metabolized by both 2D6 and 3A4 hepatic isoenzyme systems, and dose reductions
are recommended if these systems are inhibited.
pharmacologically similar to aripiprazole and brexpiprazole in that it is an antagonist
receptors and 5-HT2A receptors and a “partial” agonist at 5-HT1A
receptors. However, it has about a 10-fold greater affinity for the D3
It is unclear what differences will result from its stronger effects on
Iloperidone (Fanapt) is less likely to cause drug-induced parkinsonism, akathisia,
and hyperprolactinemia than the typical antipsychotics, but has a risk of moderate
weight gain, orthostasis, and the potential to cause QT interval prolongation that can
be of concern in some patients.
94,95 Asenapine (Saphris) needs to be administered
sublingually for rapid and adequate absorption. It has an absolute bioavailability of
35% when taken sublingually and less than 2% when swallowed. The patient should
be counseled not to eat or drink for 10 minutes after the sublingual administration.
The most common adverse reactions (≥5% and at least twice the rate of placebo) are
somnolence, dizziness, extrapyramidal symptoms other than akathisia, and weight
taken with food (about 350 calories or more) for adequate absorption. The most
common adverse events associated with lurasidone treatment are nausea, vomiting,
akathisia, dizziness, and sedation (Table 85-6).
All antipsychotic medications have at least some D2 antagonistic effects. These
antipsychotic medications have been divided into two major classes depending on
whether or not they substantially antagonize 5-HT2a
dopaminergic ones. Although activity in attenuating dopamine transmission in the
mesolimbic pathway is seen as being beneficial in decreasing the severity of positive
schizophrenic symptomatology, decreased activity of dopamine receptors in
mesocortical pathways (sometimes due to antipsychotic medication) may relate to the
severity of negative symptoms. Antagonism of 5-HT2
SGAs may balance decreased dopaminergic neurotransmission and decrease their
relative propensity to cause tardive dyskinesia.
Antipsychotic choice is based upon a number of factors, many of which are patient
specific. In making a selection, consider such patient factors as treatment history (if
any), medical comorbidities and concurrent medications, patient preferences, and
potential cost concerns. If the patient has a known history of being treated with
antipsychotics, this can help guide current selection. Previous positive response to an
antipsychotic is a good indicator of future response, just as previous lack of response
would recommend against trying that agent in the future. History of adverse effects to
particular agents is useful also. If a patient is known to have had an adverse event to
a specific agent in the past that would preclude them from receiving this agent again
(including a patient’s stated preference for this reason), then this will help guide
current medication selection. Additionally, if an adverse effect led to medication
discontinuation or poor adherence in the past, an antipsychotic should be selected
that has a minimal risk of causing that adverse effect in the future. If information
about a patient is not available, particularly in newly diagnosed patients with no
prior treatment, medication history for a first-degree relative with schizophrenia may
be useful in selecting an agent for the patient in a similar manner.
One area of debate has been selecting between FGAs and SGAs. Studies
comparing the two classes head-to-head have shown similar efficacy rates between
99,100 Where the older agents are more prone to cause movement disorders, such
as extrapyramidal syndromes (EPSs), the newer agents are thought to be more prone
to causing metabolic disturbances in patients. Although SGAs are widely considered
first choice in clinical practice,
101 most treatment guidelines now consider either
FGAs or SGAs (other than clozapine) as potential first-line choices for treatment,
depending upon the patient factors described above.
CASE 85-1, QUESTION 6: Which type of antipsychotic medication would you recommend for J.J. at this
time? What factors would you use to select a treatment regimen for her?
As J.J. has never been treated with an antipsychotic before, most any type is
potentially viable as a treatment. Atypical antipsychotics would most likely be
preferable. Typical antipsychotics, while efficacious, might lead to significant
extrapyramidal or other adverse effects that she might not tolerate well, possibly
leading to nonadherence. Also, with chronic usage typical antipsychotics (FGAs) are
more likely to cause tardive dyskinesia than SGAS. As she is young and fairly
irregularities. Pharmacoeconomic considerations should also be taken into account,
as some of the atypical antipsychotics are available generically and some are not.
In light of J.J.’s acute psychotic symptoms and agitation, a combination of both
antipsychotics and adjunctive agents should be considered at this time. Although
antipsychotics are generally the mainstay of schizophrenia treatment, they may not
reduce symptoms quickly enough. Benzodiazepines may also be useful, especially
during periods of increased agitation. Use of adjunctive medications to treat any
adverse effects, such as EPS, may also be needed. Depending upon J.J.’s compliance
to oral medications or during any periods of increased agitation, intramuscular (IM)
injections of medications, including antipsychotics, benzodiazepines, and side effect
medications, may need to be utilized acutely.
Although there are numerous studies demonstrating the efficacy of current
antipsychotic medications in comparison with placebo and accepted treatment, more
attention has been paid of late to effectiveness studies comparing currently available
antipsychotics. These effectiveness trials are intended to show the comparative value
of these agents in situations that are more comparable to routine clinical care by
utilizing less stringent eligibility criteria, longer duration, prospective design, and
in bridging the chasm between studies in ideal populations and routine clinical care.
One of the landmark effectiveness trials comparing antipsychotic agents is the
National Institute of Mental Health (NIMH) funded Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) trial. The first phase of the CATIE trial
compared the SGAs quetiapine (n = 329), ziprasidone (n = 183), risperidone (n =
333), and olanzapine (n = 330) with the middle-potency FGA perphenazine (n =
257). The main outcome variable was time to discontinuation of the antipsychotic for
any cause. Overall, 74% of the patients discontinued treatment over the 18-month
course of the study. This study showed significantly less medication discontinuation
(p <.001) in olanzapine-treated patients (64%) than in those receiving quetiapine
(82%) or risperidone (74%). After adjusting for multiple comparisons, the difference
between olanzapine and ziprasidone or perphenazine did not reach significance.
When analyzed separately, the discontinuation rates due to intolerability were
substantially higher in the olanzapine-treated patients, but there was a significantly
greater time to discontinuation with olanzapine compared to quetiapine, risperidone,
and perphenazine. The lowered number of patients in the ziprasidone group reduced
the power (and thus chance to find difference) for comparisons with this agent and
the others. The 18-month duration of the study could not yield information on the
long-term effects of these agents in causing tardive dyskinesia or metabolic
Second-Generation Antipsychotics (SGAs)
Name(Generic/Brand) Dosage Forms
Aripiprazole (Abilify) Tablet: 2, 5, 10, 15, 20, 30
Asenapine (Saphris) Sublingual tablet: 5, 10 mg Initial: 5 mg BID (no
Brexpiprazole (Rexulti) Tablet: 0.25, 0.5, 1, 2, 3, 4
Cariprazine (Vraylar) Capsule: 1.5, 3, 4.5, 6 mg Initial: 1.5 mg day 1, inc.
Clozapine (Clozaril) Tablet: 12.5, 25, 50, 100,
Iloperidone (Fanapt) Tablet: 1, 2, 4, 6, 8, 10, 12
Lurasidone (Latuda) Tablet: 20, 40, 80, 120 mg Initial: 40 mg daily taken
Olanzapine (Zyprexa) Tablet: 2.5, 5, 7.5, 10, 15,
Paliperidone (Invega) Tablet (ER): 1.5, 3, 6, 9
Quetiapine (Seroquel) Tablet (IR): 25, 50, 100,
Risperidone (Risperdal) Tablet: 0.25, 0.5, 1, 2, 3, 4
Ziprasidone (Geodon) Capsule: 20, 40, 60, 80 mg
Patients who discontinued treatment were eligible for enrollment in phase two of
the CATIE to receive a different antipsychotic if they dropped primarily for lack of
tolerance or efficacy. Those primarily not responding in the earlier phase could
instead enter in the phase two trial in which there was a clozapine treatment arm.
In the lack of tolerability arm, patients assigned to olanzapine (n = 68) or risperidone
(n = 70) showed longer time to discontinuation rates than those receiving either
quetiapine (n = 63) or ziprasidone (n = 135).
In the poor responder study arm,
patients receiving clozapine (n = 45) showed a significantly lower (p <.05) time to
discontinuation of treatment than those receiving either olanzapine (n = 17),
quetiapine (n = 14), or risperidone (n = 14).
107 The third phase of the CATIE trial
involved with the 270 patients who discontinued treatment in the earlier phases, who
went on to receive either aripiprazole, clozapine, olanzapine, perphenazine,
quetiapine, or risperidone. The lack of power made it difficult to show any
differences in effectiveness between these agents, and in this open trial few patients
received either perphenazine (n = 4) or fluphenazine decanoate (n = 9).
each subsequent phase of CATIE, statistical power was reduced as compared to the
original study due to subject attrition, thereby increasing type II error.
Another often cited study is the Cost Utility of the Latest Antipsychotic Drugs in
Schizophrenia Study (CUtLASS 1) in which 227 patients were randomized to receive
either FGAs (n = 118) or to be treated with a SGA (n = 109). This pragmatic,
nonindustry-funded study was powered only to compare the overall differences
between FGA and SGA groups and not the individual antipsychotics themselves. The
hypothesis that second-generation medications would have an advantage on any
quality of life measures over first-generation medications was disproven.
CUtLASS 2 study was similarly designed and compared clozapine to other SGAs in
patients who did not respond sufficiently to two prior treatments. Patients on
clozapine showed significant improvements on PANSS scores (p < .01) and felt they
did much better (p < .05), and there was a trend for improvement (p =.08) on their
quality of life as measured on the QLS.
SGAs have also shown better response and remission rates than haloperidol in
111 Meta-analyses and related techniques have been utilized to
attempt to overcome limitations of low power in comparative antipsychotic efficacy
trials. One meta-analysis looked at 150 double-blind RCTs in over 20,000 patients
and found only amisulpride (not available in USA.), clozapine, olanzapine, and
risperidone to be more effective than the FGAs. The SGAs showed fewer EPS and,
with the notable exception of aripiprazole and ziprasidone, caused more weight gain
than haloperidol. However, there were no significant differences in weight gain
between the low-potency typical antipsychotics such as chlorpromazine and the
combination use is a relatively common practice,
it is not recommended due to the
paucity of evidence for its safety and efficacy
; in fact, combination antipsychotic
therapy is often targeted by quality improvement programs.
situations (i.e., adding aripiprazole to a patient stabilized on risperidone to attenuate
hyperprolactinemia) in which this use can be logical and beneficial,
are other times when treatment-resistant patients should receive alternative approved
effective pharmacotherapy with clozapine.
Antipsychotics are commercially available in a variety of dosage forms to allow for
different treatment situations and settings. The most common forms consist of orally
administered products such as tablets/capsules (both short-acting and long-acting
forms), orally disintegrating tablets (ODTs), and oral liquid solutions/suspensions.
Many antipsychotics are also available as injectables, some as short-acting IM forms
and some as long-acting IM forms. Selection of an appropriate dose form can depend
upon factors such as the severity of the patient’s illness and risk of imminent harm to
themselves or others, willingness or ability to take medications, and treatment setting.
Although most every antipsychotic is available as a traditional tablet or capsule,
many are available in other oral dosage forms. In an effort to help with adherence,
several antipsychotics are available as either oral liquids or ODTs. The SGAs such
as aripiprazole, risperidone, and ziprasidone are available as oral liquids, which
may be useful in patients who have a hard time swallowing traditional tablets (or
won’t swallow them) or to achieve more specific dosing, such as might be needed
for pediatric or geriatric patients. ODTs are formulated to dissolve rapidly when
placed on the tongue, needing only for the patient to swallow their own saliva to
obtain medication absorption in the gut. This formulation is particularly useful in the
inpatient setting when “cheeking” or nonadherence is suspected. Aripiprazole,
clozapine, olanzapine, and risperidone are available as ODTs, and asenapine is
available only as a sublingually dissolving tablet.
The short-acting injectable formulations of antipsychotics are frequently utilized in
the acute phase of illness. Patients presenting to psychiatric emergency services are
often in crisis and can be at risk of harm to themselves or others. If
nonpharmacologic de-escalation techniques fail and the patient refuses PO
medication, short-acting IM injections are effective in rapidly targeting agitation
related to psychosis. IM formulations avoid first-pass metabolism and thus are
approximately 2 to 4 times as potent as oral formulations and reach peak
concentrations within 30 to 60 minutes.
121 The FGAs such as haloperidol,
fluphenazine, and chlorpromazine, as well as the SGAs such as olanzapine,
ziprasidone, and aripiprazole are currently available in short-acting IM formulations.
There are currently no head-to-head trials comparing the efficacy of the available
short-acting IM SGAs. However, their efficacy and safety were evaluated in a
review of nine double-blind, randomized controlled trials. Data were extracted to
compare olanzapine, ziprasidone, and aripiprazole to either placebo or active
comparator (haloperidol or lorazepam) in order to calculate number needed to treat
(NNT) and number needed to harm (NNH).
122 All three of the agents demonstrated
superior efficacy to placebo, and the NNT was lowest for olanzapine and
ziprasidone. Olanzapine 10 mg demonstrated superiority compared to haloperidol
7.5 mg (NNT = 5). A low-dose of aripiprazole 1 mg IM was shown to be less
effective compared to haloperidol 7.5 mg IM (NNT = −5).
Ziprasidone IM did not have an active comparator such as haloperidol or lorazepam
IM. The adverse effect profiles of the SGAs differed significantly in terms of NNH,
though all three agents were associated with less EPS than haloperidol. Olanzapine
was associated with a NNH of 50 for treatment-emergent hypotension.
line with the manufacturer’s recommendation to avoid concomitant administration
with benzodiazepines. In one of the studies, aripiprazole demonstrated a NNH of 47
for akathisia when compared to placebo.
122 Data were not available to evaluate QTc
prolonging effects of ziprasidone IM in terms of NNH. The manufacturer’s guidance
states ziprasidone IM is contraindicated in patients with a known history of QT
prolongation, recent acute MI, or uncompensated heart failure. Caution should be
taken when given with other medications known to increase the QT interval (i.e.,
Class Ia and III antiarrhythmics, thioridazine, chlorpromazine, moxifloxacin, etc.) and
in patients with renal insufficiency due to the clearance of the cyclodextrin excipient
Haloperidol short-acting IM is commonly the preferred agent on hospitals’ acute
agitation protocols because of its proven efficacy, low risk for orthostasis, and its
ability to be administered with IM lorazepam, if necessary. The cost of haloperidol
may also be advantageous versus the SGAs, but cost of IM anticholinergics (e.g.,
benztropine) must be taken into account with its higher risk of EPS. Overall, the
short-acting IM dosage forms of the antipsychotic agents are a crucial piece of the
treatment team’s armamentarium and key to ensuring the safety of a patient with
agitation related to acute psychosis (Table 85-7).
Agents Used to Treat Acute Agitation
Haloperidol PO (tablet), IM 5–10 mg every
Fluphenazine PO (tablet), IM 1–2.5 mg every 6
Chlorpromazine PO (tablet), IM 50 mg (IM); 100
Ziprasidone PO (tablet), IM 10–20 mg every
IM, intramuscularly; IV, intravenously; ODT, oral disintegrating tablet; PO, orally.
Long-acting injectable antipsychotics (LAIAs) are an option for patients with a
frequency they need to make a decision to take medications. Oral antipsychotics
require daily recommitment to be adherent versus biweekly, monthly, or quarterly
with LAIAs. Lapses in adherence are also more apparent, and early interventions can
be initiated if a patient fails to show for an injection appointment. Effectiveness and
tolerability of the oral counterpart to an LAIA should be established prior conversion
to the LAIA. Equivalent dosages of LAIAs do not pose greater risk for adverse
effects than the oral antipsychotic with the exception of injection site pain.
take months to reach steady state concentration; therefore, making dose adjustments to
acutely target symptoms or manage adverse effects is inefficient.
A number of large-scale RCTs failed to demonstrate a significant benefit of LAIAs
over oral antipsychotic medications in relapse prevention in schizophrenia.
meta-analysis including a total of 5,176 patients enrolled in 21 RCTs of at least 6-
month duration found LAIAs did not reduce relapse compared to oral
126 This finding may be due in part to selection of a population of
subjects with greater engagement in treatment, more insight, and high adherence to
PO medications relative to the real-world patient population. Increased clinician
contact, implicit or explicit efforts to monitor adherence, and free study medication
also reduce the ability of RCTs to reflect relapse rates in more unstable patients who
are often prescribed LAIAs. A 2-year, double-blind RCT, conducted by Rosenheck
and colleagues, enrolled 369 patients with schizophrenia who were at risk of
127 The patients were assigned to LAI risperidone or PO
antipsychotic of clinician’s choice. No significant differences in psychiatric
hospitalization rates, symptoms of psychosis, or measures of social functioning were
found between groups. Mirror-image studies, which compare periods of treatment
with oral antipsychotics and LAIAs in the same patient, have been proposed as a
better method to capture the real-world effectiveness of LAIAs. A systematic review
and meta-analysis examined 25 mirror-image studies of 5,940 patients with
schizophrenia greater than 12 months (greater than 6 months each of oral and LAIA
treatment). LAIAs were superior to oral antipsychotics in preventing hospitalization
(16 studies, RR = 0.43; 95% CI, 0.35–0.53; p < .001) as well as decreasing number
of hospitalizations (15 studies, RR = 0.38; 95% CI, 0.28–0.51; p < .001). These
results should be interpreted with caution because mirror-image studies can have
intrinsic expectation bias and return to a stable status may reflect the natural course
Patients with recent-onset schizophrenia have inherently less understanding of the
importance of treatment and adherence and may benefit from treatment with LAIAs.
One RCT of LAI risperidone versus oral risperidone in 86 patients with recent-onset
schizophrenia demonstrated lower rates of relapse in the LAI risperidone group (5%
recommendation of switch to LAI risperidone (n = 26) or continuation of oral
antipsychotic (n = 11). Patients were followed for up to 104 weeks, and an initial
trend towards greater adherence was seen at 12 weeks (p = 0.058) for patients
accepting LAI risperidone. However, no significant difference was seen in time to
initial nonadherence during overall study duration.
Two high-potency FGAs, fluphenazine and haloperidol, are available as decanoate
ester long-acting injectable (LAI) formulations. Conversion to the LAI formulation of
haloperidol can be achieved either by administering 10 times the oral dose the
patient is stabilized on or by administering 20 times the oral dose for a loading dose
130 The loading dose regimen more rapidly achieves therapeutic serum levels
of haloperidol and allows for earlier discontinuation of oral medication.
standard conversion requires oral overlap with the current dose of oral haloperidol
for at least one month prior to being gradually tapered.
released faster than the haloperidol decanoate and achieves Tmax in approximately
24 hours. It is recommended that the oral medication be decreased by 50% upon
administration of the first injection and discontinued after the second injection.
There are not enough data to support a loading dose regimen for fluphenazine
decanoate. The standard oral to LAI conversion is 1.25 times the oral dose
administered every 2 to 4 weeks.
131 A double-blind study reported no difference in
relapse, symptoms, or adverse effects between groups stabilized on every 2-week
versus every 6-week injection intervals.
132 These results suggest dosing intervals
longer than the usual 2 to 4 weeks may be an option to reduce antipsychotic exposure
formation, or subcutaneous lumps. However, it is more painful than standard
SGAs currently available in LAI formulations are aripiprazole (Abilify Maintena
and Aristada), risperidone (Risperdal Consta), paliperidone (Invega Sustenna and
Invega Trinza), and olanzapine (Zyprexa Relprevv). Aripiprazole monohydrate
(Abilify Maintena) requires a 14-day oral overlap and is dosed monthly.
Aripiprazole lauroxil (Aristada), a prodrug of aripiprazole, requires a 21-day oral
overlap, but can be dosed every 4 weeks or every 6 weeks at the 882-mg dosage.
The normal starting dose of aripiprazole monohydrate for most patients will be 400
mg IM monthly. However, patients with renal impairment or concomitant
administration with strong CYP3A4 and 2D6 inhibitors or inducers for greater than
14 days require dose adjustments which are detailed in Table 85-8. Dosing of
aripiprazole lauroxil is converted from the oral dose requirement of each individual
(i.e., 10-mg oral aripiprazole equates to 441-mg injection).
LAI risperidone is administered every 2 weeks and requires an oral overlap of 3
weeks due to delayed release of risperidone from suspension in copolymer
microspheres. Less than 1% of the risperidone is released within the first 3 weeks
postinjection. Paliperidone palmitate (Invega Sustenna) is dosed monthly and does
not require oral overlap with the recommended loading regimen. In patients without
renal impairment, the initial loading regimen consists of a 234-mg deltoid injection
on day 1 followed by a 156-mg deltoid injection on day 8. Paliperidone palmitate
should be avoided in severe renal impairment (CrCl <50 mL/minute). Paliperidone
palmitate is also available in a formulation administered every three months (Invega
Trinza) for patients stabilized on the monthly formulation for a minimum of 4 months.
The dose of the 3-month formulation is 3.5-fold higher than the last dose of the
monthly formulation. However, there is minimal difference in injection volume
between the two formulations (1.5 mL for Invega Sustenna 234 mg vs. 2.625 mL for
LAI olanzapine (Zyprexa Relprevv) has an associated risk evaluation and
mitigation strategy (REMS) due to the risk of postinjection delirium/sedation
syndrome (PDSS). PDSS results from supratherapeutic levels of olanzapine caused
by accidental intravascular placement of the injection and rapid dissolution of
olanzapine pamoate. Symptoms mimic olanzapine overdose and can include sedation,
coma, and delirium. The administering facility must have available access to
emergency response services and monitor the patient for at least 3 hours postinjection
for signs and symptoms of PDSS. The risk of PDSS is 0.2% per injection, and history
of prior tolerability does not translate to a lower risk of PDSS for future injections.
LAI olanzapine distribution is restricted to the Zyprexa Relprevv Patient Care
Program that requires the prescriber, facility, patient, and pharmacy be enrolled prior
to releasing the injection. The high administrative burden placed on the facility and
patient to coordinate the postinjection monitoring limits its use in clinical practice.
Long-Acting Injectable Antipsychotics (LAIAs)
Dosages PO to LAI conversion Dosage Interval
400 mg IM Q month Initial: 400
Initiate with 234 mg IM on day
Sustenna Trinza Q3Months No Not
PO dose IM dose Initial: 25 mg IM
PHARMACOKINETICS AND DRUG INTERACTIONS
Pharmacokinetics and potential for drug–drug interactions are necessary
considerations for the safe and effective dosing of antipsychotic medications. One
key point to keep in mind is the difference between the time to therapeutic effect and
time to steady state plasma concentration. Response of positive symptoms of
schizophrenia can be seen within days of treatment initiation. However, it may take 4
to 7 days, or longer dependent on the half-life of the antipsychotic, to achieve steady
state plasma concentrations. The half-life of an antipsychotic may also be misleading
in determining dosing frequency. Most antipsychotics should be dosed once daily,
with the exception of asenapine and ziprasidone due to issues with absorption.
Ability to dose these agents once daily is in part due to higher concentration and
longer receptor occupancy in the CNS as well as longer duration of pharmacologic
effect than is reflected by the serum concentration.
134 During initial titration, split day
dosing is appropriate when targeting acute agitation or as the patient develops
tolerance to peak concentration-dependent adverse effects (i.e., sedation and
orthostatic hypotension). Once the patient can safely tolerate the medication, the dose
can be consolidated to bedtime to help reduce pill burden and increase patient
Antipsychotic drug interactions can be mediated through direct pharmacokinetic
(PK) interactions or by additive pharmacodynamic (PD) effects. PK interactions
usually involve phase I oxidative metabolism through the cytochrome P450 (CYP)
system; however, interactions can occasionally involve phase II metabolism (e.g.,
glucuronidation). Many antipsychotics undergo metabolism through CYP1A2, 2D6,
and 3A4 hepatic isoenzymes (see Table 85-9). The inhibition or induction of these
CYP enzymes can result in clinically relevant changes in antipsychotic serum levels.
For example, inhibition of CYP1A2 by the antidepressant fluvoxamine can cause a
significant elevation in clozapine serum level and place the patient at risk for serious
adverse effects, such as seizures. The reverse would be true for CYP1A2 induction.
To use the same example, if a patient were to begin taking a CYP1A2 inducer, such
as carbamazepine or phenytoin, the clozapine serum level would drop and place the
patient at risk for recurrence of psychotic symptoms. A common CYP1A2 inducer
that deserves special mention is cigarette smoke and the polyaromatic hydrocarbons
(PAHs) contained within that smoke. PAHs, not nicotine, are responsible for the
induction; therefore, it is important to note when an inpatient is stabilized on an agent
metabolized by CYP1A2 (e.g., clozapine, olanzapine, asenapine) the serum level can
drop by up to 50% if they resume smoking upon discharge. Many antidepressants and
mood stabilizers also have potent effects on CYP metabolism, so caution should be
taken when adding them to an antipsychotic regimen.
when an additional agent is added to a patient’s regimen that enhances an effect of the
antipsychotic activity at the receptor site without directly affecting the serum level of
the antipsychotic. For example, adding the potent anticholinergic agent benztropine to
an SGA with anticholinergic properties, such as olanzapine or clozapine, will
compound anticholinergic adverse effects such as constipation.
Pharmacokinetic Comparisons of Antipsychotics
Antipsychotic Agent Mean Half-Life (hours) Major Metabolic Pathway
First-Generation Antipsychotics (FGAs)
Haloperidol 18 CYP 2D6, CYP 3A4
Loxapine 6–8 None (minor—CYP 1A2, CYP
Second-Generation Antipsychotics (SGAs)
Aripiprazole 75–94 CYP 2D6, CYP 3A4
Brexpiprazole 86–91 CYP 2D6, CYP 3A4
Clozapine 8–12 CYP 1A2, CYP 3A4
Iloperidone 18–33 CYP 2D6, CYP 3A4
Olanzapine 21–54 CYP 1A2, CYP 2D6
Paliperidone 23 Limited CYP 2D6, CYP 3A4
Ziprasidone 7 Aldehyde Oxidase, CYP 1A2, CYP
Adapted from Facts & Comparisons eAnswers. http://online.factsandcomparisons.com/MonoDisp.aspx?
monoID=fandc-hcp10202. Accessed May 15, 2016, with permission.
PHARMACOECONOMIC CONSIDERATIONS
When the SGAs were first introduced in the 1990s, there was great concern over
their higher cost compared to the older antipsychotics. As the FGAs were all
available in cheaper generic forms, the newly marketed SGAs were still under patent
protection and therefore anywhere from 10 to 100 times higher the cost than their
138 From 1997 to 2007, the amount spent on outpatient
antipsychotic prescriptions in the US (not including the Veterans Affairs system)
increased from $1.7 billion/year to $7.4 billion/year.
percentage of overall US mental health expenses over this time period. As the SGAs
have slowly become available in generic forms, the concern about their higher costs
has decreased slightly, but cost differences still remain.
Although actual medication cost is commonly scrutinized when examining
schizophrenia treatment, it needs to be balanced against other costs associated with
the illness. Factors such as hospitalizations rates, outpatient service utilizations, and
patient functionality also need to be considered. One study examining the outcomes of
formulary restrictions of SGAs in over 100,000 Medicaid patients with
schizophrenia found that from 2001 to 2008 these restrictions increased
hospitalization rates by 13%, inpatient costs by 23%, and total Medicaid
expenditures by 16%, while only reducing medication expenses by 4%.
selecting an antipsychotic, medication costs should be considered, especially in light
of the costs to overall public health, along with other factors mentioned previously
such as efficacy and adverse effect profile.
One of the main factors in selecting an antipsychotic includes the adverse effect
profile of the agents being considered. Although many of these adverse effects are
common across most, if not all, antipsychotics, the incidence of these effects can vary
greatly. The common, class-wide adverse effects seen with these agents include EPS,
anticholinergic effects, cardiovascular effects, metabolic effects (including
hyperprolactinemia), and others.
As in treating any illness, a careful balance must be maintained between efficacy
and tolerability. When an adverse effect is discovered in a patient, evaluation of the
benefit-to-risk ratio of the medication should take place. Medication factors such as
the degree of benefit to the patient, the severity and frequency of the adverse effect,
and level of discomfort or distress to the patient should all be considered. In any
situation, the patient should be included in any decision regarding adverse effect
management. Unresolved adverse effects that significantly bother a patient can lead to
nonadherence and potential treatment failure.
If an adverse effect is determined to be fairly mild and cause minimal patient
distress, then it may not require any intervention beyond close monitoring to ensure it
does not worsen over time. Many adverse effects may be little more than a slight
annoyance and can be approached like this. As an adverse effect becomes more
severe or distressing to a patient, it may require more direct intervention. A reduction
in antipsychotic dose may be needed or addition of a secondary medication to treat a
particular adverse effect (described below) may be required. If truly warranted, the
antipsychotic may need to be changed to another agent where the likelihood of the
adverse effect might be lower. One potential factor to consider is the risk of
decompensation when changing antipsychotics. Antipsychotics share similar
pharmacologic effects and have similar efficacy rates, but not all antipsychotics may
be effective for a given patient.
When determined that a change in antipsychotics is warranted, either due to
adverse effects, poor efficacy, or both, there are several methods that can be
employed for switching. In instances where the change needs to be abrupt, perhaps
due to a serious or life-threatening adverse effect, an immediate discontinuation of
the old agent and initiation of the new agent should be considered. When more time
can be given to the change of agents, a cross-titration from one agent to the other can
be performed. In these instances, either the new agent can be increased over time as
the old agent is simultaneously reduced, or the new agent initiated at a therapeutic
dose followed by a downward taper of the old agent over time. The rates of these
medication increases and decreases are determined by the clinical presentation and
concerns for patient safety (Table 85-10).
Extrapyramidal Adverse Effects and Tardive Syndromes
receptors in the striatum by antipsychotics can also cause acute
adverse reactions such as dystonias (involuntary contractions of skeletal muscles)
and drug-induced parkinsonism (pseudoparkinsonism). Restoring the balance
between acetylcholine and dopamine in the striatum can reduce EPS, which is why
low-potency FGAs with appreciable anticholinergic activity (i.e., chlorpromazine
and thioridazine) can be less problematic than high potency in this regard. This can
also be done using anticholinergics such as benztropine or trihexyphenidyl, by using
amantadine, by lowering the dose of the antipsychotic, or by using an SGA instead.
However, some evidence suggests that changing patients to an SGA will not always
lead to the improvement in these movement disorders to the degree expected.
Acute dystonias are uncomfortable, sustained muscle contractions which can occur as
torticollis (involving the neck), the trunk, the tongue, or as an oculogyric crisis
(where the patient’s eyes appear to roll up in the head). Oculogyric crisis and
dystonias tend to present in the first few days of treatment. Symptoms are treated
using anticholinergic medications via IM administration for rapid efficacy (i.e.,
benztropine 2 mg IM stat). Scheduled oral administration of the chosen
anticholinergic agent is continued after acute symptom resolution. However, this
rapid treatment often does not help the attitude of affected patients towards their
caregivers when clinicians are trying to develop a therapeutic alliance with a patient
who may already be prone to suspicion or paranoia.
Drug-induced parkinsonism is the most common and reversible of adverse movement
effects. It consists of rigidity, masked face, slowed gait, and tremor. These symptoms
are short lived and easily treated. These occur most often in the first 3 months of
treatment. Drug-induced parkinsonism is a separate entity from idiopathic Parkinson
disease, which is a distinct illness on its own.
The high-potency FGAs are more likely to induce drug-induced parkinsonism than
the low-potency agents. Increased dosages of FGAs in higher-risk patients (i.e.,
medication naïve, female, advanced age) increase this risk. SGAs are on the whole
less likely to induce this syndrome. Clozapine and quetiapine are the least likely to
induce drug-induced parkinsonism and often can be used without worsening the
underlying movement disorder in patients with idiopathic Parkinson disease.
However, although clozapine has been robustly effective in these patients, reports
with quetiapine are conflicting.
Strategies for reducing or eliminating antipsychotic-induced parkinsonism include
lowering the dose of antipsychotic, switching to an atypical antipsychotic (with the
lowest risk choices being quetiapine or clozapine), or treating the patient with
antiparkinsonian medication. The antiparkinsonian medications often used are
anticholinergic agents such as benztropine (Cogentin; given from 0.5 mg BID to 2 mg
TID), trihexyphenidyl (Artane), biperiden (Akineton), diphenhydramine, or the novel
agent amantadine (Symmetrel; given from 100 to 400 mg daily in divided dosages).
The anticholinergic agents add to adverse effect and pill burden, and continuation is
often not necessary after 3 months. Amantadine causes less of these problems and
works by an alternate mechanism of action; it is not as effective as the
anticholinergics in many patients though.
142 Anticholinergic adverse effects are
discussed in greater detail in the “Anticholinergic Adverse Effects” section.
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