including increased ventricular size and overall decreased total brain size. Functional MRI studies show abnormalities, both of hyperactive and hypoactive nature, in various brain regions. Neurochemical imaging studies attest to the dopamine dysregulation theory of schizophrenia namely that there is a hyperactive state of dopamine in critical brain regions which at least partially causes positive symptoms including delusions and hallucinations. However, other regions may lack sufficient dopamine action and lead to various other symptoms seen in schizophrenia. This disparity of both increased and decreased dopamine functionality explains why newer antipsychotics function as dopamine antagonists while also potentially increase dopamine in specific brain

3 regions. Additional neurotransmitters involved in the pathogenesis of this condition include primarily serotonin and glutamate, but others are likely involved as well. Considering the complexity of the numerous etiologies and multiple pathophysiologic changes in areas of the brain and neurotransmitters involved, it is not difficult to perceive how schizophrenia remains a challenge to the clinician. This complexity makes it pertinent to closely examine new therapies in order to place them appropriately in therapy. 1 II. TREATMENT Established therapies While nonpharmacologic approaches such as psychosocial rehabilitation programs and assertive community treatment are integral to the treatment plan, pharmacotherapy continues to be an essential therapeutic modality for schizophrenia. There are two types of antipsychotics available: first generation antipsychotics (FGAs) and second generation antipsychotics (SGAs). FGAs, also known as typical or conventional antipsychotics, work to treat symptoms of schizophrenia via dopamine 2 (D 2 ) receptor antagonism. Examples of some commonly used FGAs include haloperidol, fluphenazine, perphenazine and chlorpromazine. Although effective for the treatment of positive symptoms associated with schizophrenia, FGAs have been known to cause movement disorders such as extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Tardive dyskinesia usually develops after long-term use and since it is potentially irreversible, the concern for this side effect limits the use of FGAs. SGAs, on the other hand, work 3 primarily as serotonin type 2A (5-HT 2A ) and dopamine type 2 (D 2 ) receptor antagonists. This additional mechanism through the 5-HT 2A receptor may actually increase dopamine in specific areas of the brain. This may be desirable in treating the negative symptoms of schizophrenia. However, the true clinical value of this is not fully known. Compared to FGAs, SGAs have a lower incidence of EPS, but are associated with metabolic disturbances such as weight gain, hyperglycemia and hyperlipidemia. In particular, clozapine and olanzapine have the highest risk for metabolic disturbances while aripiprazole and ziprasidone have the lowest risk (see figure 1). 6 Although the SGAs have varying metabolic risk profiles, it is recommended that metabolic monitoring be performed on a regular basis for patients who are taking any of the SGAs (see table 1). FGAs as well as risperidone and paliperidone are particularly associated with hyperprolactinemia and EPS. Aripiprazole is associated with high rates of akathisia while ziprasidone has a higher incidence of QTc prolongation. 7,8 SGAs have also been shown to be useful in treating a number of other disease states such as bipolar disorder, major depressive disorder and autism spectrum disorders (see table 2). There are currently three US guidelines available that address the pharmacotherapy treatment for schizophrenia: the Texas Medication Algorithm Project (TMAP) antipsychotic algorithm for schizophrenia, American Psychiatric Association (APA) schizophrenia guideline and Schizophrenia Patient Outcomes Research Team (PORT) psychopharmacological treatment

4 recommendations. 8,9,10 These guidelines state that the choice of antipsychotic should be based on patient preference, side effect profile of the antipsychotics, cost, patient's medical history and previous patient or family history of treatment response. 8,9 For patients who are experiencing their first episode of schizophrenia, they can be treated with either a FGA or SGA. First episode patients will likely respond to lower doses of antipsychotics and be more sensitive to the side effects of the medication. 8,9 As a result, SGAs, with the exception of clozapine and olanzapine, may be preferred for first episode patients due to the risk of EPS and TD associated with FGAs. 8 Improvement of schizophrenia symptoms may not be seen for up to 6 to 8 weeks, but it is recommended that a trial of an antipsychotic should be at least 2 weeks at an optimized dose before trying another antipsychotic medication. 8 If a patient has an inadequate response or intolerable side effects to the initial antipsychotic, another antipsychotic, either a FGA or SGA, with the exception of clozapine, should be given a trial (see figure 2). For patients with 2 failed antipsychotic trials, clozapine should be considered. Additionally, clozapine should be considered for treatment in patients with suicidality, persistent symptoms of hostility or violent behavior, and comorbid substance abuse disorder. 10 Treatment with combinations of antipsychotic medications should be considered as a last line therapy due to the lack of studies documenting the safety and efficacy of such practice. 8,9,10,11 The Joint Commission s Hospital Based Inpatient Psychiatric Services (HBIPS) core performance measures require hospitals to 4 monitor the adequate documentation and appropriate justification for the use of multiple antipsychotics. The medical record of any patient discharged on two or more routine antipsychotic medications must contain documentation of appropriate justification for the use of multiple antipsychotic medications, which may include: 1) a history of at least 3 failed trials of monotherapy, 2) plans to taper down the additional antipsychotic to monotherapy or cross-taper in progress, or 3) augmentation of clozapine therapy. 11 Landmark Trials In recent years, an effort has been made to study the effectiveness of antipsychotics in schizophrenia in a more practical setting to allow for a better understanding of the ideal place in therapy of these drugs. Two examples of this include the CATIE and CUtlASS trials. 12,13 CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) sought to determine the effectiveness of multiple antipsychotics, both first and second generation, by examining a practical outcome: time to treatment discontinuation. SGAs available at the time of the study (risperidone, quetiapine, olanzapine, and ziprasidone) were included, as well as the FGA perphenazine. The authors found that an alarmingly large proportion of patients, close to 75%, discontinued their treatment for any reason by 18 months of therapy. Somewhat surprisingly at the time, no significant differences were found between the one representative from the older FGA class, perphenazine, and the SGAs studied. Additionally, the authors concluded that perphenazine was a more

5 cost-effective option in treating schizophrenia than the SGAs in the study, mostly due to its inexpensive costs and similar effectiveness to the other therapies. 14 CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) was similarly designed to detect differences in more pragmatic outcomes than schizophrenia rating scales. In this case, quality of life was chosen. This study examined multiple FGAs and SGAs and produced results in line with CATIE finding that FGAs and SGAs did not significantly differ. The reaction to these results was similar to ones found in the CATIE trial, in that they were not expected by all clinicians within the psychiatric community, especially among those holding the notion that SGAs are advantageous as compared to FGAs. 13,14 Results from these trials have challenged the beliefs that SGAs are superior to the older FGAs. Because of this, the question as to which class, if any, is held as the ultimate first line treatment has been raised. There has been a shift away from designating one drug or class as first line therapy in all patients, and more toward the consideration of factors specific to each individual patient when choosing an antipsychotic. Therefore, it is difficult to evaluate new antipsychotics with respect to older drugs until direct comparisons in randomized, controlled trials have been made. 14 III. NEW ANTIPSYCHOTICS Since 2009, three additional antipsychotics - iloperidone, asenapine, and lurasidone - have been developed and approved for schizophrenia. While each of 5 these is considered an atypical antipsychotic and does not have a novel mechanism of action, they do have unique pharmacologic and clinical characteristics (see table 3). Iloperidone Iloperidone is a second generation antipsychotic approved by the FDA in May 2009 for the treatment of schizophrenia in adults. It shares the same mechanism of action as the other atypical antipsychotics by acting primarily as a serotonin type 2A (5-HT 2A ) receptor and dopamine type 2 (D 2 ) receptor antagonist. 15 Iloperidone also has a high affinity for binding to the noradrenergic alpha 1 (α 1 ) receptors, low affinity to the histamine 1 (H 1 ) receptors and no significant binding activity to the muscarinic cholinergic type 1 (M 1 ) receptor. At this time, the clinical significance of these additional receptor affinities for each antipsychotic is unknown. However, examining these profiles is often useful in anticipating adverse effects. For example, iloperidone s high affinity for the α 1 receptor may correlate to its orthostatic hypotensive effects. The recommended maintenance dose of iloperidone is 12 to 24 mg per day given in 2 divided doses. Due to its propensity to cause orthostatic hypotension, the iloperidone dose should be started at 1 mg twice-daily and titrated to the target dose over 4 to 7 days at a rate that does not exceed 4 mg per day. In the long-term maintenance phase studies, the average daily dose of iloperidone was 12.5 mg per day and it's relapse rate was similar to haloperidol. 16 Symptom improvement may be delayed for the first 1 to 2 weeks of treatment compared to other

6 antipsychotics because of the slow dose titration. Unlike the two other newer agents in this class, asenapine or lurasidone, iloperidone can be administered without regard to food. Since iloperidone is metabolized primarily by the liver via CYP2D6 and 3A4, the dose should be reduced by one-half when administered concomitantly with strong CYP2D6 inhibitors such as fluoxetine or paroxetine or strong CYP3A4 inhibitors such as ketoconazole or clarithromycin. Likewise, patients who are poor metabolizers of CYP2D6 should reduce the iloperidone dose by one-half. Iloperidone is not recommended for patients with hepatic impairment. Due to its potential to prolong the QT interval, iloperidone should be avoided in patients with congenital long QT syndrome or a history of cardiac arrhythmias and in combination with other drugs that are known to cause QTc prolongation. 15 The most common adverse effects seen with iloperidone are dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia and increased weight. Iloperidone has a favorable EPS profile as demonstrated in multiple clinical trials. 15 It has a moderate propensity to cause weight gain with a mean change of +2.4 kg in the short-term studies and +4.8 kg in the long-term studies. Small elevations in total cholesterol, triglyceride and glucose were also seen in the long term studies. 16,17 While this agent has a relatively low propensity to cause EPS, and a moderate metabolic side effect profile, iloperidone has been shown to cause a higher incidence of orthostatic hypotension and QTc prolongation compared to other 6 antipsychotics. Orthostatic hypotension was reported in 5% of patients who received iloperidone 20 to 24 mg per day and QTc increases of 9 msec were measured at doses of 24 mg per day. When used concurrently with CYP2D6 and 3A4 inhibitors at 24 mg per day, the QTc increased by an average of 19 msec. Similar to FGAs and some SGAs, iloperidone may cause a mild elevation of prolactin levels resulting in reported cases of gynecomastia and galactorrhea. 15 Asenapine Asenapine is a potent antagonist at D 2 and 5-HT 2A receptors. However, it also acts as a strong antagonist at other serotonergic receptors and the H 1 receptor. Approved in August of 2009, it is currently the only antipsychotic among the three newest that is also indicated for treating mania in bipolar disorder. The most differentiating feature of this drug, however, is its need for sublingual or buccal administration. Bioavailability is extremely low with asenapine when swallowed, making this the only antipsychotic that is administered through the sublingual route. When absorbed through this route, asenapine is primarily directly metabolized by glucuronidation. The CYP1A2 pathway is also somewhat involved in the clearance of asenapine, leaving it vulnerable to some drug interactions. The sublingual administration increases bioavailability, but also may be burdensome as patients may not drink or eat within 10 minutes of administration. 18 Another disadvantage related to administration is its twice-daily dosing which may be an issue in patients who are already at risk for poor compliance. The starting dose for

7 asenapine when used to treat schizophrenia is 5 mg administered sublingually twicedaily, with the option to increase to 10 mg twice-daily if needed. 18 This antipsychotic has been evaluated in multiple clinical trials examining endpoints in schizophrenia such as changes in the Positive and Negative Syndrome Scale (PANSS), with favorable results. 19 A six week trial examining the efficacy of asenapine in the acute phase treatment of schizophrenia produced statistically significant reductions in PANSS total scores compared to placebo. 20 This trial, along with a similarly designed trial, also demonstrated asenapine superiority over placebo in the negative subscale scores on the PANSS. However, one failed trial and one negative trial involving asenapine have been completed as well although these are no longer available. In a study with asenapine and olanzapine, asenapine failed to demonstrate significant decreases in PANSS total score compared to placebo, while olanzapine did. Another trial using both of these antipsychotics failed to show significantly greater improvement compared to placebo with either medication. 20 The most common adverse effects seen with asenapine include insomnia, somnolence, and extrapyramidal symptoms; each of which occurred in roughly 10% of patients. Oral hypoesthesias resulting from the sublingual administration may also occur, but usually resolve within an hour. 20 Additionally, in March of 2013, the FDA updated the labeling of asenapine to include the risk of oral ulcers and blisters as well as peeling and inflammation at the site of the sublingual administration. This has led to 7 discontinuation of therapy in some cases. Rare, but serious anaphylactic reactions are also known to occur with asenapine. Patients should be counseled on the possible symptoms of a type I anaphylactic reaction such as angioedema, hemodynamic changes, difficulty breathing and rash, and should seek immediate medical attention if these develop. While data is still limited, it is believed that asenapine offers a lower risk of weight gain, lipid and glucose abnormalities, and overall metabolic changes compared to other atypical antipsychotics, particularly olanzapine and clozapine. In short term trials evaluating its use in schizophrenia, patients taking asenapine gained on average 1.1 kg. An additional favorable adverse effect profile parameter includes its minimal change on the QT interval as reported in a dedicated QT study showing a 2 to 5 msec increase compared to placebo. 18 However, because these risks are present in all atypical antipsychotics, recommended monitoring guidelines should still be following for patients treated with asenapine. 18,21 While there is not enough data to compare efficacy between asenapine and other antipsychotics, this new agent does have some distinct properties when considering its place in therapy. Its overall low incidence of metabolic adverse effects and low prolactin elevation makes it attractive to use in those who have displayed sensitivity to these adverse effects with other agents, or with those in which metabolic risks and prolactin-related adverse effects must be minimized. Also, asenapine may be suitable for patients with difficulty swallowing or gastrointestinal issues since it is the only sublingually

8 administered antipsychotic. This dosage formulation may also be useful to reduce cheeking. Lastly, asenapine is the only of the three newest agents with an indication for bipolar mania. 18 Lurasidone Lurasidone is the newest of all the SGAs, achieving FDA approval in October of While the newest agent in its class, lurasidone is still believed to work through a similar mechanism as the rest. In addition to its D 2 and 5-HT 2A antagonism, it also has potent activity at other serotonin receptors, particularly at the 5-HT 7 receptor. However, this mechanism s significance is not clear. The typical starting dose of lurasidone in the treatment of schizophrenia is 40 mg once daily. Efficacy for the treatment of schizophrenia has been demonstrated in the range of mg/day. Dosage adjustments are recommended in a variety of clinical situations. For patients with moderate (CrCl 30 - < 50 ml/min) or severe (CrCl < 30ml/min) renal impairment, the recommended starting dose is 20 mg once daily with a maximum recommended dose of 80 mg/day. These same dosing recommendations apply to patients on concomitant moderate CYP3A4 inhibitors such as diltiazem, while the use of lurasidone is contraindicated with strong CYP3A4 inhibitors such as ketoconazole or with strong CYP3A4 inducers such as rifampin. A starting dose of 20 mg/day is also recommended in patients with moderate (Child-Pugh Score 7-9) or severe (Child-Pugh Score 10-15) hepatic impairment, with a maximum daily dose of 80 and 40 mg/day, respectively. An important counseling point for lurasidone is that it needs to be taken with food (at least calories, independent of fat content) in order for it to be optimally absorbed. 22 In a three-arm dose-response study, doses of 40 and 80 mg/day of lurasidone achieved significantly better improvements in the Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) as compared to 20 mg per day over the course of 8 weeks. 23,24 Two studies have shown the 40 mg per day dose to be effective versus placebo. 23,25 Three placebo-controlled trials demonstrated statistically significant efficacy for lurasidone 80 mg per day as compared to 23, 26 placebo over 6 weeks. One of these trials showed no statistically significant difference between lurasidone 40 or 80 mg per day and placebo. Another study was considered a failed trial as it showed no statistically significant difference versus placebo for lurasidone 20 mg per day, 40 mg per day or 80 mg per day, nor for haloperidol 10 mg per day. 23 Originally, at the time of FDA approval, only the 40 and 80 mg per day doses of lurasidone were approved. The FDA cited similar efficacy but a higher incidence of adverse events seen with higher doses as its reason for approving only the lower doses. Eventually, both the 120 mg per day and 160 mg per day doses attained FDA approval as well. 22 Two sixweek trials demonstrated efficacy for lurasidone 120 mg per day versus placebo on changes in PANSS and BPRS 22,23,25 One additional 3-week trial in clinically stable outpatients showed evidence of efficacy for lurasidone 120 mg per day as compared to ziprasidone 80 mg twice daily. 27 Efficacy for lurasidone 160 mg/day was established in a 6-week placebo-controlled trial, with quetiapine XR 600 mg daily serving as an

9 active comparator. This trial also demonstrated efficacy for lurasidone 80 mg/day. 23,28 Fewer trials have explored the long-term efficacy of lurasidone to date. Two year-long trials have shown a lack of statistically significant differences in relapse rates with lurasidone mg/day as compared to flexible dosing of risperidone (2-6 mg) or quetiapine XR ( mg). 23,28, 29 Recently, Sunovion Pharmaceuticals, the manufacturer of lurasidone, announced the approval of lurasidone for the treatment of bipolar I depression, joining quetiapine and the olanzapine/fluoxetine combination as the only other therapies approved for this phase of the disorder. 30 The most common adverse effects seen with lurasidone are somnolence and akathisia which both appear to be doserelated. Other common adverse effects include nausea, parkinsonism, sedation, insomnia, agitation, anxiety and dystonia. A unique aspect of lurasidone is its seemingly low risk for metabolic side effects. Lurasidone was not associated with significant increases in weight (+0.43 kg), glucose and lipids in short-term trials when compared with placebo. 20, 22 In longterm trials completed over 6-12 months, rates of clinically significant weight gain ranged from 7% to 13.9%. 29,31,32 However, many patients who switched from other antipsychotics, in both short and long-term trials, on average lost a significant amount of weight. 32,33 Another potential advantage to the use of lurasidone is its seemingly low risk for QT prolongation. There have been no reports of significant QT prolongation (> 500 msec) in short or long-term trials, and a study evaluating changes in the QTc interval produced a maximum mean increase of msec for the 120 mg dose. 20,23 Another adverse effect which should be monitored with lurasidone is hyperprolactinemia. Although the mean increase in prolactin with lurasidone was small in most trials, it is larger than changes seen with some other atypical antipsychotics such as olanzapine. 25 Patients on higher doses of lurasidone ( 120 mg/day) and female patients appear to be at a greater risk for clinically significant hyperprolactinemia. 23 Lastly, lurasidone stands apart from both iloperidone and asenapine as well as most other antipsychotics as it is approved as pregnancy class B. 22 Clozapine is the only other antipsychotic that carries this pregnancy rating. However, the category B rating is based on animal data only. No human pregnancy data for lurasidone has been reported to date. Treatment of schizophrenia during pregnancy is complicated and is beyond the scope of this review. Long-Acting Injectable Antipsychotics One of the many challenges that patients treated with schizophrenia face is non-adherence to their antipsychotic regimens. Approximately 40-60% of schizophrenia patients are non-adherent or only partially adherent with their antipsychotic medication. 34 One potential strategy to dealing with adherence issues is use of long-acting injectable (LAI) antipsychotics. LAIs have been available since the 1960s when fluphenazine enanthate (which was later replaced on the market by fluphenazine decanoate) was first introduced and later haloperidol

10 decanoate in the 1980s. 35 Since that time, many more options have become available, including LAI formulations of several second-generation antipsychotic agents such as risperidone, paliperidone, olanzapine and aripiprazole (see table 4). In the past, LAIs were used mostly in patients with a history of non-adherence to medication and/or relapse of illness related to non-adherence. While many guidelines still recommend this approach, some recommend considering an LAI in any patient for whom long-term treatment is needed. 9,35,36 Some of the benefits of using an LAI over an oral medication include potentially earlier detection of relapse, since the patient is coming in for regularly scheduled injections (sometime as often as every two weeks), reduced risk of accidental overdose or missing doses of medication due to forgetfulness or other unintentional adherence barriers, a more consistent plasma concentration of drug, and the ability to differentiate between symptom relapse due to lack of efficacy vs. poor adherence. 34 Pharmacoepidemiologic studies also suggest that use of LAI formulations may aid in relapse prevention, although some randomized controlled trials have failed to show a difference in relapse rates when comparing a LAI with oral medication. 35 IV. EMERGING THERAPIES Recent efforts have been made in developing novel drugs for treating schizophrenia. While drugs acting on the dopaminergic and serotonergic pathways are effective, there is hope that targeting other neurotransmitter pathways may yield effective treatments as well. One pathway of particular interest involves 10 glutamate. This system was first considered after the observation that glutamate antagonists such as phencyclidine (PCP) and ketamine reproduce symptoms of schizophrenia more closely than does amphetamine, a drug which acts on the dopamine system but only produces the positive symptoms of schizophrenia. 37 Therefore, hypoactivity at the NMDA glutamate receptor is a possible confounding element to the pathophysiology of schizophrenia. Drugs in development, such as bitopertin, aim to increase NMDA activity by acting as a glycine reuptake transporter inhibitor. Glycine is a co-agonist with glutamate at the NMDA receptor, and therefore inhibiting its reuptake allows for greater glutamate activity at this receptor. 37 Trials are still ongoing, but there may soon be a new class of medications for treating schizophrenia one that may be used in conjunction with current antipsychotics to achieve improved outcomes in this challenging disease. Until then, both FGAs and SGAs will continue to be utilized as the primary pharmacologic intervention in schizophrenia. V. CONCLUSION Iloperidone, asenapine, and lurasidone are the three newest antipsychotics amongst a large selection of drugs in this class. While their primary mechanisms mirror that of other second generation antipsychotics, their individual characteristics should not be overlooked. Although none of the three is currently regarded as more efficacious than other antipsychotics, their selection

11 may be advantageous over other drugs for specific patients. Factors such as propensity for adverse effects, dosing, route of administration, and drug interactions are all crucial to consider when choosing an antipsychotic to best manage patients suffering from schizophrenia. The Pharmacists Education Foundation (PEF) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. To receive continuing pharmacy education (CPE) pharmacists MUST COMPELTE THE ONLINE QUIZ AND EVALUATION FORM. A score of 70% or above is required to receive CPE credit. The link to the quiz can be accessed from the home study section in the CE Portal of the IPA website, This is a free service of IPA members in. Initial release date: 12/3/14. Expiration Date: 12/3/17. Questions: Call IPA office at Figure 1. Risk of weight gain with atypical antipsychotics 21 Low Risk Medium Risk High Risk Aripiprazole Asenapine Lurasidone Ziprasidone Iloperidone Paliperidone Quetiapine Risperidone Clozapine Olanzapine 11

12 Table 1. Recommended monitoring for patients on second-generation antipsychotics 6,38 Baseline 4 weeks 6 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years Comments Medical /+ Evaluate both history personal and family history; evaluate smoking status Weight (BMI) /+ + /+ + Important to Waist Circumference Blood pressure Fasting glucose /+ + + /+ /+ + /+ /+ measure and document both of these. Central obesity is an independent risk factor for metabolic syndrome /+ + /+ /+ Additionally, some sources recommend monitoring HbA1c as well as signs and symptoms of diabetes Fasting lipids /+ + /+ + Lifestyle Include exercise advice and diet recommendations; should be given to the patient and caregivers Key: indicates recommendation from the ADA + indicates recommendation from other sources 12

13 Table 2. Additional FDA approved indications for second-generation antipsychotics 39 Medication Schizoaffective Disorder Schizophrenia in adolescents Major Depressive Disorder Bipolar mania/mixed Bipolar depression Clozapine Olanzapine Bipolar maintenance Irritability associated with Autism Olanzapine /+ Olanzapine/Fluoxetine (treatment resistant) Risperidone /+ (ages 5 to 17 years) Paliperidone Quetiapine + /+ + Key: Ziprasidone + FDA approved indication + FDA approved as adjunctive therapy Aripiprazole + /+ /+ (ages 6 to 17 years) Asenapine /+ Lurasidone /+ 13

14 Figure 2. Step-wise approach in treating schizophrenia* 8,9,10 STAGE 1 SGA or FGA STAGE 2 Alternate SGA or FGA STAGE 3 Clozapine STAGE 4 Clozapine + SGA or FGA *Figure 2 footnote Specific recommendations vary between guidelines. This figure represents a broad and general approach taken by many clinicians. Refer to specific guidelines for a more detailed treatment approach. 14

15 Table 3. Comparison of the three newest SGAs 15,19,22 Drug Usual starting dose for schizophrenia Maximum dose Notes Asenapine 5 mg twice daily 10 mg twice daily Must not swallow, crush, or chew the tablet Avoid food or drink for 10 minutes after administration Use not recommended in severe hepatic impairment Iloperidone 1 mg twice daily 12 mg twice daily Titrate slowly to avoid orthostatic hypotension Reduce dose by half when used with strong CYP2D6 or CYP3A4 inhibitors or for poor metabolizers of CYP2D6 Use not recommended in Lurasidone 40 mg once daily (20 mg once daily if used with a moderate CYP3A4 inhibitor) 160 mg once daily (80 mg if used with a moderate CYP3A4 inhibitor) hepatic impairment Give with a minimum of 350 calorie meal Contraindicated with strong CYP3A4 inhibitors / inducers Dose adjustments recommended with renal and hepatic impairment 15

16 Table 4. Long-acting injectable antipsychotics 39,40,41 Drugs Fluphenazine decanoate Haloperidol decanoate Risperidone long-acting injection Paliperidone Palmitate Olanzapine Pamoate Aripiprazole Monohydrate Usual starting dose 12.5 mg IM/SC 10-20x daily PO haloperidol dose given IM Target dose mg 10-15x daily PO haloperidol dose Dosing interval Q2 to 4 weeks Q4 weeks PO overlap Recommended Recommended if no loading dose given 25 mg IM mg Q2 weeks Required 234 mg IM on day 1, then 156 mg IM 7 days later mg IM Q2 weeks or 405 mg IM Q4 weeks 400 mg IM Q month 117 mg (range mg) Initiate after 8 weeks of treatment mg IM Q2 weeks or mg IM q 4 weeks 400 mg IM Q month *PDSS: Post-injection delirium sedation syndrome Q4 weeks Q2 weeks or Q4 weeks Q month Not required Not required Recommended Additional information Maximum dose of 100 mg for the first dose Initial doses greater than 100 mg should be administered in 2 separate IM injections 3 to 7 days apart Should overlap PO and IM medications for minimum of 3 weeks Recommended to give first two injections (loading doses) in the deltoid muscle Flexibility allowed in time frame of loading and maintenance doses (see package insert) Available only through a restricted distribution program called the Zyprexa Relprevv Patient Care Program Patient, prescriber, healthcare facility and pharmacy must enroll with the program Patient should be monitor for 3 hrs after each injection due to the risk of PDSS* Should overlap PO and IM medications for 14 days Dose reductions are necessary for CYP2D6 poor metabolizers and concomitant use of medications that inhibit CYP2D6 and CYP3A4 16

17 References 1. Os JV, Kapur S. Schizoprehnia. Lancet 2009; 374(9690): Saha S. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry 2007;64: Schizophrenia spectrum and other psychotic disorders. In: American Psychiatric Association: Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA, American Psychiatric Association, P McDonald C, Murphy KC. The new genetics of schizophrenia. Psychiatr Clin North Am 2003;26: Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and metaanalytic review. Am J Psychitray 2002;159: American Diabetes Association. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27(2): Abilify (aripiprazole) [package insert]. Rockville, MD: Otsuka America Pharmaceutical Inc.; 2012 Feb. 8. Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010;36(1): American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004;161: Moore TA, Buchanan RW, Buckley, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psych 2007;68: Specifications Manual for Joint Commission National Quality Measures - (v2013a1). Appropriate justification for multiple antipsychotic medications. [cited 2013 Jun 25]. Available from URL: Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353: Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on quality of life of second- vs. first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006;63: Attard A, Taylor M. Comparative Effectiveness of Atypical Antipsychotics in Schizophrenia. What have Real-World Trials Taught Us? CNS Drugs 2012;26(6):

18 15. Fanapt (iloperidone) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation;2013 Jan. 16. Kane JM, Lauriello J, Laska E, et al. Long-term efficacy and safety of iloperidone. J Clin Psychopharmacol 2008;28:S29-S Weiden PJ, Cutler AJ, Polymeropoulos MH, et al. Safety profile of iloperidone: a pooled analysis of 6- week acute-phase pivotal trials.. J Clin Psychopharmacol 2008;28:S Saphris (asenapine) sublingual tablets [package insert]. Whitehouse Station, NJ: Merck and Co;2013 Mar. 19. Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J. Clin. Psychiatry 68(10), (2007). 20. Bobo WV. Asenapine, iloperidone and lurasidone: critical appraisal of the most recently approved pharmacotherapies for schizophrenia in adults. Expert Rev Clin Pharmacol. 2013;6(1): Correll CU, Hert DM, Detraux J, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2): Latuda (lurasidone) [package insert]. Marlborough, MA: Sunovion Pharmaceuticals Inc.;2012 Dec. 23. Caccia S, Pasina L, Nobili A. Critical appraisal of lurasidone in the management of schizophrenia. Neuropsychiatr Dis Treat. 2012;8: Harvey PD, Murasaki M, Cucchiaro MO, et al. A three arm dose finding study of lurasidone: efficacy and tolerability data. Schizophr Res. 2010;117:267-Abstract. 25. Melzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168: Nakamura M, Ogasa M, Guarino J, et al. Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70: Cucchiaro J, Potkin S, Ogasa M, et al. A double-blind comparison of the safety and efficacy of lurasidone and ziprasidone in clinically stable outpatients with schizophrenia or schizoaffective disorder. Schizophr Bull. 2009;35(S1): Loebel A, Cucchiaro J, Xu J, et al. Effectiveness of lurasidone vs. quetiapine XR for relapse prevention in schizophrenia: A 12-month, double-blind, noninferiority study. Schizophr Res. 2013;147(1): Citrome L, Cucchiaro J, Sarma K, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month, double-blind, active-controlled study. Int Clin Psychopharm 2012; 27(3):

19 30. Sunovion Pharmacueticals Inc Sunovion Pharmacueticals, Inc. announces FDA approval of Latuda (lurasidone HCl) as monotherapy and adjunctive therapy in adult patients with bipolar depression. [press release] June 28, Loebel A, Cucchiaro J, Sarma K, et al. Efficacy and safety of lurasidone 80mg/day and 160mg/day in the treatment of schizophrenia: A randomized, double-blind, placebo- and active-controlled trial. Schizophr Res 2013; 145(1): Stahl SM, Cucchiaro J, Simonelli D, et al. Effectiveness of lurasidone for patients with schizophrenia following 6 weeks of acute treatment with lurasidone, olanzapine, or placebo: A 6-month, open-label, extension study. J Clin Psychiatry. 2013;74(5): McEvoy JP, Citrome L, Hernandez D, et al. Effectiveness of lurasidone in patients with schizophrenia or schizoaffective disorder switched from other antipsychotics: A randomized, 6-week, open-label study. J Clin Psychiatry. 2013;74(2): Patel MX, Taylor M, David AS. Antipsychotic long-acting injections: mind the gap. Br J Psychiatry. 2009;195:S1-S Weiden PJ, Solari H, Kim S, et al. Long-acting injectable antipsychotics and the management of nonadherence. Psychiatr Ann. 2011;41(5): Kane JM, Garcia-Ribera C. Clinical guideline recommendations for antipsychotic long-acting injections. Br J Psychiatry. 2009;195:S Alberati D, Moreau JL, Lengyel J, et al. Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology. 2012;62(2): De Hert M, Vancampfort D, Correll CU, et al. Guidelines for screening and monitoring of cardiometabolic risk in schizophrenia: systematic evaluation. Brit J Psychiat 2011; 199: Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. 40. Long-acting injectable antipsychotics: the pharmacist s role in improving patient adherence and outcomes [monograph on the internet]. Bishop JR, Kutscher EC, Villaume WA. Postgraduate Healthcare Education, LLC, producers [cited 27 June 2013]. Available from: URL: Abilify Maintena TM (aripiprazole) [package insert]. Rockville, MD: Otsuka America Pharmaceutical Inc.;2013 Feb. 19

20 Questions 1. What end-point did the CATIE trial use to evaluate antipsychotic effectiveness and why? A. Time to treatment discontinuation: this is a more practical outcome to assess effectiveness B. Time to hospitalization: this is pertinent to patients who have failed multiple antipsychotics C. Change in the PANSS: this evaluates the efficacy in reducing symptom burden D. Change in the BPRS: this evaluates how well positive symptoms respond to antipsychotics 2. Which of the following is FALSE regarding the administration of asenapine? A. It can be administered sublingually or swallowed B. The patient should not eat within 10 minutes of administration C. It must be given twice-daily which may cause some compliance issues D. The sublingual route of administration may cause oral hypoesthesias 3. RG is a 55 year old male who was diagnosed with schizophrenia six months ago. He was initially started on haloperidol, but developed severe dystonia. He was then given a trial of risperidone 1 mg twice daily, but often forgot to take both doses and continued to complain of hearing voices and a belief that the CIA has planted recording devices throughout the house. His past medical history consists of hypertension and type II diabetes. His primary care physician has instructed that he attempt to increase exercise, change his diet, and lose weight to improve his health. Which of the following antipsychotics is the best choice for RG? A. clozapine B. asenapine C. lurasidone D. olanzapine 4. RG is currently stable on iloperidone 8 mg twice daily for his schizophrenia. His psychiatrist would like to add fluoxetine 20 mg daily to his regimen. Which of the following dose adjustments should be recommended? A. No changes are needed; these two medications do not interact B. Fluoxetine should be started at 10 mg daily since iloperidone may inhibit its metabolism C. Iloperidone should be increased to 16 mg twice daily D. Iloperidone should be decreased to 4 mg twice daily 20

21 5. Which of the following antipsychotics is FDA approved for the treatment of bipolar mania? A. Asenapine B. Lurasidone C. Iloperidone D. Paliperidone 6. All of the following can be used as first line therapy for schizophrenia EXCEPT? A. Risperidone B. Quetiapine C. Clozapine D. Haloperidol 7. Which of the following is a common side effect associated with iloperidone? A. Extrapyramidal symptoms B. Orthostatic hypotension C. Weight loss D. Insomnia 8. Which of the following antipsychotics has the highest risk of weight gain? A. Ziprasidone B. Iloperidone C. Asenapine D. Lurasidone 9. Which of the following antipsychotics is available as a long-acting injection? A. Olanzapine B. Risperidone C. Aripiprazole D. All of the above 10. Which of the following does the ADA recommend to monitor more than once per year in patients taking antipsychotics? 21 A. Fasting glucose B. Medical history C. Post-prandial glucose D. All of the above