together 3 years ago, and they have been roommates for the past 2 years. The roommate says J.J. was
after they returned from summer break. She says J.J.’s behavior has gotten increasingly unusual and
violence which led to their divorce when J.J. was 14. J.J.’s paternal uncle has been diagnosed with
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.
results. No other tests were ordered.
most likely require inpatient hospitalization for psychosis.
Provisional diagnosis: psychotic episode, most likely due to schizophrenia.
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
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
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
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
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
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
38 Patients with schizophrenia have a life expectancy 9 to 10
years shorter (or more by some estimates) than the average population.
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
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,
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.
These phases are not static, and patients can move between these phases frequently
over the course of their illness.
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.
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.
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
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.
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
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.
from a combination, multidisciplinary approach to treatment. Treatment guidelines
for schizophrenia recommend a treatment plan that includes both pharmacologic and
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
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
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
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
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.
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.
treated in a clinical study, schizophrenic symptomatology may be assessed using the
Positive and Negative Symptoms Scale (PANSS),
, 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,
Rating Scale for drug-induced parkinsonism, and general adverse effects can be
Emergent Symptoms Scale (TESS).
51 These are all scales suitable to measure the
severity of these symptoms, but are not used as diagnostic instruments.
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
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
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.”
The first SGA, clozapine, differed dramatically in its pharmacology from previous
agents. It is a very potent antagonist of serotonin-2a (5-HT2a
) 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
, 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.
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
hypothalamus to the anterior pituitary gland.
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
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
Typical Antipsychotics or First-Generation Antipsychotics
Low-potency phenothiazine antipsychotics include the prototype antipsychotic
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.
Clinical Effects of Receptor Antagonism by Antipsychotics
Receptor (Subtype) Clinical Effect of Antagonism
) 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
) Treatment of negative symptoms; increased dopamine release in prefrontal
cortex; may reduce mesolimbic dopamine release
) Implicated in antipsychotic-associated weight gain
) Anticholinergic side effects (dry mouth, constipation, urinary retention, blurred
vision, hot/dry skin, memory impairment); sedation
) Increased appetite, sedation
Common middle-potency typical antipsychotics include molindone, loxapine, and
perphenazine. Molindone is the only antipsychotic associated with weight loss.
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
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
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
Atypical or Second-Generation Antipsychotics
SGAs are agents that exert more effects on antagonism of 5-HT2a subreceptors than
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,
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.
Clozapine has a unique pharmacology which makes it the only agent found to be
effective in treatment-resistant schizophrenia and suicidality in schizophrenia.
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.
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
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
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
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.
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
First-Generation Antipsychotics (FGAs)
Equivalents; Class Dosage Forms
Injectable (immediaterelease): 5 mg/mL
Injectable (immediaterelease): 2.5 mg/mL
Capsule: 1, 2, 5, 10 mg Initial: 6–10 mg daily
Tablet: 1, 2, 5, 10 mg Initial: 2–5 mg BID
Tablet: 2, 4, 8, 16 mg Initial: 4–8 mg TID
Injection (immediaterelease): 25 mg/mL
Tablet: 10, 25, 50, 100 mg Initial: 50–100 mg TID
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.
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
HT1a and antagonist at 5-HT2a and noradrenergic α-1b and α-2c receptors.
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