Additional issues arise with the prevalence of youth presenting with complex clinical presentations with multiple co-morbidities, varying symptomatic profiles over the course of time, and innumerable stressors impacting them during their years of growth and development. In the face of these challenges, there are often pressures for physicians and other prescribers to seek clinical benefit through the use of more than one medication— sometimes this makes perfect sense (as with the concurrent use of stimulants and α-agonists) but sometimes it may be a sign of a prescriber being stretched or overwhelmed and/or families being over invested in medication and underinvested in psychotherapy and behavioral interventions. While the rationale for using polypharmacy can often be quite substantial, there are obvious concerns about problems emerging.    Current trends, discussed below, highlight the importance for providers using a cautious and thoughtful approach to using multiple medication treatments in the population.

In an article published in JAMA Pediatrics (C. Zhang, MPH, and colleagues) reported on findings of a retrospective analysis of prescriptions detailing the increase in psychotropic polypharmacy over the course of 15 years, from 1999 through 2015.

With a definition of polypharmacy being the use of two or more psychotropic medications, there has been a substantial increase in youth being prescribed multiple medications for behavioral health concerns. Medication classes included in the study included stimulants, antidepressants, mood stabilizers, antipsychotics, anxiolytics, sedatives, and α-agonists.

Among the findings of the study:

1. ADHD:   Not surprisingly, the largest cohort of youngsters being treated with multiple medication were those who carried a diagnosis of ADHD (80%) as this is among the most common disorders in the population and one that is often associated with co-occurring behavioral concerns.
2. Diagnosis: There have been increased rates of diagnosing Mood Disorders (anxiety and depression) and Autism Spectrum Disorder.
3. Antipsychotic agents: Prescriptions for antipsychotics in youth prescribed multiple psychiatric medications doubled from the first to the third time periods, rising from 38% of youth in 1999-2005 to 75% between 2011 and 2015.
4. Alpha Agonists (guanfacine and clonidine) show significant increased rates of use.
5. Mood Stabilizers: In contrast, there was a significant decline in mood stabilizer use (from 61% of youth between 1999 and 2004 to 38% of youth between 2011 and 2015).
6. Antidepressants:   Still frequently prescribed, but with a modest decrease in use noted
7. Three or more medications:   Broken into five-year segments (1999-2005; 2005-2010, 2011-2015) the study demonstrated a greater than doubling (~ 210%) from the first time segment to the second with a subsequent increase for the third at ~130% over the 2005-2010 segment– all told the number of youth receiving multiple medications increased nearly threefold.
8. Racial disparities: the use of polypharmacy is significantly higher in youth of color – this, as with other issues of racial disparity is an arena of concern and one for further inquiry and sensitivity.

Some Practical Guidelines:

Dr. Oliver Wendall Holmes Sr. (1809-1894) who lived and worked in a different era, is reported to have said that ‘if all the medications in our pharmacopeia were to be dumped into the oceans, it would be all the worse for the fishes and all the better for mankind’.

We live in a different era with quite a bit more science and far better tools at our disposal, so that, in the face of rapid changes in practice patterns as described in the referenced study, it can be all too attractive to get on a “Medications are (or Polypharmacy is) Bad” soap box. But we know that proper medication regimes can be life enhancing for many and at times lifesaving for others.

The following guidelines are suggested

1. Prescribe with care, basing treatment on clarity of diagnosis and clear review of presenting symptoms.  Consider issues of co-morbidity and support a focus on behavioral and psychotherapeutic interventions.
2. Seek to coordinate care with a qualified and clinically astute therapist who can address psychosocial issues with the youth, the family and with school and community partners and one that is committed to ongoing dialogue about the patient.
3. If you are prescribing, see your patient frequently enough to monitor their progress and assess for ongoing or newly developing concerns.   Be clear in your own mind what symptoms are being targeted with medications you are prescribing and monitor for efficacy and side effects with regular contacts.
4. When clearly indicated, titrate dosing to optimize response and accept polypharmacy approaches if they make sense— but keep it simple and avoid the temptation to simply add medications when things are not getting better.
5. Sometimes careful and thoughtful de-prescribing makes more sense than ramping up dose or adding extra agents. Discontinuing a medication can often be more difficulty to do, but if an agent has not shown evidence of efficacy or benefit, removing it from the treatment regimen should seriously be considered.  In general, gradual down-titration with a med that doesn’t seem to be helpful is a good practice.
6. Utilize both clinical inquiry and screening tools to monitor progress and/or lack thereof.   Encourage parents and patients to call you if they have concerns.
7. Consult with a peer or colleague in your practice to seek input and learn collaboratively. When in doubt, refer to a trusted consultant – what you learn will help with your current patient and will enhance your comfort and capacity to address similar issues with other patients in the future.

References:

Characteristics of Youths Treated with Psychotropic Polypharmacy in the United States, 1999 to 2015

Chengchen Zhang, MPH¹; O’Mareen Spence, MPH, PhD¹; Gloria Reeves, MD²; et al; Susan dosReis, PhD¹;

JAMA Pediatr. Published online November 2, 2020. doi:10.1001/jamapediatrics.2020.4678

Brunette MF, de Nesnera A, Swain K, et al.: Public-academic partnerships: a program to improve the quality of antipsychotic prescribing in a community mental health system. Psychiatric Services 62:1004–1006, 2011

Parameters 3.8 for Use of Psychotropic Medications in Children and Adolescents; Los Angeles County Department of Mental Health, July 15, 2020 (revised)   http://file.lacounty.gov/SDSInter/dmh/1071988_Paremeters3.8ForUseOfPsychotropicMedicationInChildrenAndAdolescents.pdf

Additional issues arise with the prevalence of youth presenting with complex clinical presentations with multiple co-morbidities, varying symptomatic profiles over the course of time, and innumerable stressors impacting them during their years of growth and development. In the face of these challenges, there are often pressures for physicians and other prescribers to seek clinical benefit through the use of more than one medication— sometimes this makes perfect sense (as with the concurrent use of stimulants and α-agonists) but sometimes it may be a sign of a prescriber being stretched or overwhelmed. While the rationale for using polypharmacy can often be quite substantial, there are obvious concerns about problems emerging— current trends, discussed below, highlight the importance for providers using a cautious and thoughtful approach to using multiple medication treatments in the population.

In a recently published article in JAMA Pediatrics (C. Zhang, MPH, and colleagues) reported on findings of a retrospective analysis of prescriptions detailing the increase in psychotropic polypharmacy over the course of the past 15 years, from 1999 through 2015.

With a definition of polypharmacy being the use of two or more psychotropic medications, there has been a substantial increase in youth being prescribed multiple medications for behavioral health concerns. Medication classes included in the study included stimulants, antidepressants, mood stabilizers, antipsychotics, anxiolytics, sedatives, and α-agonists.

Among the findings of the study:

1. ADHD:   Not surprisingly, the largest cohort of youngsters being treated with multiple medication were those who carried a diagnosis of ADHD (80%) as this is among the most common disorders in the population and one that is often associated with co-occurring behavioral concerns.
2. Diagnosis: There have been increased rates of diagnosing mood disorders (anxiety and depression) and Autism Spectrum Disorder.
3. Antipsychotic agents: Prescriptions for antipsychotics in youth prescribed multiple psychiatric medications doubled from the first to the third time periods, rising from 38% of youth in 1999-2005 to 75% between 2011 and 2015.
4. α-agonists (guanfacine and clonidine) show significant increased rates of use
5. Mood Stabilizers: In contrast, there was a significant decline in mood stabilizer use (from 61% of youth between 1999 and 2004 to 38% of youth between 2011 and 2015).
6. Antidepressants:   Still frequently prescribed, but with a modest decrease in use noted
7. Three or more medications:   Broken into five year segments (1999-2005; 2005-2010, 2011-2015) their study demonstrated a greater than doubling (~ 210%) from the first time segment to the second with a subsequent increase for the third at ~130% over the 2005-2010 segment– all told the number of youth receiving multiple medications increased just shy of threefold.
8. Racial disparities: the use of polypharmacy is significantly higher in youth of color – this, as with other issues of racial disparity is an arena of concern and one for further inquiry and sensitivity.

Some Practical Guidelines:

Dr. Oliver Wendall Holmes Sr. (1809-1894) who lived and worked in a different era, is reported to have said that ‘if all the medications in our pharmacopeia were to be dumped into the oceans, it would be all the worse for the fishes and all the better for mankind’.

We live in a different era with quite a bit more science and far better tools at our disposal, so that, in the face of rapid changes in practice patterns as described in the referenced study, it can be all too attractive to get on a “Medications are (or Polypharmacy is) Bad” soap box. But we know that proper medication regimes can be life enhancing and at times lifesaving for many.

The following guidelines are suggested

1. Prescribe with care, basing treatment on clarity of diagnosis and with full consideration of the potential complexities of each individual.
2. Seek to coordinate care with a qualified and clinically astute therapist who can address psychosocial issues with the youth, the family and with school and community partners and one that is committed to ongoing dialogue about the patient.
3. If you are prescribing, see your patient frequently enough to monitor their progress and assess for ongoing or newly developing concerns.   Be clear in your own mind what symptoms are being targeted with medications you are prescribing and monitor for efficacy and side effects with regular contacts.
4. When clearly indicated, titrate dosing to optimize response and accept polypharmacy approaches if they make sense— but keep it simple and avoid the temptation to simply add medications when things are not getting better.
5. Sometimes careful and thoughtful de-prescribing makes more sense than ramping up dose of adding extra agents. Discontinuing a medication can often be more difficulty to do, but if an agent has not shown evidence of efficacy or benefit, removing it from the treatment regimen should seriously be considered.
6. Utilize both clinical inquiry and screening tools to monitor progress and/or lack thereof.   Encourage parents and patients to call you if they have concerns.
7. Consult with a peer or colleague in your practice to seek input and learn collaboratively. When in doubt, refer to a trusted consultant – what you learn will help with your current patient and will enhance your comfort and capacity to address similar issues with other patients in the future.

References:

Characteristics of Youths Treated With Psychotropic Polypharmacy in the United States, 1999 to 2015

Chengchen Zhang, MPH¹; O’Mareen Spence, MPH, PhD¹; Gloria Reeves, MD²; et al; Susan dosReis, PhD¹;

JAMA Pediatr. Published online November 2, 2020. doi:10.1001/jamapediatrics.2020.4678

Brunette MF, de Nesnera A, Swain K, et al.: Public-academic partnerships: a program to improve the quality of antipsychotic prescribing in a community mental health system. Psychiatric Services 62:1004–1006, 2011

Parameters 3.8 for Use of Psychotropic Medications in Children and Adolescents; Los Angeles County Department of Mental Health, July 15, 2020 (revised)   http://file.lacounty.gov/SDSInter/dmh/1071988_Paremeters3.8ForUseOfPsychotropicMedicationInChildrenAndAdolescents.pdf

It is important to thoroughly assess for other causes for the hallucinations before considering a psychotic disorder because primary psychotic disorders are very rare in children. It is important to conduct a thorough clinical history and physical exam, and to consider basic labs and/or brain imaging if there are other signs of a medical or neurological process. Medical causes for hallucinations include: seizures, brain tumors (particularly in the visual association areas, temporal lobes and area around the optic nerve and retina), thyroid disease, electrolyte imbalances and adrenal disorders.

Medications that can commonly cause hallucinations include steroids, anticholinergics, and stimulants. It is important to consider the possibility of illegal drug use, including marijuana, even in very young children, who may have either taken the drug on purpose or ingested it accidentally. Visual, olfactory and gustatory hallucinations in children may suggest a medication or substance-related cause. It is important to rule out hypnagogic hallucinations, which occur immediately before falling asleep and hypnopompic hallucinations, which occur during the transition from sleep to wakefulness, both of which are normal phenomena.

True hallucinations in children are more likely to be a part of a non-psychotic psychiatric disorder than a primary psychotic disorder. Hallucinations can occur in children with non-psychotic psychiatric disorders, like depression, anxiety, and disruptive disorders. Hallucinations are not uncommon in depression in children but may suggest a higher risk for developing bipolar disorder. It is common for grieving children to hear “voices” from recently deceased loved ones. It’s important to remember that children who have experienced trauma can experience hallucinations as part of the trauma reaction. Hallucinations are common in children with developmental delays, including autism spectrum disorder. Children with language disorders may talk about “voices” because they cannot describe their own thoughts. In these situations, it can be helpful to ask a child if s/he is experiencing the voice inside of outside his/her head.

After ruling out the above, one can consider a primary psychotic disorder. It is important to assess for other psychotic symptoms (like disorganized speech, bizarre behavior, delusions, paranoia) as well as negative symptoms of psychosis (apathy, amotivation, and decline in functioning) before assuming a primary psychotic disorder, because a diagnosis of a primary psychotic disorder should not be made based on hallucinations alone.

In conclusion, while the report of hallucinations in children is worrisome, it is unlikely that it represents a psychotic disorder. It is important to conduct a thorough history to determine the underlying cause of the reported symptom.

While medication for ADHD is often the first line treatment for older children and adolescents with ADHD, it is not the recommended first line treatment for young children with ADHD symptoms. Both the CDC and AAP urges healthcare providers to refer parents of young children with ADHD for behavioral therapy training before prescribing medication to treat the symptoms. Research shows that behavioral therapy can be as effective as medication, being 70-80% effective for treating the core symptoms of ADHD in young children. Where the problem lies is that less than 50% of young children are referred to parent behavioral therapy training. While behavior therapy can take more time, effort, and resources than medication, the effects last much longer past when the treatment ends, unlike medication. Another concern is that stimulant medication in young children can have problematic side effects, including irritability, increased agitation, appetite suppression, growth delay, and sleep disturbance. In clinical practice, psychotropic medication for ADHD symptoms has been shown to not work as reliably and robustly in younger children as they do in older children. This could occur when ADHD is not the correct diagnosis, as children with trauma or anxiety or sensory challenges can also present with hyperactivity and impulsivity, but would respond poorly to a stimulant medication. The other major reason is that the commonly seen side effects with stimulant medications (sleep and appetite disturbance, moodiness) can have more impact on young children, who are physically growing at a faster pace and are still developing core social/emotional and behavioral processes, as compared to older children, who are typically more mature in all of these areas.

In summary, when considering the diagnosis of ADHD in a young child, it is important to conduct a careful assessment, looking for other mood/anxiety, developmental, and medical symptoms, prior to confirming the diagnosis and considering treatment. If a young child does meet criteria for ADHD, the first-line recommended treatment is parent training for behavioral therapy, before considering medication. Because we know it is hard to help families find resources, parents can be referred to the SmartCare Parent Line to help find an appropriate program to meet their needs.

Treatment options include therapy or a combination of therapy and medication:

• For patients with mild-moderate symptoms, a therapy approach is preferred, with the option incorporate medication if the therapy is not effective.
• For patients with moderate-severe symptoms with significant impairment in daily functioning, it may be warranted to consider starting with a combination of medication and therapy.

The key is that therapy is the important component to treatment of anxiety disorders in pediatrics, with medication used as an adjunctive treatment when needed. Therapy to address anxiety can easily be tailored to work with very young patients and is very effective. Types of therapy used include: cognitive behavioral therapy, exposure response prevention therapy, and relaxation techniques, among others.

Medications used to treat anxiety fall into two general categories: medications that treat the underlying anxiety and prevent future symptomatology and medications that treat acute symptoms, such as a panic attack. Medications in the first category include the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazipine, and buspirone.  The SSRIs are the first line agents. This class includes: fluoxetine, citalopram, escitalopram, sertraline, fluvoxamine, and paroxetine.  Although prompt relief may result, just as with treating depression, the medication may take 4-6 weeks to have full impact, so patience is important.  Also of note, often a higher dose may be needed to fully treat anxiety symptoms as compared to depressive symptoms.

The motto to “start low and go slow” remains relevant to limit activation and thereby increase anxiety during the titration process. So, for example if one is considering prescribing citalopram for anxiety for a 10 year-old patient, consider starting at 5 mg q-day for one week then 10 mg q-day for 1 week then 20 mg q-day and assessing the response. Some patients experience akathisia (internal feeling of restlessness), which can feel like a worsening of their anxiety, if the dose is titrated too quickly. Other side effects include sleep disturbance, GI upset and headache but most of these symptoms are dose related and will resolve over time.

The treatment of anxiety disorders in pediatric patients is mostly off label. Only fluoxetine (ages 7+), sertraline (ages 6+) and fluvoxamine (ages 8+) have FDA approval for treatment of obsessive-compulsive disorder (OCD).

When prescribing any antidepressant medication to treat anxiety, it is appropriate to review the FDA black box warning about the increased risk of spontaneous reporting of suicidal thoughts, even if the medication is not being prescribed to treat depression per se.

When prescribing a medication, it is standard practice to first use an SSRI.  If a patient has 2 or more adequate (in terms of dose and length of treatment) trials of SSRIs that are ineffective, one could consider an alternative, either an SNRI (venlafaxine or duloxetine) or mirtazapine, but consultation or referral to psychiatry would be advised in such situations. If there is some benefit from the SSRI, one could consider augmentation with mirtazapine or buspirone. The primary side effects to be concerned with mirtazapine include sedation and increased appetite. Buspirone has an onset of action of about 2 weeks. The primary side effects to be concerned with include: dizziness, fatigue and GI upset. Occasionally the atypical antipsychotics are considered as adjunctive treatment to treatment-resistant OCD.

Benzodiazepines, are rarely used in this population. Pediatric patients can have a paradoxical reaction to them and exhibit behavioral disinhibition. Other side effects include: physiological and psychological addiction, confusion, sedation and impaired fine motor coordination. If a medication to treat acute anxiety is needed, for example for a teenager who has very occasional panic attacks, one could consider hydroxyzine 25-50 mg on a prn basis, which is not associated with dependence. Side effects include: sleepiness, dizziness, and dry mouth.

When feasible, the use of rating scales can help in these efforts by documenting severity and monitoring clinical progress.   A good tool to review, the SCARED, is accessible at. http://www.pediatricbipolar.pitt.edu/content.asp?id=2333#3304 and a broader array of tools is listed at the following website http://www2.massgeneral.org/schoolpsychiatry/screening_anxiety.asp

First, it is important to determine what makes anxiety clinically significant. Anxiety is an expected, normal, transient response to stress and can be helpful with the warning of danger or coping with the stress. Clinically significant anxiety is an excessive response to external stress or related to an unidentifiable trigger. It is persistent rather than transient. It causes functional impairment, by exceeding the patient’s ability to cope with the stress and/or leading to avoidance behaviors.

General symptoms of anxiety in children include many worries about things before they happen, constant worries or concerns about family, school, friends or activities, fears or embarrassment or making mistakes, low self-esteem and lack of self-confidence. There are often somatic complaints as well, like stomachaches, headaches, and sleep disturbance, as well as a desire to avoid school and friends.

Specific symptoms of separation anxiety include constant thoughts and intense fears about the safety of parents and caregivers, refusing to go to school, frequent stomachaches and other physical complaints, extreme worries about sleeping away from home, being overly clingy, panic or tantrums at times of separation from parents, trouble sleeping or nightmares, and refusing to sleep without parents.

Specific symptoms of a phobia include extreme fear about a specific thing or situation (ex. dogs, insects, needles) and the fears cause significant distress and interfere with usual activities (ex. child refuses to go to the park because of a fear of seeing a dog).

Specific symptoms of social anxiety include fears of meeting or talking to people, avoidance of social situations despite a desire to attend, and few friends outside the family.

Anxiety disorders have a high rate of co-morbidity with other psychiatric disorders, primarily mood disorders, ADHD and other disruptive behavior disorders, and substance use disorders. It is therefore important to assess for these co-morbidities. To complicate things further, there can be some overlap with the specific symptoms of anxiety and other psychiatric disorders. For example, patients with Generalized Anxiety Disorder may “obsess” about daily worries, patients with Autism Spectrum Disorders have rituals, and patients with Major Depressive Disorder may ruminate or “obsess” over negative self-thoughts, but it does not mean that these patients also have Obsessive-Compulsive Disorder.

Early awareness and treatment of anxiety can prevent future difficulties, such as loss of friendships, failure to reach social and academic potential, substance misuse, and feelings of low self-esteem. It is important for primary care providers to be comfortable with assessing for anxiety in pediatric patients and linking families to appropriate resources when needed. Further information about treatment of anxiety symptoms in young patients will be addressed in a future e-weekly publication.