Module 1-Schizophrenia

Schizophrenia

Deanna L. Kelly, Mary Borovicka, and Heidi J. Wehring

LEARNING OBJECTIVES

Upon completion of the chapter, the reader will be able to:

1.Recognize signs and symptoms of schizophrenia and be able to distinguish among positive, negative, and cognitive impairments associated with the illness.

2.Explain potential pathophysiologic mechanisms that are thought to underlie schizophrenia.

3.Identify treatment goals for a patient with schizophrenia.

4.Recommend appropriate antipsychotic medications based on patient-specific data.

5.Compare side effect profiles of individual antipsychotics.

6.Educate patients and families about schizophrenia, treatments, and the importance of adherence to antipsychotic treatment.

7.Describe components of a monitoring plan to assess the effectiveness and safety of antipsychotic medications.

INTRODUCTION

Schizophrenia is a challenging disorder often requiring lifelong treatment. The disorder may have many pathophysiologic pathways that ultimately manifest with psychotic symptoms, including positive symptoms such as hallucinations and delusions, as well as disordered thinking. Commonly, these symptoms are accompanied by cognitive impairment (abnormalities in thinking, reasoning, attention, memory, and perception), impaired insight and judgment, and negative symptoms including loss of motivation (avolition), loss of emotional range (restricted affect), and a decrease in spontaneous speech (poverty of speech). Cognitive impairments and negative symptoms account for much of the poor social and functional outcomes. Schizophrenia is the fourth leading cause of disability among adults and is associated with substantially lower rates of employment, marriage, and independent living compared with population norms. Persons with schizophrenia have a higher mortality rate as compared with the general population, likely due to numerous factors such as physical comorbidities, insufficient health services, poor diet, lack of exercise, substance use (including tobacco), stigma about mental illness, and low socioeconomic status. However, earlier diagnosis, treatment, advances in research, and newer treatment developments have led to better outcomes with the potential for remission and recovery.

EPIDEMIOLOGY AND ETIOLOGY

Approximately 0.7% of the world population suffers from schizophrenia, with symptoms typically presenting in late adolescence or early adulthood.1 Prevalence is equal in men and women, but symptoms appear earlier in men with first hospitalization typically occurring at 15 to 24 years compared to 25 to 34 years in women.

The etiology of schizophrenia remains unknown. A genetic basis is supported by the fact that first-degree relatives of patients

with schizophrenia carry a 10% risk of developing the disorder, and when both parents have the diagnosis, the risk to their offspring is 40%. For monozygotic twins, the concordance rate is about 50%. Many genes have been weakly associated with the development of schizophrenia; however, there is probably no single “schizophrenia gene.” Research continues to explore candidate genes, loci, and copy number variants, hoping to better understand the genetic contribution.2 Possibly, when a genetic liability is present, environmental stimuli may trigger expression of the illness. These risk factors may include intrauterine exposure to significant stress, viral or bacterial infections. Also, emerging data suggest that certain drugs of abuse during childhood or adolescence, such as marijuana, may be one of those “triggers” in susceptible individuals. More research is needed on the role of these factors in the development of schizophrenia.

PATHOPHYSIOLOGY

The dopamine hypothesis, the oldest pathophysiologic theory, proposes that psychosis is caused by excessive dopamine in the brain. This hypothesis followed the discovery that chlorpromazine, the first antipsychotic medication, was a postsynaptic dopamine antagonist. Drugs that cause an increase in dopamine (eg, cocaine and amphetamines) worsen or cause psychotic symptoms, and medications that decrease dopamine (eg, antipsychotics) improve psychotic symptoms. However, data reveal a more complicated picture with both hyperdopaminergic and hypodopaminergic brain regions in schizophrenia. Hyperdopaminergic activity in the mesolimbic pathway contributes to positive symptoms of psychosis, while hypoactivity of the mesocortical pathway in the prefrontal cortex may contribute to negative symptoms. Thus, a more modern reworking of the dopamine hypothesis is the “dysregulation hypothesis,” which takes these findings into account and also focuses primarily on presynaptic dopamine.3 It is possible, however, that the hypothesized dopamine abnormalities may

Patient Encounter, Part 1

A 22-year-old woman was brought to the emergency department (ED) at a local hospital by the police after she was found wandering her neighborhood. The neighbors saw her peering in the windows and trying to open the doors of their homes and called the police. In the ED, her appearance was disheveled and her hair was long and tangled. She was easily distracted and irritable and when asked what she was doing wandering the neighborhood, she stated “I left my home because they are plotting to kill me there. It is dangerous there and I had to leave”. During her interview with the psychiatry resident, she frequently looked over her shoulder, and her eyes darted around the room. Then she asked the resident, “Do you even understand me? I need to get out of here. It is not safe for me here and they are looking for me. There is nothing wrong with me. I am really hungry; do you have something for me to eat?”

Her attention seemed to be focused on something else and then she blurted out “my dad is my other half and he will protect me.” When asked to explain, she said “I tell the voices my dad is my other half. They tell me I am terrible and that I should die.” The patient’s mother was called to the ED to see her daughter and provide more information.

She was admitted to the inpatient psychiatric unit for further evaluation.

What diagnoses are suggested by this presentation? W hat additional information would clarify the diagnosis, and why?

Should the patient’s mother be involved in her care?

represent changes occurring secondary to other pathophysiologic abnormalities. Other implicated neurotransmitter systems include a combined dysfunction of the dopamine and glutamate neurotransmitter systems. It is hypothesized that glutamate, possibly through malfunctioning N-methyl-d-aspartate (NMDA) receptors, impacts dopaminergic activity in the mesolimbic and mesocortical pathways. NMDA antagonists such as phencyclidine (PCP) and ketamine can elicit a state resembling schizophrenia, including positive and negative symptoms and cognitive impairments.3 There is evidence for the serotonergic system in schizophrenia as evidenced by serotonin-induced hallucinations and serotonin modulation of second-generation antipsychotics (SGAs).4 It is notable that, to date, antipsychotics without any primary or secondary dopaminemodulating properties have been ineffective for the treatment of positive symptoms of schizophrenia.

CLINICAL PRESENTATION AND DIAGNOSIS

In addition to the positive, negative, and cognitive symptoms of schizophrenia, people with schizophrenia may sometimes be uncooperative, suspicious, hostile, anxious, or aggressive. Psychotic and depressive symptoms may lead to poor hygiene and impaired self-care. Sleep and appetite disturbances may be present, and people with schizophrenia may have difficulty living independently, forming close relationships with others, and initiating or maintaining employment. Co-occurring medical and substance use disorders are common with cigarette smoking and illicit drug use about four to five times more prevalent than the general population.5,6

A diagnosis of schizophrenia is made clinically because there are no psychological assessments, brain imaging, or laboratory examinations that confirm the diagnosis.

The diagnosis is made by ruling out other causes of psychotic symptoms and meeting specified diagnostic criteria. When present, a family history of mental illness supports the diagnosis. The commonly accepted diagnostic criteria for schizophrenia are from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)7 (Table 38–1).

Patients presenting with odd behaviors, illogical thought processes, fixed false beliefs, and hallucinations should be comprehensively assessed to rule out other diagnoses or contributing factors.8

At minimum, patients with psychotic symptoms should have a medical workup at the time of admission to rule out other diagnoses or contributing factors, such as medical illnesses, infections,

Table 38–1

Diagnostic Criteria for Schizophrenia

A. Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated). At least one of these must be 1, 2, or 3:

1.Delusions

2.Hallucinations

3. Disorganized speech (eg, frequent derailment or incoherence)

4. Grossly disorganized or catatonic behavior

5. Negative symptoms (ie, diminished emotional expression or avolition)

B.For a significant portion of the time since the onset of the disturbance, level of functioning in one or more major areas, such as work, interpersonal relations, or self-care, is markedly below the level achieved before onset (or when onset is in childhood or adolescence, there is a failure to achieve expected level of interpersonal, academic, or occupational functioning).

C. Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meets Criterion A (ie, active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of disturbance may be manifested by only negative symptoms or by two or more symptoms listed in Criterion A present in an attenuated form (eg, odd beliefs, unusual perceptual experiences).

D.Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been ruled out because either (a) no major depressive or manic episodes have occurred concurrently with the active-phase symptoms or (b) if mood episodes have occurred during active-phase symptoms, they have been present for a minority of the total duration of the active and residual periods of the illness.

E. The disturbance is not attributable to the physiologic effects of a substance (eg, drug of abuse or medication) or another medical condition.

F.If there is a history of autism spectrum disorder or communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms of schizophrenia, are also present for at least 1 month (or less if successfully treated).

Reproduced with permission from the American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.

or other psychiatric or substance use disorders. Often, people with psychosis are poor historians and the gathering of collateral information about symptoms and medical history from family/ friends is necessary. When considering delusional symptoms, cultural beliefs and norms should be explored. Co-occurring substance abuse, medical illnesses, and psychosocial stressors often confound the diagnosis.

COURSE AND PROGNOSIS

Treatment of schizophrenia has been associated with poor longterm outcomes in the past; however, with earlier treatment and better care, many people can achieve remission, and recovery is possible. Without early intervention, there are traditionally intermittent acute psychotic episodes with a downward decline in psychosocial functioning. Though many of the more dramatic and acute symptoms may fade with time, severe residual symptoms may persist. Involvement with law enforcement is common for vagrancy, loitering, and disturbing the peace. Life expectancy is shortened primarily because of suicide, cardiovascular disease,

Clinical Presentation of Schizophrenia

General

Schizophrenia is a chronic disorder of thought and affect, causing significantly impaired vocational and interpersonal function. Onset is usually preceded by gradual social withdrawal, diminished interests, changes in appearance and hygiene, changes in cognition, and bizarre or odd behaviors incongruent with cultural beliefs and norms. The clinical presentation of a person with schizophrenia is extremely varied.

Symptoms

Psychotic symptoms (positive symptoms): Hallucinations (distortions or exaggeration of perception). Most frequently auditory, can also be visual, olfactory, gustatory, and tactile. Can be voices or thoughts that feel distinct from the person’s mind.

Voices may be threatening or commanding (eg, commanding the person to perform a particular action).

Delusions (fixed false beliefs). Beliefs despite invalidating evidence. May be bizarre in nature.

Often paranoid in nature which may cause suspiciousness.

Thought disorder (illogical thought and speech). Loosening of associations. Tangentiality Thought blocking Concreteness

Circumstantiality. Perseveration.

Thinking and speech may be incomprehensible and illogical.

accidents, and compromised self-care. Lifetime risk of suicide for people with schizophrenia is 5% to 10%, and it is estimated that suicide risk in this population exceeds that in the general population more than eightfold.9 Persistent adherence with a tolerable medication regimen improves prognosis, while relapse without antipsychotic medication exceeds 50% in the year following discontinuation of antipsychotic treatment.

The onset of schizophrenia can be rapid with acute psychosis presenting as the first symptom, or can be insidious with negative symptoms and social impairments predating psychosis by many years. Whether insidious or acute, the period around the diagnosis is difficult for patients, families, and clinicians. Patients may hide symptoms from family and friends and isolate themselves from social support networks. Gradual development of psychosis and the misunderstanding of symptoms can delay diagnosis and treatment. Recent data suggest that people treated early in their illness may have a better prognosis. Therefore, the first challenge of optimal therapy is to initiate treatment closer to the onset of psychosis.

Negative symptoms: Impoverished speech and thinking. Lack of social drive (avolition). Flatness of emotional expression. Apathy.

May be primary or occur secondarily to medication side effects, mood disorder, environmental understimulation, or demoralization.

The best strategy for differentiating primary from secondary negative symptoms is to observe for their persistence over time despite efforts at resolving the other causes.

Cognitive impairments (diminished function in the following): Attention. Processing speed. Verbal, visual memory, and working memory. Problem solving.

Loss of, on average, one standard deviation of preillness IQ, with the average IQ between 80 and 84.

Laboratory and Other Diagnostic Assessments

An initial psychotic workup includes a thorough neurologic, medical, and laboratory evaluation to rule out other causes: Electrolytes.

Blood urea nitrogen.

Serum creatinine. Urinalysis.

Liver and thyroid function profile. Syphilis serology. Serum pregnancy test. Urine toxicology. If warranted, neuroimaging and/or electroencephalogram (EEG).

TREATMENT

Desired Outcomes

The goals of treatment are to reduce symptomatology and psychotic relapses and to improve functional and social outcomes.10 Patients should receive comprehensive treatment as early as possible, and earlier treatment can lead to better outcomes.11 In the past, the primary treatment goal was to decrease positive symptoms and associated hostile and aggressive behaviors. Newer approaches also focus on functional and social outcomes. Though antipsychotic medications may improve combativeness, hostility, sleep, and appetite, other aspects of the illness are less responsive to treatment. Improvements in negative symptoms, cognitive functioning, social skills, and judgment generally require adjunctive treatments and a longer period to improve.

General Approach to Treatment

The concept of recovery has become an increasingly prominent treatment goal. Treatment planning increasingly includes providing recovery-oriented services to people with schizophrenia. A range of nonpharmacologic interventions are now part of the long-term strategy to improve functioning. Implementation of evidence-based practice and prescribing behaviors has led to the use of interventions that promote a remission or recovery attitude, and new data suggest that one in seven people with schizophrenia

Patient Encounter, Part 2

PPH: This is her first admission to a psychiatric hospital. Her mother reports that her daughter changed during her first year away at college and did not return for her second year. She lived at home and became reclusive, no longer spending time with her family or friends. The family could often hear her talking loudly in her room, but she could not tell them who she was talking to. The patient stopped taking care of herself and would wear the same clothes several days in a row. She would wander away from home for days and then suddenly return but could not tell anyone where she had been. She was often found on the streets with dangerous people who exploited her. The patient occasionally was aggressive and threatening toward her mother.

PMH: She does not have any other medical illnesses including seizures or history of head trauma.

SH: The patient did well in grade school and graduated from high school. She was active in the band and theater. She attended her first year of college away from home, but after the first year, she did not return. The only job she has had was as a cashier at a local convenience store when she was 20, but she was let go after 3 months for wandering away during her shift.

FH: The patient grew up with her parents and one brother who is 2 years older than her. Her mother is an elementary school teacher, has a history of major depression, and has a good relationship with her daughter but does not understand why she is behaving this way. The patient’s father recently passed away from cancer, and she had been very close to him. Her brother recently graduated from college with a degree in business as an accountant and accepted his first job out of town. There is no history of schizophrenia in the family. The patient’s mother states that her mother (the patient’s

can achieve full recovery.12,13 Moreover, recent attempts to improve and measure patient satisfaction and to include shared decision making have fostered patient empowerment and hope.

The cornerstone of treatment is antipsychotic medication, and most patients with schizophrenia relapse when not medicated. Treatment with antipsychotic medications should begin as soon as psychotic symptoms are recognized. Many patients are on lifelong antipsychotic medication because nonadherence and discontinuation are associated with high relapse rates. Often, adjunctive medications may also be necessary for specific symptoms or comorbid diagnoses. If other symptoms are present, such as depression and anxiety, these symptoms should be aggressively treated. Nonpharmacologic and psychosocial treatments should also play an important role in treatment.

Nonpharmacologic Therapy ▶ Psychosocial Treatment

As previously discussed, antipsychotic medications are the cornerstone of schizophrenia treatment plans; however, psychosocial support helps improve functional outcomes. Residual symptoms often persist such as avolition, isolation, and impaired social functioning, limiting participation in social, vocational, and educational endeavors. Psychosocial interventions, as adjuncts to pharmacotherapy, help people with

grandmother) had a psychiatric diagnosis and remembers her being hospitalized for periods of time but does not know what the diagnosis was.

Mental Status Examination

Appearance: Appears disheveled, dressed in dirty clothes, and hair is long, tangled, and looks like it has not been washed for several days. No abnormal movements. Poor eye contact. She is distracted and is looking around the room and over her shoulder. Speech: Speech is loud, but normal rate.

Mood: Says she feels “normal but agitated.” Denies feeling depressed.

Affect: Guarded with restricted range. She denies feeling sad, guilty, hopeless, or helpless.

Thought content: She is not a reliable historian and cannot explain where she goes when she leaves home or how she ends up on the street with strangers. She endorses hearing voices and states that they tell her she is terrible and should die. She has passing thoughts of suicide but no plan. She denies homicidal thoughts.

Thought processes: Irritable, vague, and paranoid. Cognition: Grossly intact.

Insight and judgment: Insight and judgment are poor. She does not believe she has a mental illness.

Given this additional information, how has your differential diagnosis changed?

What medications would you consider to be first-line options, and why?

What are the goals of treatment for this patient?

schizophrenia cope with challenging aspects of their illness and set goals as medication alone is typically not sufficient for remission and recovery. In the United States, psychosocial treatments are less frequently used than in Europe, but their use is increasing, and current guidelines recommend nonpharmacologic strategies in conjunction with antipsychotic treatment. There are much data to support family education in decreasing relapse rates and vocational support to improve vocational outcomes. A few of the best-supported and most promising approaches to psychosocial rehabilitation are social skills training (SST), cognitive behavioral therapy for psychosis (CBTp), and cognitive remediation (CR). In addition, psychoeducation, supported employment, Assertive Community Treatment (ACT), and Medical Home care models have improved outcomes.12,14

Pharmacologic Therapy

▶ Antipsychotic Treatment

In the United States, we have two general classes of antipsychotic medications, the first-generation antipsychotics (FGAs; typical antipsychotics) and the second-generation antipsychotics (SGAs) (atypical antipsychotics). The SGAs include risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, iloperidone, asenapine, lurasidone, brexpiprazole, cariprazine, lumateperone, and clozapine. Clozapine, the prototype SGA, is the recommended treatment for treatment-resistant schizophrenia (TRS) as it has superior efficacy in this population. However, it has some additional monitoring and a unique side effect profile (see below). Antipsychotic medications share a common mechanism of dopamine antagonism, although there is significant variation in receptor binding among the agents as some also act as dopamine partial agonists. Dopaminergic antagonism is important in symptom treatment but also contributes to some medication-induced side effects. Of the four main dopaminergic pathways in the brain, positive symptoms are thought to be associated with hyperdopaminergic activity in the mesolimbic pathway, so blockade in this area is thought to reduce psychotic symptoms. However, blockade of dopamine activity in the other three main pathways may worsen some symptoms or lead to side effects. For example, hypodopaminergic activity in the mesocortical pathway may be associated with negative symptoms and cognitive impairments, and further reducing dopamine activity could exacerbate these issues. Blockade of dopaminergic activity in the nigrostriatal pathway can lead to motor-related side effects, and blockade of dopaminergic activity in the tuberoinfundibular pathway may lead to prolactin elevation and related side effects.3 Differences in dopaminergic and nondopaminergic receptor antagonism and receptor affinity across the antipsychotic agents and classes lead to differing potential for dopamine-related side effects.

Compared with the FGAs, the SGAs are associated with a lower risk of motor side effects (tremor, stiffness, restlessness, and dyskinesia).

With the introduction of SGAs in the 1990s, the use of FGAs has progressively decreased, and FGAs have less than 10% market share of the antipsychotics used for schizophrenia. This decline occurred because of the touted better side effect profile and other possible benefits of SGAs in nonpsychotic domains of the illness. However, a large landmark study (the Clinical Antipsychotics Trials of Intervention Effectiveness [CATIE trial]; n > 1400) examined the effectiveness of SGAs relative to a midpotency FGA, perphenazine. The study revealed that the FGA was equal to the SGAs for the primary endpoint of time to discontinuation of medication.15 SGAs have historically been much more expensive

than the FGAs; however, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, and clozapine are now available in generic formulations. When selecting an antipsychotic, the risk-to-benefit profile becomes fundamental and the varying side effect profiles must be considered.

Second-Generation (Atypical) Antipsychotics

FGAs exert most of their effects through dopamine receptor blockade at the dopamine2 (D2) receptor. SGAs may have different receptor binding profiles that contribute to their “atypicality.” This possibly includes greater serotonin to dopamine antagonism, dopamine antagonism with rapid dissociation, partial dopamine antagonism and serotonin1A (5-HT1A) partial agonism. Despite heterogeneous receptor binding, the efficacy for positive symptoms among the SGAs is similar.15 Several long-acting injectable (LAI) formulations are now available and will be discussed below. However, due to differences in specific receptor binding affinity, side effect risks may vary between these agents. Additionally, recent data for SGAs and lower doses of FGAs document similar overall efficacy with an effect size for acute treatment of 0.30 to 0.60 for most antipsychotics.16 These findings have led to a modest resurgence of FGA use. Only clozapine, however, has demonstrated superior efficacy in treatment-resistant patients. An important distinction of the SGAs is their lower propensity to cause acute as well as long-term extrapyramidal symptoms (EPSs) including tardive dyskinesia (TD). TD risk with SGAs is 1.5% annually in adults (< 54 years of age) compared to approximately a 5% annual risk with FGA treatment.17 However, side effects such as weight gain, the potential for glucose dysregulation, and lipid abnormalities may be caused by treatment with these agents. Weight gain may be caused by a combination of lifestyle and medication interaction with neurotransmitter systems that may increase appetite and food intake (serotonergic, histaminergic, and dopaminergic), and, although all antipsychotics may be associated with weight gain, certain SGAs such as clozapine, olanzapine, quetiapine, and risperidone may offer greater risk. Similarly, risk of lipid abnormalities mirrors the risk for weight gain. Risk for glucose dysregulation or new-onset diabetes generally follows the risk of agents with most weight gain potential, although it is important to note that clozapine and olanzapine have been associated with diabetic ketoacidosis in the absence of significant weight gain in isolated cases. Sexual side effects as a result of prolactin elevation may occur due to dopamine antagonism at the tuberoinfundibular tract. SGAs have differing potentials to cause these side effects, which may include gynecomastia, galactorrhea, oligomenorrhea, or amenorrhea.

The SGAs are heterogeneous with regard to side effect profiles. Many SGAs carry an increased risk for weight gain and for the development of glucose and lipid abnormalities; therefore, careful monitoring is essential. Dosing and comparative side effects of SGA are shown in Tables 38–2 and 38–3 ▶

Risperidone

Risperidone, a benzisoxazole derivative, was the initial first-line oral SGA to become available generically. It has high binding affinity to both serotonin 2A (5-HT2A) and D2 receptors and binds to α1 and α2 receptors, with very little blockade of cholinergic receptors.18 At doses less than or equal to 6 mg/day, EPSs are low, although higher doses are associated with a greater incidence of EPS. Risperidone is often associated with elevated prolactin to a greater extent than most other SGAs and FGAs. Elevated prolactin levels can, but do not always, lead to amenorrhea, galactorrhea, gynecomastia, and sexual dysfunction. Mild-to-moderate

Second-Generation (Atypical) Antipsychotics

Second-Generation Antipsychotic

Aripiprazole (Abilify; Abilify MyCite; Aristada [aripiprazole lauroxil injection])

Usual Oral Starting and Target Dose (mg/day) (Schizophrenia)

Maximum Oral Dose Likely to Be Beneficial (mg/day)Available Dosage Forms

Initial: 10–15 Target: 15–30 30 2-, 5-, 10-, 15-, 20-, and 30-mg tablets

MyCite available as 2, 5, 10, 15, 20, and 30-mg tablets with Ingestible Event Marker (IEM) sensor to track drug ingestion (adults)

1-mg/mL oral solution 10- and 15-mg orally disintegrating tablets Abilify Maintena extended-release 300- and 400-mg vial powder for suspension or prefilled syringe long-acting injection

Aristada extended-release 441, 662, 882, and 1064-mg prefilled syringes

Aristada Initio, including 675-mg long-acting injection and 30-mg oral dose

Asenapine (Saphris; Secuado [patch])

Initial: 5 twice daily Target: 10–20 total daily dose 10–20 2.5-, 5-, and 10-mg sublingual tablets Secuado (asenapine) transdermal system for once-daily administration; 3.8 mg/24 hours initial dosing; available as 3.8 mg/24 hours, 5.7 mg/24 hours, and 7.6 mg/ 24 hours

Brexpiprazole (Rexulti)Initial: 1 Target: 2–4 4 0.25-, 0.5-, 1-, 2-, 3-, and 4-mg tablets

Cariprazine (Vraylar)Initial: 1.5 Target: 1.5–6 6 1.5-, 3-, 4.5-, and 6-mg capsules

Clozapine (Clozaril, FazaClo, Versacloz, also available generically)

Initial: 12.5–25 Target: 300–450 500–800 12.5-, 25-, 50-, 100-, and 200-mg tablets FazaClo (orally disintegrating tablets) 12.5, 25, 100, 150, and 200 mg Versacloz (oral suspension) 50 mg/mL

Iloperidone (Fanapt)Initial: 1 twice daily Target: 12–24 total daily dose 24 1-, 2-, 4-, 6-, 8-, 10-, and 12-mg tablets

Lumateperone (Caplyta)

Lurasidone (Latuda)

Olanzapine (Zyprexa, also available generically)

Initial and target: 42 mg daily with food Initial: 40 Target: 40–160

42 160

42-mg capsule 20-, 40-, 60-, 80-, and 120-mg tablets

Initial: 5–10 Target: 10–20 30–40a 2.5-, 5-, 7.5-, 10-, 15-, and 20-mg tablets

Orally disintegrating tablets: 5, 10, 15, and 20 mg IM 10-mg vial (after reconstitution, ˜5 mg/mL) Zyprexa Relprevv 210-, 300-, and 405-mg/vial powder for suspension long-acting injection Paliperidone (Invega)Initial: 6 Target: 3–12 12 1.5-, 3-, 6-, and 9-mg tablets

Invega Sustenna 39-, 78-, 117-, 156-, and 234-mg prefilled syringes for long-acting injection Invega Trinza 273-, 410, 546-, or 819 mg for long-acting injection

Quetiapine (Seroquel, also available generically)

Risperidone (Risperdal, also available generically)

Regular release

Initial: 25 twice daily Target: 300–750 Extended release Initial: 300 Target 400–800

800 25-, 50-, 100-, 200-, 300-, and 400-mg tablets Seroquel XR (extended-release tablets) 50-, 150-, 200-, 300-, and 400-mg tablets

Initial: 1–2 Target: 4–6 6–8

0.25-, 0.5-, 1-, 2-, 3-, and 4-mg tablets

1 mg/mL (30-mL) solution

Orally disintegrating tablets: 0.25-, 0.5-, 1-, 2-, 3-, and 4-mg tablets

Risperdal Consta long-acting injectable 12.5-, 25-, 37.5-, and 50-mg vial/kit

Perseris long-acting subcutaneous injection; 90- and 120-mg kits

Ziprasidone (Geodon, also available generically)

Initial: 20 twice daily Target: 120–160 total daily dose

aOutside product labeling guidelines. IM, intramuscular.

160–240a 20-, 40-, 60-, and 80-mg capsules IM 20 mg/mL

Table 38–3

Comparative Side Effects Among the SGAs and Haloperidol

Side Effect ClozRispa OlanQuetZipAriIloAsenLurBrexCaripLumb Hal Anticholinergic side effects+++±++ (Higher doses)+±±±+±±±±± EPS at clinical doses ++ ± ±±++++±+±++ Dose-dependent EPS0+++ 0+++++++0+++ Orthostatic hypotension++++++++++++++±±±++ Prolactin elevation 0++++ ±+0+±±±0±+

QTc prolongation +± ± ++±+++±±0± Sedation ++++ +++++++++++++++ Seizures ++± ± ±±±±±±±±±± Weight gain ++++++++++++++++±0± Glucose dysregulation++++++±±±±±±±0± Lipid abnormalities+++++++++±±±±±±±0±

aSide effects similar for paliperidone.

bBased on 4 weeks of exposure; long-term effects not known. Long-term study in progress. No comparative data available. 0, absent; ±, minimal; +, mild or low risk; ++, moderate; +++, severe; SGA, second-generation antipsychotic; EPS, extra-pyramidal symptoms. Cloz, clozapine; Risp, risperidone; Olan, olanzapine; Quet, quetiapine; Zip, ziprasidone; Ari, aripiprazole; Ilo, iloperidone; Asen, asenapine; Lur, lurasidone; Brex, brexpiprazole; Carip, cariprazine; Lum, lumateperone; Hal, haloperidol.

weight gain and mild elevations in serum lipids and glucose may occur.

▶

Olanzapine

Olanzapine has greater affinity for 5-HT2A than for D2 receptors. It also has affinity at the binding sites of D4, D3, 5-HT3, 5-HT6, α1-adrenergic, muscarinic1–5 (M1–5), and histamine1 (H1) receptors.19 In the CATIE trial, olanzapine was associated with the longest time to treatment discontinuation,15 suggesting it may differ from the other SGAs in effectiveness. Olanzapine has a low rate of EPS and causes slight, transient prolactin elevations. Olanzapine causes significant weight gain across the dosage range, similar to that seen with clozapine and greater than that observed with the other SGAs. Olanzapine is also associated with hypertriglyceridemia, increased fasting glucose, and new-onset type 2 diabetes (ie, metabolic syndrome). Among the first-line SGAs, it is associated with the greatest elevations in these metabolic parameters.15

▶

Quetiapine

Quetiapine, structurally related to clozapine and olanzapine, has high affinity for 5-HT2A receptors and lower affinity for D2 and D1 receptors. It has some affinity for α1, α2, and H1 receptors but very little for muscarinic receptors. Quetiapine may be beneficial for anxiety and depression. Motor side effects and prolactin elevations are uncommon. Orthostasis occurred in 4% of subjects in clinical trials. Sedation is common, but generally transient. Quetiapine is sometimes used for insomnia, though this practice is off label and not considered an appropriate use. Weight gain and elevations in triglycerides can occur. Use of quetiapine with agents that can prolong the QTc interval or in patients with prolonged QTc should be avoided. Quetiapine has been associated with some dose-related decreases in thyroid hormones.

▶

Ziprasidone

Ziprasidone was developed to block D2 receptors but also to bind with greater affinity to central 5-HT2A receptors. It has a binding affinity ratio of 11:1 for 5-HT2A:D2 receptors. It has a relatively high affinity for 5-HT2C, 5-HT1D, α1-adrenergic, and D1 receptors.20 It

should be taken with food (at least 500 calories [2100 J]), as this results in absorption levels twice that of fasting administration. Liability for EPS, weight gain, and lipid elevations is low but does occur. Ziprasidone causes some prolongation of the QTc interval in adults. However, overdose data and pharmacokinetic interaction data show little evidence that significant QTc prolongation occurs. Use of ziprasidone with agents that can prolong the QTc interval or in patients with existing diseases associated with prolonged QTc should be avoided. Drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred rarely.

▶

Aripiprazole

Aripiprazole has both antagonist and partial agonist activity at the D2 receptor. Aripiprazole is also a partial agonist at 5-HT1A receptors, an antagonist at 5-HT2A receptors, and has affinity for D 3 receptors. Additionally, it has moderate affinity for α1 and H1 receptors with no appreciable affinity for the M1 receptor.21 In CYP2D6 poor metabolizers, start dosing with one-half the usual dose with adjustment to clinical efficacy. Sedation, nausea, and vomiting are the most often seen side effects. Elevations in weight, lipids, and glucose are generally negligible, and aripiprazole is not associated with elevations in serum prolactin. In fact, patients switched to aripiprazole from other antipsychotic agents may experience decreases in prolactin.

▶

Paliperidone

Paliperidone is the 9-hydroxy (9-OH) metabolite of risperidone. The efficacy of risperidone and paliperidone is similar. Receptor binding affinity is also similar between the two agents, with paliperidone having a greater affinity at 5-HT2A compared with D2 receptors. Unlike many other antipsychotic medications, paliperidone is mostly excreted unchanged, a potential advantage in patients with liver impairment, although adjustment may need to be made in renal impairment. Patients should be told to expect to see the shell of the tablet in the stool because it may not dissolve in the digestive tract.22 Side effects of paliperidone are expected to be similar to those of risperidone, including the potential for dose-related EPS and prolactin elevation.22

Iloperidone

Iloperidone exhibits high affinity for 5-HT2A, dopamine D2, and D 3 receptors and acts as an antagonist at these, as well as at the 5-HT1A and norepinephrine α1/α2C receptors. Doses must be titrated because of the risk of orthostatic hypotension, and dosing should be reduced by half in CYP2D6 poor metabolizers. Common adverse reactions include dizziness, dry mouth, fatigue, orthostatic hypotension, tachycardia, and weight gain. Dizziness, tachycardia, and weight gain were twice as common with higher dose (20–24 mg total daily dose) versus lower doses (10–16 mg total daily dose).23 Use of iloperidone with agents that can prolong the QTc interval or in patients with diseases that are associated with prolonged QTc should be avoided.

▶ Asenapine

Asenapine’s mechanism of action is thought to be its antagonistic activity at 5-HT2A and D2 receptors. It also exhibits a high affinity for other serotonergic and dopaminergic receptors, as well as α1- and α2-adrenergic receptors and H1 receptors. Asenapine tablets must be placed under the tongue and allowed to dissolve completely; tablets should not be chewed or swallowed. Patients should not drink or eat for 10 minutes after administration. No added benefit was seen with doses above 10 mg twice daily, but adverse effects increase. Common adverse effects include somnolence, dizziness, and akathisia. It has shown little effect on metabolic parameters and weight change. Labeling for asenapine was modified to address rare occurrence of hypersensitivity reactions, including anaphylaxis and angioedema.24 A transdermal formulation of asenapine has been marketed as a once-daily (every 24 hours) formulation.

▶ Lurasidone

Lurasidone antagonizes D2 and 5-HT2A receptors. It also has moderate affinity as an antagonist at α2C, is a partial agonist at 5-HT1A, and is an antagonist at α2A receptors. Lurasidone should be taken with caloric intake of at least 350 calories (1500 J) for maximal absorption. Adverse reactions reported in at least 5% of patients (and at least twice the placebo rate) include somnolence, akathisia, nausea, parkinsonism, and agitation. Lurasidone has shown only a small effect on body weight and causes minimal changes in other metabolic parameters.24

Patient Encounter, Part 3

The patient started treatment with haloperidol 5 mg/day in the hospital. After a couple of days, the dose of haloperidol was increased to 10 mg/day. Over several days, the patient started to feel less paranoid and the voices began to dissipate. She began participating in group activities on the unit and interacting with her peers. She was discharged from the hospital after 2 weeks. Her mother agreed to have her return home.

The patient had a follow-up appointment 2 weeks after discharge. At the appointment, she expressed feeling well enough to consider going back to school. During the interview, the physician noted that she had a pill-rolling tremor and masked facies. Upon examination, the patient also had cogwheel rigidity and a lack of arm swing when she walked.

▶ Brexpiprazole

Brexpiprazole is a partial agonist at 5-HT1A, D2 and D3 receptors. It is also an antagonist of 5-HT2A, 5-HT2B, 5-HT7, α1A, α1B, α1D, α2C, and H1 receptors. It has negligible affinity for muscarinic receptors. In CYP2D6 poor metabolizers, usual dosage should be reduced by one-half. This medication is slightly less stimulating and has less akathisia than aripiprazole. The most commonly occurring side effects are weight gain and akathisia.25

▶

Cariprazine

Cariprazine is a dopamine D3-preferring D2/D3 receptor partial agonist. It also acts as a partial agonist of 5-HT1A and as an antagonist of 5-HT2A receptors. It is given once daily and has a long half-life; thus, side effects should be monitored for several weeks after initiation or a dose change. Most common side effects are akathisia, EPS, nausea, vomiting, somnolence, and restlessness. Those having a known hypersensitivity reaction to cariprazine should not be treated with the medication.26

▶

Lumateperone

Lumateperone is a 5-HT2A and D2 receptor antagonist with higher affinity for 5-HT2A compared with D2, and lower affinities for α1 and H1 receptors. It also works as a presynaptic dopamine partial agonist, serotonin reuptake inhibitor, and an indirect modulator of glutamatergic systems. Due to gastrointestinal adverse effects in clinical trials, it is recommended to administer lumateperone with food. Only one dose (42 mg) is currently approved due to lack of efficacy of varying doses. Dose titration or adjustment is not required. Use of lumateperone was not associated with increased EPS risk as compared with placebo in pooled safety analyses of three clinical studies. Sedation/ somnolence and dry mouth were associated with occurrence greater than twice the rate of placebo or at least 5% of patients exposed to lumateperone. Rates of EPS-related side effects and mean change in weight were less for lumateperone and placebo compared with risperidone.27

First-Generation (Typical) Antipsychotics

The FGAs are high-affinity D2 receptor antagonists. During chronic treatment, they block 65% to 80% of D2 receptors in the striatum and other dopamine tracts in the brain.25 Clinical

After discussion with the patient and her mother, the decision was made to switch her from haloperidol to oral olanzapine 5 mg/day. The doctor called the patient a week later to discuss how she was doing on the new medication. The patient felt like some of her schizophrenia symptoms were returning, so he decided to increase the olanzapine dose to 10 mg/day. The doctor called the patient again a week later, and she stated her hallucinations and paranoia were improving as were the stiffness and rigidity she experienced on haloperidol, so the dose was maintained at 10 mg/day. What symptom was the patient experiencing on haloperidol? What other treatments could have been considered besides switching agents?

Discuss the differences in the side effect profiles of haloperidol and olanzapine.

Table 38–4

First-Generation (Typical) Antipsychoticsa

Class Agent (Brand Name)Dosage Range (mg/day) Chlorpromazine Equivalents (mg)Available Formulations

Butyrophenone

Haloperidol (Haldol) 5–30 2 T, LC, I

DibenzoxazepineLoxapine (Loxitane, Adasuve) 20–100 10 C, IP

DiphenylbutylpiperidinePimozide (Orap)b 1–10 1–2 T

Phenothiazines

Chlorpromazine (Thorazine) 300–800 100 T, I

Fluphenazine (Prolixin) 2–40 2 T, L, LC, I

Perphenazine (Trilafon)c 8–64 8–10 T

Thioridazine (Mellaril) 300–800 100 T

Trifluoperazine (Stelazine) 15–30 5 T

Thioxanthenes Thiothixene (Navane) 5–60 4 C

aLow-potency antipsychotics include thioridazine, mesoridazine, and chlorpromazine. High-potency antipsychotics include haloperidol, fluphenazine, thiothixene, and pimozide.

bPoor CYP2D6 metabolizers, alternative dosing strategies; recommend 2D6 genotyping above certain doses.

cPoor 2D6 metabolizers may demonstrate higher plasma concentration.

C, capsule; I, injection; IP, inhalation powder; LC, liquid concentrate; L, liquid solution, elixir, or suspension; T, tablet.

response is generally associated with 60% D2 receptor blockade, while 70% and 80% are associated with hyperprolactinemia and EPS, respectively. During the 1990s, SGAs began to replace FGAs as first-line therapy.

Doses for FGAs are frequently given as chlorpromazine equivalents, which are defined as the FGA equipotent dose with 100 mg of chlorpromazine. The target dose recommendation for acute psychosis is 400 to 600 chlorpromazine equivalents unless the patient’s history indicates that dose may not be tolerated. Generally, maintenance therapy is 300 to 600 chlorpromazine equivalents daily. Dosing and available dosage forms are shown in Table 38–4. All FGAs are equally efficacious when studied in equipotent doses in groups of patients. Relative potency of FGA agents is related to side effect profile, with lower potency agents such as chlorpromazine demonstrating higher risk of anticholinergic and cardiovascular side effects and higher potency agents such as haloperidol displaying more potent EPS side effects. However, an individual patient may not respond equally to each antipsychotic. Selection of a particular antipsychotic is based on patient variables, such as the need to avoid certain side effects or drug–drug interactions or previous patient or family history of response. Long-acting formulations of FGA medications are shown in Table 38–5.

Side Effects of the First-Generation Antipsychotics

As previously mentioned, the low-potency FGA agents are less likely to cause EPS than the high-potency agents (see Table 38–4). Of note, high-potency and midpotency agents may cause less EPS than once believed and were similar to SGAs in the CATIE trial.15

The FGAs are commonly associated with early-onset EPS (including akathisia [motor or subjective restlessness], dystonia [muscle spasm], and pseudoparkinsonism [akinesia, tremor, and rigidity]) caused by dopamine antagonism in the nigrostriatal pathways. SGAs also may have these side effects. Akathisia, or the feeling of restlessness, occurs in 20% to 40% of FGA patients. Roughly half of the cases of akathisia present within 1 month of FGA initiation, though it may present within 5 to 10 days after the first dose or after an increase in dosage. Younger people and those taking high doses of high-potency antipsychotics are at greater risk for development of akathisia.

Acute dystonic reactions are abrupt in onset and are usually seen within 24 to 96 hours after a first dose or increase in dosage. Characteristic signs and symptoms include abnormal positioning or spasm of the muscles of the head, neck, limbs, or trunk. Dystonia may occur in 10% to 20% of patients. There is higher risk for dystonia in young male patients and those taking high-potency FGAs.

Pseudoparkinsonism may be present in 30% to 60% of people treated with FGAs. The onset of symptoms is usually within 1 to 2 weeks after dose initiation or dose increase. Clinical presentation may include cogwheel rigidity, pill-rolling hand movements, resting tremor, shuffling gait, stooped posture, and mask facies. Risk factors include older age, female gender, high doses, and possibly those with depressive symptoms. Anticholinergic medications are used for treatment of dystonic reactions and pseudoparkinsonism, while β-blocking agents are generally first line for akathisia.28

Tardive dyskinesia is a movement disorder characterized by abnormal choreiform (rapid, objectively purposeless, irregular, and spontaneous) and athetoid (slow and irregular) movements beginning late in relation to initiation of antipsychotic therapy. It usually develops over several months or after at least 3 months of cumulative exposure to antipsychotics. When antipsychotics are tapered or discontinued, there is typically a transient worsening of abnormal movements, and movements may be irreversible in some cases. Risk factors for TD include older age; longer duration of antipsychotic treatment; and presence of EPS, substance abuse, and mood disorders. SGAs have a lower risk of approximately 2% to 4% risk of TD than FGAs (5%–6%).17 A variety of approaches have been used for treating TD including switching to clozapine, using high-dose vitamin E, and, most recently, the approval of new Food and Drug Administration (FDA)-approved medications for TD, valbenazine and deutetrabenazine, which inhibit vesicular monoamine transporter 2 (VMAT2).

Neuroleptic malignant syndrome (NMS), a life-threatening emergency characterized by severe muscular rigidity, autonomic instability, and altered consciousness, can occur uncommonly with all FGAs and may also occur with SGAs. Rapid dose escalation, use of high-potency FGAs at higher doses, and younger

Antipsychotic Dosing of Long-Acting Preparations

Drug Starting Dose Maintenance Dose Comments

Aripiprazole longacting injection (Abilify Maintena)

400 mg monthly

Give 14 consecutive days of concurrent oral aripiprazole (10–20 mg) or current oral antipsychotic after first injection

Aripiprazole lauroxil (Aristada) 441 if 10 mg/day oral 662 if 15 mg/day oral 882 if 20 mg/day or more oral Give 21 days of concurrent oral aripiprazole overlapping with first dose

Aripiprazole lauroxil (Aristada Initio)

675-mg injection and one 30-mg dose of aripiprazole as first dose

300–400 mg monthlyEstablish tolerability with oral agent first Dosage adjustments for CYP2D6 poor metabolizers, and in persons who take strong CYP2D6 or 3A4 inhibitors; recommend to avoid use if strong 3A4 inducer

Average 441–882 monthly or 882 every 6 weeks or 1064 every 2 months

To be used as a single dose and not for repeated dosing; for initiating Aristada treatment

Available as 300-, 400-mg kits

Dose adjustments for CYP2D6 poor metabolizers, and persons who take strong CYP2D6 or 3A4 inhibitors; or CYP3A4 inducers > 2 weeks

Available as 441-, 662-, 882, or 1064-mg prefilled syringes

Avoid use in CYP2D6 poor metabolizers Not interchangeable with Aristada First Aristada injection may be administered on the same day as Aristada Initio or up to 10 days after Do not inject both concomitantly into the same deltoid muscle

Haloperidol decanoate

10–20 × oral haloperidol daily dose; in the elderly use 10–15 × oral haloperidol daily dose

Generally, 100–450 mg/month

Initial dose should not exceed 100 mg regardless of previous dose requirements (if > 100 mg, give 3–7 days apart)

Oral supplementation may temporarily be necessary for first 2–3 injections unless loading dose given

10–15 × oral haloperidol daily dose, generally 50–300 mg/ month

Deep IM injection generally with 21-gauge needle; maximum volume per injection site should not exceed 3 mL

Available in 50 and 100 mg/mL (5-mL vials and 1-mL ampules)

Fluphenazine decanoate

Approximately 12.5-mg injection = 10-mg oral daily dose; usual starting dose 12.5–25 mg; generally, 12.5–mg/2–3 weeks

Give ½ oral dose after first injection, discontinue oral after second injection

Based on starting dose and clinical response but usually 2–4 weeks; doses above 50 mg increase cautiously in 12.5-mg increments; do not exceed 100 mg Generally, 12.5–25 mg dosed at 2–4-week intervals (may be up to 6 weeks in some cases)

Can be administered IM or SC; 21-gauge needle, must be dry Should not exceed 100 mg; when dosing above 50 mg, should increase in increments of 12.5 mg Available in 25 mg/mL (5-mL vials)

Olanzapine (Zyprexa Relprevv)

To target oral 10-mg/day dose: Either 210 mg/2 weeks or 405 mg/4 weeks during first 8 weeks

To target oral 15-mg/day dose: 300 mg/2 weeks for first 8 weeks

To target 20-mg/day oral dose: 300 mg/2 weeks

Establish tolerance with oral administration prior to initiation

To target oral 10-mg/day dose: after 8 weeks, give 150 mg/ 2 weeks or 300 mg/4 weeks

To target oral 15-mg/day dose: after 8 weeks, 210 mg/2 weeks or 405 mg/4 weeks

To target 20-mg/day oral dose: continue with 300 mg/2 weeks

Gluteal injection, 19-gauge needle Do not confuse with rapid-acting IM injection

Must reconstitute with included diluent Measure amount to inject from vial (there will be remaining suspension in vial)

Zyprexa Relprevv Patient Care Program: 3-hour observation period due to risk of postinjection delirium/sedation syndrome; patient must be accompanied to destination

No refrigeration needed, use within 24 hours, or immediately once suspension is in syringe

Available as 210, 300, 405 kits

Paliperidone monthly (Invega Sustenna)

Initiate with 234 mg on day 1 and 156 mg 1 week later, both in deltoid muscle

Establish tolerance with oral administration prior to initiation

Recommended monthly maintenance dose is 117 mg (range, 39–234 mg)

First two doses must be given in the deltoid muscle; after that, monthly doses given in either the deltoid or gluteal muscle

Adjust dose in mild renal impairment; avoid in moderate-to-severe impairment

Available as 39-, 78-, 117-, 156-, and 234-mg prefilled syringes

Antipsychotic Dosing of Long-Acting Preparations

Drug Starting Dose Maintenance Dose Comments

Paliperidone (every 3 months) (I nvega Trinza)

Risperidone longacting injection (Risperdal Consta)

If monthly 78 mg, 273 mg/3 months

If monthly 117 mg, 410 mg/3 months

If monthly 156 mg, 546 mg/3 months

If monthly 234 mg, 819 mg/3 months

Only initiate after at least 4 months of paliperidone monthly injections.

25 mg every 2 weeks

Previous antipsychotics should be continued for 3 weeks after initial dose of risperidone long-acting injection

273–819 mg/3 monthsAdjust dose in mild renal impairment; avoid in moderate to severe impairment

Available as 273-, 410-, 546-, or 819-mg prefilled syringes

25–50 mg every 2 weeksRecommended to establish tolerability with oral risperidone prior to initiation of longacting injection

Lower starting dose of 12.5 mg may be appropriate in some patients with renal/ hepatic impairment

Available in 12.5-, 25-, 37.5-, and 50-mg vial/ kit; must use needle supplied with kit, administer IM

Risperidone subcutaneous longacting injection (Perseris)

90 mg to 120 once monthly90 to 120 mg every monthEstablish tolerability with oral risperidone No oral supplementation recommended

Administer monthly in abdomen by subcutaneous injection by a healthcare professional;

Must reconstitute when ready to give dose; Available as 90 mg and 120 mg injection kits

IM, intramuscular; SC, subcutaneous.

patients have a higher risk of NMS. When NMS is diagnosed or suspected, antipsychotics should be discontinued and supportive, symptomatic treatment begun (eg, antipyretics, cooling blanket, intravenous fluids, oxygen, monitoring of liver enzymes, and complete blood cell count). Benzodiazepines and dantrolene are recommended treatments along with intensive care management as needed.28

Dermatologic side effects, photosensitivity, and cataracts may occur with the phenothiazine FGAs. Sedation is mediated by H1 receptor antagonism; anticholinergic side effects (constipation, blurred vision, dry mouth, and urinary retention) are caused by M1 receptor antagonism; and α1 receptor blockade is associated with orthostatic hypotension and tachycardia (Table 38–6). QTc prolongation may occur with the lowerp otency FGAs, and thioridazine has a black box warning for QTc prolongation.

Pharmacologic Treatment Guidelines and Algorithms

There have been a variety of treatment recommendations published for schizophrenia. The American Psychiatric Association (APA) Practice Guidelines for Schizophrenia8 were updated in 2020. The World Federation of Societies of Biological Psychiatry Guidelines (WFSBP),29 British Association of Psychopharmacology (BAP),30 the Canadian Schizophrenia Guidelines,31 and the National Institute for Health and Care Excellence (NICE) guidelines are also available.10 While guidelines from the early 2000s generally recommend SGAs as first-line treatment, more recent guidelines generally suggest first-line treatment with either an FGA or SGA. Choice of the FGA/SGA is guided by side effect profiles and patient clinical characteristics. Treatment with a given antipsychotic at a recommended therapeutic dose should

be continued for 4 to 6 weeks to assess response. If response is not achieved, switching and cross titration to monotherapy with a different antipsychotic in conjunction with psychosocial support are recommended. Use of two antipsychotic medications concomitantly is discouraged in most circumstances due to increased side effect burden and paucity of data for increased efficacy.

Treatment Adherence

Antipsychotic nonadherence is estimated to occur in at least 40% to 50% of patients with schizophrenia. Patients who are nonadherent have about a fourfold greater risk of a relapse than those who are adherent.32 Neurocognitive deficits, poor insight, and paranoid symptoms may hamper adherence, and identification of nonadherence by caretakers and providers can be challenging. Antipsychotic side effects such as EPS, weight gain, sexual dysfunction, substance use, and negative symptoms may all contribute to treatment nonadherence. For patients who have relapsed several times because of nonadherence have a history of dangerous behavior, or risk a significant loss of social or vocational gains when relapsed; treatment with long-acting injection (LAI) should be encouraged. However, more recent data suggest that both FGA and SGA LAIs are more effective at reducing rehospitalization risk compared to oral treatment,33 and thus may be considered for all patients as a routine treatment option. The new APA guidelines8 recommend LAI to patients who are interested in this delivery. Risperidone, paliperidone, olanzapine, and aripiprazole are available as LAIs. In general, oral tolerability of these agents should be ensured prior to initiating most of the LAIs. In recent years, many new SGA formulations have become available offering more flexibility with longer dosing intervals and easier loading strategies. Dosing and other information about these formulations are shown in Table 38–5. LAIs should be introduced early to patients as an option to improve efficacy and not just reserved for patients with lack of adherence to other treatments.

Special Populations

▶ Dosing in Renal and Hepatic Impairment

Table 38–7 shows dosing guidance on specific antipsychotic medications.

▶ Children and Adolescents

Around 10% to 30% of patients with schizophrenia have psychotic symptoms before their 18th birthday. The diagnosis of schizophrenia in children and adolescents is often challenging, and the differential diagnosis includes autistic spectrum disorders, attention-deficit/hyperactivity disorder, and language or communication disorders. The existence of prominent hallucinations or delusions helps make the diagnosis because they are not prominent in other disorders. Children and adolescents developing schizophrenia before age 18 years have premorbid abnormalities such as withdrawal, odd traits, and isolation. Treatment for psychotic children and adolescents ideally is intensive, comprehensive, and structured. Early intervention in psychosis services such as NAVIGATE should be employed in first-episode schizophrenia.34 Pharmacologic treatment is indicated if psychotic symptoms cause significant impairments or interfere with other interventions. Children and adolescents are more vulnerable to EPS, particularly dystonias, than adults. Because of concerns about EPS and TD in children and adolescents, it is recommended that antipsychotic therapy be initiated with SGAs.

Aripiprazole, risperidone, quetiapine, olanzapine, paliperidone, and lurasidone are approved by the FDA for the treatment of schizophrenia in adolescent patients. Initiation and target doses are lower for adolescents than adults.

Agents with significant sedative and anticholinergic side effects are not preferred because they can interfere with school performance. Compared with adults, children and adolescents tend to gain more weight when taking these agents.

▶ Elderly

Psychotic symptoms in late life (after 65 years of age) generally result from an ongoing chronic illness; however, a small percentage of patients develop psychotic symptoms de novo, defined as late-life schizophrenia. Other illnesses with psychotic symptoms are common in this population; approximately one-third of patients with Alzheimer disease, Parkinson disease, and vascular dementia experience psychotic symptoms.

Antipsychotics can be safe and effective for the treatment of schizophrenia in the elderly, if used at lower doses than those commonly used in younger adults. Older adults are particularly vulnerable to the side effects of the FGAs, and TD risk is over threefold risk in elderly patients.17

Orthostasis, estimated to occur in 5% to 30% of elderly patients, is a major contributing factor to falls that often lead to injuries and loss of independence. Low-potency antipsychotics and clozapine are more likely to cause significant orthostasis. Antipsychotics may cause or worsen anticholinergic effects, including constipation, dry mouth, urinary retention, and cognitive impairment. Greater antipsychotic-associated impairment in cognitive functioning may occur in the elderly compared to younger adults. In the elderly, this can lead to decreased independence, a very problematic issue. As a result of data showing a statistically significant increase in elderly dementia patients taking SGAs, a black box warning was added to the manufacturer’s information for all antipsychotics. Patients and families should be informed of this risk before using these agents in patients with dementia. Dosing in the elderly is initiated lower, and titration is slower than in younger adults. Maximum doses are often half of adult doses (see Table 38–7).

▶ Co-Occurring Substance Use Disorder

Alcohol and illicit drug use is about threefold higher in schizophrenia than the general population.5 In addition, nicotine use (most frequently, smoking tobacco) is highly prevalent in persons with schizophrenia, with rates at 58% to 90%. The most common drugs of abuse besides nicotine are cannabis, cocaine, and alcohol. Substance use often worsens the clinical course and complicates treatment. People with schizophrenia and substance use disorders are more likely to be nonadherent with treatment. They may have a poorer response rate to the FGAs, more severe psychosis, and higher rates of relapse and rehospitalization than people without co-occurring disorders. EPS may occur more frequently in substance-using patients, and alcohol use is a risk factor for developing TD. It is important to incorporate a dual treatment approach for substance use disorders and schizophrenia with nonpharmacologic and pharmacologic treatments.35

▶ Treatment-Resistant Schizophrenia

For 20% to 30% of people with schizophrenia, first-line antipsychotic treatment is ineffective, and another 30% of people have a partial treatment response.29 A consensus guideline defines treatment-resistant schizophrenia (TRS) as (a) moderately severe

Second-Generation Antipsychotic Dosing Recommendations for Special Populations

MedicationPediatric Geriatric Renal Impairment Hepatic

Aripiprazole Oral: Ages 13–17 years (schizophrenia): Initiate 2 mg every day, increasing to 5 mg daily after 2 days and target of 10 mg after several days, 30 mg/day maximum

AsenapineNo pediatric FDA indication for schizophrenia (bipolar I indication only)

BrexpiprazoleNo pediatric FDA indication

Long-acting injection: in general, dose selection should be cautious.

Oral: No adjustment recommended

No adjustment necessary based on age alone

Experience is limited; low-dose initiation, up to 3 mg/day kinetics similar to adults with MDD in safety/tolerability trial

CariprazineNo pediatric FDA indication

ClozapineNo pediatric FDA indication

IloperidoneNo pediatric FDA indication

Pharmacogenomic Considerations

No adjustment required for oral or LAINo adjustment required for oral or LAI 2D6 poor metabolizers: administer half of usual dose

No adjustments necessary No adjustment necessary for mildto-moderate impairment, but use contraindicated in severe impairment

CrCl < 60 mL/min (1.0 mL/s): maximum 3 mg Moderate to severe: Maximum 3 mg2D6 poor metabolizers: Administer half of usual dose

Experience is limited; lowdose initiation CrCl < 30 mL/min (0.50 mL/s): not recommended Mild to moderate: No adjustment required; severe: not recommended

Experience is limited; low dose and slow titration

Not sufficient information for recommendation

LumateperoneNo pediatric FDA indication Not sufficient information for recommendation. Studies did not include any patients aged 65 or older

LurasidoneAges 13–17 years (schizophrenia): Initial dose, 40 mg/day with target dose of 40–80 mg/day

OlanzapineOral: Ages 13–17 years (schizophrenia):

Initial dose, 2.5–5 mg orally every day with target dose of 10 mg/day; maximum dose, 20 mg/day

Long-acting injection: Not approved in children

Unknown if necessary to modify based on age alone

Adjustments may be necessary with significant impairment; no specific recommendations available

Adjustments may be necessary with significant impairment; no specific recommendations available

No adjustment information provided, but unlikely necessary No adjustment needed for mild impairment; exercise caution with moderate impairment; not recommended for severe impairment

No recommendations listed Not recommended for moderate-tosevere impairment

With moderate-to-severe renal impairment, recommended starting dose 20 mg daily; do not exceed 80 mg daily

With moderate impairment, initial dose 20 mg daily; maximum dose 80 mg daily

With severe impairment, initial dose 20 mg daily, maximum dose 40 mg daily

Dose reductions may be necessary in 2D6 poor metabolizers

Dose reduced by one-half in 2D6 poor metabolizers

Oral: 5 mg/day, if escalation needed use caution Long-acting injection: Consider starting dose of 150 mg every 4 weeks for elderly or debilitated patients

Oral: In renal impairment, no adjustment usually necessary; however, consider a lower initial dose of 5 mg/day

Long-acting injection: No information given

Oral: No dosage adjustment noted in prescribing information except in combination with fluoxetine Long-acting injection: No information given

Second-Generation Antipsychotic Dosing Recommendations for Special Populations

MedicationPediatric Geriatric Renal Impairment Hepatic

PaliperidoneOral: Ages 12–17 years (schizophrenia): Dose by body weight: < 51 kg, initiate 3 mg/day oral, increase at increments of > 5 days; maximum, 6 mg/day At least 51 kg, initiate at 3 mg/day, increase at increments of > 5 days, maximum of 12 mg/day

Long-acting injection: adjust dose based on renal function

Oral: For patients with normal renal function, no adjustment is required, but if renal impairment guidance is available

Long-acting injection: CrCl 50–79 mL/ min (0.83–1.32 mL/s); initiate with 156 mg IM day 1, 117 mg IM 1 week later, with maintenance at 78 mg IM monthly CrCl < 50 mL/min (0.83 mL/s): Use not recommended

Oral: CrCl 50–79 mL/min (0.83–1.32 mL/s): 3 mg once daily initiation, maximum 6 mg/day

CrCl between 10 and 49 mL/min (0.17–0.82 mL/s): 1.5 mg once daily initiation; maximum, 3 mg/day CrCl < 10 mL/min (0.17 mL/s): Use not recommended

Long-acting injection: No dosage adjustment needed for mild or moderate impairment; no guidance given for severe impairment

Oral: No dose adjustment is required for mild or moderate impairment

Pharmacogenomic Considerations

QuetiapineRegular-release tablets: Indicated for schizophrenia (ages 13–17 years): Initiate 25 mg twice daily; recommended target dose 400–800 mg/day; maximum 800 mg/day

Extended-release tablets: Initiate 50 mg/day; recommended target dose 400–800 mg

RisperidoneOral: Pediatric ages 13 years and older (schizophrenia): Initiate at 0.5 mg orally daily, adjusting at intervals of at least 24 hours and in increments of 0.5–1 mg/day as tolerated Recommended target dose 3 mg/day

Regular-release tablets: Slower dose escalation and a lower target dose

Extended-release tablets: Initiate at 50 mg/day and increase at 50-mg/ day increments based on response or tolerance

Long-acting IM: Initial dose, 25 mg IM every 2 weeks with a 3-week oral crossover; may consider 12.5 mg as starting dose

Oral: Initiate at 0.5 mg twice daily; may increase by 0.5 mg twice daily, increases above 1.5 mg twice daily done at intervals of at least 1 week

No dosing recommendations for renal dysfunction

Regular-release tablets: Lower starting dose (25 mg) and slower titration may be needed

Extended-release tablets: Should be initiated with 50 mg/ day, increasing in 50-mg/day increments

Long-acting IM: Patients with renal impairment should receive titrated doses of oral risperidone before initiation of IM (more detail in prescribing information)

Oral: Recommended initial dose in CrCl < 30 mL/min (0.50 mL/s), 0.5 mg twice daily; dose may be increased by 0.5 mg twice daily, but increases above 1.5 mg twice daily should be done at intervals of at least 1 week. Clearance of risperidone is decreased by 60% in patients with moderate-tosevere renal disease (CrCl < 60 mL/min [1.0 mL/s])

Long-acting IM: Titrate with oral risperidone (see renal dosing)

Oral: Recommended initiation in Child-Pugh Class C (see renal dosing)

ZiprasidoneNo pediatric FDA indication No official adjustment recommended; consider starting at lower end of the dosage range

Oral doses: No adjustment necessary for mild-to-moderate renal impairment

IM doses: Use with caution because of cyclodextrin sodium excipient

CrCl, creatinine clearance; FDA, Food and Drug Administration; IM, intramuscular; MDD, major depressive disorder.

No adjustment necessary for mildto-moderate hepatic impairment; however, caution is warranted

illness as defined by rating instruments with a persistence of at least 5 years, (b) moderate or worse functional impairment, (c) treatment with at least two different antipsychotics given at adequate doses (a dose equivalent to at least 600 mg of chlorpromazine) for an adequate duration (6 weeks), (d) meeting minimum criteria of being adherent to current treatment, and (e) ideally having one prospective antipsychotic trial.36

Clozapine Clozapine is the only antipsychotic with proven superior efficacy and approved by the FDA for TRS.16 It is efficacious after nonresponse to other SGAs, in partially responsive patients and patients who have had a poor response to other medication for years. According to published guidelines and recommendations, clozapine should be considered after two failed antipsychotic trials,10,28,30 but may be considered sooner if the individual patient situation warrants.8,29 Additionally, it is FDA approved for reducing the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder37 and recommended for those with a substantial risk of aggression.8

It remains unknown which pharmacologic properties account for clozapine’s superior efficacy. Clozapine interacts with a multitude of receptors but notably has a low affinity for and rapid

Table 38–8

dissociation from D2 receptors, antagonism of D1 receptors, and is a 5-HT2A antagonist.

Clozapine’s use is limited by the regulatory requirements resulting from the risk for severe neutropenia (ANC < 0.5 × 109/L [or 0.5 × 103/mm3], was termed agranulocytosis previously). This is a rare but potentially life-threatening side effect occurring in less than 1% of people treated and is a “black box” warning for the medication. The required long-term hematologic monitoring (Table 38–8) can be a barrier for both patients and care providers. Other rare side effects include seizures, myocarditis, and cardiomyopathy (also “black box” warnings). Orthostatic hypotension, bradycardia, and syncope are also “black box” warning for clozapine. Common unpleasant side effects include sedation, dizziness, constipation, enuresis, weight gain, and hypersalivation.

Registration for clozapine must first occur prior to dispensing using a Clozapine REMS website. APA guidelines recognize the underuse of this medication and encourage its more widespread acceptance.8

The optimal plasma level of clozapine is a minimum trough level of 918 to 1071 nmol/L (300–350 ng/mL or mcg/L), usually corresponding to a daily dose of 200 to 400 mg, although dosage

Monitoring of Absolute Neutrophil Count During Clozapine Treatment

General Population

Initiation to 6 monthsInitiate if ANC ≥ 1.5 × 109/L; weekly monitoring for 6 months as long as ANC remain ≥ 1.5 × 109/L

6–12 monthsEvery 2-week monitoring for 6 months as long as ANC levels remain ≥ 1.5 × 109/L

After 12 months of therapy Every 4-week monitoring as long as ANC levels remain ≥ 1.5 × 109/L

ANC 1.0–1.49 × 109/L Mild neutropenia (general population) 1.0 to 1.49 × 109/L (confirm with repeat ANC within 24 hours)

Recommendation to continue treatment Monitor ANC three times weekly until ANC ≥ 1.5 × 109/L, then return to patient’s last normal range monitoring interval if appropriate

BEN Population

Initiate if ANC ≥ 1.0 × 109/L (obtain at least 2 baseline levels); weekly monitoring for 6 months if ANC remain ≥ 1.0 × 109/L

Every 2-week monitoring for 6 months as long as ANC remain ≥ 1.0 × 109/L

Every 4-week monitoring as long as ANC levels remain ≥ 1.0 × 109/L

These ANC levels considered normal for BEN population, continue monitoring as generally indicated above

ANC 0.5–0.99 × 109/L

Moderate neutropenia (general population)

ANC 0.5–0.99 × 109/L (confirm with repeat ANC within 24 hours)

Recommend hematology consult; interrupt treatment if clozapine-induced neutropenia is suspected. Resume treatment once ANC is ≥ 1.0 × 109/L

Monitor ANC daily until ANC ≥ 1.0 × 109/L, then three times weekly until ANC ≥ 1.5 × 109/L, then check weekly × 4 weeks, then return to patient’s last normal range ANC interval, if appropriate

BEN neutropenia

0.5–0.99 × 109/L (confirm with repeat ANC within 24 hours)

Recommend hematology consult

Continue treatment

Monitor ANC thrice weekly until ANC ≥ 1.0 × 109/L or up to patient’s known baseline

Once at ANC ≥ 1.0 × 109/L or patient’s known baseline, check ANC weekly for 4 weeks, then return to patient’s last normal BEN range ANC monitoring interval, if appropriate

ANC < 0.5 × 109/L

Severe neutropenia (general population)

Daily ANC until ANC ≥ 1.0 × 109/L, then three times weekly until ANC ≥ 1.5 × 109/L

Recommend hematology consultation

Interrupt treatment for suspected clozapine-induced neutropenia; no rechallenge unless benefits > risks

If patient is rechallenged, resume treatment as a new patient under “normal range” monitoring once ANC ≥ 1.5 × 109/L

BEN severe neutropenia

Daily ANC until ≥ 0.5 × 109/L, then thrice weekly until ANC ≥ patient’s baseline

Recommend hematology consultation

Interrupt treatment for suspected clozapine-induced neutropenia. Do not rechallenge unless benefit > risk. If patient is rechallenged, resume treatment as a patient under normal range monitoring once ANC ≥1.0 × 109/L or at patient’s baseline

Whenever clozapine is discontinued

Weekly for at least 4 weeks from day of discontinuationWeekly for at least 4 weeks from day of discontinuation

ANC, absolute neutrophil count (109/L is equivalent to 103/mm3); BEN, benign ethnic neutropenia.

must be individualized. Males and smokers tend to require higher doses to achieve the targeted blood level due to more rapid metabolism.

▶ Acutely Psychotic and Agitated Patients

Psychiatric emergencies occur in emergency departments, psychiatric units, medical facilities, and outpatient settings. Although nonpharmacologic interventions such as relaxation techniques and decreasing sensory stimulation are most ideal for initial management, acutely psychotic and agitated patients also require pharmacologic interventions. Short-acting, intramuscular (IM) formulations are available for a number of FGAs (haloperidol most frequently) as well as the SGAs (ziprasidone and olanzapine). IM benzodiazepines are commonly used in addition to IM antipsychotics. IM lorazepam is generally suggested as it is the only benzodiazepine with rapid and complete IM absorption. Concomitant IM olanzapine and benzodiazepines may cause cardiorespiratory depression and should be avoided if possible. Loxapine oral inhalation is also available for acute agitation but is restricted to a REMS program and to enrolled healthcare facilities with onsite equipment and personnel to handle bronchospasm.

▶ Pregnancy and Lactation

Women with schizophrenia have higher rates of unwanted pregnancies and obstetric complications (eg, stillbirth, infant death, preterm delivery, low infant birth weight, and infants who are small for gestational age). Prolactin-related effects secondary to certain FGA and SGA treatments have led to infertility in the past. Irregular menstruation also complicates the ability to plan for pregnancies and potential false protection with sexual activity. When pregnancy occurs, the management of pregnancy and lactation in females with schizophrenia should include a multidisciplinary team and the patient’s family should be involved if possible. The decision to continue antipsychotic must be weighed by the risks and benefits. The fetus is at risk for antipsychotic side effects, but also the risk of relapse with schizophrenia during pregnancy is associated with a higher risk of birth complications. Guidelines suggest that antipsychotics are increasingly being used in pregnancy. Older data suggested teratogenic effects; however, larger and more recent epidemiologic studies find the majority of antipsychotics to be associated with no greater risk. Patients should still be cautioned that while the risk

Patient Encounter, Part 4

The patient’s olanzapine dose was maintained at 10 mg once daily for the next 3 months. She returned again for follow-up with her outpatient psychiatrist who noted the patient’s symptoms were responding very well. The patient also stated she was very pleased with her treatment, and the pseudoparkinsonism symptoms were resolved. She again brought up the idea of returning to school. She really wants to go back to school but is worried about her friends seeing her take medications for a mental illness and feels uncomfortable about it. Her mother is afraid that if she goes back to school, she may not take the olanzapine. The physician suggests that the patient consider getting “a shot” of olanzapine once a month, then she would not need to take a pill every day. The patient’s mother readily agrees that this is a reasonable solution. The patient is initially reluctant to get “a shot” but

is low, congenital malformations have occurred rarely. There is now more published safety data with SGAs than FGAs. The safety data for FGAs is primarily for haloperidol. Low-potency phenothiazines may increase the risk of congenital abnormalities when used in the first trimester. There is some evidence to suggest a higher risk of congenital malformations with risperidone; however, this risk difference is only slightly higher at 5% versus 3% in the general population comparative group. If pregnancy occurs during antipsychotic treatment, continuation of previous antipsychotic is preferred to decrease relapse risk. Data suggest that mothers who are pregnant have about a twofold risk of developing gestational diabetes; thus, monitoring and promoting healthy eating is very important. Babies born to mothers taking SGAs may also have increased birth weights compared to nonexposed mothers.35,38 A labeling change for antipsychotic medications has been implemented by the FDA to address the potential risk for EPS and symptoms of withdrawal in newborns whose mothers were treated with antipsychotics in the third trimester. Withdrawal symptoms may include agitation, abnormal muscle tone (increased or decreased), tremor, sleepiness, and difficulty in breathing or feeding, which may last for hours to days after delivery. In some newborns, specific treatment for withdrawal is not needed, whereas in others, longer hospital stays may be required. Although SGAs are excreted in breast milk, most case reports document a low frequency of deleterious effects on the infant. Breast-feeding while on clozapine should be avoided.35,38

Pharmacokinetics and Drug Interactions

Most antipsychotics are, at least to some extent, metabolized by hepatic cytochrome P450 (CYP450) metabolic enzymes to water-soluble compounds that are excreted by the kidneys (Table 38–9).39 Unlike other antipsychotics, ziprasidone is mostly metabolized by aldehyde oxidase, a metabolic system independent of the CYP450 system. Paliperidone, the 9-OH metabolite of risperidone, is mostly excreted unchanged in the urine, although up to one-third may be metabolized. The transmembrane energydependent efflux transporter P-glycoprotein may limit the ability of drugs to penetrate the blood–brain barrier and therefore impact pharmacologic activity in the brain. Antipsychotics currently known to use this pathway include perphenazine, haloperidol, fluphenazine, quetiapine, risperidone, paliperidone, aripiprazole, and olanzapine.40

finally agrees, as she also does not want to get into power struggles with her mother about whether or not she is taking her medication.

The patient receives the loading dose of olanzapine and moves back to school. She sees a provider at the school’s health clinic to receive her monthly injection. She remains stable on the long-acting intramuscular form of olanzapine. How would a clinician discuss the advantages of taking a longacting intramuscular medication?

What dose of olanzapine long-acting injection (Zyprexa Relprevv) is appropriate for someone taking oral olanzapine 10 mg once daily?

What side effects can occur and what monitoring is required with olanzapine injection?

Table 38–9

Metabolism and Drug Interactions With Antipsychotics

AntipsychoticMajor Metabolic Pathways

Other Metabolic Pathways

Increase Antipsychotic Concentrations Decrease Antipsychotic Concentrations

CYP2D6 Fluvoxamine, ketoconazoleCarbamazepine AsenapineGlucuronidation by UGT1A4 and CYP1A2 CYP3A4, CYP2D6Fluvoxamine

AripiprazoleCYP3A4

BrexpiprazoleCYP3A4, 2D6

Itraconazole, clarithromycin, ketoconazole, quinidine, paroxetine, fluoxetine

Rifampin, St. John’s wort

CariprazineCYP3A4 CYP2D6 Itraconazole, ketoconazoleRifampin, carbamazepine (use not recommended with strong CYP3A4 inducer)

ChlorpromazineCYP2D6 CYP1A2, CYP3A4

ClozapineCYP1A2 CYP3A4, CYP2D6, CYP2C19, CYP2C9

Fluvoxamine, ciprofloxacin, paroxetine Cigarette smoking

FluphenazineCYP2D6 Paroxetine

HaloperidolCYP2D6, CYP3A4 CYP1A2 Fluvoxamine, fluoxetine, ketoconazole Carbamazepine

IloperidoneCYP2D6, CYP3A4 CYP1A2, CYP2E1Ketoconazole, fluoxetine, paroxetine

LoxapineCYP1A2, CYP2D6, CYP3A4

LumateperoneCYP3A4, UGT 1A1, 1A4, and 2B15 AKR 1C1, 1B10, and 1C4 CYP2C8, CYP1A2

Moderate or strong CYP3A4 inhibitors, UGT inhibitors (valproic acid)

CYP3A4 inducers (carbamazepine)

LurasidoneCYP3A4 Ketoconazole, diltiazemRifampin

OlanzapineCYP1A2, glucuronidation by UGT1A4 CYP2D6 Fluvoxamine, ciprofloxacin, paroxetine Cigarette smoking

PaliperidoneCYP2D6, CYP3A4 (in vitro, but limited role in vivo) Divalproex sodium, paroxetineCarbamazepine (via increased renal elimination)

PerphenazineCYP2D6 Fluvoxamine, fluoxetine, paroxetine

PimozideCYP3A4 CYP1A2, CYP2D6Strong CYP2D6 inhibitors, CYP3A4 inhibitors CYP3A4 inducers

QuetiapineCYP3A4 CYP2D6 Fluvoxamine, ketoconazoleCarbamazepine

RisperidoneCYP2D6 CYP3A4 Fluoxetine, paroxetineCarbamazepine

ThioridazineCYP2D6 CYP2C19 Fluvoxamine Cigarette smoking

ThiothixeneCYP1A2

CYP1A2 inhibitors CYP1A2 inducers

TrifluoperazineCYP1A2 CYP1A2 inhibitors CYP1A2 inducers

ZiprasidoneAldehyde oxidase CYP1A2, CYP3A4Fluvoxamine, ketoconazoleCarbamazepine

AKR, aldoketoreductase; CYP450, cytochrome P450 isoenzyme; UGT, uridine 5’-diphospho-glucuronosyltransferase.

Additive side effects may occur with combined drug therapies, and a few clinically significant drug interactions are notable (see Table 38–9). Cigarette smoking decreases serum concentrations of clozapine and olanzapine by induction of CYP1A2. Although antipsychotics are highly protein bound, protein-binding interactions are generally not clinically significant. Absorption of most antipsychotics is not affected by food, with the exception of lumateperone, lurasidone, and ziprasidone. The mean maximum concentration of lurasidone increases threefold when administered with food, and ziprasidone’s absorption is increased by 60% to 70% when given with meals. Ingesting a high-fat meal with lumateperone increases the mean area under the curve (AUC) by 9%. Caloric intake of 500 calories (2100 J) is recommended with ziprasidone and 350 calories (1500 J) with lurasidone.

Among SGAs, ziprasidone, iloperidone, and quetiapine have potential to prolong the QTc interval. Using them with other agents that prolong the QTc interval should be undertaken with caution. These other agents include, but are not limited to, quinidine, sotalol, chlorpromazine, droperidol, mesoridazine, pimozide, thioridazine, mefloquine, moxifloxacin, and pentamidine. Combining higher doses of ziprasidone, iloperidone, or

quetiapine with ketoconazole or erythromycin should be undertaken cautiously.

Added pharmacodynamic effects are possible when combining antipsychotics with other drugs that can cause sedation, hypotension, anticholinergic symptoms, and weight gain or metabolic abnormalities.

Adjunct Treatments

The judicious use of pharmacologic therapies other than antipsychotics is often necessary for the treatment of motor side effects, anxiety, depression, mood elevation, and TRS that does not respond to clozapine. Anticholinergic medications (eg, benztropine, 1–2 mg twice daily; trihexyphenidyl, 1–3 mg thrice daily; and diphenhydramine, 25–50 mg twice daily) are used to treat EPS. They may be prescribed prophylactically with highD2-binding agents or in patients at risk for EPS or for treatment of EPS. β-Blockers (eg, propranolol 30–120 mg/day) are sometimes effective for patients who develop akathisia. In some situations, such as on an inpatient unit, the concomitant use of benzodiazepines (eg, lorazepam 1–3 mg/day) with the SGAs may be necessary for agitation.28

More recent guidelines suggest that regular assessment of depressive symptoms in schizophrenia is important and that waiting for the effect of antipsychotics to work instead of immediately adding an antidepressant is recommended. Evidence suggests that SGAs may be more effective than FGAs for depressive symptoms in people with schizophrenia; however, this evidence is limited.35 Antidepressants may be useful for patients with schizophrenia who have depressive symptoms in the stable phase of schizophrenia; however, these agents may have the potential to worsen symptoms in the acute phase.35 Because suicide risk may be increased, aggressive treatment may be necessary when depression is present. The selective serotonin reuptake inhibitors (SSRIs) are the preferred agents, but many (eg, fluoxetine, fluvoxamine, paroxetine, sertraline) may inhibit the CYP450 enzymes, thus potentially raising plasma concentrations of many antipsychotics. Mood stabilizers, such as lithium and the anticonvulsants, have been used adjunctively with the antipsychotics to treat the affective component of schizoaffective disorder.35 One antipsychotic, olanzapine, is marketed in combination with fluoxetine for bipolar disorder. For patients with an inadequate response to clozapine, limited treatment options are available for these patients. A number of augmentation strategies have been tried, including FGAs, SGAs, mood stabilizers (eg, lithium, valproate, and topiramate), minocycline, antidepressants, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT). Though controlled trial results are mixed, some data support the adjunctive use of risperidone, lamotrigine, or aripiprazole in clozapine-treated patients.29

Patient Education

Education of the patient and family regarding the benefits and risks of antipsychotic medications and the importance of treatment adherence must be ongoing and integrated into pharmacologic management. Medication management discussions offer an opportunity to provide illness and treatment education including the nature and course of schizophrenia and can serve as a time to hear the patient’s life goals. Key considerations include:

Patient Encounter, Part 5

The patient remained on olanzapine long-acting injection for several years and graduated from college, but eventually her paranoia returned and she felt agitated on the drug. Over the next several years, she was switched to various other agents including ziprasidone, aripiprazole, and asenapine, to which she only had a partial response. At her most recent outpatient appointment, the doctor suggested that she might benefit from a trial of clozapine, but the patient was not sure if clozapine was right for her. In a separate phone call to her mother, the doctor reviewed the pros and cons of the clozapine trial. The patient and her mother discussed everything they discussed with the doctor and agreed to a trial of clozapine.

Why is the clinician considering a clozapine trial? What are the rare serious side effects of clozapine versus the common manageable side effects?

The patient smokes cigarettes. How will cigarette smoking affect clozapine therapy?

Involve families in the education and treatment plans because family psychoeducation may decrease relapse, improve symptomatology, and enhance psychosocial and family outcomes.14

Be clear that there is no cure for schizophrenia and that medications can be effective in improving many symptoms. Explain common and rare but dangerous side effects. Stress the importance of medication and treatment adherence for improving long-term outcomes. Decision making on the best course of treatment should be a shared process. Shared decision making is a process where clinicians and patients work together to make treatment decisions based on clinical evidence. This process incorporates patient’s preference and values as well as risks and expected outcomes.

OUTCOME EVALUATION

Developing a good working alliance with the patient is essential. In the absence of a solid therapeutic relationship, patients are frequently reluctant to share their beliefs, personal experiences, and life goals.

Symptom Monitoring

Many assessments are available to objectively rate positive and negative symptoms, level of function, and life satisfaction. The most commonly used scales in clinical trials to measure symptoms include:

Positive and Negative Symptom Scale (PANSS)

Brief Psychiatric Rating Scale (BPRS)

Clinical Global Impression (CGI) Scale

Calgary Depression Scale for Schizophrenia (CDSS)

Using these scales on a regular basis, particularly when switching medications or changing doses, is a more reliable means of monitoring symptoms. Symptom assessments cannot capture the full range of possible improvements, but they can be useful in deciding whether a medication is having substantial benefit.

Side Effect Monitoring

Regularly monitor for side effects and overall health status.8,27,31 Perform orthostatic blood pressure measurements and vital sign assessments before initiating antipsychotics and regularly throughout treatment. Ask about prolactin-related side effects such as impaired menstruation, libido, and sexual performance regularly. At baseline, check body weight and height (to calculate body mass index [BMI]), screen for diabetes risk factors, and measure fasting glucose and lipid profile. BMI should be assessed at every visit for 6 months, and least quarterly thereafter. Lipid profile and either fasting glucose or hemoglobin A1C should be monitored at 4 months after initiating and at least annually thereafter. For patients at higher risk of developing diabetes and those who gain weight, check body weight more often. Every effort should be made to help with weight and metabolic side effects.6,41-43 Metformin may be an option in addition to nonpharmacologic techniques for weight loss or attenuation of weight gain.44

Additionally, perform baseline electrocardiography for patients with preexisting cardiovascular disease or risk for arrhythmia. With clozapine therapy, there is a risk for the development of severe neutropenia, which is greatest in the first 6 months of treatment. Required monitoring of absolute neutrophil count (ANC) is described in Table 38–8. Separate monitoring guidelines now

Patient Care Process

Collect Information:

Chief complaint and history of present illness.

Family history, psychiatric history (age when first diagnosed, time of first hospitalization for mental illness), medical history. Obtain collateral information from family, past medical records, and other providers to help clarify the psychiatric history.

Social history (housing arrangements, social and vocational goals, support systems, employment, substance use history). Physical examination. Key laboratory data and imaging studies. Mental status examination.

Past and current medications (psychiatric and somatic, prescription, nonprescription, herbal or other dietary supplements).

Assess the Information:

Review the patient ’s chief complaint, presenting symptoms, and history, including psychiatric history. Assess mental status examination for organization of thoughts and range of affect, presence of mood disturbance, likelihood of harm to self or others, and presence of hallucination, paranoia and/or delusions of control, evaluate judgment and insight.

Assess medical records, including laboratory and imaging studies, to rule out medical causes of psychosis.

Assess current treatments and outcomes of prior treatments for effectiveness and safety.

Assess adherence to medications and willingness to take medications.

Develop a Care Plan:

Identify medication-related problems. Determine the goals of therapy. Select or optimize the dose of an antipsychotic based on the side effect profile that is most appropriate and acceptable to the patient.

exist for general patients and those with benign ethnic neutropenia. Overall, encourage patients to have annual physical, gynecologic, and ophthalmologic examinations and regularly ask about physical health and side effects at each visit.

Commonly used rating scales to monitor for EPS include the Simpson–Angus Scale (SAS) and the Extrapyramidal Symptom Rating Scale (ESRS). Akathisia is commonly monitored by the Barnes Akathisia Scale (BAS). The emergence of dyskinesias could represent the emergence of TD. Monitor patients on SGAs for TD at least annually and patients taking FGAs at each visit. The most commonly used instrument to measure these symptoms is the Abnormal Involuntary Movement Scale (AIMS).

Abbreviations Introduced in This Chapter

5-HTSerotonin

ACTAssertive Community Treatment

Collaborate with other healthcare professionals or caregivers in the development of the plan.

Consider how income, insurance coverage, and access to care might influence pharmacotherapy choice.

Implement the Care Plan:

I nitiate, modify, discontinue, or administer the appropriate medication therapy.

Educate patient and caregiver (with patient consent) about the illness, medication treatments, possible side effects, and goals of treatment.

Discuss medication adherence and healthy lifestyle goals, including substance and cigarette use.

Enlist adjunctive treatments, including psychosocial therapies to optimize outcomes.

Coordinate referrals or transition of care to other healthcare professionals, such as social workers, home care nurses, or other medical specialists.

Recommend placement of individuals in ACT, group homes, transitional housing, rehabilitation, or long-term care.

Schedule follow-up appointments.

Follow-up: Monitor and Evaluate: Monitor medication therapy for effectiveness, using psychiatric rating scales when necessary.

Monitor medication therapy for adverse events of antipsychotics using the AIMS, Simpson–Angus Scale, and Extrapyramidal Symptom Rating Scale.

Monitor appropriate laboratory measures to prevent or minimize adverse effects, including metabolic abnormalities. Assess for emergence of new target symptoms. Monitor for adherence to the medication regimen.

Optimize dosing and consider clozapine if criteria are met for treatment resistance.

AIMSAbnormal Involuntary Movement Scale

ANCAbsolute neutrophil count

APAAmerican Psychiatric Association

BASBarnes Akathisia Scale

BPRSBrief Psychiatric Rating Scale

CATIEClinical Antipsychotics Trials of Intervention Effectiveness

CBTCognitive behavioral therapy

CGIClinical Global Impression Scale

CRCognitive remediation

CYP450Cytochrome P450 isoenzyme

DDopamine

DSM-5Diagnostic and Statistical Manual of Mental Disorders, 5th edition

ECTElectroconvulsive therapy

EPSExtrapyramidal symptoms

ESRSExtrapyramidal Symptom Rating Scale

FDAFood and Drug Administration

FGAFirst-generation antipsychotic

HHistamine

IMIntramuscular

LAILong-acting injection

MMuscarinic

NMDA N-methyl-d-aspartate

NMSNeuroleptic malignant syndrome

PANSSPositive and Negative Symptom Scale

PCPPhencyclidine

PORTSchizophrenia Patient Outcomes Research Team

QTcCorrected QT interval

SASSimpson–Angus Scale

SGASecond-generation antipsychotic

SSRISelective serotonin reuptake inhibitor

SSTSocial skills training

TDTardive dyskinesia

TIMATexas Implementation of Medication Algorithms

15. Lieberman JA, Stroup TS, McEvoy JP; The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in people with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–1223.

16.Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382: 951–962.

17.Cornett E, Novitch M, Kaye AD, Kata V, Kaye AM. Medication induced tardive dyskinesia: a review and update. Ocshner. 2017;17:162–174.

18.Schotte A, Janssen PF, Gommeren W, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology. 1996;124(1–2):57–73.

TMS

Treatment-resistant schizophrenia

TRS Transcranial magnetic stimulation

WBCWhite blood cell

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