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Another concern is that, along with known genetic factors,

209 metabolic syndrome

issues such as increased weight, serum leptin, lipids, and glucose are known risk

factors for venous thromboembolism (VTE) which also may occur in association

with antipsychotic pharmacotherapy.

210,211 The most established link is to the use of

clozapine,

212 which is one of the most metabolically problematic agents. However,

even more metabolically benign antipsychotics may eventually be linked to the

increased occurrence of VTE.

213 Pulmonary embolism is a well-documented variant

occurring with antipsychotics.

214,215 As VTE related to antipsychotics is likely rare,

the benefit-to-risk ratio should be kept in perspective.

216

Other cardiovascular effects can be problematic when utilizing antipsychotic

pharmacotherapy. Of concern, olanzapine, risperidone, and quetiapine have been

associated with a three-fold increased likelihood of cerebrovascular accidents

(CVAs) and transient ischemic attacks during the first 6 months of treatment in

elderly patients.

217,218 Other antipsychotics have also been implicated.

219 Such events

could relate to the slightly higher risk of death in elderly patients receiving these

medications.

220 As a result, all antipsychotics have a black box warning from the US

FDA regarding an increased risk of CVAs in elderly patients taking these

medications.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a rare, but potentially fatal complication

of antipsychotic therapy that can occur due to treatment with any antipsychotic or

abrupt cessation of a dopamine agonist. Therefore, early recognition and management

are crucial. There are numerous diagnostic scales to ensure accurate diagnosis of

NMS for research purposes, but the most widely utilized in clinical practice is the

DSM-5 criteria. NMS is associated with high fever (103°F–104°F), muscular

rigidity, altered consciousness, and highly elevated creatinine phosphokinase (CPK)

often greater than 1,000 mcg/L. Other signs are drooling, difficulty swallowing, fast

heart rate (greater than 100 bpm) profuse sweating, incontinence, and labile blood

pressure. It is treated by immediate cessation of antipsychotic therapy, supportive

care, and the administration of medications such as dantrolene sodium, biperiden, or

bromocriptine. Combination antipsychotic therapy was found in 39% of all NMS

cases.

221 Some believe that physical exhaustion and dehydration predispose a patient

to develop NMS, so it is important that patients on antipsychotics be cautioned to

take proper caution in hot weather. Also, the effects of antipsychotics on the

hypothalamus (which regulates temperature and food intake among other activities)

and the "body-secretion" drying activities of anticholinergic medications increase the

danger of heat exhaustion in these patients.

222

CASE 85-1, QUESTION 25: J.J.’s psychiatrist decides that in light of her weight gain and worsening glucose

and lipid profiles, he is going to change her from olanzapine to lurasidone, titrating her up to 80 mg/day. She did

well with the medication change. A few weeks after starting the lurasidone, her parents take JJ into the ER one

evening concerned she has meningitis as she feels feverish, is sweating, seems confused, and has a stiff neck.

The ER exam shows JJ has a fever of 103.1°F, blood pressure of 176/98 mm Hg, pulse of 136 bpm, respiratory

rate of 36 bpm, a stiff neck that is not painful, and is sometimes incoherent when answering questions, but

shows no outward signs of psychosis. She also is sweating profusely despite the air conditioning in the ER

room. Laboratory work is ordered and returns a couple hours later. J.J.’s chemistries are normal except for a

creatinine phosphokinase (CPK) of 5,960 mcg/L, a normal CBC, and a normal serum glucose. Repeat vital

signs 2 hours after she comes to the ER show a fever of 103.2°F, blood pressure of 96/62 mmHg, pulse of 146

bpm, and a respiratory rate of 39 bpm. What is the most likely cause of J.J.’s presentation at this time and why?

How should J.J. be managed?

J.J. is most likely suffering from neuroleptic malignant syndrome (NMS) from

lurasidone. Although NMS can occur at any time during treatment with any

antipsychotic, the timing of this episode shortly after beginning the medication makes

it more likely. As she does not have pain in her neck or an elevated WBC, it is not

likely meningitis as her parents feared (though this should be definitively ruled out).

The high fever, labile blood pressure, tachycardia, sweating, confusion (without

psychosis), and highly elevated CPK are indicative of NMS. J.J. will need to be

admitted to the hospital as NMS can be life-threatening. As she will need to stop

taking all antipsychotics for up to 2 weeks, she will most likely require

hospitalization during this time as her psychosis is

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likely to return. During the acute treatment period, she will likely need treatment

for the NMS with either dantrolene (for the fever) or bromocriptine (a dopamine

agonist), as well as other measures as needed for her fever, elevated blood pressure,

etc. During the longer period without antipsychotic treatment while waiting for the

NMS to resolve, J.J. will likely need treatment with sedatives such as

benzodiazepines as we cannot actively treat her schizophrenia.

CASE 85-1, QUESTION 26: During the subsequent admission for her episode of NMS, J.J. is eventually

started on aripiprazole for her schizophrenia. A few days into titrating the medication to an effective dose, she

develops some mild stiffness in her arms, most likely some mild parkinsonism. Fearful that this is the NMS

returning, J.J. now refuses to take any antipsychotics. Her psychiatrist decides to start her on a LAIA form of

aripiprazole, but notices there are two different versions of the medication available. Which of these two forms

would be the better choice for J.J. at this time?

Ideally we would be able to stabilize J.J. on an oral form of aripiprazole prior to

conversion to a LAIA form of the medication, but her nonadherence makes that

unlikely. Both forms of aripiprazole LAIA require an overlap of oral medication

during initiation: 14 days for the monohydrate salt and 21 days for the lauroxil salt.

The main concern is the dosing of the LAIA, however. The monohydrate salt has a

single dose for all patients, except in cases of renal impairment of P450 inhibitors or

inducers. The lauroxil salt is dosed based upon a conversion from the dose of oral

aripiprazole the patient is currently receiving. As J.J. was never stabilized on an oral

dose of aripiprazole before she stopped taking the medication, it would be very

difficult to convert her over to an equivalent dose of the lauroxil LAIA. Therefore, it

would be easier to initiate the monohydrate salt version at its usual dose of 400 mg

every month and then try to provide coverage for the initial 14-day window

recommended for the product. Regardless of which form is used, J.J. should be

monitored for the development of the parkinsonism she had when being titrated on the

oral form of aripiprazole.

CASE 85-1, QUESTION 27: Over the next few months, J.J. is maintained on aripiprazole monohydrate

LAIA 400 mg/month. As her symptoms improved but she was still showing some signs of daily auditory

hallucinations, haloperidol 5 mg/day was added to her regimen. Her hallucinations subsided within a couple

weeks after an increase to 10 mg/day of haloperidol, but now J.J. comes in with her parents to the ER attached

to the clinic. J.J.’s neck is turned clockwise to her right shoulder, and she is unable to move her head back to

her centerline and look forward. J.J. says her neck hurts a lot and she wants this feeling to go away. What is

the most likely reason for J.J.’s current complaint and how should it be managed?

J.J. is most likely experiencing a dystonic reaction, or dystonia, from the recent

addition and increase in her haloperidol dose. The specific type of dystonia she has

is called torticollis, which is dystonia causing the muscles of the upper spine to

contract and cause a twisting motion of the neck. This is another type of EPS, and as

seen in J.J. here, can often be painful due to the strong muscle contraction. FGAs are

more likely to cause this problem than SGAs, so the timing of the reaction to the

addition of haloperidol makes sense.

Acutely, J.J.’s dystonia needs to be treated as quickly as possible as it is painful to

her. Oral medications could take an hour or longer to work, so an injectable agent is

preferred for more rapid action. As with drug-induced parkinsonism, the agent of

choice is an anticholinergic medication to offset the EPS. Most ER’s will have either

benztropine or diphenhydramine (which has appreciable anticholinergic effects)

readily available in an IM/IV form for a case like this. Atropine, while also likely

available, is generally not used due to greater systemic and cardiac effects.

Benzodiazepines can also be used in IM/IV forms if needed, as they too will help

relax the contracted muscles and help J.J. calm down.

Additionally, J.J.’s medication regimen may need to be adjusted to prevent a future

dystonic reaction. A reduction in her haloperidol dose may be needed, or adjunctive

oral anticholinergics added to her regimen as prophylaxis.

CASE 85-1, QUESTION 28: J.J. has been continued on the combination of aripiprazole monohydrate LAIA

and haloperidol over the next 8 years. Over time her symptoms have returned periodically, never requiring a

hospitalization but necessitating gradual increases in her haloperidol to 15 mg/day. J.J. now presents to the clinic

with “shakes in my hands” that are bothering her. During the physical examination, J.J. is noted to have facial

grimacing, darting movements of her tongue, lip-smacking, and twisting movements in her hands. The

movements in her hands seem to disappear when she grabs an object or performs other activities with her

hands. What is the most likely cause of these movements in J.J.?

These movements are most likely an early form of tardive dyskinesia. Haloperidol,

as a high-potency FGA, has a high risk of causing this movement disorder over time:

approximately 3% to 5% per year of use, or 24% to 40% risk in J.J. The symptoms

we are observing in J.J. are consistent with those movements seen in tardive

dyskinesia which presents with arrhythmic choreoathetoid “snake-like” movements

of the orofacial areas, limbs, and trunk. The fact that the irregular hand movements

stop or decrease when J.J. performs a conscious task with her hands is also

indicative of tardive dyskinesia.

CASE 85-1, QUESTION 29: What can be done to treat the tardive dyskinesia seen in J.J. at this time?

Although there are no definitive treatments for tardive dyskinesia, there are some

strategies that might help to alleviate the problem. Slow decreases in her haloperidol

dose over time may help these movements decrease; a rapid reduction in the dose

may acutely worsen the problem, so this should be avoided. If the movements persist

despite lowering the dosage or discontinuing the haloperidol, there are some data

supporting the use of clozapine to treat the dyskinesia and schizophrenic symptoms.

This should be considered cautiously in light of the other concerns related to

clozapine treatment.

Inadequate Response

The patient with chronic schizophrenia must be evaluated in a systematic fashion to

discern whether past medication trials were indeed medication failures. Medication

nonadherence, intolerance, and inadequate dosing may often be documented as failed

trials. Patients with schizophrenia have been shown to have a deficit in perspective

habitual memory which may cause difficulty in remembering whether they took their

medications.

223 This could result in either missed or doubled dosages. An in-depth

assessment of medication adherence should be conducted in a nonpunitive and

collaborative fashion with the patient. Outreach for collateral information should

also be undertaken after acquiring appropriate releases of information. Clinical

deterioration often occurs slowly and insidiously with incomplete medication

adherence.

224 Poor therapeutic relationship and social supports may also lead to poor

adherence in patients with schizophrenia.

225 Other important predictors include lack

of insight, concomitant substance abuse, a short illness duration, issues with

discharge planning and

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environment,

226 as well as higher levels of hostility.

227 Patients who have had

difficulties with medication adherence in the past should be offered treatment with a

long-acting injectable antipsychotic.

A trial of an antipsychotic should be continued for at least 4 to 6 weeks at a

therapeutic dosage after initial partial response of symptoms. Switching and

augmentation strategies should only be considered after symptoms fail to fully

respond to an adequate trial. Patients may wind up in a stalled cross-titration,

possibly due to a transition in care, and be continued on multiple antipsychotics. This

highlights the need to carefully tease out the patient’s medication experience and

transition to effective monotherapy to avoid increased adverse effects, pill burden,

and cost for the patient.

Between 20% and 30% of patients remain unresponsive despite multiple

antipsychotic trials. The most commonly adopted and most stringent criteria for

antipsychotic treatment refractoriness were proposed in the landmark trial conducted

by Kane and colleagues that resulted in clozapine’s approval in the U.S. market.

Treatment refractoriness was defined as: (1) at least three periods of treatment in the

preceding 5 years with antipsychotics from two chemical classes at dosages

equivalent or greater to 1,000 mg/day of chlorpromazine for a period of 6 weeks, (2)

no symptom-free period within 5 years, and (3) BPRS total score >45.

57,228

Clozapine is the most efficacious medication in patients with treatment-resistant

schizophrenia and should be considered in all patients who fail to respond to at least

two adequate antipsychotic trials.

57,107,172,229

It is also the treatment of choice for those

at high risk for suicide or violence, or in patients with TD.

102,230 Despite its superior

efficacy, clozapine is often underutilized in the treatment of resistant schizophrenia

due to its adverse effect burden. Close monitoring and follow-up are necessary to

ensure safe and effective use of clozapine. Baseline monitoring should include a

physical examination (weight, blood pressure, waist circumference), HbA1c or

fasting blood glucose, a fasting lipid panel, liver function tests, serum creatinine,

blood urea nitrogen levels and pregnancy test, if indicated. Clozapine has a unique

adverse effect profile that ranges from common bothersome adverse effects to lifethreatening adverse effects listed in its five black box warnings. The black box

warnings caution for risk of agranulocytosis, seizures, myocarditis, other adverse

cardiovascular and respiratory effects, and increased mortality in elderly patients

with dementia-related psychosis.

Agranulocytosis is a rare, yet potentially life-threatening, hematologic reaction

affecting approximately 1% of clozapine-treated patients. It is defined as a drop in

neutrophil count below 500 cells/mm3

. Agranulocytosis is not dose-related and can

occur at any point in treatment though the risk is higher within the first 6 months of

therapy. Clozapine may also cause mild-to-severe neutropenia (ANC 500–2,000

cell/mm3

). Clozapine-induced neutropenia and agranulocytosis may be in part due to

selective effect on precursors of polymorphonuclear leukocytes; however, the

mechanism remains to be fully elucidated. Clozapine is only dispensed through the

clozapine risk evaluation and monitoring strategy (REMS) to ensure ANC values are

within range prior to dispensing clozapine. The pharmacy, patient, and provider must

all be enrolled in the clozapine REMS program. Monitoring of the absolute

neutrophil count (ANC) must occur 7 days prior to initiation of clozapine and weekly

thereafter for the first 6 months. Monitoring frequency can be reduced to biweekly for

the next 6 months if all ANC values are within range (>1,500/μL). Frequency of

blood draws may be decreased to every 4 weeks if all values remain within range

after 6 months of biweekly monitoring, and be maintained at every 4 weeks for the

duration of clozapine treatment if no abnormalities are seen. Certain ethnic groups,

including patients of African and Middle Eastern descent, may average a lower ANC

value than normal ranges, called benign ethnic neutropenia (BEN). The clozapine

REMS program allows for lower ANC values to compensate for patients diagnosed

with BEN as they do not suffer from repeated or severe infections as a result of their

low baseline ANC values. Severe neutropenia can be deadly due to the body’s

inability to fight off infection. This is a medical emergency that requires the abrupt

discontinuation of clozapine. In other cases, clozapine should be discontinued

gradually over a period of 2 weeks or longer, to prevent cholinergic rebound

(sweating, headache, nausea, vomiting, diarrhea) or recurrence of psychotic

symptoms. The patient should not be rechallenged on clozapine after agranulocytosis,

but patients can be successfully rechallenged after neutropenia.

231 More information

can be found at https://www.clozapinerems.com/ (Table 85-13).

Seizure risk associated with clozapine is a dose-related phenomenon. Risk of

seizure is 4.4% at a dose of 600 mg and several case reports implicate serum levels

greater than 500 to 1,300 ng/mL with higher risk of seizure.

232,233 Prophylactic use of

antiepileptic drugs (AED) is generally not recommended.

234 However, patients that

experience a seizure on clozapine can be safely continued on a lower dose of

clozapine and initiated on an AED. Valproate and lamotrigine are preferred over

carbamazepine due to its risk of agranulocytosis and extensive interaction profile.

233

Myocarditis is a potentially fatal hypersensitivity reaction that can occur

approximately 3 weeks after initiation of clozapine. Diagnosis is confounded by the

variable and nonspecific signs and symptoms of its presentation, but the incidence is

estimated to fall between <0.1 and 3%.

235 The monitoring protocol proposed by

Ronaldson and colleagues consists of obtaining baseline troponins, C-reactive

protein (CRP), and an ECG, and then monitoring troponin and C-reactive protein on

days 7, 14, 21, and 28 of treatment. In the case of mild elevation in troponins or CRP,

persistent tachycardia, or signs or symptoms resembling infection, daily troponins

and CRP should be drawn until symptom resolution. Clozapine should be

discontinued if troponins reach twice the upper limit of normal or if CRP > 100

mg/L.

61 Successful rechallenge may be possible after symptoms resolve.

236,237

The black box warning describing “other adverse cardiovascular and respiratory

effects” references the risk of orthostatic hypotension associated with clozapine.

Approximately 9% of patients will experience orthostatic hypotension, but tolerance

develops over 4 to 6 weeks.

165 Risk is higher during initiation which necessitates the

slow titration beginning at 12.5 mg twice daily and increasing at the rate of 25 to 50

mg/day or slower. Clozapine must also be retitrated after a gap in therapy of greater

than 2 days to prevent significant orthostasis and risk of falls. Patients should be

counseled to make slow transitions from prone or seated positions and maintain

adequate fluid and salt intake. In patients with persistent dizziness and orthostasis

after titration where dose reduction is not an option, treatment with the

mineralocorticoid, fludrocortisone, may be an option.

165

Clozapine is also associated with frequent, bothersome adverse effects that, if left

unaddressed, can greatly impact quality of life. Constipation is a common, yet often

overlooked adverse effect of clozapine that can result in serious complications

including paralytic ileus, small-bowel perforation, or death secondary to aspiration

of gastric contents. It affects between 14% and 60% of patients taking clozapine.

Patients should be screened at every visit for bowel habits and providers should

have a low threshold for initiating a bowel regimen. Bowel regimens consist of bulkforming laxatives and increased fluid intake, stool softeners, or short-term use of

stimulant laxatives or enemas. Anticholinergic adverse effects of clozapine can result

in GI hypomotility, small-bowel obstruction, and ileus. These are serious concerns

that may occur in up to 0.3% of clozapine-treated patients. Adjunctive anticholinergic

agents and opioids should be limited and clozapine dose tentatively decreased, or

held in cases of ileus. Sedation is usually more pronounced when first initiating

clozapine and can be managed by slowing the rate of titration and consolidating the

dose to bedtime. As previously described, a benign tachycardia can also result from

clozapine use, but patients also presenting with flu-like symptoms, dyspnea, fever,

and chest pain should have further work-up for myocarditis. Sialorrhea is an

embarrassing adverse effect that in the extreme can result in sleep disruption or

aspiration pneumonia. Treatment options include tentative dose reduction or

nonpharmacologic management, such as placing a towel on their pillow, as first line.

Topical anticholinergic agents (ipratropium 0.03%–0.06% dosed 1–2 sprays

sublingually or 1–2 atropine eye drops in 1 ounce of water swished and spit) are

preferred over systemic anticholinergics (benztropine 0.5–2 mg HS or glycopyrrolate

1–2 mg) or the α-2 adrenergic agent, clonidine.

238 Serious cases may be treated with

botulinum toxin injected into each parotid gland.

238 Nocturnal enuresis may also be

underreported due to embarrassment. Management includes avoiding fluids in the

evening, voiding prior to bed, and setting alarms to schedule nocturnal voiding.

Desmopressin may also be effectively utilized, but the patient must be monitored for

hyponatremia secondary to its use.

165

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Table 85-13

Clozapine Monitoring Requirements

ANC Level Treatment Recommendation ANC Monitoring

Normal Range for a New Patient

General Population

ANC ≥ 1,500/μL

Initiate treatment

If treatment interrupted:

<30 days, continue monitoring

as before

≥30 days, monitor as if new

patient

Weekly from initiation to 6 months

Every 2 weeks from 6 to 12

months

B Monthly after 12 months EN Population

ANC ≥ 1,000/μL

Obtain at least two baseline

ANC levels before initiating

treatment

Mild neutropenia

(1,000–1,499/μL)

a

General Population

Continue treatment

General Population

Three times weekly until ANC

≥1,500/μL

Once ANC ≥1,500/μL return to

patient’s last “Normal Range”

ANC monitoring interval

b

BEN Population

Mild neutropenia is normal range

for BEN population, continue

treatment

Obtain at least two baseline ANC

levels before initiating treatment

If treatment interrupted

< 30 days, continue monitoring

as before

≥ 30 days, monitor as if new

patient

Discontinuation for reasons other

than neutropenia

BEN Population

Weekly from initiation to 6 months

Every 2 weeks from 6 to 12

months

Monthly after 12 months

Moderate Neutropenia

(500–999/μL)

a

General Population

Recommend hematology

consultation

Interrupt treatment for suspected

clozapine-induced neutropenia

Resume treatment once ANC

normalizes to ≥1,000/μL

General Population

Daily until ANC ≥1,000/μL, then

Three times weekly until ANC

≥1,500/μL

Once ANC ≥1,500/μL check

ANC weekly for 4 weeks, then

return to patient’s last “Normal

Range” ANC monitoring

interval

b

BEN Population

Recommend hematology

consultation

Continue treatment

BEN Population

Three times weekly until ANC

≥1,000/μL or ≥patient’s known

baseline.

Once ANC ≥1,000/μL or patient’s

known baseline, check ANC

weekly for 4 weeks, then return

to patient’s last “Normal BEN

Range” ANC monitoring

interval.

b

Severe Neutropenia

(<500/μL)

a

General Population

Recommend hematology

consultation

Interrupt treatment for suspected

clozapine-induced neutropenia

Do not rechallenge unless

prescriber determines benefits

outweigh risks

General Population

Daily until ANC ≥1,000/μL

Three times weekly until ANC

≥1,500/μL

If patient rechallenged, resume

treatment as a new patient

under “Normal Range”

monitoring once ANC

≥1,500/μL

BEN Population

Recommend hematology

consultation

Interrupt treatment for suspected

clozapine-induced neutropenia

Do not rechallenge unless

BEN Population

Daily until ANC ≥500/μL

Three times weekly until ANC ≥

patients established baseline

If patient rechallenged, resume

treatment as a new patient

prescriber determines benefits

outweigh risks

under “Normal Range”

monitoring once ANC

≥1,000/μL or at patient’s

baseline

aConfirm all initial reports of ANC less than 1,500/μL (ANC <1,000/μL for BEN patients) with a repeat ANC

measurement within 24 hours

b

If clinically appropriate

BEN, Benign Ethnic Neutropenia

Clozaril (clozapine tablets) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; September

2015.

CASE 85-1, QUESTION 30: J.J.’s psychiatrist decides to start J.J. on clozapine and remove all other

antipsychotics in light of her tardive dyskinesia and past failures and adverse effects with other antipsychotics.

What adverse effects of clozapine should be monitored for in J.J.?

Any patient started on clozapine should be monitored for agranulocytosis and

metabolic adverse effects, among others. As J.J. has a history of metabolic adverse

effects (weight gain, increased glucose, and increased triglycerides) with other

antipsychotics, these are of particular concern with using clozapine with her as

clozapine has the highest risk of these adverse effects. J.J. should also be counseled

about orthostatic hypotension, sedation, anticholinergic effects (especially

constipation), and sialorrhea.

CASE 85-1, QUESTION 31: Prior to initiating clozapine therapy, what laboratories and other tests should be

performed on J.J.?

Clozapine therapy requires a baseline absolute neutrophil count (ANC) prior to

starting the medication to ensure the patient has an adequate number of neutrophils

prior to initiation. In addition, her weight, waist circumference, serum

glucose/HbA1c, and lipid panel should be measured to monitor for the development

of metabolic adverse effects. Baseline liver and kidney function tests should also be

measured. A pregnancy test should also be performed, especially if there is any

chance that J.J. could be pregnant.

CASE 85-1, QUESTION 32: Once J.J. is started on clozapine, how should she be monitored? What

parameters should be checked and how frequently?

Clozapine treatment requires weekly ANC checks for at least the first 6 months of

treatment. Assuming no problems with her ANC values (ANC ≥ 1,500/μL), she can

then go to ANC checks every other week for 6 months, and then ANC checks once

every 4 weeks thereafter. In addition, her weight should be monitored at least

monthly (and perhaps weekly) for the first few months of treatment, along with at

least quarterly serum glucose and lipid panel checks. She should also be asked about

any problems with orthostasis (dizziness), constipation, sedation, and drooling during

any office visits.

5.

1.

2.

3.

4.

6.

Serum Concentration Monitoring

Data supporting a strong correlation between antipsychotic serum concentrations and

efficacy are lacking.

239 Therefore, routine therapeutic drug monitoring of

antipsychotic serum concentration is not recommended in clinical practice. The

exception is clozapine, which has sufficient data to support a higher rate of response

at levels above 350 ng/mL.

173,240 Monitoring of serum levels is appropriate in the

following clinical scenarios:

Psychiatric decompensation on a previously effective dose

Poor response to medication despite adequate dose and trial duration

Unexpected adverse effects while on a previously tolerated dose

Addition or withdrawal of an interacting medication

Patients with potentially altered PK (e.g., medically compromised, children,

elderly)

Suspected medication nonadherence

Nonantipsychotic Agents

Antipsychotics are generally the treatment of choice for most patients with

schizophrenia. However, in some situations, other medications may be needed and

appropriate for use. Benzodiazepines may be appropriate in patients with acute

agitation, as described previously. Other medications, such as mood stabilizers and

antidepressants, may be useful for some patients based upon their clinical symptoms

and presentation.

MOOD STABILIZERS

The mood stabilizers lithium, carbamazepine, valproic acid, and lamotrigine have

been studied for use in schizophrenia. These medications are frequently used as an

adjunct to antipsychotic treatment in schizophrenia in patients with affective

symptomatology as well as core symptoms of schizophrenia. Evidence for these

common practices is sometimes found to be equivocal or conflicting.

None of these mood stabilizers have shown efficacy as monotherapy for

schizophrenia. Lamotrigine has been found to have modest effects in schizophrenic

pathology as an adjunct to antipsychotic treatment but has little efficacy in treating the

treatment-resistant patient.

241 Lithium was determined by a Cochrane review to have

some benefit as an augmenting agent in lower quality studies, but replication in higher

quality studies is needed.

242 A recent meta-analysis shows evidence that the practice

of augmentation of antipsychotic medications with valproate yields significant

improvements in patients treated for schizophrenia or schizoaffective disorder.

243 A

recent Cochrane review does not recommend carbamazepine for augmentation of

antipsychotics in the treatment of schizophrenia.

244 A need for further study of

antipsychotic augmentation with mood stabilizers is warranted. Concomitant use

should be carefully considered at this time given the potential for drug interactions,

and additional adverse effect and pill burden.

ANTIDEPRESSANTS

Depression often presents in schizophrenia

37,245 and approximately 6% to 10% of

patients with schizophrenia commit suicide in their lifetime.

29,246–248 Though

controversial, there is evidence that antipsychotics may differ in their ability to treat

depressive symptoms in schizophrenia

54,99,249,250 and many consider SGAs to be better

for this syndrome than the FGAs.

250,251 Some of the advantages of SGAs in depression

may be due in part to less antipsychotic-induced dysphoria or akinesia or effect on

treating negative symptoms.

250,251 There is also substantial literature showing that

adding an antidepressant may be a useful option in some depressed patients.

252 The

divergent pattern of antidepressant response on numerous studies suggests that those

patients whose positive symptoms are well controlled are more likely to respond

favorably to antidepressant augmentation.

28

In one trial, the antidepressant bupropion

did significantly worse than placebo in patients treated with thiothixene.

34

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Some also advocate for the possible effectiveness of antidepressant medication to

decrease the severity of negative symptoms in schizophrenia.

253 One review found

only 5 of 14 studies with SSRI antidepressants demonstrated efficacy in ameliorating

negative symptoms; however, mirtazapine was promising in 4 of 6 trials.

252 Tricyclic

antidepressants do not have robust evidence in treatment of negative symptoms.

254

CASE 85-1, QUESTION 33: J.J. responds well to clozapine, taking a dose of 450 mg/day, with higher doses

causing intolerable adverse effects in J.J. Over time, J.J. begins to become depressed as she realizes that her

life has not gone the way she thought it would. Her psychiatrist assesses her as having depression secondary to

her schizophrenia, and the decision is made to start her on paroxetine 20 mg daily. Is the addition of paroxetine

appropriate for J.J.?

Although paroxetine is an appropriate treatment for depression, it is most likely

not a good choice for J.J. There are data that show that paroxetine can cause

anticholinergic adverse effects in patients, which could overlap any anticholinergic

effects caused by clozapine. J.J. would need to be monitored for increased

anticholinergic adverse effects, and possibly be treated for them (e.g., bowel regimen

for constipation). Selection of an antidepressant with a lower risk of drug

interactions, such as Escitalopram or Sertraline, would be more appropriate.

Treatment Guidelines for Schizophrenia

Clinical guidelines on the treatment of schizophrenia are published by a number of

organizations. The most prolific and current guidelines at this time are the American

Psychiatric Association (APA), Patient Outcomes Research Team on Schizophrenia

(PORT), Texas Medication Algorithm Project (TMAP), and the National Institute for

Health and Care Excellence (NICE) of the United Kingdom.

101–103,255 These guidelines

are an excellent resource and starting point in ensuring evidence-based and safe care

of patients with schizophrenia. However, it is important to keep in mind the level of

evidence each organization requires to support a given treatment recommendation.

The PORT guidelines have a threshold of at least two randomized controlled trials

prior to publishing a treatment recommendation. The APA utilizes a less clearly

defined process of systematically evaluating the literature, then rating clinical

recommendations by the following coding system: (I) recommended with substantial

clinical confidence, (II) recommended with moderate clinical confidence, and (III)

may be recommended on the basis of individual circumstances. Other guidelines may

also incorporate expert opinion

101,103 or consensus in areas which lack high level

evidence, such as antipsychotic combination treatment or treatment after nonresponse

to clozapine. The bottom-line is these guidelines provide a systematic framework for

treatment, but should by no means be a substitute for clinical judgment and treating

the unique clinical picture each individual presents. Any treatment decision should be

aligned with the treatment team, caregivers, and most importantly—the patient. Even

the most effective treatment is destined to fail unless the patient is invested and in

agreement with their own treatment. Figure 85-2 is a consolidated view of the current

guidelines on the use of antipsychotics in the treatment of schizophrenia.

CONSIDERATIONS IN SPECIFIC POPULATIONS

Pregnancy

The peak onset of schizophrenia in the female population coincides with peak

childbearing age and unplanned pregnancies can be a concern.

256 Patients should be

routinely educated on safe sexual practices, offered contraceptives if indicated, and

receive pregnancy tests prior to prescription of antipsychotic medications. The

general goals of treatment in pregnant patients are to thoroughly weigh the risks of

teratogenicity with benefit of ongoing treatment and prevention of psychiatric

decompensation. Untreated psychosis places both the patient and the fetus at

significant risk. Effective treatment with an antipsychotic agent may enable the

mother to carry out necessary self-care and prenatal care.

257

Ideally, treatment

decisions should be made as part of a multidisciplinary team consisting of the patient,

mental health provider, obstetrician, primary care provider, and pediatrician.

General guidelines on treatment during pregnancy recommend

257

:

1.

2.

3.

Figure 85-2 Summary of Current Treatment Guidelines on Schizophrenia. (Sources:

αAmerican Psychiatric

Association [Lehman AF et al. Practice guideline for the treatment of patients with schizophrenia, second edition.

Am J Psychiatry. 2004;161(2, Suppl):1–56. doi:10.1176/appi.books.9780890423363.45859.],

βPatient Outcomes

Research Team [Buchanan RW et al. The 2009 schizophrenia PORT psychopharmacologic treatment

recommendations and summary statements. Schizophr Bull. 2010;36(1):71–93. doi:10.1093/schbul/sbp116.],

cTexas

Medication Algorithm Project [Moore T et al. The Texas medication algorithm project antipsychotic algorithm for

schizophrenia: 2006 Update. J Clin Psychiatry. 2007;68(11):1751–1762. doi:10.4088/JCP.v65n0408.],

d

International

Psychopharmacology Algorithm Project [IPAP Schizophrenia Algorithm. The International Psychopharmacology

Algorithm Project website. http://www.ipap.org/schiz/. Updated March 27, 2006. Accessed February 1,

2016.])

p. 1810

p. 1811

Utilizing antipsychotic monotherapy at an adequate dose versus combination

therapy

Avoiding medication switching to minimize exposure to the fetus and risk of

psychiatric relapse

Selecting appropriate treatment based on history of efficacy, prior exposure during

pregnancy, and available evidence on safety

4. Choosing medications with fewer metabolites, fewer interactions, and higher

protein binding are generally preferred

Data on the safety of antipsychotics during pregnancy are limited due to ethical

barriers to conducting well-designed, prospective controlled trials. There is

inconclusive evidence linking fetal exposure to antipsychotics and major congenital

malformations, perinatal mortality, high birth weight (SGAs), and low birth weight

(FGAs).

256 A large-scale prospective national pregnancy registry for atypicals

antipsychotics reported three major fetal malformations in a cohort of 214 patients

with first-trimester exposure to SGAs. The control group, which included 89 live

births, had one major malformation. This translates to an OR of 1.25 (95% CI =

0.13–12.19) between exposed and unexposed infants. Although ongoing data

collection is still underway, these results suggest SGA exposure would be unlikely to

increase the risk of major malformations higher than 10-fold of that observed in

control groups or the general population.

258

In 2011, the FDA implemented safety

labeling changes concerning the use of antipsychotic agents during the third trimester

of pregnancy. They reported a risk that newborns may experience withdrawal

symptoms or EPS; however, many cases were confounded by comorbid substance

use and concomitant psychotropic medications. Symptoms usually resolved within

hours-days without intervention; however, some may require prolonged

hospitalization.

259

CASE 85-1, QUESTION 34: Several months later, the clinic receives word from J.J.’s primary care provider

that J.J. is pregnant, as confirmed by blood test. J.J. is still receiving clozapine and is fairly stable psychiatrically

on the medication, even working part-time in a supermarket. J.J. does not want to lose the baby, but is worried

about the effect of being on medication despite knowing it is what is keeping her stable. Should J.J. be

continued on clozapine, and what are the risks to her baby if she does or does not?

Treatment of schizophrenia with antipsychotics during pregnancy must be

considered carefully. As J.J. is currently stable and functional while taking

clozapine, there is a significant risk of relapse if she stops the medication. During

this relapse, if she were to engage in high-risk behaviors, it could be quite dangerous

to both her and her baby. Maintaining stability is of great importance, as if J.J. can

take care of herself appropriately it is more likely she will also take care of her fetus

simultaneously. However, antipsychotics do carry risks of teratogenicity, and J.J.

should be counseled on these risks. Clozapine is rated as pregnancy category B by

the US FDA, which is better than most antipsychotics but still with some risk

involved. The decision to maintain J.J. on clozapine during her pregnancy should be

made by her, her psychiatrist, obstetrician, and other care providers to determine

whether continuation of clozapine, and presumptive stability of her illness, is

appropriate.

First-Episode Psychosis and Early-Onset Schizophrenia

Child and adolescent patients presenting with early psychosis are exquisitely

sensitive to EPS and metabolic adverse effects of antipsychotics.

260,261

In general,

symptoms of first-episode psychosis (FEP) respond to lower antipsychotic dosages.

Therefore, the minimum effective dose should be utilized to minimize adverse effect

burden. The question of which interventions are appropriate to initiate and when is

complicated. Multiple studies support the effectiveness of antipsychotics in the

treatment of early psychosis.

262–265 However, the treatment of prodromal symptoms is

an area of debate. Prompt recognition of prodromal symptoms and patients with

psychosis risk syndrome is crucial. Features associated with greater rates of

conversion to psychosis in patients at ultra-high risk of psychosis include: genetic

risk for schizophrenia, high levels of unusual thought content, high levels of suspicion

and paranoia, social impairment, and history of substance use.

266 There is emerging

evidence to support early initiation of omega-3 fatty acids or antidepressants to

reduce rates of conversion to psychosis in high-risk patients.

261,267,268 Early

engagement with appropriate comprehensive, multidisciplinary clinics results in

improved quality of life and psychopathology, greater involvement in educational and

vocational pursuits, and increased treatment follow-up.

269,270 Reduction of the

duration of untreated psychosis leads to improved long-term prognosis and greater

likelihood of achieving symptom remission.

44,271,272 Neurocognitive impairment is

also a key predictor of functional outcome in early schizophrenia. Unfortunately,

available pharmacologic options have limited impact on neurocognition.

273 Cognitive

enhancement therapy, in conjunction with antipsychotic medication, can lead to

durable improvements in neurocognitive functioning, social adjustment, and

employment for patients with early psychosis.

274,275

After achieving initial remission, guidelines recommend continued maintenance

treatment with an antipsychotic for at least 1 year.

44,102,255 Studies of medication

discontinuation demonstrated 5 year relapse rates from 80%.

276 However, cautious

dose reduction strategies as soon as 6 months after remission may improve long-term

functional recovery. Wunderink and colleagues conducted a seven-year follow-up

study of a two-year open RCT comparing maintenance therapy (MT) versus dose

reduction/discontinuation (DR) after 6-month remission of FEP. In the initial RCT,

128 patients were randomized to MT or DR and followed for 18 months. The MT

group showed benefit in short-term relapse rates over the DR group.

277 However, the

DR group had approximately twice the recovery rate of patients in the MT group

(40.4% vs. 17.6%, respectively) at the seven-year follow-up and there were no

significant differences in long-term relapse rates.

278 A limitation to the

generalizability of the study is the population who agreed to enrollment in the initial

phase had a higher level of functioning, greater adherence, and was easier to engage.

These findings demonstrate the potential impact of limiting total antipsychotic burden

on functional recovery rates of patients with remitted FEP. The lower adverse effect

burden from minimizing the antipsychotic dose allows for improved social

engagement, improved therapeutic alliance, and lower risk of self-discontinuation

due to tolerability issues. Functional recovery is the key treatment goal in the early

course of schizophrenia. Getting patients engaged in treatment early on in the illness

course, utilizing the lowest clinically effective dosages of

p. 1811

p. 1812

antipsychotics, and providing psychoeducation can mean the difference in a patient

recovering from a psychotic episode and completing college, returning to work, or

engaging in meaningful social outlets.

CASE 85-1, QUESTION 35: J.J. gives birth to a son, R.J., who has a normal delivery. Over the course of

time, R.J.’s pediatrician notes he is not socializing like other children, especially into adolescence. He is now age

15 and tends to isolate himself, does not have many peer friends, and recently has started performing poorly in

school. His teachers have asked the pediatrician to evaluate R.J. for potential attention deficit hyperactivity

disorder (ADHD) as he is often found not paying attention in class. J.J. also tells the pediatrician that she thinks

R.J. still has “imaginary friends” as she often sees him alone in his room talking to people who are not there.

What is potentially happening with R.J. and how should he be treated at this time?

R.J. is at higher risk for and potentially showing symptoms of early-onset

schizophrenia. His lack of socialization and his isolation could be symptoms of the

prodromal phase of schizophrenia. His “imaginary friends” could be R.J. responding

to auditory and/or visual hallucinations; imaginary friends are not usually seen into

adolescence. If these are hallucinations, this could also explain his lack of attention

in school, which would not be ADHD. Considering his mother has schizophrenia,

there is a definite genetic link to the illness in R.J. Once R.J. is evaluated for

schizophrenia, it may be appropriate to initiate an antipsychotic at that time. If so, he

should be started on an agent with minimal adverse effect burden at a minimal dose

to control his symptoms. He should be evaluated regularly for possible medication

discontinuation if warranted, but may require more long-term treatment depending

upon his response and prognosis.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

American Diabetes Association et al. Consensus development conference on antipsychotic drugs and obesity and

diabetes. Diabetes Care. 2004;27:596. (193)

Buchanan RW et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and

summary statements. Schizophr Bull. 2010;36:71. (102)

Leucht Set al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multipletreatments meta-analysis. Lancet. 2013;382(9896):951–962. doi:10.1016/S0140-6736(13)60733-3. (172)

Lieberman JA et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med.

2005;353(12):1209–1223. doi:10.1056/NEJMoa1404304. (64)

Marder SR et al. The Mount Sinai conference on the pharmacotherapy of schizophrenia. Schizophr Bull.

2002;28(1):5–16. (198)

Key Websites

American Psychiatric Association. Treatment of Patients With Schizophrenia, Second Edition.

http://www.psychiatryonline.com/pracGuide/pracGuideTopic_6.aspx.

Clozapine REMS Program.

https://www.clozapinerems.com/CpmgClozapineUI/home.u

National Institute for Health and Clinical Excellence. Schizophrenia (update).

http://guidance.nice.org.uk/CG82.

National Institute of Mental Health. Schizophrenia.

http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml

US Food and Drug Administration. FDA Drug Safety Communication: Antipsychotic drug labels updated on use

during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns.

http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm. Accessed March 17, 2016.

COMPLETE REFERENCES CHAPTER 85 SCHIZOPHRENIA

Tandon R et al. Schizophrenia, “Just the Facts” What we know in 2008. 2. Epidemiology and etiology. Schizophr

Res. 2008;102(1–3):1–18. doi:10.1016/j.schres.2008.04.011.

Lopez AD. The evolution of the Global Burden of Disease framework for disease, injury and risk factor

quantification: developing the evidence base for national, regional and global public health action. Global Health.

2005;1:5. doi:10.1186/1744-8603-1-5.

Ayuso-Mateos JL. Global burden of schizophrenia in the year 2000 : version 1 estimates. World Heal Organ.

2001:1–11. http://www.who.int/healthinfo/statistics/bod_schizophrenia.pdf. Accessed January 1, 2016.

Wu EQ et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psych. 2005;66(9):1122–

1129.