For children and adolescents with uncomplicated psychiatric disorders, pediatricians are often the first prescriber of psychiatric medications. Mental health disorders commonly treated by pediatricians include attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety. There are several safe and effective first-line medications for these disorders. For ADHD, stimulants and nonstimulants can be used as first-line interventions. For anxiety and depression, selective serotonin reuptake inhibitors are well-established treatments and often well-tolerated. With appropriate support and training, pediatricians can increase access for children to necessary mental health treatments. [Pediatr Ann. 2018;47(8):e311–e316.]
Many visits to pediatricians and pediatric primary care providers involve a mental health or behavioral complaint. Given the shortage of child and adolescent psychiatrists and other specialized child mental health prescribers, primary care providers are often called on to prescribe psychiatric medications for children under their care. This article reviews commonly prescribed first-line psychiatric medications for children and provides information relevant to their use in a pediatric primary care setting.
Psychostimulants are the most globally effective medication treatment option for attention-deficit/hyperactivity disorder (ADHD), and they are available in many formulations. All psychostimulants increase release of dopamine into the synaptic cleft, although they do so by differing mechanisms.1 For the purposes of first-line prescribing, stimulants can be separated into two classes: methylphenidate and dextroamphetamine. It is generally accepted that both classes are equally effective, although patients may respond much better to one class than the other.2 Therefore, if one stimulant is tried and found to be insufficiently effective, switching to a medication from the other stimulant class is typically the next best step in care before moving on to other medication options.
The Preschool ADHD Treatment Study (PATS)3 was a randomized control trial that studied the use of methylphenidate in children between ages 3 and 5.5 years. Although there are multiple studies supporting the superiority of stimulant treatment over nonpharmacologic treatment,2 the PATS trial required participants to continue to meet ADHD criteria after 10 weeks of parent training to be included in the medication trial. Effective doses in the PATS trial ranged from 2.5 to 7.5 mg three times daily. Optimal dosing was found to be 0.7 ± 0.4 mg/kg per day.3 Younger children are more susceptible to side effects and should typically be started on lower doses relative to weight compared with older children. Short-acting formulations should be used in children who weigh less than 16 kg to allow for dosing appropriate for weight2,4 (Table 1).
Stimulant Medications for ADHD
The Multimodal Treatment of ADHD (MTA) study5 was performed many years ago but is still highly referenced due to its powerful design as a randomized control trial with four arms of school-age children (age 7 to 9.9 years) comparing careful medication management with methylphenidate, medication combined with behavioral therapy, behavioral therapy alone, and usual care (community-based prescribing). The study showed that carefully titrated methylphenidate in mean doses of 30 to 37 mg daily was superior to both behavioral therapy alone and usual community care, which at the time of the trial meant lower average dose of prescription (23 mg/day). Combined treatment was not more effective than medication management for symptoms of ADHD, although participants in the combined treatment arm did require lower doses of stimulants.5
Dextroamphetamines are thought to exert therapeutic effects by increasing synaptic concentration of both norepinephrine and dopamine.6 This medication class is available as mixed amphetamine salts (dextroamphetamine and amphetamine), dextroamphetamine, and lisdexamfetamine. Long- and short-acting formulations are available of mixed amphetamine salts, and dextroamphetamine. Lisdexamfetamine is a prodrug requiring hydrolysis to activate the drug in the gastrointestinal tract, which partially reduces the potential for abuse7 (Table 1).
Pretreatment screening for a family history of sudden death and for patient history of cardiac disease or symptoms is recommended, given the small potential for stimulants via increases of pulse and blood pressure to increase the risk of a serious underlying cardiovascular problem. A clinical screening includes a history of cardiac symptoms in the patient, family history, and physical examination with vital signs. In the absence of concern for cardiac disease in the patient, pretreatment electrocardiograms are not recommended. If there are clinical symptoms suggestive of a significant underlying cardiac condition, a referral to a cardiologist should be made for recommendations on safety of stimulant use.2
Common side effects to monitor include irritability, appetite suppression, and sleep disturbance. Compared to school-age children, preschool children have been shown to experience a higher rate of emotional adverse events from stimulants.2
During treatment, weight gain and growth should be monitored, and efforts should be made to ensure adequate food intake in cases of appetite suppression. Adjustments in dosing or trial of an alternate stimulant can be effective in moderating the side effect of reduced appetite. Although there have been concerns in the past about stimulant medications slowing growth in height, this difference is thought to be quite small and possibly not sustained into adulthood.2
Long-acting vs short-acting formulations
Long-acting stimulant formulations typically eliminate the need for twice or thrice daily dosing, increasing chances of care plan adherence and enhancing privacy by eliminating the need for in-school dosing. See Table 1 for general formulations of long-acting stimulants. In certain cases, a long-acting stimulant can be augmented with a short-acting stimulant from the same class. There are no robust safety data for combined use of multiple stimulant classes, and this is not recommended.
Rare side effects
Rarely, psychotic symptoms or significant mood elevation can develop after initiation of treatment with a stimulant. Psychosis induced by the drug of abuse, methamphetamine, is a well-established phenomenon,8 but there is also emerging evidence that prescription stimulant use may be associated with earlier onset of psychosis,9 as well as risk for hospitalization for psychosis or mania.10
Alpha 2 agonists
Guanfacine and clonidine are both alpha-2 adrenergic agonists and can be used as alternatives to stimulant medications for treatment of ADHD. In some cases, alpha agonists are used for augmentation of stimulant treatment. Extended-release clonidine and extended-release guanfacine are both approved by the US Food and Drug Administration (FDA) for treatment of ADHD and for use in combination with stimulants.11,12 Short-acting formulations of clonidine and guanfacine are not FDA-approved for ADHD but are often used off-label to target hyperactivity and impulsivity.2 Short-acting clonidine is noted to be more sedating, and at times is used for treating insomnia in children with ADHD.2
Dosing. Dosing of extended-release guanfacine typically starts at 1 mg/day and can be increased if tolerated. Usual-care dosing goes up to 4 mg/day.2 The short-acting formulation of guanfacine may be preferable for younger children, or in cases in which the physician would like to start with lower doses, as these pills can be divided (Table 2).
Nonstimulant Medications for ADHD
Long-acting clonidine comes in 0.1-mg tablets and is also available in a patch form, although this carries risks of its own, with the most concerning being unintentional overdose.13 Guanfacine and clonidine should not be used in combination due to risks of cumulative sedative and antihypertensive effects.11,12 It can take several weeks of treatment to see results with these medications.
Monitoring. Vital signs should be monitored before therapy and with each dose change. Orthostatic vital signs should be monitored as well. Prior to initiating therapy, a screen should be done for cardiac concerns given the medications' recognized role in blood pressure suppression.11,12 All alpha agonists can be sedating and have the potential to cause cognitive blunting.11,12 There is a small risk of withdrawal hypertension when stopping these agents, such that a gradual taper would be advisable if the child is using a high dosage.
Atomoxetine is a norepinephrine reuptake inhibitor and is FDA approved for patients age 6 years and older through adulthood.14 It is recommended as an alternative to treatment with a stimulant plus selective serotonin reuptake inhibitors (SSRIs) in cases of anxiety,4 and is also a consideration for patients who cannot take stimulants for other reasons, such as substance use disorders.
Dosing. Dosing is weight-based, starting at 0.5 mg/kg per day and should be titrated over at least 3 to 7 days to a therapeutic dose range of 0. 8 to 1.2 mg/kg per day.2 Doses larger than 1.2 mg/kg per day have not been shown to provide further benefit. The FDA maximum recommended dosing is 1.4 mg/kg per day, or 100 mg/day, whichever is less. Results can be seen within 1 week, but study data support that maximum benefit can take up to 6 weeks to manifest15 (Table 2).
Monitoring. Atomoxetine carries an FDA black box warning for suicidal ideation,16 and this should be reviewed with families and patients when this medication is being prescribed. Similar to the black box warning for SSRI medications, the total number of patients who developed suicidal ideation was small but statistically significant.17 Risk for development of suicidal ideation needs to be weighed against the potential benefit of ADHD treatment.17
Rare cases of hepatotoxicity have been reported with atomoxetine,2 and the medication now carries an FDA warning for hepatotoxicity.16 Patients and families should be counseled regarding clinical signs of hepatotoxicity, but in the absence of clinical concern, liver enzymes do not need to be monitored.2,17
As with stimulants, it is recommended to screen for symptoms of cardiac disease and for family history suggestive of structural cardiac disease. Through its noradrenergic stimulation, atomoxetine is likely to increase heart rate, and so should be used with caution in conditions in which an increase in heart rate could be problematic. Prolonged QT interval is an additional potential side effect to consider, and screening for personal or family history of prolonged QT is recommended. For patients in whom there is concern for significant underlying cardiac disease, a cardiologist should be consulted before initiation of atomoxetine therapy.17
Depression and Anxiety Medications
Selective Serotonin Reuptake Inhibitors
The SSRIs are the mainstays of pharmacologic treatment of depression and anxiety in the pediatric population. This class includes fluoxetine, sertraline, fluvoxamine, citalopram, and escitalopram. Although paroxetine is also an SSRI, it is not commonly recommended for use in children and adolescents given reports of higher risk for suicidal ideation and adverse events.15
SSRIs block the reuptake of serotonin in presynaptic neurons, causing an increase in serotonin in the synaptic cleft immediately, as well as downstream effects that occur over time. Although patients may indicate improvement early in the course of treatment, maximum benefit at any given dose typically takes 4 to 6 weeks to manifest.1
Fluoxetine is FDA-approved for treatment of obsessive-compulsive disorder (OCD) and major depressive disorder in children. In combination with olanzapine, it is also approved for treatment of bipolar depression in the pediatric population. Due to its long half-life, it may be a preferred agent to avoid withdrawal symptoms in patients with a higher likelihood of missing doses. A delayed-release formulation exists, which is FDA-approved for once-weekly dosing.19 In the Treatment of Adolescents with Depression Study,20 fluoxetine was shown to be effective for treatment of depression in adolescents and superior to cognitive-behavioral therapy (CBT) alone. Escitalopram has also been FDA-approved for treatment of depression in adolescence, although the overall randomized controlled trial evidence support is less strong for this medication (and its citalopram analogue) than for fluoxetine (Table 3).21
SSRIs Used for Treatment of Major Depressive Disorder, Obsessive-Compulsive Disorder, and Anxiety Disorders
Sertraline is FDA approved for OCD,22 although it has also been shown to in other randomized control trials to be effective for children with one or more of the following anxiety disorders: separation anxiety disorder, generalized anxiety disorder, and social phobia.23,24 Average dosing in the Child/Adolescent Anxiety Multimodal Study using sertraline varied based on whether participants were taking medication alone, or medication and CBT.24 Average dose in the combination-therapy group was 133 mg/day, and average dose in the medication-alone group was 146 mg/day.
SSRIs are generally well tolerated, with most common side effects being mild and self-limited. However, there are a few rare but serious side effects that should be reviewed with patients and families prior to initiating treatment.
Common side effects for SSRIs include appetite changes, gastrointestinal complaints (nausea, diarrhea, stomach ache), headache, sleep disturbance, and motor overactivity. Certain agents are more likely to be sedating (sertraline, citalopram, escitalopram), but adverse effect patterns vary. Sexual side effects (reduced drive) are a possibility with all SSRI medications.
In 2004, the FDA released a black box warning for SSRI medications being used in children and adolescents, based on pooled data that showed a small but statistically significant increase in suicidal ideation in children and adolescents that were treated with SSRIs versus placebo.25 Although the risk is small, it should be discussed with families and patients before initiation of therapy, and a plan should be developed for how to respond if the patient experiences this rare adverse effect. Most importantly, the risk of not treating depression needs to be considered and weighed against the risk of possible development of suicidal thoughts in response to SSRI treatment.
There are a number of safe and effective first-line agents that can be used in pharmacologic treatment of common mental health conditions. Although medications are only one component of the required treatment, it is often a rate-limiting step for families to find a mental health prescriber as nonpharmacologic treatment can be easier to access. Pediatric primary care providers can diagnose and provide initial pharmacologic treatment, and by doing this increase their patients' access to comprehensive mental health treatment.
- Schatzberg AF, DeBattista C. Manual of Clinical Psychopharmacology. 8th ed. Arlington, VA: American Psychiatric Publishing; 2015. doi:10.1176/appi.books.9781615370047 [CrossRef]
- Pliszka SAACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894–921. doi:. doi:10.1097/chi.0b013e318054e724 [CrossRef]
- Greenhill L, Kollins S, Abikoff H, et al. Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry. 2006;45(11):1284–1293. doi:. doi:10.1097/01.chi.0000235077.32661.61 [CrossRef]
- Pliszka SR, Crismon ML, Hughes CW, et al. Texas Consensus Conference Panel on Pharmacotherapy of Childhood Attention Deficit Hyperactivity Disorder. The Texas Children's Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006;45(6):642–657. doi:. doi:10.1097/01.chi.0000215326.51175.eb [CrossRef]
- [No authors listed]. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999;56(12):1073–1086. doi:10.1001/archpsyc.56.12.1073 [CrossRef]
- Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present–a pharmacological and clinical perspective. J Psychopharmacol. 2013;27(6):479–496. doi:. doi:10.1177/0269881113482532 [CrossRef]
- Blick SK, Keating GM. Lisdexamfetamine. Paediatr Drugs. 2007;9(2):129–135; discussion 136–128. doi:10.2165/00148581-200709020-00007 [CrossRef]
- Glasner-Edwards S, Mooney LJ. Methamphetamine psychosis: epidemiology and management. CNS Drugs. 2014;28(12):1115–1126. doi:. doi:10.1007/s40263-014-0209-8 [CrossRef]
- Moran LV, Masters GA, Pingali S, et al. Prescription stimulant use is associated with earlier onset of psychosis. J Psychiatr Res. 2015;71:41–47. doi:. doi:10.1016/j.jpsychires.2015.09.012 [CrossRef]
- Cressman AM, Macdonald EM, Huang A, et al. Prescription stimulant use and hospitalization for psychosis or mania: a population-based study. J Clin Psychopharmacol. 2015;35(6):667–671. doi:10.1097/JCP.0000000000000406 [CrossRef]
- Tenex [package insert]. Bridgewater, NJ: Promius Pharma; 2013.
- Catapres [package insert]. Ridgefield. CT: Boehringer Ingelheim; 2009.
- Broderick-Cantwell JJ. Case study: accidental clonidine patch overdose in attention-deficit/hyperactivity disorder patients. J Am Acad Child Adolesc Psychiatry. 1999;38(1):95–98. doi: . doi:10.1097/00004583-199901000-00025 [CrossRef]
- Truven Health Analytics. http://www.micromedexsolutions.com/micromedex2/librarian. Accessed July 16, 2018
- Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry. 2002;159(11):1896–1901. doi:.= doi:10.1176/appi.ajp.159.11.1896 [CrossRef]
- Strattera [package insert]. Indianapolis, IN: Eli Lilly & Co; 2003.
- Garnock-Jones KP, Keating GM. Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. Paediatr Drugs. 2009;11(3):203–226. doi:. doi:10.2165/00148581-200911030-00005 [CrossRef]
- Mulder R, Rucklidge JJ, Toop L. Restoring Study 329: paroxetine neither effective nor safe for adolescents. Aust N Z J Psychiatry. 2016;50(9):922–923. doi:. doi:10.1177/0004867416657412 [CrossRef]
- Prozac [package insert]. Indianapolis, IN: Eli Lilly & Co; 1987.
- March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA. 2004;292(7):807–820. doi:. doi:10.1001/jama.292.7.807 [CrossRef]
- Lexapro [package insert]. St. Louis, MO: Forest Pharmaceuticals; 2009.
- Zoloft [package insert]. New York, NY: Pfizer Inc.; 2016.
- Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA. 2004;292(16):1969–1976. doi:. doi:10.1001/jama.292.16.1969 [CrossRef]
- Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753–2766. doi:. doi:10.1056/NEJMoa0804633 [CrossRef]
- Friedman RA. Antidepressants' black-box warning--10 years later. N Engl J Med.2014;371(18):1666–1668. doi:. doi:10.1056/NEJMp1408480 [CrossRef]
- Biederman J, Melmed RD, Patel A, et al. SPD503 Study Group. A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2008;121(1):e73–e84. doi:. doi:10.1542/peds.2006-3695 [CrossRef]
- Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry.1999;38(12):1551–1559. doi:. doi:10.1097/00004583-199912000-00017 [CrossRef]
- Kodish I, Rockhill C, Ryan S, Varley C. Pharmacotherapy for anxiety disorders in children and adolescents. Pediatr Clin North Am. 2011;58(1):55–72. doi:. doi:10.1016/j.pcl.2010.10.002 [CrossRef]
Stimulant Medications for ADHD
||FDA Approval for ADHD
Intermediate acting Long acting
||Age 6+ years (short acting not approved for adults)
||10–60 mg /day
||Available in long-acting liquid formulation
||Age 6+ years (short and long acting)
Adults (long acting only)
||Short acting: 5 mg/day in divided doses up to 20 mg/day
Long acting: 5–30 mg/day
|Mixed amphetamine salts
||Age 3+ years (short acting) to adult
Age 6+ years (long acting) to adult
||Age 3–16 years (short acting)
Age 6–16 years (long acting)
(Not approved for adults)
||Single formulation; has up to 12-hour duration
||Age 6+ years (including adults)
||Prodrug may be a better choice for patients with a history of substance abuse
Nonstimulant Medications for ADHD
||FDA Approval for ADHD
||Common Side Effects
||Age 6–17 years
||Somnolence, sedation, fatigue, headache, vomiting, insomnia
||Age 6+ years
||Initial: 0.5 mg/kg/day if <70 kg, 40 mg/day if >70 kg
Target: 1.2 mg/kg/day if <70 kg, 80 mg/day if >70 kg
||Tachycardia, dizziness, irritability, fatigue, nausea, somnolence, vomiting, decreased appetite, abdominal pain, headache
||Age 6–17 years (not for adults)
||0.1– 0.4 mg/day (divided doses if total daily dose is >0.1 mg/day)
||Sedation, irritability, hypotension, sleep disturbance, dry mouth, dizziness, depression, skin irritation (patch), ECG changesb
||0.5–4 mg/day in divided doses (weight-based guidelines apply)
||Similar to guanfacine ER, possibly more sedation
||0.2–0.4 mg/day (weight-based guidelines apply)
||Similar to clonidine ER, except skin irritation
SSRIs Used for Treatment of Major Depressive Disorder, Obsessive-Compulsive Disorder, and Anxiety Disordersa
||Age 7+ years (OCD)
Age 8+ years (MDD)
Age 10+ years (combination with olanzapine for bipolar depression)
||10–60 mg/day (OCD)
10–40 mg/day (MDD)
Available in liquid formulation
||Age 6+ years (OCD)
||FDA warning requiring ECG for doses >40 mg/day (risk for QT prolongation)
||Age 12+ years (MDD)
||Age 8+ years (OCD)
||25–200 mg/day (divided doses if total daily dose >50 mg/day)
||Divided dosing may affect adherence