Medication treatment has proven effective as adjunctive treatment along with cognitive-behavioral therapy for separation anxiety and school refusal and may hasten return to normal activities. Medication as the only treatment should not be used initially as treatment for separation anxiety disorder.
Neuroleptics (ie, antipsychotic agents) are contraindicated in separation anxiety disorder. Cases of children with Tourette syndrome have been reported in which separation anxiety disorder develops after initiation of haloperidol or pimozide or other neuroleptic medication.
Associated weight gain with neuroleptics, particularly olanzapine, may increase later risk for potentially life-threatening cardiovascular disease due to persistent elevation of serum cholesterol and triglycerides, either because of the direct effect of the neuroleptic or secondarily because of the effects of weight gain on the turnover of cholesterol and related compounds in the body.
Other agents such as tricyclic antidepressants, selective serotonin reuptake inhibitors, anxiolytics, alpha-adrenergic agonists, and beta-adrenergic blocking agents have been used.
TCAs are not recommended as the first-line treatment of separation anxiety disorder and school refusal; however, the FDA has approved these medications for pediatric use as long as the substantial risk of mortality and morbidity in overdose and the potential for adverse cardiac effects (heart block, arrhythmias) are carefully monitored.
Imipramine inhibits the reuptake of norepinephrine or serotonin (5-hydroxytryptamine, 5-HT) at presynaptic neurons. Only imipramine is FDA-approved for panic disorder and use in children, although its usage in separation anxiety disorder is considered off-label. Intolerable adverse effects, including dry mouth, headache, narrow-angle glaucoma, cardiac complications (including rare events of sudden death), and partial or complete heart block, limit use. Extremely dangerous in overdose (deaths have occurred).
Selective Serotonin Reuptake Inhibitors
In the past, SSRIs were recommended as the first-line pharmacologic treatment for separation anxiety disorder because of efficacy; however, except for fluoxetine, the FDA has not approved most SSRIs for use in children younger than 12 years. Safety concerns because of complications (eg, increased risk of suicidal ideation or plan or disinhibition with aggression) preclude their current use in children and adolescents unless the patient's response is closely monitored (weekly basis for at least the first month) or unless the patient has had a past history of good response to SSRIs or SNRIs.
SSRIs have proven an unparalleled relative safety in overdose and have few cardiac or anticholinergic adverse effects. Efficacy studies of medication use for separation anxiety have shown promising results with respect to SSRIs and symptom remission. However, practitioners are advised against prescribing SSRIs, specifically paroxetine or venlafaxine, in children and adolescents.
Physicians are advised to be aware of the following information and use appropriate caution when considering treatment with SSRIs in the pediatric population.
In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of depressive illness. After review, this agency decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, with the exception of fluoxetine, which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.
In October 2003, the FDA issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA has asked that additional studies be performed, because suicidality occurred in treated and untreated patients with major depression and thus could not be definitively linked to drug treatment.
A study of more than 65,000 children and adults treated for depression between 1992 and 2002 by the Group Health Cooperative in Seattle found that suicide risk declines, not rises, with the use of antidepressants.  This is the largest study to date to address this issue.
Currently, evidence does not associate OCD and other anxiety disorders treated with SSRIs with an increased risk of suicide.
Children at high risk for pediatric bipolar mood disorder (ie, positive first-degree family history for bipolar disorder or alcoholism along with history of aggression, impulsivity, and/or sleep disturbances related to initiation or maintenance of sleep) should be administered SSRIs with caution, because hypomania or frank mania or psychosis along with behavioral disinhibition may result.
This is the first SSRI ever used in children and adolescents. It has relative safety in overdose. Fluoxetine may cause more adverse GI effects than other currently available SSRIs.
This agent is available in liquid and cap form. Some case reports suggest that despite a possible association with rare occurrences of behavioral disinhibition, fluoxetine may be relatively safer in pediatric usage than are paroxetine or venlafaxine.
However, fluoxetine still carries risk and, therefore, has a "Black Box" warning. Do not use in children who are physically aggressive, have a family history of suicidal or parasuicidal ideation or behaviors, or are at increased risk of self-harm.
Sertraline can be helpful in those who do not respond to fluoxetine; however, it is only FDA approved for pediatric obsessive-compulsive disorder, at a dose of 25 mg/day for (age 6-12 y) and 50 mg/day (age 12 y and up). Sertraline is FDA approved in adults for major depression, social anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder, and panic disorder.
These agents reduce anticipatory and acute situational anxiety, as well as reduce muscle tension symptoms. They reduce symptoms in panic disorder. Anxiolytic agents are not the first-line treatment in children or adolescents because of concerns regarding drug dependence, withdrawal symptoms, and tolerance.
Alprazolam is a benzodiazepine and it is not recommended for prolonged use in children or adolescents because of concerns regarding drug dependance and tolerance. Use alprazolam for the shortest duration (< 2-3 wk to prevent addiction) and gradually taper it to prevent symptoms of withdrawal that could become potentially life threatening (ie, status epilepticus).
Buspirone has been approved for use since 1986 in adults for anxiety, and its mechanism of action may be stimulating 5-HT1A and 5-HT2 receptors, as well as other minor effects on dopamine D2 receptors. Unlike benzodiazepines, it does not cause sedation. It is available in 5 strengths (5, 7.5, 10, 15, and 30 mg) and generally should be given in 2 or 3 divided doses starting at 10-15 mg/day, not to exceed 60 mg/day.
Do not take buspirone with warfarin (Coumadin) or grapefruit juice, owing to an increased risk of bleeding or elevated levels of buspirone. Buspirone is primarily metabolized by the liver, so medications that interfere with liver metabolism (nefazodone, erythromycin, itraconazole, rifampin) can potentially cause toxic or subtherapeutic levels of buspirone. It is not FDA approved for use in children or adolescents.
No controlled studies are available to evaluate the efficacy of antihistamines in the treatment of separation anxiety; however, possible adverse effects include a decrease in sleep latency and in midsleep awakenings.
Diphenhydramine competes with histamine for H1-receptor sites on target cells in the gastrointestinl tract, blood vessels and respiratory tract. Used as a sedative to establish proper sleep patterns. It is available in syrup, strip, liquid, solution, chewable, and cap formulations.
Hydroxyzine competes with histamine for H1-receptor sites on target cells in the gastrointestinl tract, blood vessels and respiratory tract. It is FDA approved for use in children younger than 6 years (at 50 mg/day PO) and in children older than 6 years (at 50-100 mg/d PO) for short term use for anxiety, especially anxiety associated with medical procedures.
Beta-Adrenergic Blocking Agents
These block the physiological symptoms of anxiety and inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation. Do not use in patients with asthma because they may precipitate an acute asthmatic crisis.
Propranolol is a nonselective beta-adrenergic blocker. The drug blocks adrenergic stimulation that may cause the physiologic symptoms of anxiety and may thus be helpful for decreasing the severity of somatic anxiety symptoms.
However, do not use propranolol in patients with asthma. In addition, the drug may cause unpleasant cardiovascular and GI adverse effects and is not the drug of choice, especially because hypotension and/or cardiac block can develop.
Initiation of therapy should be performed with close monitoring of blood pressure to prevent hypotensive crisis. Do not discontinue propranolol abruptly, because this may precipitate hypertensive crisis.
Anticonvulsants such as gabapentin have apparent anxiolytic properties.
Gabapentin is a membrane stabilizer, a structural analogue of inhibitory neurotransmitter gamma-amino butyric acid (GABA), which paradoxically is thought not to exert effect on GABA receptors. Gabapentin is not FDA approved for use in children for anxiety, but it is FDA approved for use in children aged 3 year and older for seizure disorders (40 mg/kg/day; with a half-life of 5-7 h, necessitating tid dosing). Gabapentin is FDA approved for use in adults with neuropathic pain or seizures; however, some concern exists about the possible addictive potential with this medication.
Alpha-adrenergic agents such as clonidine and guanfacine (Tenex) are not FDA approved for use in children but may be effective for anxiety, especially social anxiety associated with performance anxiety; children may be more likely than older adolescents or adults to have adverse reactions (eg, new-onset hallucinations, paradoxical excitation) to these agents.
Guanfacine stimulates alpha2A-adrenergic receptors, which reduces sympathetic nerve impulses and results in a reduction of sympathetic outflow.
Clonidine is a central alpha-adrenergic agonist that stimulates alpha2-adrenoreceptors in the brain stem and activates an inhibitory neuron, resulting in a decrease in vasomotor tone and heart rate.
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