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This is an intermediate-level course. After taking this course, mental health professionals will be able to:
The materials in this course are based on the most accurate information available to the author at the time of writing. New developments in the field of psychopharmacology occur each day, and new research findings may emerge that supersede these course materials. This course is updated regularly as new practice guidelines are developed. This course will equip clinicians to evaluate the needs for medical treatment for their psychotherapy clients, assess responses to treatment, and more effectively collaborate with primary care physicians, psychiatrists, nurse practitioners, and prescribing psychologists.
Note: Portions of this online course were initially adapted from prior versions of the Handbook of Clinical Psychopharmacology for Therapists (9th Ed.) (2021) and Child and Adolescent Clinical Psychopharmacology Made Simple (4th Ed) (2021). This course has been updated by Steven E. Curtis, Ph.D., NCSP, MSCP, using these two revised texts and other resources (see References section).
Youth frequently present to healthcare providers with symptoms of depression, irritability, emotional reactivity, anxiety, attention difficulties, hyperactivity, and other behavioral issues seen as inconsistent with others their age. Some youth will be diagnosed with a mood disorder such as major depressive or bipolar II disorder. Some may be diagnosed with additional disorders such as attention-deficit/hyperactivity disorder (ADHD) or even autism spectrum disorder (ASD) since the co-occurrences, or “comorbidities,” are pretty high. Some depressed youth will initially be diagnosed with only one disorder.
Once diagnosed, parents, healthcare providers, and the patient are faced with the question, “Should we medicate or wait and see?” For youth with a mood issue, the obvious course of treatment is to talk with the young person, offer support, address environmental stressors, provide a balanced diet, monitor sleep, and ensure a healthy lifestyle. Simultaneously, the young person can start psychotherapy with a cognitive behavior treatment (CBT) approach to address maladaptive thinking, or insight therapy to more comprehensively address current and past stressors. If these strategies do not work, then medication may be indicated. When medication is suggested, concerns arise, such as: Will the side effects be dangerous? Will medication be taken forever? Won’t the young person lose their personality? Psychotropic medication for mood issues can be beneficial, does not necessarily have to be taken forever, and can be quite safe if side effects are monitored and managed.
In this course you will learn about mood disorders in youth. The Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition – Text Revision (DSM-V-TR), separates mood disorders into depressive and bipolar disorders. We will use these terms in this course. We understand that the word “disorder” may be troubling to some, but we use this since we are working within the broad field of psychiatry when we discuss medications. “Psychotropic medication” will be used for “psychiatric medication,” “mental disorders” will be used for “behavioral health disorders,” and “youth” will refer to “children and adolescents.”
As a prescriber, I have noticed that other prescribers, such as pediatricians and family practice physicians, walk around with their laptops and constantly review resources online or with their apps to ensure that they provide the most appropriate treatment. Non-prescribing mental health professionals (e.g., social workers, mental health counselors, and psychologists) tend to have a pad of paper to take notes, and that is all. Looking up information on the computer while having a patient in front of you has been taboo, especially for older clinicians such as myself. However, I have learned to review resources regularly since becoming a prescriber. I encourage you to use references listed in the Suggested Resources for Practice section regularly. There is no need to memorize everything. However, it is essential to know where to turn for more information. These references offer a good start.
Historically, mental disorders in youth were primarily limited to ADHD, ASD, and behavior disorders. Even the presence of these disorders in childhood was questioned by some. The “more severe” disorders were primarily thought to form during late adolescence or early adulthood. Major depression in youth was not officially recognized by the National Institute of Mental Health until 1975. Before this time, stating that a child is depressed would have been met with skepticism. Since 1975, there have been more studies of youth depressive and bipolar disorders, with several extensive studies looking at the effects of medication in treatment. The presence of bipolar disorder in some youth has been established, but the child onset of bipolar disorder has been met with considerable controversy. What has become clear is that some forms of depressive disorders and bipolar disorder first emerge in childhood or early adolescence. Such cases often go unrecognized and untreated for years, eventually evolving into severe, and often very chronic, treatment-resistant conditions.
Over my 30-plus-year career, the fact that youth may become depressed has finally become universally accepted. However, I still encounter parents who do not believe that their child is depressed since there are no outward signs of depression. For my dissertation, I studied cognitive-behavioral group treatment of adolescent depression. A high school was screened for depression and the most depressed students were placed in a treatment and control group. All students in the group eventually received treatment. My main takeaway, which has lasted ever since, is that two types of students were in my study. The first group of depressed youth looked depressed and in dire need of psychotherapy. The parents of these youth accepted that their youth were depressed. The second group mainly consisted of high-functioning high school students, many being popular with no outward signs of depression. These students reported significant symptoms of depression on the questionnaires and in the clinical interviews. The parents of these youth had a more challenging time accepting that their youth were depressed. A parent accused me of making it all up!
In 2021, the US Surgeon General published an advisory report, Protecting Youth Mental Health (US et al., 2021). Before the COVID-19 pandemic, mental health challenges in youth were the leading cause of disability, with one in five youth having reported mental, emotional, or behavioral disorders. Between the years 2009 and 2019, the number of high school students reporting symptoms of depression increased by 40%. Globally, since the pandemic began, depressive symptoms amongst youth have doubled, with over 25% experiencing depressive symptoms. According to Mental Health America (MHA) (2023), 16.39% of youth ages 12-17 experienced at least one clinically significant major depressive episode (MDE) during 2022. This represents about a 4% increase since the MHA report of 2018, which reported that 12.63% of youth age 17 had at least one MDE in the past year. This increase could be due to the COVID-19 pandemic and other factors. Those of us who worked with youth during COVID-19 have realized that some youth enjoyed being at home and studying online because these young people were more introverted and preferred not going to school. Other youth became very depressed during this time because they missed the social aspect of their lives. The effects of having to stay at home during the COVID-19 pandemic or being more careful with whom they were around were most likely negative for some and positive for others.
Suicide is a leading cause of death in the United States. According to the CDC, there was a 2.6% increase in suicide by death for all people, but it decreased among youth, declining 8.4%. Preventing youth suicide remains a top health concern, even while seeing positive change in this area is nice. Youth suicide remains a serious issue amongst youth. Not all depressed youth become suicidal, and not all suicides are committed by those who are depressed. Mood issues are risk factors for suicidal ideation. Assessment for suicidal ideation should be a standard procedure for any type of mental health practice.
Until recently, in child psychiatry and related fields, there appeared to be an assumption that youth with psychiatric disorders were quite similar, if not identical, to adults, both concerning diagnostic and pharmacologic treatment issues. The recommended approach was to diagnose and treat youth as you would adults, although generally starting treatment with lower doses of medications. Fortunately, seeing youth as little adults who need similar treatment but less of it is changing. It is now recognized that many, if not all, mental disorders have symptoms that began somewhere in childhood. In the past, it seemed that you could not have a mental disorder other than ADHD or ASD before age 18. Now, we know this is not true. Youth develop major depression, and some youth even develop bipolar disorder. Although there is some degree of symptomatic overlap between adult and childhood-onset disorders, it is also clear that significant features distinguish psychiatric syndromes and pharmacologic treatments in youth and adults.
Psychotropic medication prescribed for youth can be quite different from those for adults. In youth, the target of psychiatric drugs (the central nervous system) continually undergoes maturational changes throughout childhood and adolescence. Specific neurotransmitter systems are not entirely online in youth, and some brain structures have not fully developed. In a sense, using psychotropic drugs with younger clients is like shooting at a moving target. Likewise, there are significant differences between adults and younger people regarding how drugs are metabolized. Youth are not just a smaller version of adults. Treatment guidelines should not simply be extracted from guidelines developed for adults. However, there are times when the only guidelines for treatment are those for adults. In these situations, the prescriber must proceed with caution. Note: All of us are developing, regardless of our age. However, youth have development that is unique to their age group.
The average hepatic (liver) metabolism rate is high in youth until puberty. The result is that most medications are aggressively metabolized in the liver and rapidly excreted. Thus, dosing for pre-pubertal youth requires doses that may approach or equal adult dosing because what ultimately matters is how much of the drug enters circulation. The use of seemingly high doses for young children may be counterintuitive for many parents, and thus, it will be helpful to explain to them the role of increased rates of drug metabolism.
During a period (2-4 months) surrounding entry into puberty, the rate of hepatic metabolism significantly slows. For this reason, youth who have been on a dose of psychiatric medication, tolerating it well, may begin to show increasing side effects when this change in metabolic rate occurs and as more drugs begin to escape the liver and enter circulation. Dosage adjustments may then be required to minimize side effects.
Historically, very few psychiatric drugs were FDA-approved for treating youth and adolescents. Fortunately, the number of FDA-approved drugs for youth has increased. In psychiatry, as in general medicine, it is a widespread practice to prescribe other non-FDA-approved drugs, “off-label.” This refers to using drugs that are FDA-approved for specific uses but are used to treat a condition without FDA approval. For example, the antipsychotic medication, haloperidol (Haldol) is FDA-approved for treating childhood schizophrenia, but not FDA-approved for use in bipolar disorder. However, haloperidol has been used to treat some cases of mania. Since there is clinical and research support for using this drug in treating mania when other treatments have failed, this practice is in keeping with medical standards. Thus, the use of haloperidol in treating mania is not considered to be either illegal or unethical. Likewise, many drugs approved for use with adults, but not approved for youth, are used to treat child psychiatric patients. Currently, there are only two antidepressants approved by the FDA for the treatment of major depression in youth, fluoxetine (Prozac) and escitalopram (Lexapro), yet many other antidepressants, such as, e.g., sertraline (Zoloft] are used to treat childhood-onset depression.
Some drug classes, most notably antidepressants, have been found to have efficacy in treating a host of disorders other than depression, such as,, panic disorder, OCD, and social anxiety.
Most mental disorders are caused by genetic, pre-natal, peri-natal, and post-natal factors. This is called the biopsychosocial model, which is extensively used in developmental psychopathology. Some disorders may be seen as caused by mostly genetic factors (e.g., bipolar disorder). Other disorders may be seen as primarily due to situational factors (e.g., depression caused by environmental stressors).
Much emotional suffering experienced by youth is related to situational stress and responds best to non-medical, psychological treatments (e.g., family therapy). However, it is also becoming increasingly clear, as noted above, that many major mental illnesses begin in childhood (e.g., 25% of cases of obsessive-compulsive disorder); and although there is a good deal of controversy about childhood-onset bipolar disorder, recent international meta-analyses suggest that among people who ultimately show clear-cut bipolar disorder, between 1.8% and 2.8% have prepubertal onset, and another 35% have an onset between the ages of 13 and 18. Not only do these disorders cause considerable suffering in youth, but they also can markedly interfere with normal social and academic developmental experiences. For example, over one-half of youth experiencing major depression continue to be symptomatic for more than two years. During depressive episodes, many experience significant social withdrawal and academic failure, often due to impaired concentration. Many youths find it hard to “catch up” academically or develop age-appropriate social skills even if they do recover.
There is also increasing evidence that some psychiatric disorders are subject to progressive neurobiological impairment if untreated (i.e., kindling model of disease progression). Toxic levels of neurotransmitters (e.g., glutamate) or stress hormones (e.g., cortisol) may damage neural tissue or interfere with typical patterns of neuro-maturation (See Figure 1-A). Pharmacologic treatment of these disorders may not only be successful in improving symptoms but may also be neuroprotective; medication treatment may protect against brain damage or promote normal neuromaturation. In some instances, medications may promote the regeneration of nerve cells (neurogenesis in the hippocampus).
Figure 1-A. |
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In addition to clinical considerations, there are other unique challenges in prescribing psychotropic medications for youth. With youth, there is no true informed consent (unless the youth resides in a state that allows medical decision-making at a younger age than 18) since parents are the ones who usually decide whether to allow medication treatment. At least four concerns arise regarding this: 1) Parental fears about drug use (or possible addiction) may lead them to withhold treatment from some youth who need it; 2) Some parents may adopt a view of psychiatric drug treatment in which they see the disorders simply as a “chemical imbalance,” think pills will fix the problem, and ignore psychological factors (e.g., dysfunctional family dynamics) as a focus for treatment; 3) Medications may be used primarily for behavioral control even if this means incurring detrimental side effects. For example, using excessively high doses of stimulants may markedly reduce hyperactive behavior in ADHD youth even causing lethargy and sedation and, if doses become too high, there can be a price that is paid in terms of decreased cognitive functioning; and 4) The young person is left out of the loop, that is, not spoken to or allowed to discuss in detail how they feel about medication treatment.
Most child clinicians agree that youth should be included in discussions about psychiatric medication treatment. This inclusion is especially proper for youth ages seven and older where cognitive development has proceeded enough to enable the youth to understand some information regarding medication treatment. They encourage the child to voice concerns about treatment. Many youth conclude that if they need medicine, it must mean they are very ill or “crazy”. Also, these early experiences with psychiatric treatment, if perceived to be positive by the child, may go a long way to instill positive attitudes about mental health treatment. A positive attitude is critical since many of the more severe disorders that warrant medical treatment during childhood are the first manifestations of what may be lifelong mental illnesses. Including the youth in discussions regarding medication and treatment can often foster a positive relationship with the therapist, as the child feels respected enough to be included.
Parents need to be given time to address all their concerns about drug treatment. Parents who do not wholeheartedly endorse treatment may hinder future progress. Informed consent should also include the risks of not treating certain disorders.
Many parents are understandably concerned about using habit-forming drugs to treat their youth. It is essential to talk openly with parents about these concerns, even if they do not initiate the conversation since many do harbor such fears. Among psychiatric medications, only two classes of drugs are potentially drugs of abuse: stimulants (e.g., amphetamine [Ritalin]) and benzodiazepines (e.g., antianxiety drugs such as alprazolam [Xanax]). However, most youth with psychiatric disorders do not abuse these medications. For instance, although stimulants can be abused by those genetically predisposed to substance abuse, such drugs generally do not produce euphoria in ADHD youth. Many youth with ADHD experience stimulants as causing mild dysphoric effects. Many adolescents with ADHD do not want to take medications. Additionally, data now exist to strongly indicate that among those with ADHD, using stimulants decreases the risk of substance abuse by about 50% when compared to drug abuse rates, which are high among non-treated ADHD subjects. (Biederman et al., 1999; Kuczenski et al., 2002). Studies have verified that non-treated boys and girls are at increased risk of substance abuse in adulthood. Early initiation of treatment with a stimulant resulted in reduced risk (Dalsgaard, et al. (2014). A recent finding by Widding-Havneraas et al., (2023) is that pharmacological treatment of ADHD reduced crime related to impulsive-reactive behavior.
Substance abuse and impulsive-reactive behavior by youth is a common and serious concern in our society. It must also be remembered that untreated mental illnesses result in significant emotional suffering and contribute to a much higher likelihood of drug abuse. Low self-esteem, depression, anxiety, and alienation often prompt the use of illicit drugs as a form of self-medication. Thus, any risk-benefit assessment of medication treatment and drug abuse must undoubtedly consider the risks of failure to treat the psychiatric disorder. There is evidence that psychotropic medications can be neuroprotective in that “acute intervention with proper drugs at a critical point in time will allow for a shorter duration of treatment needed, and perhaps neuroprotection or neuroplastic change will then eliminate the need for a lifetime of medications” (Singh et al., 2012).
Research studies and clinical experience certainly influence prescribing practices. However, the media has profoundly affected public opinion and, ultimately, clinical practice. Public opinions are often influenced both by drug company marketing efforts (i.e., profit motives) and by headline news (e.g., concern over antidepressant use in youth and possible increased suicidality, an issue discussed in more detail in the section on treating depression).
In the late 1980s, negative attention was focused on Ritalin, a widely prescribed stimulant used to treat attention deficit hyperactivity disorder (ADHD). Andrew Brotman, summarizing the work of Safer and Krager (1992), states, “The media attack was led by major national television talk show hosts and, in the opinion of the authors, allowed anecdotal and unsubstantiated allegations concerning Ritalin to be aired. There were also over twenty lawsuits initiated throughout the country, mostly by a lawyer linked to the Church of Scientology” (Brotman, 1992). The stance of Tom Cruise and the Church of Scientology continues to cause controversy (Jackson, July 22, 2022).
In a study of the effects of this negative media and litigation blitz conducted in Baltimore, Maryland, Safer and Krager (1992) found that during the two years following the negative media attention, prescriptions for Ritalin had dropped by 40%. What were the consequences? Thirty-six percent of those youth who discontinued Ritalin experienced significant academic maladjustment, such as failing grades or being suspended, and another 47% had mild-to-moderate academic problems. Further, during this time, there was a 400% increase in the prescription of tricyclic antidepressants, which were then being used in place of Ritalin. Studies had demonstrated that some tricyclics are somewhat effective in treating ADHD symptoms but much less effective than stimulants. Further, tricyclics are considerably more toxic, have much higher rates of side effects, and have been associated with sudden cardiac-related deaths in youth. Parents understandably heard the adverse reports in the media and approached their pediatricians with concerns about Ritalin, and many youth were taken off the stimulant and put on a class of drugs that is less effective and considerably more dangerous.
Media attention is significant because it can alert consumers and professionals, including the FDA, to possible medication problems. When this leads to more thorough investigations of medications, sometimes drugs are found to be problematic or unsafe. However, it can also lead to unwarranted fears and ultimately to clinical decisions that may not be in the best interest of our clients. The point is that among the numerous factors that come to bear in deciding upon appropriate treatments, media-driven concerns raised by our clients and the parents of youth in treatment can be significant. As clinicians, we must be aware of and sensitive to such concerns
In most cases, youth treated with psychiatric medications should also be engaged in psychotherapy. This is not always possible due to the shortage of mental health clinicians and the costs of psychotherapy services. However, treatment with both psychiatric medication and psychotherapy is highly recommended for ideal treatment. Family practice physicians, pediatricians, and other primary health care professionals prescribe most psychotropic medications for youth. These practitioners are well-equipped to prescribe medications for ADHD, depression, anxiety, and other disorders commonly seen in their practices. When mental health challenges become more complex, finding a psychiatric prescriber with more expertise is best. Accurate diagnoses require extensive expertise and time.
The term “unipolar depression” is often used for depressive disorders. We will use “depressive disorders” in this course. Depressive disorders are common in youth. It has been estimated that 3% of youth worldwide have a depressive disorder. Between 7.5% and 11% of teenagers in the United States have a major depressive disorder, with over 30% reporting thoughts of suicidality in the past year. According to the JAACAP article, only 35% of these teenagers received treatment from the mental health sector. Rates of depression in younger youth are lower (.5% to 1.9%). Severe depressive episodes in youth also likely herald the onset of either severe or highly recurrent major depressive disorders (35% of cases) or bipolar disorder (49%)based on a ten-year follow-up after an index episode of depression first seen in pre-pubertal youth (Geller et al., 2002; Geller & DelBello, 2003). The ratio of depression in females to males is two to one in adolescence. In prepubertal children, depression is more common in boys than in girls. Among the risk factors are low birth weight, family history of depression, family dysfunction, gender and sexual orientation issues, bullying, negative thinking, and chronic illness (Bonin, 2023).
In the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition– Text Revision (DSM-5-TR) among the eight depressive disorders listed are disruptive mood dysregulation disorder (DMDD), major depressive disorder (MDD), and persistent depressive disorder (PDD). The common symptoms of all depressive disorders are sadness, emptiness, or irritable mood associated with changes in functioning. These disorders differ by issues of duration, timing, or etiology. For example, MDD (more fully discussed below) is characterized by symptoms of depression (e.g., depressed mood) during a two-week period and a change of previous functioning. PDD is diagnosed when a patient has a depressed mood most of the day over a period of at least one year (two years for adults).
Disruptive mood dysregulation disorder (DMDD) is a new diagnosis to the DSM-5 and its subsequent text revision (DSM-5-TR). The authors of the DSM-5-TR stated that due to the concern of the overdiagnosis of bipolar disorder in youth and the resulting treatment, the diagnosis of DMDD was created to refer to youth with irritability and frequent episodes of “behavioral decontrols.” DMDD was placed under depressive disorders since most diagnosed with DMDD typically develop later anxiety and depressive disorders rather than bipolar disorder. DMDD is treated with cognitive behavior therapy (CBT), family therapy, and medications (e.g., SSRIs versus mood stabilizers for bipolar disorder) (NIMH, n.d.). Bipolar disorders will be discussed in the next section.
Comorbidity is “the rule rather than the exception” for depressive disorders in childhood. Youth with depression often have associated anxiety, attention issues, disruptive behavior, or substance abuse problems. Central to the treatment of severe depression is not only reducing the suffering and disability experienced in the current episode but also anticipating these extraordinarily high rates of recurrence and having treatments to address relapse prevention.
The assessment of youth for depressive or bipolar disorders is straightforward and complex at the same time. Assessment should always involve the following:
Except for some psychiatrists, mental health professionals do not conduct physical examinations. A physical examination by a health care professional should be obtained before making diagnoses and starting treatment with medication. Assessment becomes complicated when youth have multiple disorders. In these situations, it is best to diagnose multiple disorders and decide which one should be treated first. When mental health challenges become more complex, finding a psychiatric prescriber with more expertise is best. Accurate diagnoses require extensive expertise and time.
Although there are similarities between childhood-onset and adult-onset major depression, there are also notable differences. Using standard DSM-IV criteria for diagnosing major depression, using adult criteria, it was found that this failed to accurately diagnose 76% of young youth judged to be suffering from major depression (Luby et al., 2000). Note: This problem still exists with DSM-5-TR. For more diagnostic precision, Luby et al. recommend the following modified diagnostic criteria (Figure 2-A):
Figure 2-A. |
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Interestingly, it was held that youth did not have vegetative signs (such as sleep or appetite disturbances) for many years. However, these symptoms do occur in many youth suffering from major depression. Also, it is important to note that many youth with major depression do not exhibit a sad or depressed mood and thus do not show a classic depressive affect. These youth may have many depressive symptoms, but mood changes often involve marked irritability and/or anhedonia. This is very relevant because many parents, teachers, and some healthcare providers believe that those with severe depression should look sad and depressed. This may account for the fact that many such depressed youth go undiagnosed and thus untreated. See Figure 2-B for a list of additional depressive symptoms.
Figure 2-B. |
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Assessment of depressive disorders follows the guidelines for assessment discussed above. Medical difficulties should be investigated. A thorough clinical interview should be conducted and the use of a specific questionnaire for depression should be utilized (e.g., PHQ-9, Mood and Feelings Questionnaire, or Child Depression Inventory – Second Edition (CDI-2). Assessment for suicidal or homicidal ideation and behavior and risk and protective factors should also be assessed. The subtypes of depressive disorders should be diagnosed using the DSM-5-TR criteria.
The average duration of depressive episodes in children ranges from eight to 12 months, and in adolescence it is four to nine months. Twenty percent to 70% of these youth will develop a recurrence of depression, especially if there is a family history of mood disorder. Adolescents with major depression are likely to suffer depression in adulthood.
The American Academy of Child and Adolescent psychiatry (AACAP) recommends that the first line of treatment for major depressive disorder (MDD) or persistent depressive disorder (PDD) could be cognitive-behavioral or interpersonal therapy. The second recommendation is to use an SSRI, except paroxetine, preferably fluoxetine, for youth with MDD.
Treatment starts with low doses for the first week (see Figure 2-C), then gradually increased doses if tolerated. The reason for a low starting dose is that approximately 5% of youth have a condition called 2D6 hypometabolism. 2D6 is a liver enzyme metabolizing several antidepressant (and other) drugs. In these youth, inadequate first-pass metabolism results in high blood levels of a drug and, thus, very significant side effects. If they were to be started on higher doses, the initial side effects could be overwhelming, hence the starting low-doses.
One of the most common problems in initiating treatment is activation. This acute onset side-effect may occur within a few hours after taking the first drug dose or when dosages are increased. It presents anxiety, initial insomnia, and sometimes agitation. It is important to note that this is different than switching. Switching is when an antidepressant provokes the emergence of mania or hypomania in a person with bipolar disorder. Switching generally does not occur until the medication has been taken for two or more weeks. The main differential feature of activation versus switching is the time of onset (i.e., an acute event with activation). Activation can be unpleasant, but possibly a more significant problem is that when parents see it, it may lead to them not only stopping the medication but also becoming afraid of and pessimistic about psychiatric drug treatment in general. Thus, parents need to be warned that this can happen and to contact the doctor immediately if it does. Another commonly used strategy is to co-prescribe a low-dose minor tranquilizer (e.g., lorazepam, 0.125 mg) and instruct the parent to give it to their child if signs of activation occur. Fortunately, if activation is evident, it can be controlled with minor tranquilizers and generally subsides within one to two weeks (tranquilizers are no longer necessary by the end of one month of treatment).
The general rule of thumb is to start with a low dose, as mentioned above, and then increase the dose while carefully watching for signs of either a clinical response or the emergence of side effects (suggesting that the dose is too high and cannot be tolerated). There are no well-established guidelines regarding how long to wait between dosage adjustments. However, it is common practice to treat for a month to six weeks and then to increase the dose if there has been no sign of clinical improvement (generally, this is a better first step strategy than switching to a different drug or augmenting, i.e., adding a second medication). Please also keep in mind that there are a number of late responders among youth, and there is some positive yield by continuing to treat for a number of weeks until clinical improvement is noted.
How long does continuation treatment last if there is a positive clinical response? This also has not been determined in efficacy studies. It is well known that, in adults and older adolescents, it is essential to continue treatment at the same dose of antidepressant for a minimum of six months, and in most cases, a whole year, following symptomatic improvement, followed by gradual discontinuation. This guideline has also often been adopted in the treatment of youth despite the absence of empirical support for this strategy.
The clinician should be alert to the possible development of two late-onset side effects in some patients treated with antidepressants (this is the case for all antidepressants except bupropion). The adverse effects are: 1) Apathy and emotional blunting (ultimately occurring in 35%-50% of people using these medicines); or 2) Emotional disinhibition. These appear to be due to the downstream effect of serotonin on the dopamine neurotransmitter system in the frontal lobes (Barnhart et al., 2004). This often-unrecognized side-effect completely subsides with medication discontinuation or may respond favorably to the co-administration of bupropion (which activates the dopamine system).
Antidepressants and Suicidality |
There has been much media attention regarding the potential risks of antidepressants and increased suicidality (especially in youth and adolescents). The initial fear came from a study in England that raised concerns about increased suicidality in young patients treated with the antidepressant Paxil. In this study, which included 1,300 patients, Paxil was compared to placebo, and reports of increased suicidality were seen in 1.2% of placebo and 3.4% of Paxil-treated subjects. This difference is statistically significant. It is important to note that there were no actual suicides in this group of youth, and a number of so-called suicidal “events” occurred in the Paxil group during the 28 days following the discontinuation of Paxil. One significant problem in trying to understand and address this issue, is that the concept of “suicidality” has been loosely defined in this and other studies. It often includes reports of increased thoughts about suicide, suicide gestures, non-lethal-intent self-harm (as is often seen in borderline personality disorders), and, in one instance, even a report of a child slapping herself qualified as a suicide attempt (Brown University, 2004). Of course, actual suicides and lethal attempts are also included under this umbrella of suicidality. Concerns regarding increased suicidality have had a significant impact. In the United States, the FDA has responded to concerns about increased suicidality by requiring drug companies to issue warnings about using these drugs with younger clients (i.e., youth, adolescents, and young adults ages 10-24). They have also conducted a study to investigate the data from a database of 4,400 teenagers treated with antidepressants. Those treated with placebos had a 2% rate of treatment-emergent suicidality, while those treated with antidepressants had a 4% rate. It is interesting to note that in this large group of adolescents treated with antidepressants, there have been no suicides. It has also been documented that in geographic areas where antidepressants are widespread, suicide rates have dropped among adolescents (Mahler, 2004). From 1950 to 1990, actual suicide rates among ages 10-24 have increased by 300%. With the advent of new generation antidepressants (Prozac, Paxil, Zoloft, etc., beginning in the late 1980s) for the first time in 40 years there has been a decrease in suicides in this group of people; this coincided with a four-fold increase in prescriptions for antidepressants. Ever since the negative media attention regarding antidepressants and suicidality began (2003), the number of antidepressant prescriptions for youth has significantly declined, by some estimates, 30%-40%. This raises significant questions about the impact of the decision to issue the FDA warnings. Although correlation does not imply causality, these data warrant close and ongoing monitoring. Even though the likelihood of increased suicidality may be low in large group studies, the clinician must be on the lookout for the emergence of suicidal tendencies in all patients who suffer from major depression. It is certainly possible that, in some cases, the drug can contribute to this problem. The following may account for the increased suicidality seen in some individuals treated with antidepressants:
Almost 20 years later, after a black box warning was required for antidepressants, the debate about antidepressant suicidality continues. Ignaszewski and Spielmans (2020) stressed that the FDA black box warning should not be ignored. The resulting wisdom over the years has been that the black box warning resulted in decreased prescribing of antidepressants and increased suicide rates. Spielmans stated that there are times when suicidality is drug-induced and should not be misinterpreted. The patients and parents should be informed that if suicidal ideation emerges, it could be drug-induced. If the suicidal ideation is attributed to worsening depression, prescribers may increase doses when a more thoughtful approach is warranted. |
The term antidepressants refers to medications that are used to treat depression. These medications are often grouped according to their mechanism of action. A common medication used to treat depression in youth and adolescents is fluoxetine (generic name), better known as Prozac (trade name). Fluoxetine is an SSRI (selective serotonin reuptake inhibitor). This medication theoretically helps depression by blocking the reuptake of serotonin in the synaptic cleft between two neurons. Examples of other antidepressants include tricyclic antidepressants (e.g., amitriptyline), named after their chemical structure of having three rings of atoms; SNRIs (e.g., duloxetine [Cymbalta]); NRI (norepinephrine reuptake inhibitor) (e.g., atomoxetine [Strattera]); and others noted in Figure 2-C.
Early case reports and clinical experience have shown that very severely depressed, hospitalized youth and adolescents often did respond to treatment with tricyclic antidepressants (Walkup, 2004). However, significant side effects plague tricyclics; they are very toxic in overdoses, and there have been cases of sudden death in youth due to cardiac effects with the tricyclic desipramine. Additionally, in the small number of controlled studies, tricyclics are no more effective than placebos in the treatment of mild-to-moderate major depression (recall that in such studies, severely ill youth are not included). Thus, in this section, we will only address the newer antidepressants.
The double-blind, placebo-controlled studies of antidepressants in treating major depression in youth have mostly been limited to SSRIs. Placebo responses in these child studies are higher than that seen in adult studies, so in order to be judged to be statistically significantly better than placebo, the drug must have a very high level of demonstrated efficacy in large sample sizes. The limited studies in this area of investigation reveal that SSRIs are much better tolerated than tricyclics and are more effective than either placebos or tricyclics (Emslie & Mays, 2001; Wagner et al., 2003; March, et al., 2004; Whittington et al., 2004). However, the effect sizes are small. A meta-analysis of studies by Jureidini et al. (2004) shows an effect size across six randomized, placebo-controlled studies of just 0.26. This is a very small effect size and may suggest that antidepressant efficacy is limited compared to placebo.
Most of the studies reviewed in this meta-analysis suffered from significant methodological flaws (Walkup, 2004). These studies were supported by pharmaceutical companies and mainly done in response to an FDA incentive: “Companies could extend their patents for a drug for six months by testing it on youth … whether the trial demonstrated that the drug worked or not. In other words, there was a powerful incentive to do the trials, but no incentive to do them well.” (Mahler et al. 2004)
A large-scale, federally funded program, Treatments for Adolescents with Depression Study (TADS), has addressed many methodological issues raised in other studies. The sample included 432 adolescents (ages 12-17) suffering from major depression. The subjects were randomly assigned to one of four groups. After 12 weeks of treatment, the percentages of responders were placebo: 35%; cognitive-behavioral therapy (CBT): 43%; fluoxetine (Prozac): 61%; and combination CBT and fluoxetine: 71%. Here, drug treatments were significantly better than placebo or psychotherapy alone. The effect sizes were 0.8 and 0.6 for the combination treatment and fluoxetine alone, respectively (March et al., 2004; Glass, 2004). These results are promising. However, this study was with teenagers, and we cannot assume that the results apply to prepubertal youth.
In evaluating the commonly found high placebo response rate, it is very important to remember that although acute treatment placebo responses in youth are impressively high, no study has evaluated the ability of placebos to prevent breakthrough symptoms or reduce recurrence. Efficacy studies have been limited in duration (8-18 weeks), and there is an absence of long-term follow-up. Typically, positive placebo responses, if they occur, tend to be time-limited.
Two findings that are important to note from these empirical studies and clinical experience appear to be that: 1) The time to onset of positive medication effects may be somewhat longer for youth than for adults. With youth, although symptomatic improvement may be noted within four weeks, in some instances an adequate trial of 8-12 weeks may be required; and 2) A syndrome of apathy/amotivation or emotional disinhibition, sometimes seen in adults on chronic SSRI treatment (see below), is more commonly encountered in youth (Walkup, 2004; Barnhart et al., 2004).
The Journal of the American Academy of Child & Adolescent Psychiatry (JAACAP) treatment guidelines published in 2023 were based on an extensive review of studies (Walter et al., 2023). A total of 27 studies of pharmacological interventions met the criteria for review. These included 14 RCTs of selective serotonin inhibitors (SSRIs), with eight RCTs of fluoxetine (Prozac) and one RCT of escitalopram (Lexapro). The remaining RCTs were citalopram (Celexa), vilazodone (Viibryd) (SNRI), and paroxetine (Paxil). There was insufficient evidence for other classes of medication (e.g., other SNRIs or SNDRIs). SSRIs, as a class, compared to placebo, improved depressive symptoms in youth and adolescents. As to efficacy compared to placebo, significant improvements in depression in youth and adolescents were found for fluoxetine (Prozac) and escitalopram (Lexapro).
Currently, there are two antidepressants approved by the FDA for the treatment of major depression in youth: fluoxetine (Prozac) (ages eight and older) and escitalopram (Lexapro) (ages 12-17). However, as previously mentioned, many antidepressants are in widespread “off-label” use. Antidepressants are commonly listed by reference to the neurotransmitters they target: SSRI (selective serotonin reuptake inhibitors), NRI (norepinephrine reuptake inhibitors), SNRIs (serotonin and norepinephrine reuptake inhibitors), NDRIs (norepinephrine and dopamine reuptake inhibitors), and atypical antidepressants (trazodone, vortioxetine [Trintellix] and mirtazapine [Remeron]). Antidepressant medications are listed by class, names, recommended starting doses, and daily doses in Figure 2-C, and common side effects are listed in Figure 2-D.
Figure 2-C. C: pre-pubertal youth. A: adolescents |
||||
Generic Name |
Brand Name |
Starting Dose |
Daily Dose |
Daily (weight adjusted) |
SSRI |
||||
fluoxetine |
Prozac, Sarafem |
C:
5 mg |
5-40 mg |
0.25-0.75 mg/kg |
sertraline |
Zoloft |
C:
25 mg |
25-200 mg |
1.5-3.0 mg/kg |
paroxetine |
Paxil |
C:
5 mg |
10-30 mg |
0.25-0.75 mg/kg |
citalopram |
Celexa |
C:
10 mg |
10-40 mg |
0.25-0.75 mg/kg |
escitalopram |
Lexapro |
C:
5 mg |
5-20 mg |
0.125-0.375 mg/kg |
fluvoxamine |
Luvox |
C:
25 mg |
25-200 mg |
1.5-4.5 mg/kg |
| vilazodone | Viibryd | C:
not established |
C: not established A: 10-40 mg |
Not yet established |
SNRI |
||||
venlafaxine, XR |
Effexor XR |
C:
12.5 mg |
C:
12.5-37.5 mg |
C: 1-2 mg/kg |
| desvenlafaxine | Pristiq | C: not established A: 50 mg |
C: not established A: 50-400 mg |
|
duloxetine |
Cymbalta |
C:
not established |
A: 10-60 mg |
A: 1 mg/kg |
levomilnacipran |
Fetzima |
C:
not established |
C:
not established |
Not yet established |
NRI |
||||
atomoxetine |
Strattera |
C:
10 mg |
C:
10-60 mg |
C: 1.2-1.8 mg/kg |
NDRI |
||||
bupropion |
Wellbutrin |
C: 100 mg |
C: 50-150 mg |
C: 3-6 mg/kg |
Atypical |
||||
mirtazapine |
Remeron |
C:
7.5 mg |
C:
15-30 mg |
Not yet established |
trazodone (1) |
Oleptro |
C:
25 mg |
C:
25-75 mg |
C: 1-3 mg/kg |
vortioxetine |
Trintellix |
C:
not established |
C:
not yet established |
Not yet established |
(1) Trazodone is technically an antidepressant, but has limited efficacy in treating depression. However, it is often a non-habit-forming medication for treating initial insomnia. |
||||
Figure 2-D. |
|||||
Medication |
Activation (1) |
Sedation |
Nausea |
Sex. Dysfunction (2) |
Weight Gain |
SSRI |
|||||
fluoxetine |
+++ |
+/- |
+ |
++ |
(3) |
sertraline |
++ |
+/- |
++ |
++ |
(3) |
paroxetine |
+ |
++ |
+ |
++ |
(3) |
citalopram |
+ |
+/- |
+ |
++ |
(3) |
escitalopram |
+ |
+/- |
+ |
++ |
(3) |
| vilazodone | +/- |
(4) |
(4) |
(4) |
(4) |
fluvoxamine |
+/- |
++ |
++ |
++ |
(3) |
SNRI |
|||||
venlafaxine |
+ |
+ |
+ |
++ |
(3) |
| desvenlafaxine | + |
+ |
+ |
++ |
(3) |
duloxetine |
+ |
+ |
+ |
+ |
(4) |
levomilnacipran |
+ |
+ |
+ |
+ |
(4) |
NRI |
|||||
atomoxetine |
+ |
++ |
+/- |
0 |
0 |
NDRI |
|||||
bupropion |
++ |
0 |
+ |
0 |
0 |
Atypical |
|||||
mirtazapine |
+/- |
++ |
0 |
++ |
+++ |
trazodone (5) |
0 |
+++ |
0 |
0 |
0 |
vortioxetine |
+ |
0 |
+ |
(4) |
(3) |
(1) Activation is an acute side-effect occurring within a few hours after taking the first dose of the medication or when there is a dosage increase. Activation includes anxiety and insomnia that can continue during the first two weeks of treatment but often subsides. At times, this may last longer. It has been estimated that this side effect occurs in 10%-15% of youth and 10% of adolescents and adults. (2) Primarily anorgasmia. (3) Acute weight gain is rare. A small percentage (possibly 10%) may experience weight gain after being on medication for 6+ months. One exception is the drug Remeron, where up to 50% of people taking it experience weight gain. Data is not available regarding this side effect in youth. (4) Not yet determined. (5) The low incidence of side effects (except sedation) assumes the use of low doses (see Figure 2-C). |
|||||
In addition to prescription antidepressants, two over-the-counter products have some demonstrated efficacy in treating depression, St. John’s Wort and SAMe. Although there are a number of outcome studies with these drugs in the treatment of adults with depression, there are no such studies with youth or adolescents, and thus, they should be considered to be experimental. It should be noted that St. John’s Wort has been associated with significant effects on liver metabolism and can adversely interact with other medications. This has particular relevance if it is used in treating adolescent females. St. John’s Wort can interfere with the metabolism of birth control pills, rendering them ineffective.
There are several non-blinded studies showing the effectiveness of antidepressants in the treatment of dysthymia in youth (Nobile et al., 2003). (DSM-5-TR identifies this as persistent depressive disorder [PDD] but it continues to be commonly referred to as dysthymia). Treating dysthymia is essential since it generally lasts three to four years without treatment, substantially negatively affecting psychosocial functioning and development. Additionally, many youth with dysthymia eventually develop major depression. It is unclear if early treatment can further prevent later, more serious, major depression, although there is speculation that it can. Further study is needed to confirm the efficacy of antidepressants in treating dysthymia.
SSRIs are effective agents for treating premenstrual dysphoric disorder (PMDD). (Note that the non-serotonin antidepressants such as NRIs (e.g., Strattera) and NDRIs (e.g., Wellbutrin) are not effective in treating PMDD.) Unlike treating all other depressive disorders, PMDD patients often have an acute positive response to treatment with SSRIs (i.e., showing symptomatic improvement several hours after taking the first dose). Additionally, in general, patients need only take the medication for the period that they typically experience emotional symptoms (for many young women, this may be for only a few days a month), thus avoiding the burden of longer-term side effects.
Many severe major depressions in young people present with psychotic symptoms. Often, psychotic symptoms are not as easy to observe in people with mood disorders as schizophrenia or drug-induced psychosis. Many very depressed youth harbor delusional thinking (e.g., somatic or paranoid delusions) but keep it to themselves, and clinicians may treat them for months, not appreciating that there is a psychotic element to the disorder. Thus, it is essential to carefully assess for the presence of these less obvious signs of psychosis. If psychotic symptoms are present, this necessitates the use of antipsychotic medications (in conjunction with antidepressants) or the use of electroconvulsive therapy (ECT). Additionally, the presence of psychotic symptoms should increase the index of suspicion that the patient has bipolar disorder and may respond to treatment with mood stabilizers – see Bipolar Disorder, below.
Discontinuation withdrawal symptoms have been well documented. These occur if there is abrupt discontinuation and generally present with nausea, nervousness, insomnia, a peculiar “electrical shock” sensation experienced periodically, and generalized body aches (like having the flu). There are reports of increased suicidality upon rapid discontinuation, and this may be due to two factors: the medication was controlling the depression and it is no longer having this effect, and/or the distress caused by withdrawal symptoms has provoked the emergence of suicidal feelings. Severe withdrawal symptoms are most likely to be seen in two drugs, both of which have short half-lives: paroxetine (Paxil) and venlafaxine (Effexor). It can occur in most other antidepressants as well, except fluoxetine (Prozac) where it occurs very rarely due to its long half-life. Withdrawal symptoms can generally be avoided entirely if the medication is gradually discontinued over four to eight weeks.
Adults and adolescents experiencing a third episode of major depression are best treated by ongoing, long-term antidepressant therapy to reduce the likelihood of recurrence (those suffering a third episode have a better than 90% chance of having a fourth episode). As noted earlier, many, if not most, youth experiencing major depression will have recurrences. However, there is inadequate data to recommend chronic use of antidepressants with youth. Until more research is conducted to address this issue, it is probably prudent to discontinue medications after six months to one year of asymptomatic status (as noted above) and educate the patient or his/her parents to be on the lookout for signs of possible recurrence (and if spotted, to seek treatment as soon as possible).
Bipolar disorder in youth is characterized by episodic mood elevations that exceed that expected for the youth’s age.
Multiple studies have reported that up to 60% of adults with bipolar disorder had onset mood symptoms before age 20 (Birmaher, 2023). Pediatric bipolar disorder is often unrecognized and many youth do not receive treatment. Many with pediatric bipolar disorder have not been diagnosed for several years. The following history and clinical features should alert the clinician to a higher risk of bipolar disorder (Figure 2-E):
Figure 2-E. |
|
The diagnosis of bipolar disorder in prepubertal youth is controversial. Mahli, et al. (2023) recommend that a definitive diagnosis of bipolar disorder should not be made with pre-pubertal youth since “cognitive and emotional symptoms of mania may be difficult to detect against a background of normative symptoms.” A diagnosis of “adolescent bipolar” can be made, but the “threshold should be far greater than that used in adults.” Before puberty, these authors recommend using the term “prepubertal miasma” to refer to symptoms that occur during this time (e.g., irritability and aggression). The diagnosis of DMDD should also be considered prior to a diagnosis of bipolar disorder as well.
The average age of onset of bipolar disorder is 19 years. There are cases of childhood onset, but diagnosing bipolar in pre-pubescent children is controversial. Meta-analyses of international studies suggest that 1.8%-2.8 % of those who develop bipolar disorder had onsets before puberty. The data from Robert Post (NIMH) from a study of 529 adults with bipolar disorder suggests that in 35%, the onset occurred between ages 13 and 18 (Post et al., 2010). At the same time, as noted above, it must be recognized that there remains controversy about the diagnosis of childhood onset bipolar disorder. Bipolar disorder in children was said to occur in 35% or more of those ultimately diagnosed with the disorder. It is now believed that this finding was inaccurate, and there is, as noted above, a very small percentage of true childhood onsets. In some other countries, it is rarely diagnosed. We must remember that many disorders in young people present with affect instability.
As mentioned above, 70% of cases of early onset bipolar illness (children and young teenagers) first become manifest in major depressive episodes; 30% begin with mania or hypomania. The signs and symptoms of childhood-onset mania (Figure 3-A) differ from the adult presentation of the disorder (the more typical adult version generally is seen to emerge as early as age 15-16).
Figure 3-A |
|
An important and often difficult differential diagnosis to make is childhood mania versus ADHD. This is complicated by the likelihood that although bipolar disorder and ADHD may represent distinct disease entities, there is considerable symptom overlap (see Figure 3-B).
Figure 3-B. |
|
Possible diagnoses of co-morbidities may exist, including:
An accurate diagnosis matters since inappropriate medical treatment may worsen the clinical condition (e.g., antidepressants may cause cycle acceleration in bipolar patients). Figure 3-C lists clinical features and other factors that help to differentiate ADHD from bipolar illnesses.
Figure 3-C. |
|
|
In addition, many children who present with severe emotional lability may not have actual bipolar disorder. One such group has been recently called Disruptive Mood Dysregulation Disorder (DSM-5-TR). This disorder is characterized by the following:
Unfortunately, this youth group typically does not respond well to mood stabilizers. Upon follow-up (10-year and 20-year follow-up periods) as adults, people with this disorder typically do not show symptoms of bipolar disorder; instead, they are much more likely to experience chronic or recurrent depression and/or anxiety disorders. Other diagnoses that need to be considered and ruled out are reactive attachment disorder, agitated major depression, PTSD, post-head injury, conduct or oppositional disorder, pre-schizophrenic, substance abuse disorders, borderline personality, and a history of fetal alcohol or other drug exposure.
The choice of treatment will depend on the current clinical presentation. The primary treatment for pediatric mania is a second-generation antipsychotic (e.g., aripiprazole) or lithium (Axelson, 2023). Other medications are utilized or taken away depending on responses and comorbidities. Some possible combinations and tips are below (written by John Preston, PsyD, in the original form of this manuscript).
Details regarding side effects and drug interactions for what is often very complex polypharmacy are beyond the scope of this course. However, some side effects and drug interactions can be especially problematic for children and teenagers.
Childhood-onset bipolar disorder, albeit rare, clearly is a more severe version of the disorder. Treatment is more complex than treating older teenagers or adults, and long-term prognosis is guarded. Unfortunately, to complicate matters, many children go for months before the diagnosis. Early recognition, accurate diagnosis, appropriate acute treatment, and ongoing maintenance treatment are necessary to reduce the intense suffering and prevent kindling and suicide (which is an all-too-common outcome of untreated or poorly treated bipolar disorder in young people).
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