​The use of second generation antipsychotics in the pediatric population is commonplace on inpatient psychiatric units and outpatient psychiatric clinics. Should this class of medications be in the primary care provider’s “toolbox” of medications for their patients with behavioral and/or mood symptoms when the first and second-line medications fail?

There are currently seven second generation, or atypical, antipsychotics approved for use in children and adolescents. These include risperidone (irritability associated with autism, schizophrenia, bipolar disorder), aripiprazole (irritability associated with autism, schizophrenia, bipolar disorder), quetiapine (schizophrenia and bipolar disorder), olanzapine (schizophrenia and bipolar disorder), lurasidone (schizophrenia and bipolar disorder), paliperidone (schizophrenia), and asenapine (bipolar disorder).

The child or adolescent with schizophrenia or bipolar disorder is typically having medications managed by a psychiatric provider. However, children with autism spectrum disorder and major depressive disorder are often managed by primary care. 

You may notice that augmentation of a SSRI medication with a second generation antipsychotic such as aripiprazole for major depression is not an FDA-approved use for adolescents. This use is only FDA approved for adults, so this would be off-label use, but also a reasonable strategy for augmenting treatment of depression in adolescent patients in the primary care clinic. I have found this to be helpful in adolescents who have partial benefit from SSRI or SNRI medication, but with residual symptoms of depression, especially irritability. A typical starting dose of aripiprazole for antidepressant augmentation is 1mg, which can be titrated to 2-5mg.

Both aripiprazole and risperidone can be quite helpful for managing behaviors and irritability in children with ASD. Aripiprazole can be started at 1mg daily, and titrated up to 5-10mg daily depending on tolerability. 1-2 mg is often a beneficial dose. Risperidone is started at 0.25mg daily, and titrated in increments of 0.25mg to max of 3mg total daily dose. Oftentimes 0.25mg BID is a beneficial dose.

The most common side effect from these two medications is weight gain. Also there is the risk of dyslipidemia and development of type 2 diabetes. Fasting lipids and glucose should be obtained at baseline, and again after three months of treatment, and every year thereafter. Weight should be checked at each appointment. Some psychiatrists obtain a baseline prolactin level prior to initiation of risperidone, though not necessarily the community standard of practice. The risk of gynocomastia should be discussed with the patient and guardian prior to initiation.

Extrapyramidal side effects are a risk with second generation antipsychotics. There continues to be a risk of tardive dyskinesia, though is relatively rare when compared with first generation antipsychotics. Second generation antipsychotics also carry the risk of dystonic reaction, akathisia, and rarely neuroleptic malignant syndrome.

EKG is not routinely obtained when starting aripiprazole or risperidone. This can be considered in a patient with a history of arrhythmia, or if used in combination with other potentially QT-prolonging medications (guanfacine/clonidine or stimulant medication, high dose (30-40mg) citalopram).
Another consideration with risperidone and aripiprazole specifically is their drug-drug interaction with fluoxetine (and paroxetine, though this is not routinely used in children). These SSRI medications inhibit the metabolism of both risperidone and aripiprazole, so lower starting doses are advised. Children with known deficiency of cytochrome 2D6 metabolism should start on lower doses as well.
Sources:

1. Prim Care Companion J Clin Psychiatry. 2002; 4(6): 233–241.
2. Atypical Antipsychotic Medications: Use in Pediatric Patients
3. UpToDate Neuroleptic Malignant Syndrome

The key feature of pediatric generalized anxiety disorder is excessive or uncontrollable worry lasting >6 months, with the worry being out of proportion to the situation. This article aims to briefly review the typical treatment algorithm for GAD, and also discuss newer pharmacologic interventions and alternative treatments.
 
The typical first line treatment for mild GAD is psychotherapy, specifically Cognitive Behavioral Therapy (CBT). For moderate and severe GAD, combination therapy and medication has demonstrated superior efficacy to either treatment alone. Interestingly, the only medication FDA approved for pediatric GAD is Duloxetine (Cymbalta), approved for ages 7-17. However, in practice, SSRI medication remains the typical first line pharmacologic intervention. There is no evidence that any SSRI is more effective than another. Fluoxetine (Prozac), Sertraline (Zoloft), and Escitalopram (Lexapro) are the most commonly prescribed, though Fluvoxamine (Luvox), Paroxetine (Paxil), and Venlafaxine (Effexor) have all shown efficacy in placebo-controlled trials. A typical algorithm (for medication intervention) is first SSRI, if not effective second SSRI, and if again not effective SNRI.
 
A typical PAL consult is what to do when the second SSRI is not effective or not tolerated. In a typical case, Duloxetine would be the recommendation, as this has shown efficacy in placebo-controlled trials, and has the FDA approval. Things become trickier if Duloxetine is not tolerated or not helpful. In this case, I would want to make sure Duloxetine is appropriately dosed. If there is no benefit at 60mg for 4-6 weeks, I would consider this a failed trial. However, if there is a partial response at 60mg, increasing to 90-120mg is reasonable, though doses above 60mg have not been found via placebo-controlled trial to provide additional benefit [5].
 
Benzodiazepines, while clearly efficacious and approved for adult GAD, have not shown clear benefit for the pediatric population [2]. For pre-pubertal children, these are known to have disinhibiting properties. I reserve benzodiazepine use for severe adolescent cases with clear functional impairment, active and trustworthy parents to help with administration, and no personal history of substance abuse. These should obviously be outlined as a short-term treatment to be used while the SSRI/SNRI are building up. I typically start with Clonazepam 0.25mg given bid-tid, either PRN or scheduled.
 
An alternative “PRN” medication for GAD is Hydroxyzine (Vistaril, Atarax). I have found 25mg to be sedating for many children, so usually start with a 10mg dose given tid PRN. This can be titrated up to 50mg per dose.
 
The non-SSRI Buspirone (Buspar) was studied in an unpublished placebo-controlled trial (N=559). No statistically significant difference with Buspar and placebo was observed. There are case reports of successful treatment of GAD with Buspar, and it has been shown to be well-tolerated. In a primary care setting, I would reserve this for adolescents, starting dose of 7.5mg bid, increased by 5-10mg per week to max of 30mg bid [1].
 
For the child with comorbid ADHD, and/or “activation” with SSRI/SNRI treatments, Guanfacine extended-release (Intuniv), an alpha 2A –adrenergic receptor agonist, may be a reasonable alternative. Agents that decrease norepinephrine release may decrease the fear response, producing anxiolytic effects. A recent study by JR Strawn, et al. [4], aimed to demonstrate safety and tolerability, and potential efficacy of this medication. It was shown to be well-tolerated, with most common side effects of headache, fatigue/somnolence, abdominal pain, and dizziness. No significant difference was observed compared to placebo on the PARS (pediatric anxiety rating scale) or SCARED (screen for child anxiety related emotional disorders) scales. There was improvement in the Clinical Global Impression-Improvement (CGI-I) score with Intuniv versus placebo. Overall, this study was under-powered to show direct evidence of efficacy. Doses used in this trial were 1-6mg daily.
 
Sources:

1. Green’s Child and Adolescent Clinical Psychopharmocology, Fifth Edition. Pages 302-314.
2. Hussain FS, et al. Pharmacologic Treatment of Pediatric Anxiety Disorders. Curr Treat Options Psychiatry. 2016 Jun; 3(2): 151–160.
3. Strawn JR, et al. Efficacy and tolerability of antidepressants in pediatric anxiety disorders: a systematic review and meta-analysis. Depress Anxiety. 2015 Mar;32(3):149-57.
4. Strawn JR, et al. Extended Release Guanfacine in Pediatric Anxiety Disorders: A Pilot, Randomized, Placebo-Controlled Trial. Journal of Child and Adolexcent Psychopharmacology. 2017 Volume 27, Number 1: 29-37.
5. Strawn JR, et al. A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder. J Am Acad Child Adolesc Psychiatry. 2015 Apr;54(4):283-93

Pharmacogenomic testing is becoming more commonplace in the world of psychiatry, leading to “guided treatment” and “precision medicine.” Genetic information can be helpful in choosing medication, choosing starting and target doses, and in predicting/explaining adverse events. The evidence base for this testing, as far as clinical outcomes, has gaps. This brief article aims to help the primary care provider decide when obtaining pharacogenomic testing is indicated, and how to interpret those results. This article will focus on guided antidepressant therapy.

There are multiple resources from which to obtain this testing, found in table 2 of this NIH paper. In my clinical practice, I tend to reserve pharmacogenomic testing for those who have failed at least two adequate medication trials for the same diagnosis, or has not tolerated typical therapeutic doses, though I do not necessarily always obtain testing in this situation. Some providers obtain a pharmacogenomic profile prior to initiation of the first medication. Though I do not personally advocate this for children and adolescents, this may have utility in achieving remission sooner.

For example, a 16 year old has had failed trials of both Fluoxetine and Escitalopram for depression and/or anxiety. Reasons for the failed trials include the possibility of this patient being a poor metabolizer at cytochrome 2D6, 2C19, and/or 3A4 and does not tolerate therapeutic doses, or an ultra-rapid metabolizer and is not achieving therapeutic plasma levels (though FDA label indicates Escitalopram should not be affected by a single cytochrome polymorphism or inhibition). SSRI medications may not be helpful or may not be tolerated due to a polymorphism in the serotonin transporter gene or the serotonin 2A receptor. At this point pharmacogenomic testing may help guide the next step in pharmacotherapy.

As far as interpreting the results of pharmacogenomic testing, some of the reports are easier to digest than others. One of the local providers has a liaison who is typically available to discuss results. Also the psychiatrists staffing the PAL service are more than willing to go over these reports with you. The most commonly utilized test in the Twin Cities is arranged in a green, yellow, red format, which is based on drug-gene interactions. The yellow and red categories do not imply that these medications cannot be used, but have the possibility of drug-gene interactions, which can affect dosing considerations and increase risk of side effects. A common problem is the “green” category containing only medications that are not FDA approved for children, and oftentimes not covered by insurance. In these cases, more careful interpretation of the results is necessary than basing treatment decisions solely on the color status. The pharmacogenomic test results are however reasonable justification for obtaining a prior authorization for second tier or off-label medications, especially if there have been failed trials of first-line medications.
​
Sources:

1. Bousman, et al. Antidepressant prescribing in the precision medicine era: a prescriber's primer on pharmacogenetic tools. BMC Psychiatry. 2017; 17: 60.
2. Drozda et al. Pharmacogenomic Testing for Neuropsychiatric Drugs: Current Status of Drug Labeling, Guidelines for Using Genetic Information, and Test Options. Pharmacotherapy. 2014 Feb; 34(2): 166–184.
3. Tantisira et al. Review of pharmacogenomics. Uptodate.com
4. Lexapro FDA prescribing information. 

Recently the Psychiatric Assistance Line (PAL) team was asked about validated screening measure and scales for use within the primary care setting. Scales such as the PHQ-9 and the GAD-7 are routinely used in primary care settings, but are these sensitive/specific and validated for children and adolescents? This is a valid(ity) question.

There are multiple screening tools available to the primary care provider for several different mental health concerns and situations. The PHQ-9 does have a “modified” version for the teenager, the PHQ-A. After carefully comparing this with the PHQ-9, the only discernable difference is that the PHQ-A includes “irritability” as a possible symptom of depression, otherwise the two scales are identical. There are additional questions regarding suicidal symptoms on the PHQ-A. A 2012 study did find the PHQ-9 as valid for screening adolescents ages 12-18. Sensitivity and specificity each ranged from 85-88% depending on the source (1,4,7). Other “free” options for screening depression in a pediatric setting include the KADS, with 92% sensitivity and 71% specificity (4,7). Proprietary scales such as the Beck Depression inventory and the Child Depression Inventory are also validated child depression scales, the BDI with sensitivity and specificity of 91% (4,7).

Regarding generalized anxiety disorder, the GAD-7 is a well-validated scale for ages 13 and over (4). The Beck Anxiety Inventory, which is proprietary, has also shown validity and reliability for ages 14-18 (3). The Spence Children’s Anxiety Scale also is found to be valid from ages 8-18, and additionally has subscales for panic, social phobia, and OCD, as well as GAD (4).

As far as ADHD, the Vanderbilt assessment scale is a psychometrically reliable and valid scale using parent and teacher questionnaires. The VADPRS (parent Vanderbilt scale) produced a sensitivity of .80, and a specificity of .75 (2).

This summary of free assessment measures may be a useful tool to identify scales that may work well for your clinic. Also, this guideline for depression treatment of adolescents in primary care has information on screening, diagnosis, safety assessment, therapy, medication algorithms, and parent information, as well as a nice summary of the FDA black box warning on antidepressant medications.  

Sources:

1. Allgaier AK, et al. Screening for depression in adolescents: validity of the patient health questionnaire in pediatric care. Depress Anxiety. 2012 Oct;29(10):906-13.
2. Bard DE, et al. The psychometric properties of the Vanderbilt attention-deficit hyperactivity disorder diagnostic parent rating scale in a community population. J Dev Behav Pediatr. 2013 Feb;34(2):72-82
3. Grant MM. Beck Anxiety Inventory. See here.
4. Mental Health Screening and Assessment Tool For Primary Care.
5. Guidelines for Adolescent Depression in Primary Care Tool Kit
6. Center for School Mental Health Summary of Free Assessment Measures.
7. Adolescent Depression—enhancing the outcomes in primary care. http://www.acpm.org/?AdDepresTTClinRef

​PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. This post-strep disorder, however, is not as well-defined as Sydenham’s chorea, the neurological manifestation of rheumatic fever. PANDAS does have a body of evidence supporting its existence, though it remains a controversial diagnosis. PANS is an expanded clinical entity, standing for Pediatric Acute-onset Neuropsychiatric Syndrome and includes all cases of abrupt onset OCD, not just those associated with streptococcal infections. The role of autoimmunity in PANDAS remains controversial.
 
The hallmark of PANDAS, as opposed to classic OCD, is the abruptness of onset. With PANDAS, the obsessive thoughts, compulsive behaviors, motor and/or vocal tics (among other possible psychiatric symptoms) can develop overnight, reaching full scale intensity in 24-48 hours. OCD typically emerges over the course of weeks or months. Other symptoms of PANDAS can include acute onset mood swings, hyperactivity, separation anxiety, handwriting changes, and nocturnal enuresis. PANDAS typically has a relapsing/remitting course, leading some providers to prescribe antibiotic prophylaxis for suspected cases.
 
Diagnostically, the child must have acute onset of OCD/tics, typically in a pre-pubertal child, and an association with a Group A beta-hemolytic streptococcal infection. This is confirmed via throat culture. Also available to help establish past strep infection are Antistrepolysin O (ASO) titer, which rises 3-6 weeks after a strep infection, and Antistreptococcal DNAse B (AntiDNAse-B) titer, which rises 6-8 weeks after a strep infection. It should be noted that some children have chronically elevated titers.
 
Psychiatric treatment for this type of OCD and tic disorder are the same as for a typical diagnosis, with cognitive behavioral therapy the mainstay, and SSRI medications as needed. Obviously a confirmed active strep infection should be treated with antibiotic. In the case of a negative throat swab, if the child does meet criteria of acute onset OCD, it would be up to the discretion of the provider the risk versus benefit of a course of antibiotics for a possible occult infection.
 
There is limited evidence regarding prophylactic antibiotic treatment for PANDAS/PANS. A 2005 randomized controlled study did show 64% decrease in neuropsychiatric symptoms in 23 children with PANDAS treated prophylactically with Penicillin V-K or azithromycin. IV Immune globulin may be a consideration for severely ill patients. There is no formal treatment protocol for treating PANDAS/PANS.
 
Sources:

1. NIMH website: Orefici, et al, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), Streptococcus pyogenes : Basic Biology to Clinical Manifestations, 2016.
2. DSM-5

Obsessive-Compulsive Disorder (OCD) is an anxiety disorder consisting of the presence of obsessions, compulsions or both. Content of obsessions can vary, but are intrusive and unwanted, and typically cause distress. Compulsions are repetitive behaviors or mental acts the individual feels driven to do to alleviate anxiety or prevent a dreaded event. Children may not realize these behaviors are unreasonable or excessive.
  
OCD has a strong genetic component, and even more pronounced with childhood-onset OCD. A first-degree relative of an individual with childhood-onset OCD has a risk 10-fold normal population. The point prevalence in children and adolescents is 0.5%. There is high comorbidity of OCD and Tourette's (or other tic disorder) and ADHD, and other anxiety disorders. Comorbidity rates of OCD and Autism Spectrum Disorder vary widely depending on the study. However, there is significant overlap between symptoms of OCD and rigidity/ritualistic behavior seen in Autism Spectrum disorders.
  
The most commonly reported obsessions in children and adolescents include fears of contamination, followed by worries related to harm coming to themselves, family or fear of harming others. Common compulsions include cleaning, counting, checking and repeating/rituals. The most-used clinical scale is the Children's Yale Brown Obsessive-Compulsive Scale (CYBOCS), which has both a checklist and a scale.
  
A typical first-line treatment for mild-moderate OCD in children and adolescents is cognitive-behavioral therapy (CBT). However, a multi-site NIH study, the Pediatric OCD Treatment Study (POTS), showed medication and CBT combination therapy as superior to either treatment alone.
  
Four medications are FDA approved for use in pediatric OCD. Sertraline for age >6 (50-200mg), Fluoxetine >7 (20-60mg), Fluvoxamine >8 (up to 200mg), and the tricyclic Clomipramine >10. Though not FDA-approved, atypical antipsychotic agents have evidence for efficacy as an adjunctive therapy for OCD as well.
  
Sources:

1. Kaplan & Sadock's Synopsis of Psychiatry tenth edition, DSM-5, Child and Adolescent Clinical Psychopharmocology fourth edition, WH Green.