Another concern is that, along with known genetic factors,
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
212 which is one of the most metabolically problematic agents. However,
even more metabolically benign antipsychotics may eventually be linked to the
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.
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
217,218 Other antipsychotics have also been implicated.
could relate to the slightly higher risk of death in elderly patients receiving these
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
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
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.
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
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
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
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
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
grimacing, darting movements of her tongue, lip-smacking, and twisting movements in her hands. The
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
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
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
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
226 as well as higher levels of hostility.
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,
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.
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.
It is also the treatment of choice for those
at high risk for suicide or violence, or in patients with TD.
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
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
). 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.
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.
antiepileptic drugs (AED) is generally not recommended.
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.
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
61 Successful rechallenge may be possible after symptoms resolve.
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
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.
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
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.
Clozapine Monitoring Requirements
ANC Level Treatment Recommendation ANC Monitoring
Normal Range for a New Patient
Weekly from initiation to 6 months
B Monthly after 12 months EN Population
Mild neutropenia is normal range
Obtain at least two baseline ANC
levels before initiating treatment
< 30 days, continue monitoring
Discontinuation for reasons other
Weekly from initiation to 6 months
Interrupt treatment for suspected
Daily until ANC ≥1,000/μL, then
return to patient’s last “Normal
Once ANC ≥1,000/μL or patient’s
weekly for 4 weeks, then return
Interrupt treatment for suspected
prescriber determines benefits
If patient rechallenged, resume
Interrupt treatment for suspected
Three times weekly until ANC ≥
If patient rechallenged, resume
prescriber determines benefits
BEN, Benign Ethnic Neutropenia
CASE 85-1, QUESTION 30: J.J.’s psychiatrist decides to start J.J. on clozapine and remove all other
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.
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
Serum Concentration Monitoring
Data supporting a strong correlation between antipsychotic serum concentrations and
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
173,240 Monitoring of serum levels is appropriate in the
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,
Suspected medication nonadherence
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
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
241 Lithium was determined by a Cochrane review to have
some benefit as an augmenting agent in lower quality studies, but replication in higher
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.
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.
Depression often presents in schizophrenia
37,245 and approximately 6% to 10% of
patients with schizophrenia commit suicide in their lifetime.
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
250,251 There is also substantial literature showing that
adding an antidepressant may be a useful option in some depressed patients.
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.
In one trial, the antidepressant bupropion
did significantly worse than placebo in patients treated with thiothixene.
Some also advocate for the possible effectiveness of antidepressant medication to
decrease the severity of negative symptoms in schizophrenia.
only 5 of 14 studies with SSRI antidepressants demonstrated efficacy in ameliorating
negative symptoms; however, mirtazapine was promising in 4 of 6 trials.
antidepressants do not have robust evidence in treatment of negative symptoms.
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.
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
The peak onset of schizophrenia in the female population coincides with peak
childbearing age and unplanned pregnancies can be a concern.
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.
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
Figure 85-2 Summary of Current Treatment Guidelines on Schizophrenia. (Sources:
Am J Psychiatry. 2004;161(2, Suppl):1–56. doi:10.1176/appi.books.9780890423363.45859.],
Research Team [Buchanan RW et al. The 2009 schizophrenia PORT psychopharmacologic treatment
schizophrenia: 2006 Update. J Clin Psychiatry. 2007;68(11):1751–1762. doi:10.4088/JCP.v65n0408.],
Algorithm Project website. http://www.ipap.org/schiz/. Updated March 27, 2006. Accessed February 1,
Utilizing antipsychotic monotherapy at an adequate dose versus combination
Avoiding medication switching to minimize exposure to the fetus and risk of
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
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.
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
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
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.
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
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.
evidence to support early initiation of omega-3 fatty acids or antidepressants to
reduce rates of conversion to psychosis in high-risk patients.
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.
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.
enhancement therapy, in conjunction with antipsychotic medication, can lead to
durable improvements in neurocognitive functioning, social adjustment, and
employment for patients with early psychosis.
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%.
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.
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.
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
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.
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.
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
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)
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.
American Psychiatric Association. Treatment of Patients With Schizophrenia, Second Edition.
http://www.psychiatryonline.com/pracGuide/pracGuideTopic_6.aspx.
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
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
Res. 2008;102(1–3):1–18. doi:10.1016/j.schres.2008.04.011.
2005;1:5. doi:10.1186/1744-8603-1-5.
2001:1–11. http://www.who.int/healthinfo/statistics/bod_schizophrenia.pdf. Accessed January 1, 2016.
No comments:
Post a Comment
اكتب تعليق حول الموضوع