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Addressing Adverse Effects of Antipsychotic Treatment in Young Patients With Schizophrenia

Christoph U. Correll, MD

Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, and the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY

Antipsychotics have proven efficacy for treating the severe and often debilitating symptoms of early-onset schizophrenia. However, children and adolescents are at a greater risk than adults for psychotropic-induced adverse effects, which can have long-term health consequences for young patients and may lead to treatment nonadherence or discontinuation.1 Clinicians should proactively monitor for these adverse effects to optimize physical as well as psychiatric outcomes for their young patients.

Monitoring Strategies

Current recommendations2,3 state that, before patients receive an antipsychotic, the physician should assess their personal and family medical histories, particularly regarding diabetes and cardiovascular disease risk factors, and their lifestyle behaviors, such as dietary and exercise habits. Height and weight should be assessed, and patients’ BMI percentiles and BMI z-scores should be calculated. (One Web-based BMI calculator for children and adolescents is located at http://www.bcm.edu/cnrc/bodycomp/bmiz2.html.) atients should undergo fasting blood tests at baseline for glucose and lipid levels, and these tests should be repeated at 3 months and every 6 months thereafter in order to detect any metabolic abnormalities that may occur during treatment (AV 1).3,4

Weight should be checked at each visit, taking into account normal growth during development, as data5 suggest that early weight gain predicts later weight gain. Patients should also be assessed for sedation or somnolence at baseline and at every visit. Blood pressure, pulse, liver function, and tardive dyskinesia should be assessed at baseline, at 3 months, and annually thereafter. Patients should be assessed for EPS and akathisia at baseline, during titration of medication, at 3 months, and then annually.3 Depending on patient risk factors or emerging abnormalities, assessments may need to be made more frequently.

Some antipsychotic agents, such as ziprasidone, have been associated with QT prolongation.6 If a young patient is taking a drug associated with QT prolongation, a careful clinical assessment should be made and an ECG may be performed during titration and at maximum dose.3 An ECG is warranted for patients taking any antipsychotic agent (1) if the patient has a family history of early sudden cardiac death or prolonged QT syndrome, or (2) if the patient has a personal history of QT prolongation on prior medications or of an irregular heartbeat, heart murmur, dizziness, fainting upon exertion, or blackout.

Prolactin measurement is usually recommended only if the patient has sexual or reproductive side effects such as amenorrhea or oligomenorrhea, which can be difficult to assess in patients who have not yet established routine menses. Breast tenderness or galactorrhea in females and gynecomastia or galactorrhea in males, symptoms that may be dose-dependent, are additional reasons to measure prolactin levels.3

Medical Risk Management Strategies

Patients and their family members should be included in a careful risk-benefit assessment when choosing an antipsychotic, and healthy lifestyle counseling should be performed prior to initiating treatment (AV 2).7 Overweight or obese patients might require a healthy lifestyle intervention, and an antipsychotic with a relatively low risk of producing weight gain should be considered for these patients. If an adverse metabolic effect or excessive weight gain occurs once treatment has begun, healthy lifestyle counseling or lifestyle interventions should be intensified, the patient’s medications should be reviewed, a switch to a lower risk agent should be considered, and/or treatments to target serious adverse effects should be initiated.

Lifestyle counseling and interventions. Lifestyle counseling provides patients and their families with education and guidelines regarding nutrition and exercise (AV 3).8 A thorough patient and family history is needed to create a list of those areas in which the patient needs the most help in achieving a healthy lifestyle. Patients, along with their families, should then choose an item from the list that will be easiest for them to address, and they should work to resolve that issue until the next visit. Once that goal has been achieved, the patient/family can choose the next easiest item on the list to target, and continue until each issue is improved or, ideally, resolved.

More

Switching medications or lowering the dose. A patient’s medication may need to be changed to one with a lower risk for a particular adverse effect. When a medication switch is considered in order to improve adverse effects, the pharmacodynamic properties of each drug should be considered to avoid a potential rebound effect.1 For example, a patient switching precipitously from an antipsychotic with high antihistaminergic or anticholinergic effects (eg, clozapine, olanzapine, quetiapine) to one with minimal blockade effect for these receptors (eg, aripiprazole, paliperidone, risperidone, ziprasidone) may experience transient rebound anxiety, agitation, insomnia, or even withdrawal akathisia. Switching precipitously from a full dopamine antagonist to a partial agonist (eg, aripiprazole) may cause a transient worsening of psychosis, agitation, or restlessness. In these situations, an overlapping, “plateau” cross-titration strategy should be considered to avoid a too-abrupt discontinuation of the initial antipsychotic.9

Many adverse effects, such as sedation, are dose-dependent, and lowering the dose may help alleviate those effects; however, higher doses (250 mg/d to 300 mg/d) of quetiapine seem to result in reduced somnolence rates compared with lower doses.9 Lowering the dose or slowing down the titration of the antipsychotic can also be helpful for combating parkinsonism and akathisia.

If a patient has gained weight or has underlying metabolic conditions and a higher-risk medication must be used because others do not stabilize the patient, then a pediatric specialist or endocrinologist should be consulted to manage medical issues such as hypertension, dyslipidemia, or hyperglycemia.

Adjunctive treatment. In addition to switching medications or lowering the dose, specific adverse effects can be treated with add-on medication.3 Modafinil may be helpful for treating sedation and somnolence, and anticholinergic agents, antihistamines, or benzodiazepines can treat acute EPS, particularly dystonia. Akathisia can be treated with benzodiazepines, antihistamines, mirtazapine, and β-blockers.9

Tardive dyskinesia can be very difficult to treat. Ideally, the antipsychotic should be stopped; however, if this is not possible, lowering the dose may help.3 Conversely, increasing the dose can mask the involuntary movements. Adding 400 IU of Vitamin E for 4 weeks and then 800 IU for the next 4 weeks may help, but, if it does not help after 8 weeks, it should be stopped. Replacing the antipsychotic with clozapine, which is associated with a very low rate of tardive dyskinesia, might also be considered.

Asymptomatic prolactin elevation, which may normalize over time, should be monitored.3 Symptomatic prolactin elevation that does not respond to lowering the dose of medication or to switching medications may require the addition of a full or partial dopamine agonist.8,10 In the event that prolactin levels are very high (ie, 200 ng/dl and above), do not respond to dose/medication adjustment, or, particularly, when visual field defects are apparent, patients should be referred to an endocrinologist to rule out a prolactinoma.

Weight gain, dyslipidemia, and hyperglycemia are problematic with atypical antipsychotics. Weight loss agents may be used if switching to a lower-risk drug and intensifying the healthy lifestyle intervention do not resolve metabolic adverse effects.3 Currently, the most evidence11 exists for the addition of metformin or topiramate to the atypical antipsychotic. However, these agents may cause adverse effects, ranging from gastrointestinal side effects such as nausea, vomiting, and diarrhea with metformin to cognitive dysfunction and possible depression with topiramate, which must be monitored. Clinically relevant lipid, blood pressure, or glucose abnormalities may require referral to a pediatrician or endocrinologist for treatment with a statin, antihypertensive, or antihyperglycemic agent.

For Clinical Use

 

  • Perform dietary and lifestyle counseling when initiating antipsychotic treatment in children and adolescents with early-onset schizophrenia
  • Obtain baseline health assessments and conduct routine, proactive monitoring of adverse effects
  • Use strategies to manage adverse effects, including switching medications, lowering the dosage of medications, and initiating adjunctive medications to reverse or prevent specific adverse effects

 

Drug Names

aripiprazole (Abilify), clozapine (Clozaril, FazaClo, and others), metformin (Riomet, Fortamet, and others), mirtazapine (Remeron and others), modafinil (Provigil), olanzapine (Zyprexa), paliperidone (Invega), quetiapine (Seroquel), risperidone (Risperdal and others), topiramate (Topamax and others), ziprasidone (Geodon)

Abbreviations

BMI = body mass index
EPS = extrapyramidal symptoms
ECG = electrocardiogram
HDL = high-density lipoprotein
IU = international unit

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References

  1. Correll CU. Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents. J Clin Psychiatry. 2008;69(suppl 4):26–36.
  2. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity. Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care. 2004;27(2):596–601.
  3. Correll CU. Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry. 2008;47(1):9–20.
  4. Cook S, Weitzman M, Auinger P, et al. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988–1994. Arch Pediatr Adolesc Med. 2003;157(8):821–827.
  5. Kinon BJ, Kaiser CJ, Ahmed S, et al. Association between early and rapid weight gain and change in weight over one year of olanzapine therapy in patients with schizophrenia and related disorders. J Clin Psychopharmacol. 2005;25(3):255–258.
  6. Blair J, Scahill L, State M, et al. Electrocardiographic changes in children and adolescents treated with ziprasidone: a prospective study. J Am Acad Child Adolesc Psychiatry. 2005;44(1):73–79.
  7. Correll CU. Balancing efficacy and safety in treatment with antipsychotics. CNS Spectr. 2007;12(10 suppl 17):12–20, 35.
  8. Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006;45(7):771–791.
  9. Correll CU. From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry. 2010;25(suppl 2)S12–S21.
  10. Shim JC, Shin JG, Kelly DL, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo controlled trial. Am J Psychiatry. 2007;164(9):1404–1410.
  11. Maayan L, Correll CU. Management of antipsychotic-related weight gain. Expert Rev Neurother. 2010;10(7):1175–200.