key: cord-0780651-jo4ud0b6
authors: Noel, Jason M; Jackson, Cherry W
title: ASHP Therapeutic Position Statement on the Use of Antipsychotic Medications in the Treatment of Adults with Schizophrenia and Schizoaffective Disorder
date: 2020-09-01
journal: Am J Health Syst Pharm
DOI: 10.1093/ajhp/zxaa303
sha: 973d66de5e30f978cce2ecc204b1bff023585c67
doc_id: 780651
cord_uid: jo4ud0b6

In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

supportive services that can impose a significant burden on society. 1 In addition, high rates of suicidal behavior and completed suicides have been observed in patients with schizophrenia or schizoaffective disorder. 2 The management of the psychotic symptoms associated with these disorders typically requires long-term treatment with antipsychotic medications, the use of adjunctive pharmacologic treatments, and ongoing psychosocial and supportive interventions to reduce morbidity and mortality.

For the pharmacologic management of psychosis associated with schizophrenia and schizoaffective disorder, ASHP encourages health professionals to select either a firstgeneration antipsychotic (FGA) or a second-generation antipsychotic (SGA) based upon the adverse effect profile of the drug and the individual characteristics of the patient.

Antipsychotics, both first-and second-generation agents, have similar efficacy and are the treatment of choice in individuals with schizophrenia or schizoaffective disorder with psychosis.

All antipsychotics have limitations and, in the usual dosage range doses, FGAs are generally equivalent in tolerability to SGAs. 3 Patients have different reasons for not tolerating a particular agent, and antipsychotic selection should be individualized to the A c c e p t e d M a n u s c r i p t patient. Upon selection of an effective treatment, clinicians must monitor therapy on an ongoing basis to ensure tolerability and adherence in order to optimize treatment outcomes.

The goal of this therapeutic position statement (TPS) is to provide a summary of FGAs and SGAs and provide recommendations for the clinician to consider when selecting an appropriate agent to treat psychosis in the adult patient with schizophrenia and schizoaffective disorder.

Schizophrenia and schizoaffective disorder are serious, chronic mental illnesses that affect perceptual, behavioral, affective, and cognitive functioning. Individuals with schizophrenia generally exhibit a mixture of positive, negative, and cognitive symptoms with varying intensity throughout the course of the illness. The DSM-5 diagnostic criteria for schizophrenia state that at least 2 out of 5 symptoms must be present for at least 1 month, and at least one of those symptoms must be delusions, hallucinations, or disorganized speech (Table 1) . 4 The symptoms of schizophrenia must be continuous for at least 6 months. Schizoaffective disorder differs from schizophrenia in that delusions or hallucinations only have to occur for a minimum of 2 weeks without signs of a mood disturbance sometime during the course of the illness. Symptoms of mania or depression are present during the majority of the longitudinal course of the illness. 4 Unlike in schizophrenia, social and occupational dysfunction need not occur for diagnosis of schizoaffective disorder, according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) criteria (Table 1) . 4 The worldwide lifetime prevalence of A c c e p t e d M a n u s c r i p t schizophrenia and schizoaffective disorder is about 1.2%. 5, 6 Schizophrenia and schizoaffective disorders have been studied together in many clinical trials and will be considered together for the purpose of this document.

First episode psychosis (FEP) refers to the first acute episode of psychosis following a prodromal period. The prodromal period is defined as a period of time in which an individual begins to experience behavioral changes (eg, anxiety, sleep disturbances, social withdrawal, irritability, a reduction in concentration and motivation and/or suspiciousness) prior to the onset of the first episode of psychosis. As many as 100,000

teens and young adults in the United States experience FEP each year, with the peak onset occurring between 15 and 25 years of age. 7 It is important to recognize and treat FEP because the duration of untreated psychosis, defined as the time between the first psychotic symptoms and initiation of antipsychotic treatment, plays a major role in clinical patient outcomes. 8 The longer an individual goes untreated, the worse their long-term behavioral and cognitive symptoms, morbidity and mortality, quality of life, and functional capacity. 8 Patients with FEP tend to present late for medical attention; on average, the duration between the first symptoms and adequate treatment is 7 to 10 years. 8 In addition, as many as 80% of individuals with FEP will experience a relapse of symptoms requiring inpatient care and adding to the total cost of care. 9 The highest risk of suicide in individuals with psychosis occurs during the first 5 years of the illness, deemed the critical period. 10 A recent study assessed 12-month mortality for patients with FEP as being 24 times higher than for the general US population. 11 Childhood-onset schizophrenia resembles the essential features seen in adultonset schizophrenia. Prodromal symptoms of psychosis occurring in children and A c c e p t e d M a n u s c r i p t adolescents (eg, apathy, social withdrawal) may be present before the first psychotic break, but the full symptoms of these disorders are rare in this population. In children, delusions and auditory and visual hallucinations are common but may be less sophisticated than those symptoms seen in adults. It is important to differentiate between childhood-onset schizophrenia and other diagnoses seen in children, such as autism spectrum disorder and attention deficit/hyperactivity disorder, post-traumatic stress disorder, as well as normal fantasy play. Childhood-onset schizophrenia includes significant negative symptoms and typically has a poor outcome, including significant, progressive impairment in the social, occupational, and academic functioning of affected individuals. 12 Late-onset schizophrenia, occurring after 40 years of age, may have an otherwise similar course to typical adult-onset schizophrenia. Often individuals with late-onset illness will maintain affect and social functioning; often they will be or have been married during their life. Often the symptoms of psychosis, such as hallucinations and delusions, may not be as severe as they appear in those with an earlier onset of the illness. 13 Very late onset of schizophrenia is diagnosed if the first appearance of the illness occurs after the age of 65.

This occurs more frequently in women and in those with general neurological conditions like dementia. 13 

The effectiveness of FGAs whose primary mechanism of action, blockade of dopamine in the brain, led to the initial hypothesis regarding dopamine's role in schizophrenia. 14 While it is apparent that increased dopamine in the mesolimbic pathway A c c e p t e d M a n u s c r i p t is responsible for the positive symptoms of schizophrenia, it is now understood that psychosis frequently involves numerous neurochemical abnormalities. 14, 15 Psychosis has been observed in individuals with idiopathic and drug-induced hypofunction of the glutamate system. 16, 17 In addition, the high rate of nicotine dependence in individuals with schizophrenia-up to 88% in one study -led to the identification of alpha 7 nicotinic acetylcholine-receptor abnormalities in the pathophysiology of schizophrenia. 18, 19 Pharmacologic characteristics of antipsychotic drugs A c c e p t e d M a n u s c r i p t difficulty with visual accommodation). Other adverse effects include seizures, difficulty regulating body temperature and increased incidence of falls. 20 The SGAs share the common pharmacologic action of dual serotonin-dopamine antagonism (Table 3. ). Aripiprazole, brexpiprazole and cariprazine differ slightly in that they function as partial agonists at dopamine receptors, reducing dopamine activity in the mesolimbic pathway. 21 

Negative symptoms are considered to be the core deficit in schizophrenia. 23 Primary negative symptoms include flattened or blunted affect, avolition, asociality, amotivation, alogia, and apathy. 24 Individuals diagnosed with schizophrenia typically experience a prodromal period, characterized by negative symptoms, in their late teens to mid-twenties. The prodromal period precedes the onset of psychotic or positive symptoms. Based upon DSM-5 criteria, positive symptoms such as delusions and hallucinations have to last for at least 1 month (untreated), but often last for 3 to 6 months prior to resolution. 4, 24 After the resolution of positive symptoms the period of A c c e p t e d M a n u s c r i p t chronicity is called residual schizophrenia. This period is marked by continued negative symptoms which is a source of poor outcomes for many individuals. 24,25 Because of the difficulty in treating a deficit syndrome, greater effort has been given to treating positive symptoms of schizophrenia with antipsychotics, but it has been suggested that antipsychotics aggravate negative symptoms. 26,27 Some references divide negative symptoms into primary negative symptoms (disease related) and secondary negative symptoms (due to side effects of medications, substance abuse, and environmental issues). 28 For the purposes of this TPS, we will focus on primary negative symptoms.

Negative symptoms have been difficult to treat. Antidepressants, stimulants and antipsychotics are among the treatment strategies that have been studied for negative symptoms. 29 There was initial excitement with the use of SGAs because many of them appeared to demonstrate efficacy for both positive and negative symptoms in initial registration studies. 30 Clozapine, olanzapine, quetiapine, risperidone, asenapine,

paliperidone, and lurasidone all demonstrated effectiveness for negative symptoms in these studies. 25 Unfortunately, these studies suffered from small sample sizes, inconsistent diagnoses or stage of illness, and length of trial (typically 6-12 weeks 

Patients with FEP are more responsive to treatment than patients with multiple psychotic episodes, but can also be more sensitive to the side effects of antipsychotics. 58 The majority of patients with FEP are responsive to treatment with more than 70%

achieving full remission of signs and symptoms of psychosis within 3 to 4 months, and 83% achieving stable remission by the end of 1 year. 1, 59 Studies have shown that patients with FEP often respond well to low-dose antipsychotic medication. 58-60 Selection of an antipsychotic should be based upon patient preference, adverse effect profile, route of administration, presence of co-morbid medical conditions, and potential interactions with other prescribed medications, and cost.

Patients with FEP initiated on an antipsychotic should be monitored closely to evaluate treatment response. 60 Adherence to treatment is crucial and can minimize the emotional distress and disruption of the patient's life. 60 Patients with a first episode of psychosis should continue treatment for at least 12 months after remission. 31,58 As many as 83% of patients with FEP will experience a relapse in symptoms within 5 years. 61

Multi-episode schizophrenia or relapse is part of the natural continuum of psychotic illness. The most common causes of relapse include stress, nonadherence, and substance A c c e p t e d M a n u s c r i p t use. 58 It is important to recognize that it is not uncommon to have a relapse in psychotic symptoms even while maintaining adherence. 58 The average rate of relapse is between 15 and 37% after 1 year of maintenance antipsychotic therapy, while the rate of relapse for patients on placebo is between 60% and 80%. 31,58, [62] [63] When relapse occurs it is important to determine the reasons behind it, and to reestablish treatment as quickly as possible with the same or another medication. 58 The antipsychotic chosen should be based on the patient's previous response, side effects, route of administration, co-morbid medical conditions, potential drug interactions and the patient's preference. 58 Once an antipsychotic agent has been chosen, the dose should be initiated at an appropriate starting dose and titrated to a therapeutic dose. Titrating the dose too rapidly or using a dose above the therapeutic range may be associated with nonadherence and intolerance. Improvement in symptoms may take between 6 to 12 weeks. 58 If no symptom improvement is seen in 2 weeks at therapeutic doses, consider switching medications. 58 If a partial response is seen within 12 weeks, consider increasing the dose to the highest therapeutic dose as long as the patient is not experiencing side effects. 58 If the patient continues to experience only a partial response to this dose, consider augmentation with a different agent or switching to another antipsychotic agent.

While evidence supporting augmentation is based upon limited and sometimes mixed results, it may benefit individuals who have a partial response versus initiating a new antipsychotic. Lifetime treatment with the lowest effective dose of an antipsychotic is recommended in individuals who have experienced multiple relapses.

A c c e p t e d M a n u s c r i p t A trial of clozapine is generally warranted for patients who demonstrate a suboptimal response to 2 or more trials with first-and second-line antipsychotic agents, and it is considered to be the third-line agent for all guidelines. 58 In addition, the adjunctive use of antidepressants, mood stabilizers, or anxiolytics may be beneficial in select patients. 58 The combined use of more than 1 antipsychotic drug is a controversial and costly practice. 67 Very little published evidence supports the use of multiple oral antipsychotics, except when attempting to transition a patient from one agent to another. 68 In the case of non-response or inability to tolerate clozapine other treatment strategies include treatment with other SGAs, augmentation, antipsychotic combinations, and electroconvulsive therapy, although there is limited evidence for these strategies. 69 Clozapine, the first SGA introduced in the United States, has an established level of efficacy for use in individuals with psychosis resistant to treatment with other antipsychotics. Kane et al conducted the landmark trial that demonstrated the superior efficacy of clozapine in individuals with treatment resistant psychosis. 65 This trial enrolled only patients whose psychosis was treatment resistant, defined as not responding to at least 3 periods of treatment in the preceding 5 years with antipsychotics from 2 different chemical classes at dosages equivalent to 1,000 mg/day of chlorpromazine for 6 weeks.

The previous antipsychotic trials must have failed to provide periods of good functioning or significant symptomatic relief.

A c c e p t e d M a n u s c r i p t A 6-week trial of haloperidol (mean dosage, 61 mg/day) and benztropine followed to confirm lack of drug response. Participants whose psychosis did not respond to haloperidol were randomized to receive clozapine (up to 900 mg/day) or chlorpromazine (up to 1800 mg/day) with benztropine. Using a priori criteria, response rates were 30% for patients treated with clozapine versus 4% for the chlorpromazine group. The authors found that improvements in the Brief Psychiatric Rating Scale (BPRS) total scores and Clinical Global Impression (CGI) scale were 3 times greater in the patients treated with clozapine. These results were confirmed in large pragmatic trials and meta-analyses in which clozapine was compared to SGAs in treatment resistant patients resulting in symptom improvement and median time to discontinuation.

Since the efficacy between FGAs and SGAs in treating psychosis is equivalent, the decision for choosing a particular agent often rests on the individual person with psychosis and the adverse effect profile of a specific antipsychotic. SGAs were originally marketed as having fewer adverse effects, especially fewer neurologic and motor symptoms and increased tolerability compared to FGAs. Much of this information came from short-term, industry-sponsored trials with carefully selected patient populations, and non-inferiority comparisons of symptom ratings. 72, 73 Non-industry-sponsored studies with rigorous randomized studies designed to match real-world treatment scenarios have provided information that demonstrates first-and second-generation agents have nearly equal limitations; this supports the widely held notion that selection of an antipsychotic drug should be an individualized process.

Motor symptoms. Treatment with FGAs has long been associated with both acute A c c e p t e d M a n u s c r i p t and chronic motor adverse effects. Acute extrapyramidal symptoms (EPS)-dystonia, pseudoparkinsonism, and akathisia (a syndrome of subjective anxiety and restlessness)are thought to be related to drug-induced blockade of dopamine receptors in the nigrostriatal pathway in the brain.

Improved tolerability with SGAs has given this class of medications some advantage over the first generation agents; however experience has shown that all of the SGAs excluding clozapine, quetiapine and iloperidone, have the propensity to cause some degree of EPS. 74 Recent trials have shown that there is no advantage to SGA agents in improving tolerability and effectiveness over FGAs. Akathisia is estimated to occur in 25% of patients taking a FGA while it is estimated to occur with SGAs at an incidence of 7% to 30% depending on the SGA used.

Tardive dyskinesia, a potentially irreversible chronic motor disorder caused by longterm exposure to dopamine antagonists, has been another serious concern with FGAs. The average rate of tardive dyskinesia with the FGAs is between 24% to 30%. 85,86 SGAs were initially thought to have a lower risk of treatment emergent tardive dyskinesia with maintenance treatment. Studies suggest that the risk of tardive dyskinesia with SGAs (excluding clozapine) is more than half of that with FGAs, or more than two-thirds of the risk with clozapine. 87 A meta-analysis of 203 studies from 2017 reported that the prevalence of tardive dyskinesia with SGAs (20.7%) is slightly lower than with treatment using FGAs (30%). 87 The data suggest that the risk of tardive dyskinesia may be slightly lower with SGAs, but not eliminated. 88 The first step in treating tardive dyskinesia is to discontinue the antipsychotic that is thought to have caused the adverse effect. 89 If discontinued too quickly the patient may A c c e p t e d M a n u s c r i p t experience withdrawal dyskinesia, so a slow taper is recommended. 89 A risk benefit analysis regarding discontinuing the offending agent may find that the individual will continue to need an antipsychotic agent. 89 In this case, switching to an agent with a lower risk of tardive dyskinesia, such as clozapine is recommended.

Clozapine appears to have an especially favorable profile for the prevention and management of antipsychotic-induced movement disorders. In comparative trials, clozapine exhibited little to no evidence of inducing treatment emergent EPS. 65, 90, 91 The risk of tardive dyskinesia associated with clozapine treatment also appears to be minimal. 92, 93 In fact, clozapine has been used to successfully treat preexisting tardive dyskinesia. Remission of symptoms has been reported in some, but not all, cases of preexisting tardive dyskinesia treated with clozapine. 58, 65, 66 In addition, withdrawal of clozapine in patients with tardive dyskinesia has resulted in either maintenance of reduced movements or worsening of dyskinesias. 94 The inconsistent nature of tardive dyskinesia treatment makes prevention of this syndrome a very important consideration in the pharmacotherapy of schizophrenia and schizoaffective disorder. 95 Valbenazine, a VMAT2 (vesicular monoamine transporter 2) inhibitor, has been FDA approved for the treatment of tardive dyskinesia. 96 occur. These effects may lead to a decrease in bone mineral density and to osteoporosis. 111 The degree of prolactin elevation that an antipsychotic agent may exert appears to be related to its dopamine-and serotonin-binding properties. Significant prolactin elevation and its associated adverse effects can occur with moderate-to-high doses of the FGAs, paliperidone, and risperidone. 111 Risperidone has been consistently associated with the greatest degree of prolactin elevation among both the SGAs and the FGAs. 112, 113 Clozapine causes the least prolactin elevation (<5%), while olanzapine, quetiapine, ziprasidone, asenapine, lurasidone, and brexpiprazole cause low to moderate hyperprolactinemia (10%-40%). [114] [115] [116] Cariprazine does not appear to affect prolactin levels. 117 Aripiprazole causes hypoprolactinemia and may be used adjunctively to decrease prolactin level elevations occurring with other antipsychotics. [118] [119] [120] Weight gain. The metabolic effects of antipsychotic drug therapy have become a source of concern for clinicians and patients. Schizophrenia and antipsychotic drug A c c e p t e d M a n u s c r i p t treatments have long been associated with comorbid obesity and its related conditions: type 2 diabetes mellitus and cardiovascular disease. [121] [122] [123] [124] [125] In addition, drug treatments and lifestyle changes aimed at weight reduction may be ineffective or difficult to implement in this population. [126] [127] [128] In multiple published analyses, clozapine and olanzapine have been associated with the greatest degree of weight gain among the antipsychotics ( Drugs associated with a moderate degree of treatment-emergent weight gain include SGAs iloperidone, quetiapine, and risperidone and the FGA chlorpromazine. These agents typically produce weight gain of about 2 to 3 kg in the first 10 to 12 weeks of treatment. 129, 133 A lower degree of weight gain is seen with higher potency FGAs, such as haloperidol and fluphenazine, and SGAs aripiprazole, asenapine, lurasidone, and ziprasidone. Mean observed weight gain with these agents in 10-to 12-week clinical studies have been 2 kg or less. 118, 122 Diabetes mellitus. Individuals with a prodromal and first episode schizophrenia have an increased incidence of developing diabetes regardless of treatment with antipsychotics. 121, 134 In addition, new-onset hyperglycemia and diabetes mellitus have been observed with antipsychotic treatment. In some instances, the initial presentation consists of lifethreatening diabetic ketoacidosis or hyperosmolar coma. 135 Frequently, clinically significant weight gain does not occur before the diagnosis of diabetes. 136 M a n u s c r i p t

In an analysis of public health registries and commercial databases carried out by The FGAs thioridazine, pimozide, and droperidol have been implicated in numerous cases of sudden unexpected death. 151 Electrocardiographic data have revealed that patients receiving droperidol and thioridazine are more likely to have an abnormally A c c e p t e d M a n u s c r i p t long QTc interval. 152 Numerous reports of patient fatalities and the availability of safer alternatives have prompted the FDA to recommend that thioridazine, pimozide, and droperidol only be used as alternative agents with extreme caution. 153 Although regulatory scrutiny for cardiac assessment heightened during the development of SGAs, these agents are generally associated with a low risk of electrocardiologic abnormalities. Ziprasidone was found to be associated with modest QTc prolongation during its premarketing studies. A comparative study that sought to determine the extent of QTc prolongation seen with the target therapeutic dosages of haloperidol, risperidone, olanzapine, quetiapine, and ziprasidone was later presented to the FDA. 153 Thioridazine was associated with an average QTc interval increase of 35.8

milliseconds. Of the second-generation agents included in the study, ziprasidone was associated with the greatest mean increase in the QTc interval (20.6 milliseconds).

Haloperidol-treated subjects had an average QTc interval increase of 4.7 milliseconds, the smallest change observed in this study. 154 Coadministration of other interacting drugs (eg, cytochrome P-450 isoenzyme inhibitors) did not lead to significant changes in QTc measurement. Ziprasidone's labeling warned of its greater potential of QTc interval prolongation and discouraged use in patients with electrolyte abnormalities, cardiac comorbidity, or concomitant use of metabolic inhibitors. 155 Since this study was completed several new antipsychotics have come to market and several of those have QTc ranges that have been measured in clinical trials. Of those agents, iloperidone appears to have a QTc of 9 milliseconds, but when combined with CYP-450 inhibitors its

QTc can increase to 19 milliseconds. 156 It is important to recognize that most of the SGA's do cause QTc prolongation, but currently there is not enough data to stratify agents by A c c e p t e d M a n u s c r i p t potential to cause QT prolongation, so drug choice should be made keeping the cardiovascular risk factors and the QTc of the patient in mind. 157 Clozapine has been associated with treatment-emergent myocarditis and cardiomyopathy. Myocarditis associated with clozapine treatment presents as an acute inflammation of the myocardium, which may lead to congestive heart failure. 158 The incidence has been estimated between 0.7% and 3%. [159] [160] [161] The greatest risk of fatal events appears to exist during the first month of therapy. Cardiomyopathy associated with clozapine is an insidious process characterized by ventricular dilatation, impaired contraction, and symptoms of congestive heart failure. 158 Cerebrovascular events. The use of antipsychotics for the treatment for dementiarelated agitation and psychosis in elderly patients is an unlabeled use that is generally supported by efficacy data in published controlled clinical trials. 162 However, post hoc analyses of the safety data for these trials revealed an elevated risk of cerebrovascular adverse events (CVAEs), including stroke and transient ischemic attacks, among patients treated with antipsychotics. [163] [164] [165] [166] In 2003, the FDA requested that manufacturers of antipsychotic agents place a black box warning describing this treatment risk on the labeling of these products. 167 A closer look at the applicable safety data reveals that the patients in the dementia trials were often at elevated risk for CVAEs because of advanced age, poor control of chronic cardiovascular disease, and the underlying etiology of the dementia. 168 168 The nature of this type of safety data makes it difficult to determine causality. It has been postulated that the adverse effects of sedation, hypotension, pseudoparkinsonism, and enhanced platelet aggregation may contribute to the observed increase in CVAEs. 168 In addition; these findings have not been widely observed among patients with schizophrenia and schizoaffective disorder. It would therefore be advisable to monitor high risk elderly patients on antipsychotics for symptoms of stroke.

Hematologic toxicity. Transient cases of agranulocytosis can occur in 0.01% of patients receiving FGAs during the first 8 weeks of therapy. The greatest incidence of agranulocytosis in the FGAs occurs with thioridazine and chlorpromazine. Among the SGAs the greatest incidence of neutropenia occurs with clozapine and olanzapine. 169 Despite its superior efficacy for treatment-resistant schizophrenia, clozapine has remained underutilized due to concerns about its minor risk of agranulocytosis. [170] [171] [172] Agranulocytosis has been estimated to occur in 0.38% of patients treated with clozapine. 173 Episodes tend to occur between 2 and 6 months after initiation of treatment. 174 

With the notable exception of clozapine, the principal differences among the available antipsychotics lie in their adverse-effect profiles and dosage forms. Selection of an initial treatment for a patient whose psychosis is not considered to be treatment resistant should be individualized based on the patient's specific tolerability concerns. 189, 190 For example, individuals with a known sensitivity to EPS may benefit from quetiapine. Patients with preexisting metabolic disorders or those at risk for developing metabolic disorder may benefit from high-potency FGAs or SGAs, such as aripiprazole, lurasidone, and ziprasidone, that have a lower propensity for causing metabolic adverse effects.

The availability of orally disintegrating tablets, sublingual tablets, oral liquid formulations, and long-acting injectable formulations of several antipsychotics provide options for patients who have difficulty taking standard oral tablets or capsules, those with a M a n u s c r i p t history of poor treatment adherence, or those with an expressed interest for these dosage forms. [191] [192] [193] Loxapine is also available as a powder for oral inhalation that has been FDA approved for treatment of acute agitation associated with schizophrenia or bipolar disorder. Its use is restricted by an FDA-approved REMS program which requires that it be given in a healthcare facility due to the risk of bronchospasm, pulmonary distress, and pulmonary arrest.

Dosing. The dosage ranges of antipsychotic drugs used for symptom remission in acute schizophrenia have been established in registration trials and in some post-marketing analyses. [194] [195] [196] The target doses of FGAs and SGAs for acute treatment are listed in Tables 2   and 3 .

Maintenance therapy can frequently be achieved with lower dosages, thereby reducing toxicity. Special populations, such as the elderly or individuals with hepatic impairment, may require lower doses due to increased sensitivity to adverse effects. In some individuals with a history of suboptimal response to antipsychotic treatment, additional benefit has been gained using SGAs with doses higher than the maximum recommended in the product labeling. 206 Long-acting injectable formulations. The development and use of long-acting injectable (LAI) antipsychotic formulations have sought to reduce some barriers to treatment adherence and provide more convenient options for patients. 191, 192, 197 LAI agents are administered in intervals ranging from 2-to 12-weeks between doses, reducing the need to administer oral drug on a daily basis.

The available LAI antipsychotics are described on Table 5 . The first generation agents, fluphenazine decanoate and haloperidol decanoate are oil-based formulations that are released gradually from muscle tissue after injection and hydrolyzed to the active A c c e p t e d M a n u s c r i p t drug. 198 The newer second generation LAIs are water-based products that use a variety of delivery technologies to release the active drug over time.

While LAI antipsychotics have consistently demonstrated symptomatic efficacy and reduced relapse frequency compared to placebo, it has been more difficult to establish these outcomes in head-to-head studies with oral antipsychotics due to methodologic limitations. 199 Adverse effect profiles of LAI antipsychotics are generally comparable to those of the corresponding oral drug. However, due to their extended duration of action, any untoward effects from LAI treatment are not easily reversible.

The LAI formulations should be considered in patients with a stated preference for their use or in individuals with a previous history of poor adherence. They may be initiated after patients have achieved a degree of clinical stability with the corresponding oral medication.

Frequent and continuous monitoring is necessary for individuals treated with antipsychotics in order to assess for therapeutic response and adverse effects. An evaluation of efficacy is warranted after week 2 of treatment, as it has been shown that nonresponse at this point predicts a low likelihood of response. 200 A longer trial is generally warranted for clozapine. Gradual reductions in the severity of psychotic symptoms (eg, suspiciousness, hallucinations) are expected with adequate treatment.

Monitoring for metabolic adverse effects of antipsychotic therapy should consist of regular assessments of body weight, glucose levels, and lipid values (Table 6) . 149, 201 Treatment with clozapine requires weekly assessment of complete blood count and absolute neutrophil count for the first 6 months. If no evidence of neutropenia or granulocytopenia is A c c e p t e d M a n u s c r i p t found, the monitoring frequency can be reduced to every two weeks for the next 6 months and then every 4 weeks thereafter.

Despite the lower propensity for causing adverse motor effects, all patients receiving SGAs, in addition to patients receiving FGAs, should be monitored for symptoms of dystonia, parkinsonism, akathisia, and tardive dyskinesia. 201 Patients should be evaluated for acute EPS weekly until two weeks after dose stabilization, from when antipsychotics are initiated or adjusted. Assessments for tardive dyskinesia should be conducted at least once yearly for individuals receiving continuous treatment with antipsychotics. 201 Measurement of antipsychotic plasma levels is not clinically indicated, except to assess for treatment adherence or suspected drug interactions. However, a minimum plasma clozapine concentration of 350 ng/mL has been correlated with treatment response among patients whose psychosis has been identified as treatment resistant. [202] [203] [204] In maintenance treatment, a clozapine serum level of at least 200 ng/mL optimally correlated with low risk of relapse. 205 

Schizophrenia is a complex illness with an etiology involving environmental factors and approximately 80% heritability. 206 Studies have shown that there is a higher incidence of synaptic pruning in the brains of those individuals diagnosed with schizophrenia versus those in the general population. 207 Genome wide association studies have shown multiple susceptibility loci for schizophrenia, yet these studies have been difficult to replicate. 208 Treatment of schizophrenia can be difficult due to lack of an empirical approach to A c c e p t e d M a n u s c r i p t choosing appropriate medications. Individuals with schizophrenia are typically treated based on a "trial and error" basis which can lead to non-adherence and adverse effects. 209 As many as 30-40% of individuals taking an antipsychotic will not respond to an individual agent, even though other individuals taking the same medication at the same dose for the same amount of time will exhibit response and even remission. 210 Metabolic adverse effects, including weight gain, glucose abnormalities, and hyperlipidemias, cause significant concern for patients receiving SGAs and must be managed proactively by clinicians. Extrapyramidal effects, including dystonic reactions, parkinsonism, and akathisia affect the tolerability of antipsychotics and should be monitored throughout the treatment course. Pharmacists and health care professionals in all settings should play an active role in assisting in the selection of an appropriate antipsychotic agent, ensuring appropriate monitoring, and providing counseling to help achieve optimal outcomes with treatment.

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CUtLASS: can we handle the truth?

Atypicality of atypical antipsychotics revisited

EPS profiles: the atypical antipsychotics are not all the same

Tardive dyskinesia and antipsychotics: a review

Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis

Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies

Drug-induced dyskinesia, part 2: treatment of tardive dyskinesia

Tolerability and therapeutic effect of clozapine: a retrospective investigation of 216 patients treated with clozapine for up to 12 years

Extrapyramidal side effects of clozapine and haloperidol

Clozapine: neuroleptic-induced EPS and tardive dyskinesia

Tardive dyskinesia (syndrome): current concept and modern approaches to its management

Clozapine and tardive movement disorders: a review

Clozapine withdrawal-emergent dystonias and dyskinesias: a case series

NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: a randomize, double-blind, placebo-controlled study

KINECT 3: a phase 3 randomized, doubleblind, placebo-controlled trial of valbenzapine for tardive dyskinesia

Tetrabenazine: spotlight on drug review

Randomized controlled trial of deutetrabenzaine for tardive dyskinesia: the ARM-TD study

FDA OKs deutetrabenazine (Austedo) for tardive dyskinesia

Vitamin E (alpha-tocopheol) in the treatment of tardive dyskinesia: a statistical meta-analysis

Vitamin E for neuropetic-induced tardive dyskinesia

Clonazepam treatment of tardive dyskinesia: a practical GABAmimetic strategy

Effects of amantadine on tardive dyskinesia: a randomized, double-blind, placebo-controlled study

Extract of Gingko biloba for tardive dyskinesia: meta-analysis of randomized controlled trials

Pyridoxal 5 phosphate for neuroleptic-induced tardive dyskinesia

Efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men

Hormonal side effects in women: typical versus geneation antipsychotic treatment

Galactorreha and hyperprolactineia in schizophrenic patients on neuroleptics: frequency and etiology

An overview of side effects caused by typical antipsychotics

Prolactin and antipsychotic medications: mechanisms of action

The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia

Attenuation of antipsychoticinduced hyperprolactinemia with clozapine

Antipsychotic-induced hyperprolactinemia

Differences in prolactin elevation and related symptoms of atypical antipsychotics in schizophrenic patients

Spotlight on brexpiprazole and its potential in the treatment of schizophrenia and as adjunctive therapy for the treatment of major depression

Cariprazine for schizophrenia and bipolar I disorder

Aripiprazole-associated hypoprolactinemia in the clinical setting

Adjunctive aripiprazole in the treatment of risperidone-induced hyperprolactinemia: a randomized, double-blind, placebocontrolled, dose response study

Add-on effects of a low-dose aripiprazole in resolving hyperprolactinemia induced by risperidone or paliperidone

Prevalence of metabolic syndrome in female and male patients at risk of psychosis

The distribution of body mass index among individuals with and without schizophrenia

Diabetes mellitus in schizophrenic patients

Glucose-insulin metabolism in chronic schizophrenia

Physical diseases in schizophrenia and affective disorder

Phenylpropanolamine appears not to promote weight loss in patients with schizophrenia who have gained weight during clozapine treatment

A program for treating olanzapine-related weight gain

Weight gain from novel antipsychotic drugs: need for action

Antipsychotic-induced weight gain: a comprehensive research synthesis

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis

Almost all antipsychotics result in weight gain: a meta-analysis

Differential effects of olanzapine and clozapine on plasma levels of adipocytokines and total ghrelin

Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of bipolar disorder: a systematic review and exploratory metaanalysis

Meta-analysis of glucose tolerance, insulin, and insulin resistance in antipsychotic-naïve patients with nonaffective psychosis

Diabetes mellitus associated with second-generation antipsychotic medications: new case report and review of the literature

Phenomenology of and risk factors for new onset diabetes mellitus associated with second-generation antipsychiotcis: an analysis of 45 published cases

Second-generation antipsychotics and metabolic side effects: a systematic review of population-based studies. Drug Saf

The METEOR study: frequency of metabolic disorders in patients with schizophrenia. Focus on first and second generation and level of risk of antipsychotic drugs

Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders-a systematic review and meta-analysis

Lipid profile disturbances in antipsychotic naïve patietns with first-episode non-affective psychosis: a systematic meta-analysis

Novel antipsychotics and sever hyperlipidemia

Antipsychotic-induced metabolic alterations: focus on adipose tissue and molecular mechanisms

Hyperlipidemia following treatment with antipsychotic medications

The effect of chlorpromazine on serum cholesterol in chronic schizophrenic patients

The effects of antipsychotic therapy on serum lipids: a comprehensive review

Atypical antipsychotic treatment and hyperlipidemia: a review

Consensus development conference on antipsychotic drugs and obesity and diabetes

Standards of medical care in diabetes-2017

The BAP guidelines on the management of weight gain, metabolic disturbances, and cardiovascular risk associated with psychosis and antipsychotic drug treatment

Minimizing cardiovascular adverse effects of atypical antipsychotic drugs in patients with schizophrenia

A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland

QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients

Psychopharmacological Drugs Advisory Committee. Briefing document for Zeldox capsules (ziprasidone HCl)

FDA background on Zeldox (ziprasidone hydrochloride capsules) Pfizer, Inc. Psychopharmacological Drugs Advisory Committee

Vanda Pharmaceuticals

QTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: a comprehensive review

Adverse cardiac effects associated with clozapine

Clozapine-induced myocarditis, a widely overlooked adverse reaction

Incidence of three presentations of acute myocarditis in young men in military service. A 20-year experience

Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during

Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence

Antipsychotics and the risk of cerebrovascular accident: a systematic review and meta-analysis of observational studies

Risk of death in elderly users of conventional vs. atypical antipsychotic medications

Antipsychotic medications and stroke in schizophrenia: a case-crossover study

Use of antipsychotics and risk of cerebrovascular events in schizophrenic patients: a nested case-control study

FDA public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances

Do atypical antipsychotics cause stroke?

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic induced side effects

Clozapine underutilization in the treatment of schizophrenia: how can clozapine prescription rates be improved?

Clozapine underutilization: addressing the barriers

Clozapine underutilization in treatment-resistant schizophrenia

Clozapine: key discussion points for prescribers

Clozapine-induced agranulocytosisincidence and risk factors in the United States

Severe neutropenia and agranulocytosis

Clozapine safety, 40 years later

FDA drug safety communication: FDA modifies monitoring for neutropenia associated with schizophrenia medicine clozapine

Benign ethnic neutropenia: what is a normal absolute neutrophil count?

Neutrophil counts in persons of African origin

Benign ethnic neutropenia and clozapine use: a systematic review of the evidence and treatment recommendations

Olanzapine in ED patients: differential effects on oxygenation in patients with alcohol intoxication

Safety evaluation of the concomitant use of clozapine and benzodiazepines: a retrospective, cross-sectional chart review

Potential complications of combining intramuscular olanzapine with benzodiazepines in emergency department patients

Seizure associated with clozapine: incidence, etiology, and management

Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports

Antipsychotic medications and seizures

Effects of psychotropic drugs on the seizure threshold

A guide to the management of clozapine-related tolerability and safety concerns

Selection of atypical antipsychotics for the management of schizophrenia

Individualizing antipsychotic treatment selection in schizophrenia: characteristics of empirically derived patient subgroups

The attitude of patients towards antipsychotic depot treatment

Depot and oral antipsychotics: patient preferences and attitudes are not the same thing

Olanzapine orally disintegrating tablet: a review of efficacy and compliance

A dose-outcome analysis of risperidone

Dosing of quetiapine in schizophrenia: how clinical practice differs from registration studies

How dosing of ziprasidone in a state hospital system differs from product labeling

Antipsychotic adherence and rehospitalization in schizophrenia patients receiving oral versus long-acting injectable antipsychotics following hospital discharge

Haloperidol decanoate: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis

The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence

Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review

Physical health monitoring of patients with schizophrenia

Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics

Plasma clozapine levels and clinical response for treatment refractory schizophrenic patients

Therapeutic drug monitoring of clozapine in relapse prevention: a five-year prospective study

Serum concentrations of clozapine and norclozapine in the prediction of relapse of patients with schizophrenia

The role of genetics in the etiology of schizophrenia

Prenatal inflammation and neurodevelopment in schizophrenia: a review of human studies

Genome wide studies (GWAS) and copy number variation (CNV) studies of the major psychoses: what have we learnt?

Pharmacogenomics can improve antipsychotic treatment in schizophrenia

Treatment resistant schizophrenia-the role of clozapine

Pharmacogenetics of antidepressants and antipsychotcis: the contribution of allelic variations to the phenotype of drug response

Pharmacogenetic tests for antipsychotic medications: clinical implications and considerations

Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options

Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia

Cognitive impairment associated with schizophrenia: a review of the humanistic burden

Negative symptoms of schizophrenia: clinical features, relevance to real world functioning and specificity versus other CNS disorders

Psychosocial treatments for schizophrenia

Rehospitalization rates of chronically ill schizophrenic patients discharged on a regimen of risperidone, olanzapine, or conventional antipsychotics

A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia

The lifetime risk of suicide in schizophrenia: a reexamination

Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment

Drugs@FDA: FDA Approved Drug Products

CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network

Comparison of the guidelines of the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenomics Working Group

Vanda Pharmaceuticals

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t B. Level of function in a major area (personal or occupational functioning) must be less than prior to the onset of symptoms.C. There must be continuous signs of the illness for at least 6 months. During this 6month time frame there must be a least 1 month of symptoms from A above, and may include prodromal, residual or negative symptoms.D. Schizoaffective, depressive or bipolar disorder has been ruled out.E. The disturbance is not due to the effects of a substance (medication or drug of abuse) or a medical condition.F. If there is a history of autism spectrum or a communication disorder or childhood, a diagnosis of schizophrenia is only made if hallucinations or delusions are prominent.A. An uninterrupted period of illness during which there is a major mood episode (major depressive or manic) concurrent with Criterion A of schizophrenia. (Note: The major depressive episode must include Criterion A1: Depressed mood.)B. Delusions or hallucinations for 2 or more weeks in the absence of a major mood episode (depressive or manic) during the lifetime duration of the illness.C. Symptoms that meet criteria for a major mood episode are present for the majority of A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t All drugs: at baseline, then monthly for the first 3 months and every 6 months thereafter; more frequent assessments are indicated for individuals noted to be gaining weight Weight assessmentAll drugs: at baseline and monthly thereafter (self-monitoring of weight should be encouraged) ElectrocardiogramClozapine and ziprasidone: at baseline and annually thereafter; more frequent assessments may be indicated in patients over age 50 years and in patients with a history of cardiac arrhythmias Complete blood count with differential Clozapine: weekly for the first 6 months, every other week for the next 6 months, and every 4 weeks thereafter if no abnormalities are noted Fasting total cholesterol, low-and high-density lipoproteins All drugs: at baseline and every 2 years thereafter if no abnormalities are noted; every 6 months for individuals noted to have hyperlipidemia or receiving lipid-lowering therapy A c c e p t e d M a n u s c r i p t Dutch Pharmacogenomics Working Group recommends using no more than 10 mg of aripiprazole in CYP2D6 PMs. 230