Secondary Schizophrenia (155 page)

5%–10% risk during 1 year of treatment
[10].

year of drug exposure
[8].

These drugs differ significantly from one another
in side effects, including risk of EPS, weight gain
Low-potency conventional antipsychotics

and metabolic dysregulation, sedation, anticholinergic
Neuroleptics with lower potency tend to be highly
effects, and cardiac effects. They have not been shown
sedating and strongly anticholinergic, but to have
to differ from one another in efficacy as established
somewhat less risk of EPS. These drugs include chlor-in randomized, placebo-controlled trials
[11].
They
promazine, thioridazine, and mesoridazine. The latter
may, however, differ in effectiveness in community set-two drugs have recently been implicated in sudden car-tings, as represented in the CATIE study. They also
diac deaths apparently related to prolongation of the
have significant differences in mechanism of action,
qT interval of heart conductivity. Consequently, they
pharmacokinetics, and route of administration. Con-are no longer recommended for first-line antipsychotic
sequently, each drug will be reviewed briefly, in alpha-treatment. The drugs within this class show few dif-betical order.

ferences from one another in efficacy; they do differ
Aripiprazole is unique among the antipsychotics
in terms of their propensity to cause a variety of side
as a dopamine D2 partial agonist, binding the recep-effects such as cardiac risk.

tor, but eliciting a reduced response compared with
intrinsic dopamine. The drug has clearly demonstrated
Medium-and high-potency conventional antipsychotics

efficacy for primary schizophrenia and acute bipolar
Conventional antipsychotics with higher potency are
mania and mixed episodes
[12],
with less evidence
less sedating than their low-potency counterparts and
available for other uses. Aripiprazole is available as
are only mildly anticholinergic, but carry a higher risk
standard tablets, orally disintegrating tablets, and ster-of EPS. Haloperidol, fluphenazine, thiothixene, and
ile solution for intramuscular injection. In clinical tri-perphenazine are among the common members of this
als among schizophrenia patients, the average dose
class. The recent CATIE study, which included per-found to be effective was 15 mg/day, with a range of 10–
395

phenazine, highlighted the strengths and weaknesses
30 mg/day. Among manic patients, the modal dose was
Treatment – Section 5

30 mg/day, the highest recommended by the manufac-disorders, 300 mg/day for bipolar depression, 400–800

turer. The drug is absorbed slowly following either oral
mg/day for schizophrenia, and 600 mg/day for mania.

or injectable administration and has a 75-hour clear-The manufacturer recommends doses no higher
ance half-time. Drug–drug interactions are uncom-than 800 mg/day for any condition. The drug has
mon with aripiprazole, but because of its metabolism
an intermediate time to peak concentration and is
via the cytochrome P450 system, it may require dose
cleared with a relatively rapid 6–7 hour half-time.

adjustment if given concurrently with carbamazepine,
Although twice daily dosing is recommended by the
fluoxetine, or ketoconazole. The most common side
manufacturer, at least one study found no difference
effects with aripiprazole are headache, nausea, vomit-in efficacy when the drug was given once per day
ing, akathisia, tremor, and constipation. Weight gain
[36].
Drug–drug interactions are uncommon with
and other metabolic dysregulation are generally mini-quetiapine, but its levels are affected by inhibitors or
mal, as are cardiac effects.

inducers of the cytochrome P450 system. The most
Olanzapine has been shown to be effective for
prominent side effects with the drug are sedation,
schizophrenia, acute and maintenance treatment of
orthostatic hypotension, akathisia, dry mouth, and
bipolar mania, and acute agitation
[13].
A smaller
weight gain. Sedation and hypotension may limit the
body of evidence supports its efficacy for behavioral
rate of titration of the medication, although increases
disturbance in dementia
[14, 15, 16],
delirium
[17,

as rapid as 100 mg/day may be well tolerated. Its side
18],
Tourette’s syndrome
[19],
and borderline person-effects are noteworthy for the absence of EPS in most
ality disorder
[20]
. Olanzapine is available as standard
studies, making it the preferred drug in patients at
tablets, orally disintegrating tablets, and sterile solu-risk for movement disorders.

tion for intramuscular injection. Clinical trials of the
Risperidone is the oldest of this group of drugs,
oral drug have generally limited doses to 20 mg/day,
and has accumulated a substantial body of evidence
the highest recommended by the manufacturer, but
for its efficacy in schizophrenia
[37],
bipolar mania
doses up to 30 mg/day of the injectable drug have
[38],
agitation
[39],
and behavioral disturbances in
been well tolerated in controlled studies
[21].
The drug
autism
[40].
It has also been used for behavioral
is absorbed slowly, reaching peak serum concentra-problems in dementia
[41]
, bipolar maintenance ther-tion at 5 hours with either standard or disintegrating
apy
[42],
and delirium
[43].
Risperidone is available
tablets. It is cleared with a half-time of 30 hours by
in standard tablets, orally disintegrating tablets, liq-the cytochrome P450 system. Of special note is a 30%

uid concentrate, and long-acting injectable formu-drop in serum levels among smokers. Its most com-lation. Although approved for use at oral doses up
mon side effects are weight gain, sedation, akathisia,
to 16 mg/day, it is typically administered in the 2–
hypotension, dry mouth, and constipation
[22, 23].
Its
6 mg/day range, and is rarely used at doses higher
risk of metabolic dysregulation appears higher than
than 8 mg/day because of dose-dependent EPS. The
that of other conventional or atypical agents
[24, 25].

long-acting injectable formulation is recommended
Its major advantages are extensive clinical experience
at doses up to 50 mg every 2 weeks. The drug
and possibly superior effectiveness in community set-has rapid oral uptake and is cleared with a 20-tings related to its greater ease of dosing.

hour half-time. Drug–drug interactions are uncom-Quetiapine
has

demonstrated

efficacy

for

mon and only slight changes in serum levels occur
schizophrenia
[26, 27]
, acute bipolar mania
[28],

with inducers or inhibitors of the cytochrome P450

bipolar depression
[29],
and acute agitation
[30].
The
system. The most common side effects of risperi-drug has also been used for delirium
[31],
dementia
done are mild sedation, hypotension, akathisia, pro-

[32, 33]
, and has been broadly used for mood and
lactin elevation, and weight gain. Compared with
anxiety disorders
[34]
, obsessive-compulsive disorder,
other atypical agents, its risk of EPS is somewhat
aggression, hostility, posttraumatic stress disorder,
higher, although well below that of conventional drugs.

borderline personality disorder, and comorbid sub-Although prolactin elevation occurs in more than half
stance abuse
[35].
Its low risk of movement disorder
of patients, clinical effects, such as galactorrhea or
make it especially useful in Parkinson’s Disease and
sexual dysfunction are less common
[44, 45].
Impor-Lewy-body dementia. Quetiapine is available in
tant advantages of risperidone include its extensive
standard tablets only. Clinical trials have focused
clinical experience and availability of a long-acting
396

on somewhat different dose ranges for different
formulation.

Chapter 32 – Drug treatment of secondary schizophrenia

Ziprasidone

has

demonstrated

efficacy

for

medications, clozapine’s side effects tend to be promi-schizophrenia
[46],
acute bipolar and mixed mania
nent and enduring. Clozapine is most commonly used
[47],
and psychotic agitation
[48]
. Case reports are
at doses between 300 and 600 mg/day. In addition to its
also available describing its use in dementia, delirium,
unique effectiveness, clozapine carries no risk of EPS

and borderline personality disorder. The medication
or TD, and is the only proven treatment for TD caused
is available in capsules and intramuscular injectable
by other drugs
[56].

formulations. The highest dose recommended by
the manufacturer is 160 mg/day, but doses up to 240

Antipsychotics for secondary schizophrenia
mg/day are common in the community. The medica-A limited body of evidence is available for secondary
tion is absorbed slowly, and then metabolized with a
psychosis, including a few small, randomized tri-7-hour clearance half-time, hence twice daily dosing
als, but consisting mostly of case series and open-is recommended. Its bioavailability is 60% when taken
label trials. In general, these data support the use of
with a meal, compared with only 30% when taken
antipsychotic agents for symptomatic relief of psy-alone. Side effects include mild sedation early in
chotic symptoms in the context of other medical
treatment, nausea, weakness, nasal congestion, and
conditions. An important consideration, however, is
mild qT prolongation (
∼
10 msec)
[49].
It shows only
the potential of the drugs to worsen certain under-mild interactions with inducers and inhibitors of the
lying conditions, such as seizure disorders, move-cytochrome P450 system, but should be used with
ment disorders, or anticholinergic delirium. They may
caution in conjunction with cardiac medications that
also pose a threat to certain populations, including
prolong qT interval. Post-marketing surveillance has
patients with Alzheimer’s Disease, cardiac arrhyth-found no evidence of increased mortality or morbidity
mias, or metabolic derangements such as diabetes or
in the absence of a concurrent cardiac problem or
hyperlipidemia.

administration of another drug that extends the qT

interval
[50].
Its primary advantage is its low risk of
Antipsychotics for schizophrenia secondary to

weight gain.

neurological disorders

Clozapine

Dementia

Although clozapine is the prototype atypical drug,
Antipsychotics have been studied more extensively in
it is sufficiently unique to merit separate classifica-dementia than in other neurological disorders, and
tion and consideration. It has well-established efficacy
have been widely used for psychotic symptoms in
for schizophrenia
[51]
and bipolar disorder
[52, 53],

the context of Alzheimer’s Disease and other types of
including those patients who do not respond to other
dementia. Despite their general acceptance for treat-medications. Among these treatment-refractory indi-ment of this population, several recent studies have
viduals, 30%–50% respond to clozapine. It has also
suggested that they offer little benefit and may cause
been used for aggression and behavioral problems
significant problems. This was the conclusion of the
associated with dementia, brain injury, mental retar-CATIE-AD study, which found no advantage of olan-dation, and personality disorders, intermittent explo-zapine, quetiapine, or risperidone over placebo, but
sive disorder, and posttraumatic stress disorder
[54,

noted that 16%–24% of the 421 patients enrolled in the
55].
Because of the potential for life-threatening agran-study discontinued antipsychotics due to side effects
ulocytosis, the medication is recommended only for
[57].
A large study comparing risperidone to placebo
treatment-refractory cases, generally after at least three
had similar results
[58].
Two recent meta-analyses, in
other medications have been tried, including at least
contrast, found a small but significant positive effect
one conventional and one atypical drug. Agranulo-size for risperidone
[59]
, and for both risperidone and
cytosis occurs in 1%–2% of patients, usually in the
olanzapine
[60].
The latter study, however, also found
first 6 months of treatment. More common side effects
significantly increased risk of cerebrovascular events
include orthostatic hypotension, tachycardia, weight
and extrapyramidal side effects with both drugs, for
gain and metabolic dysregulation, sialorrhea, seda-which the entire class of drugs now carries an FDA-tion, and constipation. Seizure risk is dose dependent,
mandated warning. Polled experts nevertheless rec-increasing from 2% per year at 300 mg/day to 6% per
ommend atypical antipsychotics for control of psy-