US Pharm. 2012;37(11):Epub.
ABSTRACT: Schizophrenia is a psychotic
disorder that is characterized by positive and negative symptoms as well
as cognitive dysfunction, although the etiology is unknown.
Antipsychotics have been the mainstay of therapy for symptom management
since the introduction of chlorpromazine in the 1950s. It was observed
that typical (first-generation) antipsychotics caused extrapyramidal
symptoms; hence, newer atypical (second-generation) antipsychotics were
researched. However, some atypical antipsychotics may cause metabolic
disturbances and therefore may not be useful in certain patients. There
are presently a number of antipsychotics on the market, and the choice
of agent depends upon individual preference, prior treatment response,
side-effect profiles, and patient medical history.
Schizophrenia is a chronic remitting and relapsing
psychotic disorder that impairs mental and social functioning and often
leads to comorbid conditions.1 It is not a disease but rather a cluster of symptoms that last for a particular time.2 Schizophrenia occurs in approximately 1% of the population in all cultures and is found equally in men and women.1 This translates to about 2.4 million adults in the United States who have schizophrenia.3
Even with its relatively low prevalence, schizophrenia
places a high economic burden on the U.S. economy. In 2002, the overall
cost of schizophrenia in the U.S. was estimated to be $62.7 billion in
direct and indirect health care costs.4 The largest share was a result of costs due to unemployment.4
Furthermore, it has been shown that approximately one-third of all
schizophrenics will attempt suicide and about 1 out of 10 will
eventually take his or her own life.5
ETIOLOGY, RISK FACTORS, AND PATHOPHYSIOLOGY
The etiology of schizophrenia is primarily attributable to
genetics; having a close relative with the disorder increases one’s own
risk 15-fold.1 Schizophrenia is a polygenic disorder that is
influenced by environmental and developmental factors including season
and location of birth, socioeconomic status, and maternal infections.1
These underlying causal factors are overtly expressed through neurochemical abnormalities.2
To date, dopamine is the only neuro-transmitter that is confirmed to be
involved in schizophrenia. It has been shown that positive symptoms are
associated with increased dopaminergic transmission and that most
antipsychotics exert their effect by reducing dopaminergic transmission.
The role of other neurotransmitters such as gamma-aminobutyric acid
(GABA) is still under investigation.1
The first symptoms that are diagnostic of schizophrenia were listed by Kurt Schneider in the 1930s. Known as Schneider’s first-rank symptoms,
these include thought insertion, withdrawal, broadcasting, passivity
experiences, delusional perceptions, écho de la pensée ( a condition
whereby the individual hears voices that echo thoughts immediately after
they have occurred to the person), running commentary, and third-person
Today, schizophrenia is characterized by three major
symptom clusters: positive (+) symptoms, negative (-) symptoms, and
disorganized behavior.1,2 Positive symptoms include
hallucinations, voices that converse with or about the patient, and
delusions that are often paranoid.1 Negative symptoms include
flattened affect, loss of a sense of pleasure, loss of will or drive
(avolition), and social withdrawal.1 Disorganized behavior
refers to affect, thought, and behavior resulting in disorganized speech
including moving through multiple topics quickly.2
The types and severity of the symptoms vary from patient
to patient, and as such, five different subtypes of schizophrenia have
been identified (TABLE 1).1
Furthermore, the onset may be either abrupt or insidious.1
Typically, a prodromal phase demonstrated by slow and gradual
development of negative symptoms is followed by the active phase. The
prodromal phase includes social withdrawal, loss of interest in school
or work, deterioration in hygiene and grooming, unusual behavior, and
outbursts of anger; the active phase is characterized by psychosis.1
No one symptom is diagnostic of schizophrenia.1
Furthermore, the diagnosis changes with time in many cases. A diagnosis
of schizophrenia may change to bipolar or organic disorders, while
organic disorders, psychotic disorders, and major depression may
eventually change to schizophrenia.1 Patients are often
misdiagnosed because the symptoms overlap. A number of diagnoses, such
as depression, bipolar disorder, or substance abuse, can produce
symptoms similar to that of schizophrenia.1
The effective management of schizophrenia includes a
combination of pharmacotherapy and psychosocial interventions, as will
be discussed in the following sections.6
Antipsychotics have become the cornerstone of
pharmacologic treatment of schizophrenia since the introduction of the
first antipsychotic, chlorpromazine, in the 1950s.6 First-generation antipsychotics (FGAs), also known as neuroleptics,
are “conventional” agents that confer a high degree of extrapyramidal
symptoms (EPS) such as tardive dyskinesia (TD) and akathisia.
Second-generation antipsychotics (SGAs) are atypical agents that have a
lower degree of EPS than the FGAs. A recent study has demonstrated
inconclusive benefits of FGAs versus SGAs for treating schizophrenia
because of variation in assessing outcomes and lack of clinically
important differences for most comparisons.7 However, SGAs may have more modest benefits for cognitive impairments of schizophrenia compared to FGAs.
There are oral and long-acting injectable forms of both
FGAs and SGAs; the depot injections are useful for patients who are
nonadherent to oral medications.7
Typical Antipsychotics (FGAs): All typical
or conventional antipsychotics are dopamine D2 antagonists, and the
agents currently on the U.S. market can be divided into five classes (TABLE 2).2 The first FGA was chlorpromazine, but this drug is no longer available in the U.S.6
Symptoms usually begin to improve within a week with drugs of this
class, and the effect continues to accrue with a peak effect seen at 6
weeks of treatment.2 Conventional antipsychotics may also be
used for maintenance therapy to suppress the psychotic symptomatology
and/or prevent the recurrence of a psychotic episode.2
FGAs have a broad range of side effects, the most important ones being EPS such as akathisia, dystonia, tremor, and TD.8
High-potency FGAs such as haloperidol and fluphenazine are more likely
to cause EPS and neuroleptic malignant syndrome (NMS), whereas
low-potency antipsychotics including thioridazine are more prone to
causing sedation and orthostatic hypotension.2 NMS is
characterized by muscle rigidity and autonomic instability (elevated
pulse rate and blood pressure). It is interesting to note that EPS
constitute a major cause of nonadherence in patients. Other side effects
that are associated with chlorpromazine and may be experienced by
patients taking other FGAs include8:
- Antimuscarinic: dry mouth, blurred vision, urinary retention, tachycardia, and mydriasis
- Cardiac: altered ECG, hypotension, and, rarely, cardiac arrhythmias
- Hematologic: hemolytic anemia, aplastic anemia, thrombocytopenia, purpura, leukocytosis, and potentially fatal agranulocytosis
- Endocrine: endocrine and metabolic function may
translate into amenorrhea, galactorrhea, gynecomastia, weight gain,
hyperglycemia, and altered glucose tolerance.
Additionally, patients often complain about delirium,
agitation, catatonic-like states, insomnia, drowsiness, nightmares,
depression, and nasal congestion. Minor abnormalities are found in liver
function tests, and males taking chlorpromazine may experience
inhibition during ejaculation, impotence, and priapism.8
Atypical Antipsychotics (SGAs): Atypical antipsychotics were developed with the aim of reducing EPS and TD (TABLE 3).
The first atypical antipsychotic, clozapine, was introduced in the late
1960s but was not approved for use in the U.S. until 1990. It is the
only atypical antipsychotic that is effective for the management of
positive symptoms that are resistant to conventional antipsychotics.9 In addition to having potent dopamine D2 antagonist and 5-HT2A
antagonist activity, atypical antipsychotics have noradrenergic,
histaminergic, and cholinergic effects, the extent of which varies
between the individual agents. Furthermore, their varied affinities for
neuroreceptors result in different side-effect profiles.6
While FGAs confer a higher risk of developing EPS, the
atypical agents are associated with a higher risk of metabolic side
effects such as diabetes, hypercholesterolemia, and weight gain.1
The diabetogenic potential seems to be reversible if the medication is
discontinued. Even though clozapine is not associated with EPS or
tardive dyskinesia, its use is associated with a greater risk for
agranulocytosis, a factor that has greatly limited its use.6
Greater interest in atypical antipsychotics developed when clozapine was
found to be more effective in the treatment of refractory schizophrenia
and in reducing suicidality. Since the 1980s, nine more atypical antipsychotics have become available in the U.S.6
Consensus Guidelines: There are five major algorithms for the management of schizophrenia in the U.S. (TABLE 4).10
These guidelines vary somewhat in scope, focus, goals, and
recommendations, although none are incorrect or more correct in their
assessments. The difference is in the way that they are established. In
general, SGAs are considered first-line therapy.10
Selecting the correct drug therefore requires a
consideration of the risk and benefits to the particular patient
together with patient preference, goals of therapy, patient history,
possible drug-drug interactions, and prior medication adherence history.
The expert consensus guidelines recommend that patients either
cross-taper or overlap, then taper, antipsychotics when switching from
one to another.10
Psychotherapy covers a wide range of interventions
including individual, group, and family treatments. Family treatment may
be one of either therapy with individual families, psychoeducation with
groups of families, and family group therapy.1 Individual
programs incorporate social skills training to enable the individual to
function as normally as possible from a social perspective. Assertive
community treatment and supported employment are also recommended
An understanding of the prognosis of the disorder will
allow pharmacists to make therapeutic drug choices. Schizophrenics
typically have a high rate of substance abuse resulting in first
hospitalization at earlier ages, more frequent hospitalizations, and
more interpersonal and family discord.1 They are poor at executive functioning and suffer low marital and high divorce rates.1 A schizophrenic, particularly one with severe psychotic disturbances, often exhibits aggressive behavior.1
These patients develop accelerated heart disease, the most common cause
of death in schizophrenics. An individual suffering from schizophrenia
has a 10% lifetime risk of suicide.1
ROLE OF THE PHARMACIST
Since therapeutic compliance rates are so low and side
effects are varied, pharmacists have an important role to play in the
management of schizophrenia. A recent study showed that 74% of
schizophrenic patients discontinued their medication within 18 months.12
The likelihood that a patient will develop a particular side effect
depends upon the patient’s vulnerability as well as the dose being
administered and other coadministered medications.6
Pharmacists can monitor side effects and hence improve compliance by
inquiring about positive and negative symptoms when the patient refills
prescriptions, and communicate regularly with the patient’s other health
care professionals about changes in symptoms. In addition to ensuring
the correct dosing of appropriate drugs, pharmacists are key in guiding
patients about where they can obtain further help (e.g., through
individual or group therapy).
While existing antipsychotic medications are often
effective for treating positive symptoms, they have little impact on
negative symptoms and cognitive deficits. Therefore, there is a need to
develop drugs that will allow for patient-specific treatment of
symptoms. For example, lurasidone is a newer SGA that may be effective
for cognitive symptoms. Additionally, while the newer therapies have
addressed the issue of motor side effects, safety, and tolerability,
there are increased concerns regarding weight gain and metabolic
Untreated schizophrenia contributes to increased
mortality, poor vocational and social functioning, and a reduced quality
of life. Since it is not currently possible to predict which
antipsychotic will suit a particular patient, pharmacists can be very
useful in the trial and error process to find the correct drug and
dosage for a particular patient. While the impact of antipsychotics on
the social functioning and quality of life in schizophrenia is not well
documented, increasing research efforts are being focused on developing
new agents with increased efficacy for the treatment of the cognitive
and negative symptoms of schizophrenia.15
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