Pediatricians are increasingly called upon to assess and treat common psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD), anxiety, and depression. Additionally, children who are prescribed psychotropic medications by a psychiatric specialist present to pediatricians for well-child care, so pediatricians should be familiar with psychotropic medications and their effects on their patient's health. In this article, we discuss medications most likely to be encountered by pediatricians.
Stimulants and Nonstimulants
Methylphenidate and amphetamine-based stimulants and alpha-agonists (eg, guanfacine and clonidine) and norepinephrine agonists (eg, atomoxetine) are commonly prescribed for treatment of ADHD. Most children with ADHD taking stimulants do well and tolerate the medication. Common side effects can include appetite suppression, insomnia, and behavior and mood changes. Strategies to address stimulant-induced appetite suppression include reframing eating as an activity to “fuel the body” and not simply as an activity in response to hunger. Thus, encouraging breakfast and regular meals, moving dinner later in the day, having calorie dense snacks and “drug holidays”or periods of time when a stimulant is discontinued, such as on weekends and on breaks from school to allow for normal appetite levels and caloric intake. Although extended treatment with stimulants has been associated with height suppression, the data supporting this finding are suboptimal.1 Close monitoring is the best management approach and if weight gain and growth emerges as an issue, changing medication to a nonstimulant is reasonable. The bigger challenge is when stimulants are the best treatment option and there continue to be concerns about growth; in such cases, consultation with a pediatric growth specialist may be indicated.
In a healthy child, stimulants pose no increased cardiac risks. Although stimulants are not specifically contraindicated in patients with history of structural cardiac disease and/or family history of cardiac issues, children who are affected and those with a positive family history (ie, arrhythmia, nonvasovagal syncope and sudden, premature death) should receive further cardiac evaluation. Tics are common in children with ADHD and naturally emerge in the same time frame as ADHD. Although it has been thought that stimulants may induce or worsen tics, it appears that observations of new or worsening tics on stimulants reflect a coincidence rather than a causal relationship.2
Common adverse effects of alpha-agonists include low blood pressure, fatigue, sedation, headache, and dry mouth. Slow titration to the lowest clinically effective dose may mitigate these effects. Slow discontinuation is recommended. Common adverse effects of atomoxetine include nausea and sedation. To monitor stimulant side effects, obtain weight, height, body mass index (BMI), blood pressure, and pulse at every visit.
Antidepressants: Selective Serotonin Reuptake Inhibitors and Serotonin Norepinephrine Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) are commonly used to treat pediatric anxiety and depression. Although called antidepressants, these medications are highly effective for anxiety disorders as well. Several SSRIs have US Food and Drug Administration (FDA) approval for indications for children and adolescents: fluoxetine, sertraline, and fluvoxamine are indicated for use in obsessive-compulsive disorder; fluoxetine is approved for treatment of depression in children age 8 years and older; escitalopram is approved for treatment of depression in children age 12 years and older; and duloxetine, an SNRI, is approved for generalized anxiety disorder in children age 7 years and older.3 As a class, antidepressant medications are likely all effective for anxiety and depression but vary by mechanism and may vary in efficacy and tolerability across patients. That said, antidepressant medications are generally well tolerated, and side effects are readily managed and do not frequently lead to discontinuation of the antidepressant. Adverse effects are reviewed below. There are no reports of significant long-term side effects of antidepressants in children and adolescents.
Somatic Side Effects
Most somatic adverse effects are transient, readily managed, do not interfere with functioning, and are not a cause of discontinuation. If somatic adverse effects do not improve or cause unacceptable distress to the child, consider a lower dose. If still symptomatic, a taper and discontinuation may be required. In such cases, an alternative SSRI can be used, although all SSRIs may cause similar somatic adverse effects. Changing antidepressant class with a different side-effect profile may also be useful.
Nausea and gastrointestinal distress are common side effects of SSRIs/SNRIs, particularly during the first weeks of treatment or early dose increases. Starting at a low dose and taking medication with meals reduces the likelihood of gastrointestinal side effects. For headaches arising after starting an antidepressant, encourage adequate hydration and water intake. Although starting low and going slow is good general advice, going too slow and holding at too low a dose can result in unneeded suffering related to ineffective treatment dosing.
Depression and anxiety have a complex relationship with weight and appetite; some children gain weight once mood/anxiety symptoms improve, whereas others lose weight if eating was their coping mechanism. Weight changes can be associated with antidepressant treatment and may include weight loss or gain, generally in small amounts. It is helpful to discuss with patients that weight could change with the use of the medication and the specific response is patient dependent.
There is also a complex relationship between sleep and psychiatric disorders; often sleep issues pre-date medication management of psychiatric illness, and other times sleep issues arise during treatment. In children, sleep issues are commonly seen in anxiety, depression, and behavioral disorders. Antidepressants can reduce anxiety- and depression-related sleep disturbance but may increase latency to rapid eye movement (REM), suppress REM sleep, and may impair sleep continuity.4 Patients may report hypersomnia, insomnia, vivid dreams, and nightmares. Taking a good sleep history prior to initiation of medication can help with the assessment of potential treatment-emergent adverse sleep effects. Strategies to manage SSRI-emergent insomnia include dosing medication in the morning and considering supplemental treatment with a sleep aid such as melatonin.
Activation and Treatment-Emergent Mania
Activation, a syndrome characterized by increased energy, restlessness, insomnia, irritability, and/or agitation, occurs shortly after initiation of SSRI treatment or dose increases. Management should include either lowering the dose or discontinuation. Again, lowering the dose may reduce activation but too low a dose may not be clinically effective, and a medication change may be required.
Activation is much more common in younger patients and those with neurodevelopmental disturbance such as autism spectrum disorder.5 Activation is a common reason for discontinuation of SSRI in clinical practice. Higher initial doses and fast upward adjustments are associated with higher risk of activation.
Activation is clinically distinct from a manic reaction.6 Treatment-emergent mania or hypomania7 occurs later in treatment within weeks to months of starting an SSRI, often after an improvement in anxiety or mood. To be considered a manic reaction, symptoms should reflect cardinal symptoms of mania (and not just irritability) such as expansive/elevated mood, decreased need for sleep, hypersexuality, and increased goal-directed activities. This is an infrequent adverse effect in SSRI clinical trials. If it occurs, discontinuing antidepressant medication is imperative and mood-stabilizing medication may be needed.
Serotonin syndrome is extremely rare with SSRI monotherapy but can occur when combining multiple serotonin-enhancing medications or in overdose. Serotonin syndrome may cause renal failure, rhabdomyolysis, seizure, coma, and death. Clinical signs include elevated temperature, mental status changes, myoclonus, hyper-reflexia, sweating, tremor, and diarrhea. Treatment includes stopping the medication and medical stabilization.
In 2004, the FDA labeled all antidepressants with a boxed warning for increased risk of suicidal thinking and behavior. Analyses conducted by the FDA suggest number needed to harm of 50 to 100 or 1 in 50 to 100 children who are treated.8 Bridge et al.9 re-analyzed the FDA data and included more studies and found the number needed to harm of 140 to 200. The mechanism by which antidepressant might cause changes in suicidal thinking is unknown. Review of clinical vignettes suggest interpersonal conflict early in treatment may be a triggering event.
There is a risk for QTc prolongation with use of some SSRI/SNRI. For patients with a prior history of prolonged QTc, arrhythmia or family history of arrhythmia, nonvasovagal syncope, and sudden cardiac death may require consultation with a cardiologist.
Sexual Side Effects
SSRIs may contribute to decreased sexual desire, erectile difficulties, delayed ejaculation, and female anorgasmia. Sexual side effects are dose-dependent and reversible. SSRI sexual side effects can significantly affect patient medication adherence. It is important to educate adolescents about these effects proactively because it is unlikely that they will report their occurrence spontaneously.10 Many pharmacological strategies to mitigate sexual dysfunction have been proposed. Changing antidepressant class maybe required.
Duloxetine and other SNRI medications have side effects similar to SSRIs but have a smaller overall risk of activation and greater risk for increased blood pressure and heart rate.
Antipsychotics are indicated for treatment of schizophrenia, bipolar disorder, irritability associated with autism, and used off-label for impulsivity and aggression. The antipsychotic medications most prescribed in children and adolescents are called “atypical” or second-generation antipsychotics (SGA) antipsychotics. First-generation antipsychotics reduced positive symptoms of schizophrenia but caused significant extrapyramidal symptoms and tardive dyskinesia. Emerging in the 1980s, SGAs were less associated with tardive dyskinesia and quickly acquired pediatric indications.
Metabolic Side Effects
The most concerning and common adverse effects of the SGAs are metabolic: increased appetite, weight gain, often quite rapid, and increases in blood glucose or lipids. SGA-related increase in glucose and lipids may be a direct effect, not necessarily correlated with weight gain. Although neither the American Academy of Child and Adolescent Psychiatry nor the American Academy of Pediatrics have published formal guidelines on metabolic monitoring of SGAs in children, most experts recommend pediatric adaptation of the American Diabetic Association guidelines.11 These guidelines recommend measuring fasting glucose, fasting lipids, and blood pressure at baseline and at 3 months. If normal, measuring fasting glucose, fasting lipids and blood pressure are recommended annually. Monitoring should be done more frequently if there are abnormalities. BMI should be obtained at baseline, at 4, 8, and 12 weeks, and every 3 months thereafter. Medication discontinuation should be seriously considered if early weight gain is identified. It is the responsibility of the prescribing clinician to conduct this monitoring; unfortunately, adherence to this mandate is low. The pediatrician can have an important role in monitoring weight gain and metabolic effects as they have more ready access to blood draw and clinical labs than psychiatric prescribers.
Psychoeducation around lifestyle measures to minimize adverse effects should occur before and during treatment with SGAs. Increased appetite associated with SGAs may drive behavioral problems that outweigh other benefits. Olanzapine, quetiapine, and risperidone appear to carry the highest risks.12
Role of Metformin
Metformin has been found effective in treating SGA-related weight gain in randomized controlled trials in pediatric patients with serious mental illness13 and with autism spectrum disorder.14 Consider metformin use when there is an absolute need to continue use of the SGA and there is rapid weight gain, early signs of metabolic syndrome, or a family history of diabetes.
SGAs can be associated with hyperprolactinemia, particularly high-potency D2 antagonists such as risperidone. Routine prolactin monitoring is not recommended, but signs of hyperprolactinemia including gynecomastia, galactorrhea, or amenorrhea should prompt consideration of stopping the implicated SGA or replacing it with a D2 partial agonist such as aripiprazole. Adolescents taking SGAs may also experience sexual side effects similar to that caused by SSRIs.
Antipsychotics are associated with neurological effects including Parkinsonian symptoms, dyskinesia, akathisia (sensation of motor restlessness) and, less commonly, tardive dyskinesia. Classic Parkinsonian symptoms include rigidity, cogwheeling, reduced arm swing, turning “en bloc,” fixed facial expression, and occasionally drooling. Dyskinesias can occur de novo with initial treatment and upon withdrawal of antipsychotics. Tardive dyskinesia is associated with long-term use of high-potency antipsychotics, and presents as potentially irreversible dyskinetic movements. The pediatrician should collaborate with the prescribing psychiatrist if these signs manifest. If prescribing, reconsider the need for ongoing treatment with antipsychotics, and if possible, discontinue. Although there is no standard consensus for how to discontinue, consider reducing dose slowly by 25% every few weeks to avoid withdrawal dyskinesia.
Baseline or routine electrocardiogram (ECG) is not recommended before prescribing antipsychotics, except for prescribing ziprasidone, which may prolong the QTc. ECG should be considered if there is a history of nonvasovagal syncope, arrhythmia, or family history of sudden death or cardiac conditions.
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome, a rare but potential life-threatening complication of antipsychotic use, presents with altered mental status, fever, autonomic instability, and muscle stiffness with elevated creatinine phosphokinase. It is rare with SGAs.
Psychotropic medications are an essential component of treating pediatric mental health disorders. Medications used to treat ADHD, anxiety, and depression are generally safe and well tolerated. The antipsychotics required should be used judiciously and carefully monitored.
- Swanson JM, Arnold LE, Molina BSG, et al. MTA Cooperative Group. Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression. J Child Psychol Psychiatry. 2017;58(6):663–678. doi:10.1111/jcpp.12684 [CrossRef] PMID:28295312
- Cohen SC, Mulqueen JM, Ferracioli-Oda E, et al. Meta-analysis: risk of tics associated with psychostimulant use in randomized, placebo-controlled trials. J Am Acad Child Adolesc Psychiatry. 2015;54(9):728–736. doi:10.1016/j.jaac.2015.06.011 [CrossRef] PMID:26299294
- Stahl S. Stahl's Essential Psychopharmacology: Prescriber's Guide. 6th ed. Cambridge University Press; 2017.
- Doghramji K, Jangro WC. Adverse effects of psychotropic medications on sleep. Psychiatr Clin North Am. 2016;39(3):487–502. doi:10.1016/j.psc.2016.04.009 [CrossRef] PMID:27514301
- Safer DJ, Zito JM. Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents. J Child Adolesc Psychopharmacol. 2006;16(1–2):159–169. doi:10.1089/cap.2006.16.159 [CrossRef] PMID:16553536
- Walkup J, Labellarte M. Complications of SSRI treatment. J Child Adolesc Psychopharmacol. 2001;11(1):1–4. doi:10.1089/104454601750143320 [CrossRef] PMID:11322738
- Wilens TE, Wyatt D, Spencer TJ. Disentangling disinhibition. J Am Acad Child Adolesc Psychiatry. 1998;37(11):1225–1227. doi:10.1097/00004583-199811000-00024 [CrossRef] PMID:9808935
- Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332–339. doi:10.1001/archpsyc.63.3.332 [CrossRef] PMID:16520440
- Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007;297(15):1683–1696. doi:10.1001/jama.297.15.1683 [CrossRef] PMID:17440145
- Levine A, McGlinchey E. Assessing sexual symptoms and side effects in adolescents. Pediatrics. 2015;135(4):e815–e817. doi:10.1542/peds.2014-3003 [CrossRef] PMID:25802347
- American Diabetes AssociationAmerican Psychiatric AssociationAmerican Association of Clinical EndocrinologistsNorth American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267–272. doi:10.4088/JCP.v65n0219 [CrossRef] PMID:15003083
- De Hert M, Detraux J. The urgent need for optimal monitoring of metabolic adverse effects in children and youngsters who take on-label or off-label antipsychotic medication. JAMA Psychiatry. 2018;75(8):771–772. doi:10.1001/jamapsychiatry.2018.1080 [CrossRef] PMID:29898215
- Correll CU, Sikich L, Reeves G, et al. Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial. World Psychiatry. 2020;19(1):69–80. doi:10.1002/wps.20714 [CrossRef] PMID:31922663
- Handen BL, Anagnostou E, Aman MG, et al. A randomized, placebo-controlled trial of metformin for the treatment of overweight induced by antipsychotic medication in young people with autism spectrum disorder: open-label extension. J Am Acad Child Adolesc Psychiatry. 2017;56(10):849–856.e6. doi:10.1016/j.jaac.2017.07.790 [CrossRef] PMID:28942807