This medication treatment algorithm outlines evidence-based pharmacological interventions for adolescent depression, incorporating safety considerations, efficacy, and potential adverse effects. The algorithm can serve as a guide and should be individualized based on clinical judgment, patient preferences, and specific clinical circumstances. Regular monitoring and reassessment are essential throughout the treatment process.

Step 1: Initial Assessment

• Comprehensive Evaluation: Conduct a thorough assessment, including psychiatric history, symptom severity, medical history, family history, and suicidality risk. Consider differential diagnosis and co-morbidities.
• Psychotherapy: Initiate or continue evidence-based psychotherapy, such as cognitive-behavioral therapy (CBT) or interpersonal therapy (IPT). Inform psychotherapist of planned psychopharmacologic treatment and maintain ongoing collaborative dialogue as warranted
• Education and Informed Consent: Educate the patient and their family about the potential benefits, risks, and side effects of medication treatment. Obtain informed consent.

Step 2: First-Line Pharmacotherapy

• Selective Serotonin Reuptake Inhibitors (SSRIs):
  • Fluoxetine: Start with a low dose (10 mg/day) and titrate gradually to therapeutic range (20-60 mg/day).
  • Escitalopram: Initiate at 5-10 mg/day, titrate up to 10-20 mg/day.
  • Sertraline: Begin with 25-50 mg/day, titrate up to 50-200 mg/day.
• Monitoring:
  • Close monitoring for therapeutic response and adverse effects, especially during the first 4-6 weeks and following future dose increases, if instituted.
  • Assess for emergence or worsening of suicidal ideation, agitation, or behavioral activation.

Step 3: Treatment Response Assessment

• Response Evaluation: Evaluate response to SSRI treatment after 4-6 weeks.
• Adjustment: If partial response or inadequate response, consider:
  • Increasing SSRI dose, gradually at q 2-4 week intervals.
  • Switching to another SSRI.
  • Adding psychotherapy or non-pharmacological interventions.

Step 4: Second-Line Pharmacotherapy

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):
  • Venlafaxine: Initiate at 37.5 mg/day, titrate up to 75-225 mg/day.
  • Duloxetine: Start with 30 mg/day, titrate up to 60-120 mg/day.
  • Bupropion: Consider in cases with atypical depression symptoms or when SSRIs or SNRIs are ineffective or not tolerated. Begin with 75 mg/day, titrate up to 150-300 mg/day.
• Monitoring:
  • Continuously monitor for therapeutic response and adverse effects.
  • Assess for potential drug interactions, especially with other psychotropic medications.

Step 5: Consultation and Collaboration

• Collaboration: Maintain open communication with the patient, their family, and involved healthcare professionals throughout treatment.
• Consultation: Consider consultation with a child and adolescent psychiatrist for complex cases, treatment-resistant depression, or significant comorbidities.

Step 6: Continuation and Maintenance

• Continuation Phase: Once remission is achieved, continue the effective medication at the same dose for at least 6-12 months to prevent relapse.
• Maintenance Phase: For recurrent depression or chronic conditions, consider long-term maintenance treatment with medication and/or psychotherapy.

Safety Considerations:

• Suicidality Risk: Monitor closely for emergence or worsening of suicidal ideation, especially during the initial weeks of treatment.
• Serotonin Syndrome: Educate about symptoms and signs, especially if combining SSRIs or SNRIs with other serotonergic medications.
• Drug Interactions: Be cautious with concomitant use of other medications metabolized by cytochrome P450 enzymes. Avoid monoamine oxidase inhibitors (MAOIs).
• Monitoring Parameters: Regularly assess for efficacy, adverse effects, vital signs, and growth parameters in adolescents.

Author:

Shawn Singh Sidhu, M.D., DFAPA, DFAACAP

​Medical Co-Director, Vista Hill Foundation

References:

• American Academy of Child and Adolescent Psychiatry (AACAP). (2019). Practice parameter for the assessment and treatment of children and adolescents with depressive disorders.
• Cheung, A. H., & Emslie, G. J. (2015). Treatment-resistant depression in adolescents. Pediatric Drugs, 17(6), 383-392.
• National Institute for Health and Care Excellence (NICE). (2019). Depression in children and young people: identification and management (Clinical guideline [CG) 28).
• Zhou, X., Hetrick, S. E., Cuijpers, P., Qin, B., Barth, J., Whittington, C. J., … & Xie, P. (2015). Comparative efficacy and acceptability of psychotherapies for depression in children and adolescents: A systematic review and network meta-analysis. World Psychiatry, 14(2), 207-222.
• Baldwin, D. S., & Montgomery, S. A. (2005). Serotonin selective reuptake inhibitors. Journal of Psychopharmacology, 19(2_suppl), 4-6.
• Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., … & Fava, M. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. The American Journal of Psychiatry, 163(11), 1905-1917.
• Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., … & Geddes, J. R. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet, 391(10128), 1357-1366.
• Taylor, D., Paton, C., & Kapur, S. (2019). The Maudsley prescribing guidelines in psychiatry. John Wiley & Sons.
• Nutt, D. J. (2008). Relationship of neurotransmitters to the symptoms of major depressive disorder. The Journal of Clinical Psychiatry, 69, 4-7.

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

Depression is highly co-morbid with other psychiatric disorders, like anxiety disorders, substance abuse disorders and disruptive behavior disorders. If an adolescent is presenting with depressive symptoms, it is important to take a careful history of bipolar symptoms (including current and past manic, hypomanic or psychotic symptoms), family history of bipolar disorders, and history of medication-induced manic or hypomanic symptoms. Twenty percent of children and adolescents with depression go on to develop some degree of bipolar symptomatology as adults with symptoms of fluctuating moods and mood lability. Retrospective surveys also indicate that the typical timeline for adults with bipolar disorder indicated that they first experienced depressive symptoms starting in childhood or adolescence.

In 2014, the American Academy of Pediatrics updated their well child visits for adolescents (ages 11-17 years) to include screening for depression.  The PHQ-2 (PHQ 2) has good sensitivity and specificity for detecting major depression. These properties, coupled with the brief nature of the instrument, make this tool promising as a first step for screening for adolescent depression in primary care.  The more detailed PHQ-9 Adolescent ( PHQ 9 Adolescent ) can be administered for positive findings on the PHQ-2.

Adolescents will sometimes turn to drugs, like alcohol or marijuana or cigarettes/e-cigarettes, to self-medicate. If they are using on a regular basis, the use can be contributing to their depressive symptoms, and psycho-education about that interaction will be important. Ongoing regular drug use can also limit the efficacy of a medication treatment for depression. Therefore it is important to talk with teens about limiting their drug use if they are interested in a medication intervention.

In terms of general treatment guidelines, consider therapy alone for mild-moderate cases of MDD and consider combination therapy and medication treatment for moderate-severe cases of MDD, particularly if there is a significant impairment from their symptoms. Fluoxetine is the medication that has been studied the most for MDD in children and adolescents, but the other SSRIs, like citalopram, escitalopram and sertraline, can also be utilized. Other options to consider are bupropion and mirtazapine. The antidepressants to consider avoiding include: paroxetine and venlafaxine (because of their short half-lives, there is a higher risk of side effects and discontinuation symptoms with inconsistent use) and duloxetine (because of limited data in children and adolescents).

It is important to conduct a slower titration, starting with ½ the usual starting dose, to minimize the risk of side effects including akathisia (internal restlessness), behavioral activation and increased anxiety. So, for example, if considering fluoxetine, a starting dose of 10mg q day would be appropriate with a plan to increase to 20mg after 2 weeks if tolerated and needed.  Advancing the dose higher may be warranted but should be done after 3-4 weeks on a standard therapeutic dose and with care and with close follow up as to efficacy and to assess for potential side effects.  It is important to discuss the length of time it can take for a patient to see a full positive result, so that the teen and family is realistic with their expectations. It is also important to carefully discuss with the teen and family the FDA black box warning about the increase in risk of spontaneous reporting of suicidal thinking and have close monitoring (follow-up in 1-2 weeks either in person or by phone), particularly when medication is started or when the dose is being increased.

Helpful resources for families:

• https://www.aacap.org/AACAP/Families_and_Youth/Resource_Centers/Depression_Resource_Center/Depression_Resource_Center.aspx
• https://www.appi.org/dulcan

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