Search This Blog

468x60.

728x90

 


It is

metabolized by both 2D6 and 3A4 hepatic isoenzyme systems, and dose reductions

are recommended if these systems are inhibited.

89 Cariprazine (Vraylar) is

pharmacologically similar to aripiprazole and brexpiprazole in that it is an antagonist

at the D2

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

receptor than

the D2

receptor.

90

It is unclear what differences will result from its stronger effects on

D3

receptors.

91–93

p. 1789

p. 1790

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

gain.

96 Lurasidone (Latuda) is an effective agent with a low propensity to cause druginduced parkinsonism, metabolic complications, or QTc prolongation. It needs to be

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).

97

Mechanism of Drug Action

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

receptors as well as

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

receptors in the striatum by

SGAs may balance decreased dopaminergic neurotransmission and decrease their

relative propensity to cause tardive dyskinesia.

98

Selection of an Antipsychotic

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

them.

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.

102,103

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

healthy, we would also want to select an atypical antipsychotic with minimal longterm risks of metabolic adverse effects, such as weight gain and glucose

irregularities. Pharmacoeconomic considerations should also be taken into account,

as some of the atypical antipsychotics are available generically and some are not.

CASE 85-1, QUESTION 7: What pharmacologic agents should be considered first to treat JJ considering her

acute symptoms?

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.

EFFICACY

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

large sample size.

104 Still, they are randomized double-blind trials using intent-totreat analysis just as if they were efficacy studies. Interpreting these studies is a help

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

disorders.

64

p. 1790

p. 1791

Table 85-6

Second-Generation Antipsychotics (SGAs)

288–296

Medication

Name(Generic/Brand) Dosage Forms

Adult Dosing

Schedules Dose Adjustments

Aripiprazole (Abilify) Tablet: 2, 5, 10, 15, 20, 30

mg

ODT: 10, 15 mg

Injectable (short-acting):

9.75 mg/1.3 mL

Injectable (long-acting):

Initial: 10–15 mg/day,

titrate at 2 week intervals

Usual range: 15–40 mg

Max: 30 mg/day

Renal/Hepatic: No dose

adjustment necessary

300 mg/vial and 400

mg/vial

Solution: 1 mg/mL

Asenapine (Saphris) Sublingual tablet: 5, 10 mg Initial: 5 mg BID (no

benefit demonstrated with

higher doses)

Renal/Hepatic: No dose

adjustments necessary;

use not recommended in

severe hepatic impairment

Brexpiprazole (Rexulti) Tablet: 0.25, 0.5, 1, 2, 3, 4

mg

Initial: 1 mg days 1–4; 2

mg days 5–7; 4 mg day 8

Usual range: 4 mg daily

Renal: 3 mg max in CrCl <

60 mL/minute

Hepatic: 3 mg max in

Child-Pugh score ≥ 7

Cariprazine (Vraylar) Capsule: 1.5, 3, 4.5, 6 mg Initial: 1.5 mg day 1, inc.

to 3 mg day 2, inc. in 1.5–

3 mg increments as

needed

Usual range: 1.5–6 mg

Renal: Not recommended

in CrCl <30 mL/minute

Hepatic: Not

recommended in severe

impairment (Child-Pugh

score 10–15)

Clozapine (Clozaril) Tablet: 12.5, 25, 50, 100,

200 mg

ODT: 12.5, 25, 100 mg

Initial: 12.5–25 mg/day,

titrate by 25–50 mg/day to

target of 300–450 mg/day

Usual range: 350–600 mg

Max: 900 mg/day

Renal/Hepatic: No

specific recommendations

Iloperidone (Fanapt) Tablet: 1, 2, 4, 6, 8, 10, 12

mg

Initial: 1 mg BID, increase

by 2 mg/day to target dose

of 12–24 mg/day

Max: 24 mg/day

Renal: No adjustments

necessary

Hepatic: Use not

recommended

Lurasidone (Latuda) Tablet: 20, 40, 80, 120 mg Initial: 40 mg daily taken

with food

Usual range: 40–160

mg/day

Max: 160 mg/day

Renal: Initial dose of 20

mg/day and max of 80

mg/day in moderate–

severe impairment

Hepatic: Initial dose of 20

mg/day and max of 80

mg/day in moderate

impairment and max of 40

mg in severe impairment

Olanzapine (Zyprexa) Tablet: 2.5, 5, 7.5, 10, 15,

20 mg

ODT: 5, 10, 15, 20 mg

Injection (short-acting):

10mg/vial (5mg/ml after

reconstitution)

Injection (long-acting):

210, 300, 405 mg/vial

Initial: 2.5–10 mg/day

Usual range: 20–40

mg/day

Max: FDA recommended

max is 20 mg/day

Renal: Initial dose of 5

mg/day should be

considered

Hepatic: Childs Pugh

Class A and B, no

adjustment necessary

Paliperidone (Invega) Tablet (ER): 1.5, 3, 6, 9

mg

Injectable (long-acting):

39, 78, 117, 156, 234 mg

prefilled syringes

Initial: 6 mg/day; increases

should not exceed 3 mg

every 5 days

Usual range: 9–12 mg

Max: 12 mg/day

Renal:

CrCl 50–79 mL/minute:

initiate at 3 mg, max 6

mg/day

CrCl 10–49 mL/minute:

initiate at 1.5 mg, max 3

mg/day

CrCl <10 ml/minute: use

not recommended

Hepatic: Child-Pugh Class

A and B no adjustment

required

p. 1791

p. 1792

Quetiapine (Seroquel) Tablet (IR): 25, 50, 100,

200, 300, 400 mg

Tablet (ER): 50, 150, 200,

300, 400 mg

Initial (IR): 25 mg BID;

titrate in 25–50 mg

increments, given 2–3

times daily, to a target

range of 300–400 mg/day

by day 4; further

adjustments at 25–50 mg

increments with at least 2

days between

adjustments; usual range

300–750 mg/day

Initial (ER): 300 mg/day;

target 400–800 mg/day

Max: 800 mg/day

Renal: No specific

recommendations

Hepatic: Initiate IR tablets

at 25 mg/day and increase

by 25–50 mg/day

increments/day; initiate

ER tablets at 50 mg/day

and increase by 50 mg/day

increments

Risperidone (Risperdal) Tablet: 0.25, 0.5, 1, 2, 3, 4

mg

ODT: 0.5, 1, 2, 3, 4

Solution: 1 mg/mL

Injectable (long-acting):

12.5, 25, 37.5, 50 mg

Initial: 1–2 mg/day; usual

4–6 mg/day

Usual range: 4–8 mg/day

Max: 16 mg/day

Renal/Hepatic:

Recommend initial dose of

0.5 mg BID; may increase

dose 0.5 mg BID;

increases above 1.5 mg

BID should be completed

over 1 week intervals

Ziprasidone (Geodon) Capsule: 20, 40, 60, 80 mg

Injectable (short-acting):

20 mg/mL

Initial: 20 mg BID with

food; dose adjustments at

≥48 hour intervals

Max: 80 mg BID

Renal: No adj. necessary

in mild-mod. Impairment

use IM with caution

Hepatic: No adj.

necessary in mild-mod.

impairment

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.

105

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).

106

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).

108 Of note, at

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.

109 The

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.

109,110

SGAs have also shown better response and remission rates than haloperidol in

first-episode patients.

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

second-generation agents.

112

One controversial topic not clearly covered by effectiveness trials or metaanalysis is the use of combinations of antipsychotic medications.

113 Although

combination use is a relatively common practice,

114

it is not recommended due to the

paucity of evidence for its safety and efficacy

115,116

; in fact, combination antipsychotic

therapy is often targeted by quality improvement programs.

117 Although there are

situations (i.e., adding aripiprazole to a patient stabilized on risperidone to attenuate

hyperprolactinemia) in which this use can be logical and beneficial,

28,113,118,119

there

are other times when treatment-resistant patients should receive alternative approved

effective pharmacotherapy with clozapine.

120

DOSAGE FORMS

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.

p. 1792

p. 1793

Alternate Oral Dose Forms

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.

Short-Acting Injectables

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).

122 The available RCTs for

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.

122 This is in

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

through the kidney.

123

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).

Table 85-7

Agents Used to Treat Acute Agitation

121,296–303

Medication Dosage Form

Dosing

Schedule (As

Needed)

Onset

(minutes)

Max Dose/24

hours

Duration of

Action (hours)

Lorazepam PO (tablet), IM,

IV

1–2 mg 60–90 (PO); 15

(IM)

10 mg 8–10

Typical Antipsychotics

Haloperidol PO (tablet), IM 5–10 mg every

0.5–2 hours

30–60 minutes 30 mg Up to 24

Fluphenazine PO (tablet), IM 1–2.5 mg every 6

hours (tablet);

1.25 mg every 6

hours (IM)

Not available 10 mg 6–8

Chlorpromazine PO (tablet), IM 50 mg (IM); 100

mg (PO) every

1–4 hours

15–60 200 mg Not available

Atypical Antipsychotics

Olanzapine PO (tablet), IM,

ODT

5–10 mg every

2–4 hours

15–45 30 mg (IM), 20

mg (ODT)

24

Risperidone PO (tablet,

liquid), ODT

1–2 mg every

0.5–2 hours

60 4 mg Not available

Ziprasidone PO (tablet), IM 10–20 mg every

2–4 hours

30–60 40 mg 4

Aripiprazole PO (tablet,

liquid), IM, ODT

10–15 mg

(tablet); 9.75 mg

(IM) every 2

hours

1–3 hours 30 mg Not available

IM, intramuscularly; IV, intravenously; ODT, oral disintegrating tablet; PO, orally.

p. 1793

p. 1794

Long-Acting Injectables

Long-acting injectable antipsychotics (LAIAs) are an option for patients with a

history of medication nonadherence or in those patients that prefer LAIAs over oncedaily oral antipsychotics. LAIAs allow the patient the option to decrease the

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.

124 LAIAs

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.

125 A

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

antipsychotics.

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

psychiatric hospitalization.

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

of illness.

125

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%

vs. 33%).

128 Another prospective, open-label RCT randomized patients with firstepisode schizophrenia, schizophreniform, or schizoaffective disorder in a 2:1 ratio to

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.

129

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

regimen.

130 The loading dose regimen more rapidly achieves therapeutic serum levels

of haloperidol and allows for earlier discontinuation of oral medication.

124,130 The

standard conversion requires oral overlap with the current dose of oral haloperidol

for at least one month prior to being gradually tapered.

124 Fluphenazine decanoate is

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.

124,131

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

without risk of relapse. Both decanoate ester formulations require utilizing the “Ztrack technique” for administration. This prevents loss of medication, abscess

formation, or subcutaneous lumps. However, it is more painful than standard

injections.

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.

132

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

Invega Trinza 819 mg).

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.

p. 1794

p. 1795

Table 85-8

Long-Acting Injectable Antipsychotics (LAIAs)

304–311

Available

Dosages PO to LAI conversion Dosage Interval

Loading

Dose

PO

overlap

Fluphenazine

decanoate

25 mg/mL

(5 mL

multi-dose

vial)

10 mg PO = 12.5 mg

Q3weeks IM

Initial: 12.5–

25 mg

Target:

12.5–50 mg

Q2–4W No Decrease

PO by

50% after

1st

injection;

d/c PO

after 2nd

injection

Haloperidol

decanoate

50 mg/mL;

100 mg/mL

(1 mL

single-dose

vial & 5 mL

multi-dose

vial)

10–20 × PO dose 10–15 × PO

dose

administered

monthly;

max 100 mg

first injection

if naive to

haloperidol

decanoate

Q4W 20x PO

dose 1st

injection

then 10x PO

dose

maintenance

Continue

PO × 2–3

injections

if loading

dose not

used

Aripiprazole

monohydrate

(Abilify

Maintena)

300 & 400

mg kits

400 mg IM Q month Initial: 400

mg IM

monthly;

300 mg IM

monthly

(poor

CYP2D6

metabolizers,

concomitant

strong

CYP2D6 or

3A4

inhibitors, or

side effects

at higher

dose);

200 mg

monthly

(poor

CYP2D6

metabolizers

taking

CYP3A4

inhibitors,

concomitant

strong

CYP2D6

and 3A4

inhibitors)

Q month No Continue

PO × 14

days

Aripiprazole

lauroxil

(Aristada)

441, 662,

882 mg

PO Dose

(mg)

IM Dose (mg) Initial: 441,

662, or 882

mg monthly

Q4–6W No 21 days

10 441

15 662 depending

on PO dose

882 mg may

be given

Q6W

≥20 882

Olanzapine

pamoate

(Zyprexa

Relprevv)

210, 300, &

405 mg kits

PO

dose

IM

dose

first 8

weeks

IM dose

maintenance

Initial: 150–

300 mg IM

Q2W or 405

mg Q4W

Target: 300

mg Q2W or

405 mg

Q4W

Q2W or

Q4W

Yes Not

required

10

mg/day

210

mg

Q2W

or 405

mg

Q4W

150 mg

Q2W or 300

mg Q4W

15

mg/day

300

mg

Q2W

210 mg

Q2W or 405

mg Q4W

20

mg/day

300

mg

Q2W

300 mg

Q2W

p. 1795

p. 1796

Paliperidone

palmitate

(Invega

Sustenna)

39, 78,

117,

156, &

234 mg

kits

Initiate with 234 mg IM on day

1 and 156 mg IM on day 8

(both deltoid)

Mild renal impairment (CrCl

≥50 mL/minute and <80

mL/minute): Initiate with 156

mg IM on day 1 then 117 mg

IM day 8

PO dose IM dose Q4W Yes Not

required 3 mg/day 39–78

mg

6 mg/day 117 mg

12 mg/day 234 mg

Mild renal

impairment

78 mg

Paliperidone

palmitate

(Invega

Trinza)

273,

410,

546, 819

mg

Convert from Invega Sustenna

dosage

Sustenna Trinza Q3Months No Not

required 78 273

117 410

156 546

234 819

Risperidone

long-acting

injection

(Risperdal

Consta)

12.5, 25,

37.5, 50

mg dose

packs

PO dose IM dose Initial: 25 mg IM

Q2W with PO

overlap × 3W

Target: 25–50 mg

IM Q2W

Q2W No Continue

PO × 3

weeks

2–3 mg 25 mg

4–5 mg 37.5 mg

6 mg 50 mg

p. 1796

p. 1797

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

adherence.

135

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.

136,137 PD interactions occur

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.

Table 85-9

Pharmacokinetic Comparisons of Antipsychotics

Antipsychotic Agent Mean Half-Life (hours) Major Metabolic Pathway

First-Generation Antipsychotics (FGAs)

Chlorpromazine 24 CYP 2D6

Fluphenazine 14–16 CYP 2D6

Haloperidol 18 CYP 2D6, CYP 3A4

Loxapine 6–8 None (minor—CYP 1A2, CYP

2D6, & CYP 3A4)

Perphenazine 9–12 CYP 2D6

Trifluoperazine 3–12 CYP 1A2

Thioridazine 5–27 CYP 2D6

Thiothixene 34 CYP 1A2

Second-Generation Antipsychotics (SGAs)

Aripiprazole 75–94 CYP 2D6, CYP 3A4

Asenapine 24 UGT1A4, CYP 1A2

Brexpiprazole 86–91 CYP 2D6, CYP 3A4

Cariprazine 48–336 CYP 3A4

Clozapine 8–12 CYP 1A2, CYP 3A4

Iloperidone 18–33 CYP 2D6, CYP 3A4

Lurasidone 18 CYP 3A4

Olanzapine 21–54 CYP 1A2, CYP 2D6

Paliperidone 23 Limited CYP 2D6, CYP 3A4

Quetiapine 7 CYP 3A4

Risperidone 3–20 CYP 2D6

Ziprasidone 7 Aldehyde Oxidase, CYP 1A2, CYP

3A4

Adapted from Facts & Comparisons eAnswers. http://online.factsandcomparisons.com/MonoDisp.aspx?

monoID=fandc-hcp10202. Accessed May 15, 2016, with permission.

p. 1797

p. 1798

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

older counterparts.

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.

139 This represents a large

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%.

140

In

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.

ADVERSE DRUG REACTIONS

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

The blocking of D2

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.

141

Dystonia

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.

142

Parkinsonism

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.

143–145

However, although clozapine has been robustly effective in these patients, reports

with quetiapine are conflicting.

75

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.

p. 1798

p. 1799

No comments:

Post a Comment

اكتب تعليق حول الموضوع

mcq general

 

Search This Blog