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her. She states J.J. is often up late at night on her computer, which she says is to “look for traces of the

enemy spies.”

Medical History: J.J. has no significant medical or psychiatric history. She has never been hospitalized or

treated for any psychiatric condition in the past. Her roommate has known her since they started college

together 3 years ago, and they have been roommates for the past 2 years. The roommate says J.J. was

fairly normal—quiet and shy, getting good grades—until the unusual behavior started almost a year ago

after they returned from summer break. She says J.J.’s behavior has gotten increasingly unusual and

erratic since then.

Psychosocial History: A call to J.J.’s mother finds that her father has a history of alcoholism and domestic

violence which led to their divorce when J.J. was 14. J.J.’s paternal uncle has been diagnosed with

schizophrenia and has been hospitalized multiple times over his lifetime. J.J.’s mother says she has always

been a very good student, but not very social when in high school, tending to isolate from her classmates.

She screamed at them one day in schoolsaying she would defend herself if they carried out their plans and

the police were called. No charges were filed and J.J. was entered into the school’s anger management

program, to which she never showed up. J.J.’s roommate states she only drinks socially at occasional

parties and denies any illicit substance abuse.

Physical Examination/Laboratory Tests: J.J.’s physical examination shows no significant or contributory

findings other than some bruising on her knuckles from punching the walls. J.J. states this is from “fighting

off the FBI agents” when they find her. Laboratory tests, including complete blood count (CBC), SMA-28

panel, and liver and thyroid function tests, all return normal. A urine drug screen returns all negative

results. No other tests were ordered.

Mental Status Exam: Appearance and Behavior: J.J. is a tall, average build, neat but casually dressed

young woman who appears her stated age. She shows signs of paranoia and agitation as she is constantly

looking around the room and pacing. She constantly asks to be released “before they find me.” Mood: J.J.

is anxious and concerned that the “FBI will find me” and prevent her from completing her mission. Affect

is animated due to his level of agitation. She does not report any depressive ideation. Memory: Long-term

memory appears to be intact (confirmed by roommate) but patient will not cooperate with recall tests of

immediate- and short-term memory as “this is a waste of time and I need to be released.” Orientation: J.J.

is oriented to person, place, time, and situation. Thought Content: J.J. is fixated on needing to leave in order

to complete her mission. She is convinced the longer she stays the more likely the FBI will find her here

and she will “need to fight my way out.” She also states she is trying to use her implanted transmitter to

read the thoughts of the people in the room. She denies any suicidal or homicidal ideation. She accuses you

of keeping her there to help the FBI. Thought Process: J.J.’s speech is highly disorganized such that she

can be difficult to comprehend. Perception: J.J. is clearly responding to internal stimuli and most likely

auditory hallucinations. She also keeps asking the staff whether something is burning and where the smell

is coming from. Insight and Judgment: J.J. has poor insight into her symptoms and mental state, and will

most likely require inpatient hospitalization for psychosis.

Provisional diagnosis: psychotic episode, most likely due to schizophrenia.

What hallmark symptoms of schizophrenia is J.J. presenting with at this time? How might these symptoms be

used in monitoring treatment?

J.J. currently presents with a number of hallmark symptoms of schizophrenia. She

has olfactory as well as auditory hallucinations (hearing her CIA supervisor and

others), delusions (she works for the CIA and the FBI is after her, having a

transmitter in her head), and magical thinking (she can read people’s thoughts). She

shows conceptual disorganization in her speech. She is also agitated and

uncooperative, and has acted out on her delusions by getting into arguments with

people she feels are from the FBI. These symptoms should begin to decrease and

subside with time as effective medication treatment is utilized, allowing us to

determine whether J.J. is responding appropriately.

CASE 85-1, QUESTION 2: What information from J.J.’s history also contributes to a diagnosis of

schizophrenia? What is the prognosis for J.J.?

Although J.J. has had no previous psychiatric treatment, she is in the age range for

an initial psychotic episode of schizophrenia (late teens to mid-20s). J.J. has been

showing increasingly unusual behavior for over 6 months, and possibly up to a year

according to her roommate, with more drastic changes more recently. Prior to this,

J.J. did show some prodromal symptoms, most notably some difficulty interacting

with peers while in high school and isolating herself. There is also a family history

of schizophrenia (paternal uncle) and alcoholism (father). J.J.’s prognosis is

variable, because her young age of onset, family history of schizophrenia, and

unstable home environment at a young age indicate a poor prognosis, but her

relatively high baseline functioning and intelligence (she did very well in high school

and is currently in college) would increase the chances for a better long-term

outcome. As J.J. is early in her illness, it will take time to better determine her longterm prognosis more clearly.

Typical Course of the Illness and Prognosis

The course of schizophrenia can vary between individuals. However, a common

pattern entails a premorbid phase with possible signs of cognitive, motor, and social

deficits in childhood at 12 years old or under, a prodromal phase during adolescence

and young adulthood (12–18 years old) including a functional decline with brief or

attenuated positive symptoms, and then an active phase which includes florid

positive symptoms as part of psychosis.

20,38 An improved prognosis is associated

with female gender, a preponderance of positive and mood symptoms versus negative

symptoms, rapid onset of symptoms, older age at symptom onset, and high premorbid

functioning.

39,40

Generally, the negative (or deficit) and cognitive symptoms of schizophrenia

predominate earlier in the development of the disorder. Florid positive symptoms

usually emerge between 18 to 25 years of age in men and 20 to 30 years of age in

women.

22 During the prodromal phase, patients may show what resembles negative

symptoms: blunted affect, decreased motivation and energy, social withdrawal, and

others. Cognitive symptoms may also present, such as poor concentration and

memory, which may manifest as declining school or work performance. Low-level

positive symptoms may also be seen, mostly in the form of disorganized thinking.

Other symptoms such as depression, anxiety, or irritability may also present. Often

these symptoms will go unrecognized in adolescents and be mistaken for anything

from puberty, relationship problems, or drug abuse. This phase may last from weeks

to years and often is not attributed to schizophrenia until the first psychotic episode.

In many instances, patients will convert to a full schizophrenia diagnosis with more

significant positive symptoms and go months or more before receiving

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treatment. This delay may affect the long-term prognosis of the illness as early

treatment can decrease later morbidity as response to treatment in first-episode

schizophrenia in critical.

41

After an active phase of schizophrenia, which can last a large part of adulthood,

patients usually enter a residual phase of chronic disability. Later in this phase,

symptoms may become somewhat similar to the prodromal phase. As the disease

progresses, residual symptoms may increase between episodes and make normal

day-to-day functioning difficult. As the patient ages, the medical complications of

schizophrenia, treatment-emergent metabolic syndrome, and effects of tobacco use

increasingly take hold.

38 Patients with schizophrenia have a life expectancy 9 to 10

years shorter (or more by some estimates) than the average population.

42 The disease

often becomes characterized by a preponderance of negative symptoms and cognitive

deficits in those living into the later years.

27 However, with early intervention and

support, many patients can achieve symptom control and lead meaningful and

fulfilling lives.

TREATMENT

Schizophrenia is generally considered a chronic, lifelong illness consisting of

varying periods of illness severity, with resulting effects on patient functionality.

Although pharmacotherapy can have positive effects on reducing symptoms of the

illness and improving functionality, there are often symptoms that may not respond

adequately to treatment. In addition, despite adequate treatment, patients may have

relapses of their illness, leading to acute psychotic episodes needing more intensive

treatment. Treatment is therefore usually lifelong and is often multidisciplinary in its

approach, consisting of pharmacotherapy, psychosocial therapy, case management,

and other methods.

Goals of Treatment

The overall goal for the treatment of schizophrenia is to reduce the symptoms of the

illness in order to improve patient functionality and quality of life. Depending upon

the patient’s current level of acuity, the specific goals for the patient at that time may

vary. Although similar pharmacotherapy and nonpharmacotherapy methods may be

employed across the spectrum of severity of schizophrenia, they may be utilized

differently. Patients are generally described as being in one of three treatment phases

according to the American Psychiatric Association: acute, stabilization, and stable.

27

These phases are not static, and patients can move between these phases frequently

over the course of their illness.

ACUTE PHASE

The primary goal of treatment in the acute phase of illness is to reduce the threat of

harm to the patient or others. Patients experiencing acute psychosis will present with

prominent positive symptoms and exhibit disorganized speech and/or behaviors.

Negative symptoms and suicidal ideation may also be more pronounced and severe.

This will often require a higher level of care than the outpatient setting can provide

and necessitate inpatient psychiatric hospitalization where the patient is stabilized.

Medications, including short-acting injectable antipsychotics and benzodiazepines,

are usually required to target agitation in acute psychosis. However, psychosocial

interventions and collaboration with family and caregivers for collateral information

are also crucial in this phase of illness.

43 Antipsychotic should be initiated as soon as

clinically possible to decrease duration of untreated psychosis and improve longterm prognosis.

44

The reason for psychiatric decompensation should be ascertained through patient

report and collateral information (e.g., caregiver insight, pharmacy fill records).

Schizophrenia has a variable course. Exacerbations can occur even on a therapeutic

regimen in the context of psychosocial stressors, illicit substance use, and other

reasons. However, if the exacerbation was due to nonadherence, the reasons should

be explored with the patient. If the patient was nonadherent due to intolerable

adverse effects, a lower dose or alternative medication could be considered. If

difficulty remembering to take medication was the issue, a long-acting injectable

formulation could be considered. In either scenario, the decision to initiate or change

the antipsychotic should be based on patient preference, prior history of response,

tolerability, and relevant medical comorbidities.

STABILIZATION PHASE

The aim during the stabilization phase is to promote continued recovery, maintain

symptom control, begin facilitating referrals for supportive outpatient services, and

reduce adverse effects and likelihood of future relapse. The patient and involved

caregivers should be educated on the timeline of symptom response, possible

medication adverse effects and their management, importance of adherence, and

recognizing early signs of symptom recurrence. Risk for relapse is highest within the

first 6 months post initial psychotic episode. Therefore, medications should be

maintained for at least 6 months at the dose found to be effective in reducing positive

symptoms during the acute phase.

45 Patients and caregivers should be counseled that

partial response, such as decreased volume, intensity, or frequency of auditory

hallucinations, should not be considered a failure of treatment. Residual symptoms

can persist beyond the acute and stabilization phases, but may remit with maintenance

treatment.

STABLE PHASE

The main focus of the stable phase is quality of life and functional recovery. This is

achieved through ensuring optimized treatment of symptoms, minimizing risk of

adverse effects, and psychosocial interventions. The question of how long

antipsychotics need to be continued is often raised by patients. Antipsychotics have

been shown to significantly reduce rates of relapse at one year versus placebo.

46

Therefore, maintenance antipsychotic treatment should be continued for at least one

year in all patients recovering from a psychotic episode. Caveats to this include

intolerable adverse effects to the antipsychotic or uncertainty of the diagnosis of

schizophrenia. Lifelong treatment is recommended in patients who have experienced

multiple episodes of psychosis, at least two episodes within 5 years, or those who

pose a significant risk to themselves or others when symptoms are left untreated. A

slow, cautious taper off antipsychotics can be considered after one year in firstepisode patients with close follow-up established.

45 Routine monitoring for adverse

effects, especially EPS and metabolic syndrome, is recommended during the stable

phase. Patients may not connect an adverse effect to their medications, particularly a

somatic complaint when the main therapeutic target of their medication is in the CNS,

so education and close follow-up are needed. The nonpharmacologic aspects of

treatment are an important adjunct to pharmacologic management in functional

recovery. Psychosocial interventions include assertive community treatment teams

for high-risk patients, vocational training or supported employment, and cognitive

behavioral therapy. Adjunctive treatments for comorbid conditions, such as

depression and anxiety, should also be addressed during this phase.

Nonpharmacologic Interventions

In addition to medication-based treatments, there are a variety of nonpharmacologic

treatments that have also been found to be useful in the treatment of schizophrenia.

Most patients will benefit

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from a combination, multidisciplinary approach to treatment. Treatment guidelines

for schizophrenia recommend a treatment plan that includes both pharmacologic and

nonpharmacologic treatment.

45 Nonpharmacologic interventions may include

individual or group psychological therapy as well as family therapy, cognitive skills

training, vocational skills training, and others. When utilized, these interventions

have increased patient understanding of their illness, decreased patient symptoms and

relapse rates, and improved social and occupational functioning.

Selection of one of these interventions is based upon the patient’s level of acuity

and specific needs, but should be considered during all phases of the illness. For

example, a patient having an acute episode of psychosis might not be appropriate for

cognitive or vocational skills training, but might benefit from individual therapy to

help develop insight into their illness and understand why they are being treated.

During an acute phase, other, more simplistic interventions can also play a key role.

For example, inpatient settings may utilize techniques to minimize stimulation or

stress for patients, particularly those who are agitated or potentially aggressive.

Group therapy sessions can assist patients with social interaction, something that

might be difficult for many patients.

As the patient moves from an acute phase into a stabilization or stable phase,

addition of skills training could be considered. Many patients will have lingering

negative and cognitive symptoms that might not fully respond to pharmacotherapy.

Cognitive skills training can assist with both of these areas, helping patients to

overcome functional deficits arising from these symptoms. Vocational skills training

can teach patients a variety of skills to prepare them to re-enter the workforce, even

if only in a minor role.

Family therapy can be helpful for both patient and family. Many families are

greatly affected when a family member is diagnosed with schizophrenia. Improving

family understanding of the illness and how to interact appropriately with the patient

can be of great impact to all involved. Additionally, the stress on the family can be

mitigated through family therapy and assistance programs.

Pharmacists can also play a role in nonpharmacologic treatment by assisting with

patient education (particularly in regard to medications) and patient adherence to

medication. Assistance with adverse effects to medications is also an area in which

pharmacists can play a role.

CASE 85-1, QUESTION 3: What are the management goals for J.J.?

First and foremost is to ensure J.J.’s safety. While not serious, she has already

injured herself by punching her walls. She is also very argumentative due to her

paranoia, which could inadvertently lead to an altercation. A reduction in J.J.’s

symptoms is also desired, ideally leading to an improvement in her functionality and

insight into her illness. In light of J.J.’s symptoms and lack of insight into her illness,

she will most likely require hospitalization to both ensure her safety and effectively

treat her symptoms.

CASE 85-1, QUESTION 4: What nonpharmacologic treatment would you recommend for J.J. at this time?

During the acute phase, especially while J.J. still displays prominent positive

symptoms, nonpharmacologic treatment should center on stress reduction and

education on her illness. By reducing her stress, the goal is that J.J.’s paranoia and

agitation will decrease, allowing her to more meaningfully engage in treatment.

Illness education can be accomplished through both individual and group therapy and

education sessions. As J.J. moves from an acute phase into a stabilization phase,

more specific interventions can be started, such as vocational skills training,

depending upon her need and her level of functionality at that time.

J.J. would also benefit from medication education, such as from a pharmacist, once

she is more stable in order to better understand her medications and any potential

adverse effects.

CASE 85-1, QUESTION 5: How should J.J. be best communicated with by the staff treating her at this

time? What recommendations would you provide her family and friends for communicating with her, both

currently and once she is sent home?

The staff should attempt to use methods of communication that will not agitate J.J.

or increase her paranoia. This includes both verbal and nonverbal (body language)

communication. If J.J. does become paranoid or agitated, she should be approached

with calmness in an attempt to deescalate the situation. Directly challenging her

hallucinations and delusions will most likely only increase her paranoia, so this

should be avoided. If possible, speak to J.J. during times when she is calm and

having fewer symptoms and inquire about what methods she would prefer employed

to calm her down when she does become agitated, such as being put in a room alone

to relax, listening to music, conversing with a staff member, etc.

J.J.’s family and friends should be educated about her illness to help them

understand how to avoid upsetting her and potentially increasing her symptoms,

especially during the acute phase. Avoidance of topics that would make her upset

would also be appropriate. Once J.J. is sent home, they should interact with her as

they normally would, but being aware that her symptoms could return at any time and

they should be vigilant for this. If they observe any significant change in her status,

they should attempt to get J.J. to a medical provider to evaluate her situation.

Assessment

The issues and conducting a differential diagnosis of schizophrenia have been

previously discussed above. Patients are assessed for the severity of their

symptomatology after diagnosis using information from direct assessment via patient

interview, discussions with family and friends of the patient as well as treatment

staff, and review of the medical records. There are no laboratory tests to measure

progress in schizophrenia at this time. It is important to obtain laboratory baseline

monitoring tests that can be relevant for the differential diagnosis and for the

monitoring of adverse effects of medications. First, it is important to obtain a

complete psychiatric and medical history including all past medications. It is

suggested that patients receive a physical examination and that clinical laboratory

tests of thyroid, liver, and renal function be obtained. A complete cell blood count

with differential as well as a urinalysis and urine toxicology screen (if drug abuse is

suspected) should be obtained. A fasting blood glucose and serum hemoglobin A1c

(HbA1c) level is useful considering the high rate of type 2 diabetes prevalent in

patients with schizophrenia. Obtaining an electrocardiogram is also useful,

especially if the patient is over 40 years of age or likely to receive a medication with

significant QTc prolongation effects.

The most prevalent way to record the results of a clinical assessment in the patient

with schizophrenia would be via the mental status examination.

47

If a patient is to be

treated in a clinical study, schizophrenic symptomatology may be assessed using the

Positive and Negative Symptoms Scale (PANSS),

48

the Brief Psychiatric Rating

Scale (BPRS)

49

, and Clinical Global Impression (CGI) scale. Adverse effects to

antipsychotic treatment can be assessed using instruments such as the Abnormal

Involuntary Movements Scale (AIMS) or Dyskinesia Identification System

Condensed User Scale (DISCUS) for tardive dyskinesia,

50 or the Simpson-Angus

Rating Scale for drug-induced parkinsonism, and general adverse effects can be

recorded via the Treatment

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Emergent Symptoms Scale (TESS).

51 These are all scales suitable to measure the

severity of these symptoms, but are not used as diagnostic instruments.

Pharmacotherapy Interventions

ANTIPSYCHOTICS

Classification and Nomenclature of the Antipsychotics

The first effective antipsychotic medication used in western medicine was

chlorpromazine, a low-potency sedating “typical” antipsychotic first developed in

1951 to augment anesthesia, and was termed by its inventor Laborit to be a

“vegetative stabilizer.”

52 While its introduction resulted in a sharp decrease in the

number of hospitalized patients with schizophrenia, it was imperfect in that it caused

adverse effects such as drug-induced parkinsonism, acute dystonias, sedation,

anticholinergic effects, and orthostasis. The knowledge that D2 antagonism was a key

in making effective agents for treating schizophrenia led to the development of a

plethora of new agents, some of which were much more specific in selectively

antagonizing these receptors. The medications with greater dopamine specificity

tended to have fewer effects on other neurotransmitter systems (Fig. 85-1).

Therefore, these “high-potency” first-generation antipsychotics (FGAs), such as

haloperidol or fluphenazine, were less likely to cause related adverse effects such as

sedation, increased appetite, dry mouth, constipation, and orthostasis than “lowpotency” agents, such as chlorpromazine and thioridazine. However, high-potency

FGAs have a greater propensity to cause acute dystonias and drug-induced

parkinsonism than the low-potency agents. The middle-potency agents, such as

loxapine, molindone, and perphenazine, have more moderate adverse effects. These

medications have other unique properties that differentiate them. For example,

molindone was found to induce modest weight loss,

53,54 and loxapine was thought to

be somewhat atypical in its effects on serotonergic receptors. These recognized

properties helped lead to the development of the second-generation antipsychotics

(SGAs) or “atypical antipsychotics.”

55

The first SGA, clozapine, differed dramatically in its pharmacology from previous

agents. It is a very potent antagonist of serotonin-2a (5-HT2a

) and serotonin-2c (5-

HT2c

) receptors. It was later determined that the ability to antagonize serotonergic

receptors was critical to creating other new “atypical” agents that could act in a

manner similar to clozapine, but without its critically serious adverse effect profile.

Clozapine was shown to have robust effectiveness in treating resistant

schizophrenia

56

, to cause agranulocytosis in about 1% to 2%57 and to induce seizures

in 6% of those taking it at higher dosages,

58 possesses nuisance side effects such as

sialorrhea and constipation, and is even associated with myocarditis.

59–61 Because

clozapine is restricted to only the treatment-resistant or antipsychotic-intolerant

patient, newer agents that were introduced, such as risperidone, olanzapine,

quetiapine, and ziprasidone, were used with initial excitement. This excitement was

tempered with caution when it was discovered that these agents could also be

associated with obesity, hypertriglyceridemia, and even the onset of type 2 diabetes

mellitus. Later, somewhat unique agents were introduced with possible advantages

such as aripiprazole, lurasidone, paliperidone, iloperidone, asenapine,

brexpiprazole, and cariprazine. The terms FGA and SGA will be utilized for clarity

throughout the chapter.

Figure 85-1 Four dopamine pathways in the brain. The neuroanatomy of dopamine neuronal pathways in the brain

can explain both the therapeutic effects and the side effects of the known antipsychotic agents. (1) The

nigrostriatal pathway projects from the substantia nigra to the basal ganglia and is thought to control movements.

(2) The mesolimbic pathway projects from the midbrain ventral tegmental area to the nucleus accumbens, a part of

the limbic system of the brain thought to be involved in many behaviors, such as pleasurable sensations and the

powerful euphoria of drugs of abuse, as well as delusions and hallucinations of psychosis. (3) A pathway related to

the mesolimbic pathway is the mesocortical pathway. It also projects from the midbrain ventral tegmental area, but

sends its axons to the limbic cortex, where it may have a role in mediating positive and negative psychotic

symptoms or cognitive side effects of neuroleptic antipsychotic medications. (4) The fourth dopamine pathway of

interest is the one that controls prolactin secretion, called the tuberoinfundibular pathway. It projects from the

hypothalamus to the anterior pituitary gland.

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General Differentiating Characteristics of Antipsychotics

It is sometimes useful to conceptualize the different antipsychotic medications in

terms of their action at different receptor subtypes or by potency (Table 85-4). The

second-generation antipsychotics (SGAs) are more potent at blocking 5-HT2a

serotonergic receptors than they are at blocking D2

receptors. The SGAs are

generally less likely to cause drug-induced parkinsonism and tardive dyskinesia than

first-generation medications, but some of these agents may be more prone to cause

metabolic issues than the FGAs.

52 Low-potency antipsychotics are often given in

hundreds of milligrams per day and tend to have greater antihistaminic,

anticholinergic, and α-1 antagonist effects than their high-potency (roughly 1–20 mg

daily) counterparts.

Typical Antipsychotics or First-Generation Antipsychotics

Low-potency phenothiazine antipsychotics include the prototype antipsychotic

chlorpromazine as well as thioridazine and its metabolite mesoridazine. Lowpotency typical antipsychotics are strong histamine-1 blockers and are associated

with more weight gain than the high-potency ones. They also tend to be strong

blockers of α-1, inducing orthostasis, and muscarinic receptors, which results in dry

mouth, blurred vision, and constipation. Thioridazine is distinctive in that it can

cause a retinopathy in doses over 800 mg daily. Moreover, it has received a black

box warning as it can cause prolonged QTc

intervals that can be clinically

significant, especially if a 2D6 P450 isoenzyme antagonist (which increases its

serum levels) is also being used.

63 Use of thioridazine is restricted to treatmentresistant patients due to these proarrhythmic effects, and use in clinical practice is

uncommon.

Table 85-4

Clinical Effects of Receptor Antagonism by Antipsychotics

Receptor (Subtype) Clinical Effect of Antagonism

Dopamine (D2

) Mesolimbic pathway (basal ganglia)—treatment of positive symptoms

Mesocortical pathway (prefrontal cortex)—may worsen negative symptoms

Nigrostriatal pathway (substantia nigra)—extrapyramidalsymptoms (EPS)

Tuberoinfundibular pathway (hypothalamus–anterior pituitary)—increased

prolactin release

Serotonin (5-HT2a

) Treatment of negative symptoms; increased dopamine release in prefrontal

cortex; may reduce mesolimbic dopamine release

Serotonin (5-HT2c

) Implicated in antipsychotic-associated weight gain

Muscarinic (μ1

) Anticholinergic side effects (dry mouth, constipation, urinary retention, blurred

vision, hot/dry skin, memory impairment); sedation

Histamine (H1

) Increased appetite, sedation

Alpha (α1

) Orthostatic hypotension

Common middle-potency typical antipsychotics include molindone, loxapine, and

perphenazine. Molindone is the only antipsychotic associated with weight loss.

53,54

Loxapine is regaining use due to its inhalation dose form, and perphenazine has had a

resurgence in use of sorts due to it being the chosen typical antipsychotic in the

CATIE-1 trial.

64 These agents tend to fall in between the high- and low-potency

agents in terms of adverse effects.

The high-potency typical antipsychotics are very selective for D2

receptor

blockade, thus causing fewer adverse effects related to antihistaminic,

anticholinergic, or α-1 receptor blocking effects. However, they are more likely to

induce adverse extrapyramidal effects such as dystonia, drug-induced parkinsonism,

and akathisia than the lower-potency typical agents. Their availability as long-lasting

depot injections of haloperidol and fluphenazine and reduced rate of adverse

metabolic effects encourage their continued use. Other, less often utilized highpotency agents include thiothixene and trifluoperazine (Table 85-5).

Atypical or Second-Generation Antipsychotics

SGAs are agents that exert more effects on antagonism of 5-HT2a subreceptors than

on D2

receptors and cause dramatically less drug-induced extrapyramidal symptoms.

The SGAs such as clozapine, quetiapine, and olanzapine are more likely to induce

metabolic disorders, such as weight gain,

65 hypertriglyceridemia,

66–70 and possibly

glucose dysregulation

71

than other antipsychotic medications. Atypical antipsychotics

are thought by many to have greater efficacy in the treatment of negative and cognitive

symptoms of schizophrenia and a reduced risk of tardive dyskinesia.

62

Clozapine has a unique pharmacology which makes it the only agent found to be

effective in treatment-resistant schizophrenia and suicidality in schizophrenia.

56,62

Clozapine is associated with a higher incidence of agranulocytosis and neutropenia

relative to other antipsychotics which requires frequent serum monitoring. This agent

will be discussed more in the section on treatment-resistant schizophrenia.

Risperidone (Risperdal) is considered to be an atypical antipsychotic that is

effective and less likely to cause extrapyramidal system adverse effects at doses less

than 6 mg/day. Akathisia can be a problem especially in the elderly. Paliperidone

(Invega), or 9-hydroxyl risperidone, is the active metabolite of risperidone and has

shown itself to be as effective as the parent drug.

72 Paliperidone is a controlledrelease OROS oral dosage form that utilizes osmotic pressure to deliver the

medication in a controlled fashion. Patients should be counseled not to be alarmed if

the insoluble outer tablet shell is found in their stool. The long-acting injectable

dosage forms of paliperidone and its parent compound risperidone are discussed in

the section regarding long-acting agents.

Olanzapine (Zyprexa) is an atypical antipsychotic that is very effective, but it can

cause significant weight gain with related glucose dysregulation as well as increased

serum triglycerides.

68,73 Doses may need to be adjusted in smokers due to the

induction of the cytochrome p450 1A2 isoenzyme system by the polycyclic aromatic

hydrocarbons (PAHs) in cigarette smoke.

74 Quetiapine (Seroquel) is a low-potency

D2 antagonist.

64 Due to its minimal risk of drug-induced movement disorders, it is

often utilized in patients with psychosis in Parkinson disease prior to use of

clozapine.

75

It is recommended that patients be counseled regarding diet and exercise

prior to and during the use of these agents and clozapine. Ziprasidone (Geodon)

should be administered with at least 500 calories to ensure sufficient absorption.

76

It

causes little weight gain or dyslipidemia and has minimal anticholinergic or

extrapyramidal adverse effects. Although there were initial warnings about cardiac

conduction delays (prolonged QT interval), there have been sparse reports linking

the medication to death due to this concern.

77–79 An electrocardiogram prior to and

during treatment is advised.

80

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Table 85-5

First-Generation Antipsychotics (FGAs)

279–287

Medication Name

(Generic/Brand);

Potency—

Chlorpromazine

Equivalents; Class Dosage Forms

Adult Dosing

Schedules Dose Adjustments

Haloperidol (Haldol)

High—2

Butyrophenone

Tablet: 0.5, 1, 2, 5, 10, 20

mg

Oralsolution: 2 mg/mL

Injectable (immediaterelease): 5 mg/mL

Injectable (long-acting):

50, 100 mg/mL

Initial: 0.5–5 mg BID or

TID (depending on

symptom severity)

Usual range: 5–40 mg

Renal: No specific

recommendations

Hepatic: No specific

recommendations

Fluphenazine (Prolixin)

High—2

Phenothiazine

Tablet: 1, 2.5, 5, 10

Oral Elixir: 2.5 mg/mL

Oral Solution: 5 mg/mL

Injectable (immediaterelease): 2.5 mg/mL

Injectable (long-acting): 25

mg/mL

Initial: 2.5–10 mg q6–8

hours

Usual range: 1–40 mg/day

Renal: Use with caution

(nondialyzable)

Hepatic: Use with caution

Thiothixene (Navane)

High—4

Thioxanthene

Capsule: 1, 2, 5, 10 mg Initial: 6–10 mg daily

(divided doses)

Usual range: 5–60 mg/day

Renal: Use with caution

(nondialyzable)

Hepatic: Consider dose

reduction

Trifluoperazine (Stelazine)

High—5

Phenothiazine

Tablet: 1, 2, 5, 10 mg Initial: 2–5 mg BID

Usual range: 15–20

mg/day

Renal: Use with caution

(nondialyzable)

Hepatic: Consider dose

reduction

Perphenazine (Trilafon)

Mid—8–10

Phenothiazine

Tablet: 2, 4, 8, 16 mg Initial: 4–8 mg TID

Usual range: 8–64 mg/day

Renal: No specific

recommendations

Hepatic: Consider dose

reduction

Loxapine (Loxitane)

Mid—10

Dibenzoxazepine

Capsule: 5, 10, 25, 50 mg

Inhalation powder: 10 mg

Initial: 10 mg BID

Usual range: 20–250

mg/day (PO)

Renal: No specific

recommendations

Hepatic: No specific

recommendations

Chlorpromazine

(Thorazine)

Low—100

Phenothiazine

Tablet: 10, 25, 50, 100,

200 mg

Injection (immediaterelease): 25 mg/mL

Initial: 100–200 mg/day in

divided doses; increase

20–50 mg/day q3–4 days

as indicated

Renal: No specific

recommendations

Hepatic: Consider dose

reduction

Thioridazine (Mellaril)

Low—100

Phenothiazine

Tablet: 10, 25, 50, 100 mg Initial: 50–100 mg TID

with gradual dose

increases

Usual range: 50–800

mg/day

Renal: Use with caution

(nondialyzable)

Hepatic: Consider dose

reduction

Aripiprazole (Abilify) should be dosed in the morning as it may be activating in

some patients due to its partial D2

receptor agonism. Typical adverse effects include

nausea, vomiting, and insomnia in the first weeks of treatment. It has a lower risk of

weight gain, dyslipidemia, and QT delays, and can actually cause decreases in serum

prolactin and triglycerides. In fact, it has been used as augmentation to remedy

hyperprolactinemia induced by other antipsychotics.

81–83

It also seems to have a low

risk of EPS. Although aripiprazole’s unique differential effect on dopaminergic

systems can be beneficial, dopamine-3 (D3

) partial agonism may induce an increase

in risky, reward-based behaviors, such as gambling.

84,85 Brexpiprazole (Rexulti) is a

recent addition to the antipsychotic armamentarium that showed superiority to

placebo in both key clinical trials (at 4 mg daily) with pharmacologic and therapeutic

similarities to aripiprazole.

86,87

It is a partial agonist at D2

receptors and serotonin 5-

HT1a and antagonist at 5-HT2a and noradrenergic α-1b and α-2c receptors.

88