Learning Objectives

This is an intermediate level course. After taking this course, mental health professionals will be able to:

• Diagnose mood disorders in children and adolescents using revised diagnostic criteria
• Discuss recently developed treatment algorithms for mood disorders
• Evaluate risk factors associated with pharmacological treatments, including the use of antidepressants and suicidality

Introduction

Note: Portions of this online course are adapted from Handbook of Clinical Psychopharmacology For Therapists (2010) and Child and Adolescent Clinical Psychopharmacology Made Simple (2009), both from New Harbinger Publications, Oakland, CA. For more information on these books, please visit the link to New Harbinger Publications.

During the past seven years there has been a good deal of media attention focusing on concerns regarding the use of antidepressants in children and adolescents. In particular, the public has been exposed to news stories involving possible increased suicide risks associated with the use of antidepressants in youngsters. It has also been during the past decade that a significant amount of research has focused on mood disorders in young people, discovering high prevalence rates of some very malignant forms of affective illnesses (e.g., pediatric bipolar disorder). In 1621, Robert Burton wrote his famous manuscript, Anatomy of Melancholy, in which he offered a highly astute description of severe childhood depression. Yet, for most of the 20^th century, depression in children was seldom, if ever, mentioned in the psychiatric literature. Major depression in children was not even officially recognized by the National Institute of Mental Health until 1975.

What has become clear is that some forms of unipolar 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.

Mental health professionals must keep abreast of new developments in the treatment of children. This online course is designed to present an overview of psychopharmacology of mood disorders in children and adolescents. It must be stated from the outset that many if not most emotional problems experienced by children are the direct result of encounters with psychologically difficult or traumatic circumstances, such as exposure to neglect or domestic violence. Also most of these problems do not represent severe mental illnesses, but rather painful adjustment disorders. In most instances, these types of emotional suffering do not require medical treatment; rather, they respond best to psychological and social interventions. However, in this course we will focus on those mood disorders that are considered to be both very severe and likely due, at least in part, to abnormalities in neurobiology. Even in bipolar disorder, for which there is substantial evidence for clear-cut neurobiological causation, psychological factors always contribute to morbidity, mortality, and human suffering. Likewise, in these disorders the best possible treatment outcomes can only be realized by the use of integrated approaches, i.e., psychopharmacology, psychotherapy, and adjuncts such as sleep hygiene and other forms of life style management.

Chapter One: Issues in Psychopharmacologic Treatment of Children and Adolescents

In this first chapter we address a number of general issues that are important to consider prior to discussing diagnosis and treatment in the chapters that follow.

Diagnosing and Treating Children and Adolescents

Until just recently in child psychiatry, there appeared to be an assumption that children with psychiatric disorders were quite similar, if not identical, to adults both with respect to diagnostic and pharmacologic treatment issues. The recommended approach was to diagnose and treat as you would with adults, although generally starting treatment with lower doses of medications. Although there is some degree of symptomatic overlap between adult and childhood-onset disorders, it is also clear that there are significant features that distinguish psychiatric syndromes as well as pharmacologic treatments in children and adults. It must also be kept in mind that the target of psychiatric drugs (the central nervous system) is continually undergoing maturational changes throughout childhood and adolescence. Certain neurotransmitter systems are not fully online in children, and some brain structures have not reached full development. 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 in terms of how drugs are metabolized. Kids are not just a smaller version of adults.

As noted above, it is likely that the majority of emotional suffering experienced by youngsters is related to situational stress and responds best to non-medical, psychological treatments (e.g. family therapy). However, it is also becoming increasingly clear that many major mental illnesses begin in childhood (e.g. 33 percent of cases of obsessive-compulsive disorder and up to 20 percent of cases of bipolar disorder have childhood/early adolescent onset). Not only do these disorders cause considerable suffering in young children, but they also can markedly interfere with normal social and academic developmental experiences. For example, over one-half of children 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 an impaired ability to concentrate. Even if they recover, many of these children find it hard to ever “catch up” academically or in terms of developing age-appropriate social skills.

There is also increasing evidence that some psychiatric disorders are subject to progressive neurobiological impairment if they go 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 normal patterns of neuro-maturation (See Figure 1-A). Pharmacologic treatment of these disorders may not only be successful in terms of improving symptoms, but may also be neuroprotective (i.e., medication treatment may either protect against brain damage or promote normal neuromaturation; in some instances, medications may promote the regeneration of nerve cells (neurogenesis).

Figure 1-A. Disorders with Evidence of Progressive Neurobiological Impairment

Bipolar Illness Attention Deficit/Hyperactivity Disorder Schizophrenia Some cases of Recurrent, Unipolar Depression Some cases of Post-Traumatic Stress Disorder

Informed Consent and Addressing Parental Concerns

In addition to clinical considerations, there are other unique challenges in the prescribing of psychotropic medications for children. With children, there is no true informed consent since parents are the ones who usually make the decision whether or not 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 children 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 side effects that are detrimental (e.g. using excessively high doses of stimulants may markedly reduce hyperactive behavior in ADHD children 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/or 4. the young person is left out of the loop (i.e., not spoken to or allowed to discuss in detail how they feel about medication treatment).

Most child clinicians agree that children should be included in discussions about psychiatric medication treatment (especially true for children ages 7 and older where cognitive development has proceeded enough to enable the children to understand some information regarding medication treatment) This is important in order to encourage the child to voice concerns about treatment (e.g. many children conclude that if they need medicine, it must mean that 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 (this 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 child in discussions regarding medication treatment can often foster a positive relationship with the therapist, as the child feels respected enough to be included.

Parents need to be provided with a good deal of time devoted to addressing all of their concerns about drug treatment. Parents who do not wholeheartedly endorse treatment will often sabotage treatment. Informed consent should also include the risks of not treating certain disorders.

Parental Fears Regarding Drug Addiction

Many parents are understandably concerned about the use of habit-forming drugs to treat their children. It is important 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 potential drugs of abuse: stimulants (e.g. Ritalin) and benzodiazepines (e.g. antianxiety drugs such as Xanax). However, the vast majority of children 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 children. In fact, many children with ADHD experience stimulants as causing mild dysphoric effects. Additionally, data now exists to strongly indicate that among those with ADHD, the use of stimulants actually 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)

Substance abuse by children and adolescents is a common and serious concern in our society. It must also be kept in mind 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 a sense of 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 certainly take into consideration the risks of failure to treat the psychiatric disorder.

Medications and the Media

Research studies and clinical experience certainly influence prescribing practices. However, in recent years the media has had a profound effect on public opinion and ultimately on clinical practice. Public opinions are often influenced both by drug company marketing efforts (and thus profit motives) and by headline news (the most recent example is the concern over antidepressant use in children and possible increased suicidality (an issue discussed in more detail in the chapter on treating depression)).

In the late 1980s negative attention was focused on the drug Ritalin, a widely prescribed stimulant used to treat attention deficit hyperactivity disorder. 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, most by a lawyer linked to the Church of Scientology” (Brotman, 1992).

In a study of the effects of this negative media and litigation blitz conducted in Baltimore, Maryland, Safer and Krager found that during the two-year period just following the negative media attention, prescriptions for Ritalin had dropped by 40%. What were the consequences? 36% of those children who discontinued Ritalin experienced major 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 tricyclics are somewhat effective in treating ADHD symptoms, but clearly much less effective than stimulants. Further, tricyclics are considerably more toxic, have much higher rates of side effects, and had been associated with sudden cardiac-related deaths in six children). Parents understandably heard the negative reports in the media, approached their pediatricians with concerns about Ritalin, and many children were taken off the stimulant and put on a class of drugs that is less effective and considerably more dangerous.

Media attention is important in that it can alert consumers and professionals (including the FDA) to possible problems with certain medications. 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 children in treatment can be significant and as clinicians, we must be aware of and sensitive to such concerns.

Drug Research and Outcome Studies

As important as efficacy studies are, there is a relative paucity of good studies in child psychopharmacology (with one notable exception — there are numerous, well-controlled studies of the treatment of ADHD with stimulants). Historically, pharmaceutical companies did not conduct tests of psychiatric drugs on children. However, in 1998, the Food and Drug Administration mandated that safety studies be carried out for new psychiatric drugs with child subjects and recently have offered financial incentives (by way of extensions of patents) if efficacy studies are done with children. Thus, in very recent times, better-controlled studies have been initiated, however many of these are not yet published and some suffer from significant methodological flaws. In the next few years, the database of well-done studies should increase significantly.

Another issue regarding research in this area is that many studies do not include severely ill children (the reason is that it is not judged to be ethical to expose severely disturbed children to placebos over a period of months). Thus, in research in some areas of child psychiatry where there is random assignment and placebo arms of the study, groups of subjects (e.g. those with major depression) often include only mild-to-moderately severe cases. Information about treatment outcomes for severely ill children is often limited to clinical experience and case studies. It is important to keep these research limitations in mind when evaluating the outcomes of medication studies.

One important area of concern is the effect of very long-term use of psychiatric medications in children. This is a concern for clinicians and also is one of the most frequently asked questions from parents. Short-term side effects are well documented and will be discussed in detail in subsequent chapters. However, there is relatively little in terms of hard data to indicate risks associated with long-term treatments. Yet, for many of the disorders discussed in this book, long-term medication treatment is strongly recommended (e.g. bipolar disorder, ADHD, and psychotic disorders). It is our belief that when this topic arises in discussions with patients and their parents, the only appropriate response is to be completely candid about the lack of knowledge regarding long-term drug exposure, but to also be clear about the risks of not treating certain disorders (e.g. it is well known that there is grave morbidity and mortality associated with untreated bipolar illness, including a lifetime suicide rate of 19-20%). It is always a matter of risk versus benefit, and parents need to be offered as much information as is available so they can make informed choices.

Medication Metabolism in Young Clients

The normal rate of hepatic (liver) metabolism is high in children until the time of puberty. The result is that most medications are aggressively metabolized in the liver and rapidly excreted. Thus dosing for prepubertal children requires doses that may approach or equal adult dosing (because what ultimately matters is how much 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 about the role of increased rates of drug metabolism.

During a period of time (2-4 months) surrounding the entry into puberty, the rate of hepatic metabolism significantly slows. For this reason, youngsters who have been maintained 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.

Approved Drugs and “Off Label” Use

Currently very few psychiatric drugs are FDA approved for use in treating children and young adolescents. Yet these drugs are also in widespread use in child psychiatry. It is very common practice in psychiatry, as it is in general medicine, to prescribe drugs “off label.” This refers to the use of drugs that are FDA approved for certain uses but are being used to treat a condition for which there is no FDA approval. For example, the anticonvulsant medication, Tegretol is FDA approved for the treatment of epilepsy, but not approved for use in bipolar disorder. However, Tegretol has been used for a number of years to treat some cases of mania. Since there is clinical and research support for the use of this drug in treating mania, it is considered to be in keeping with medical standards of practice and thus its use in treating mania is not considered to be either illegal or unethical. Likewise many drugs approved for use with adults (but not approved for children) are used to treat child psychiatric patients. For example, currently there is only one antidepressant approved by the FDA for the treatment of major depression in children (fluoxetine: Prozac), yet many other antidepressants are used to treat childhood-onset depression. No medications are yet FDA approved for treating childhood-onset bipolar disorder.

Some drug classes, most notably antidepressants, have been found to have efficacy in treating a host of disorders other than depression, e.g. panic disorder, OCD, social anxiety, etc. Thus we will discuss antidepressants in more detail (e.g. side effects; standard dosage guidelines) in the chapter on treating depression, and in later chapters only address how such drugs play a role in treatment of other disorders (the reader is thus referred to the earlier chapter for more details, such as medication side effects).

Attitudes and Realities Regarding Psychopharmacology with Children and Adolescents

Despite the fact that some of the disorders discussed in following chapters are deemed to be due largely to a primary neurobiological cause and require drug treatment, I must state categorically that no child should ever be treated with psychiatric medications without concurrent psychotherapy. Also, there is the widespread practice of having pediatricians diagnose and prescribe psychotropic medications. It is only in very rare exceptions, that pediatricians have both appropriate training for diagnosing and treating psychiatric disorders as well as enough time to conduct a comprehensive evaluation. Yet the reality is that, in these managed care days, most primary care doctors are overwhelmed with patients and have grossly inadequate amounts of time to devote to the taking of a careful history and conducting an adequate diagnostic evaluation. Children with serious mental illnesses are best evaluated and treated by mental health specialists.

Chapter Two: Depression

Accurate prevalence rates for adjustment disorders with depressed mood in children are not available although the rates are likely to be high. However, it has been established in epidemiologic studies that yearly prevalence rates of major depression are significant (2% for children and 10% for teenagers). Of great concern is that serious depressive episodes in children and young adolescents also likely herald the onset of either severe and highly-recurrent unipolar depressions (35 percent of cases) or bipolar disorder (49 percent) (based on ten-year follow-up after an index episode of depression (Geller, et al. 2002; Geller and DelBello, 2003)).

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 address relapse prevention.

Diagnostic Issues

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 failed to accurately diagnose 76% of young children judged to be suffering with major depression (Luby, et al. 2000). For more diagnostic precision these authors recommend the following modified diagnostic criteria (Figure 2-A):

Figure 2-A. Symptoms of Major Depression

Depressed or irritable mood for more days than not Plus four of the following (vs. 5 required for adults) Anhedonia Significant weight loss or gain Insomnia or hypersomnia more days than not Psychomotor agitation or retardation Fatigue more days than not Feelings of worthlessness or excessive guilt Impaired concentration Recurrent thoughts of death or suicide

It is of interest that for many years it was held that children did not have vegetative signs (such a sleep or appetite disturbances) although these symptoms do occur in 80 percent or more of youngsters with major depression. Also it is important to note that with children, an irritable or anhedonic mood is much more common than a sad/depressed mood. See Figure 2-B for a list of additional depressive symptoms.

Figure 2-B. Additional Diagnostic Signs and Symptoms of Major Depression in Children

Most Common Symptoms Irritability Social withdrawal Anhedonia Low self-esteem Play themes of death, suicide, or self-destruction Vegetative symptoms (e.g. sleep disturbance) Common Symptoms School failure Loneliness Sadness Low energy Associated Signs and Symptoms Vague, nonspecific physical complaints Running away from home Being bored Extreme sensitivity to rejection or failure Reckless behavior; acting out Difficulty with relationships Substance use/abuse

As note above, in almost half of prepubertal children with episodes of major depression, the episode ultimately turns out to have been the first manifestation of bipolar illness. Seventy percent of people with prepubertal bipolar disorder initially present with depression, and on average have between two and four depressive episodes prior to their first manic episode (Geller and DelBello, 2003). It is very important to try and determine if these first episodes are associated with an underlying bipolar disorder. This is especially critical since there has been growing concern that the use of antidepressants may, in the long run, be risky in bipolar patients (potentially exacerbating a manic episode or causing cycle acceleration, a worsening of the disorder which is discussed in Chapter 3). Thus the clinician, in addition to making a diagnosis of major depression, must also conduct a comprehensive evaluation to rule out potential bipolarity in all depressed children and teenagers. The following history and clinical features should alert the clinician to a higher risk of bipolar disorder (Figure 2-C):

Figure 2-C. Red Flags for Possible Bipolar Disorder

Atypical depressive symptoms (e.g. hypersomnia (excessive sleeping), severe fatigue, increased appetite, carbohydrate craving, and weight gain). Seasonal (winter) depressions Psychotic Symptoms History of separation anxiety disorder History of ADHD or ADHD-like symptoms (note: most children with a history of ADHD do not develop bipolar disorder, but some prepubertal-onset bipolar disorders do show a history of behaviors during infancy and early-childhood that resemble ADHD). Positive family history of bipolar disorder History of hypomania

Psychopharmacology

Efficacy of Antidepressants:

Early case reports and clinical experience have shown that very severely depressed, hospitalized children and adolescents often did respond to treatment with tricyclic antidepressants (Walkup, 2004). However, tricyclics are plagued by significant side effects, they are very toxic in overdoses, and there have been six cases of sudden death in children (due to cardiac effects with the tricyclic, desipramine). Additionally, in the small number of recent controlled studies, tricyclics have been found to be no more effective than placebos in the treatment of mild-to-moderate major depression (recall that in such studies severely ill children are not included). Thus, in this chapter we will only address the newer antidepressants.

To date, the double blind, placebo-controlled studies of antidepressants in the treatment of major depression have been limited to SSRIs and one study of venlafaxine (although drugs such as bupropion are in common use and other classes of drugs are undergoing trials). 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 and large sample sizes. The limited studies in this area of investigation reveal that SSRIs are much better tolerated than tricyclics and are significantly more effective than either placebos or tricyclics (Emslie and 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.

However, it is important to note that most of the studies reviewed in this meta analysis suffered from significant methodological flaws (Walkup, 2004). These studies were supported by pharmaceutical companies and done largely in response to an FDA incentive: “Companies could extend their patents for a drug for six months by testing it on children … whether the trial demonstrated that the drug worked or not. There was, in other words, a powerful incentive to do the trials, but no incentive to do them well.” (Mahler, J., et al. 2004)

A more recent, large-scale, federally-funded program, Treatments for Adolescents with Depression Study (TADS), has addressed many of the 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, J., et al. 2004; Glass, R.M., 2004). These results, obviously, are more promising.

In evaluating the commonly found high placebo response rates it is very important to keep in mind that although acute treatment placebo responses in children are impressively high, no study has evaluated the ability of placebos to prevent breakthrough symptoms or to reduce recurrence. Currently available efficacy studies are 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. Owing to the highly recurrent nature of depression in youngsters, the issue of longer-term effects is crucial, although no systematic data exist to address this issue.

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 mediation effects is longer for children than for adults (with children, 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 children (Walkup, 2004; Barnhart, et al. 2004).

Antidepressant Medications

Currently only one antidepressant is FDA approved for the treatment of major depression in children (ages 8 and older), fluoxetine (Prozac, Sarafem). However, as mentioned in Chapter One, 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 and mirtazapine). Antidepressant medications are listed by class, names, recommended starting doses and daily doses in Figure 2-D; and common side effects are listed in Figure 2-E.

Figure 2-D. Antidepressant Medications C: prepubertal children… A: adolescents
Generic Name	Brand Name	Starting Dose	Daily Dose	Daily (weight adjusted)
SSRI
Fluoxetine	Prozac, Sarafem	C: 5 mg A: 10 mg	5-40 mg	0.25-0.75 mg/kg
Sertraline	Zoloft	C: 25 mg A: 50 mg	25-200 mg	1.5-3.0 mg/kg
Paroxetine	Paxil	C: 5 mg A: 10 mg	10-30 mg	0.25-0.75 mg/kg
Citalopram	Celexa	C: 10 mg A: 10 mg	10-40 mg	0.25-0.75 mg/kg
Escitalopram	Lexapro	C: 5 mg A: 5 mg	5-20 mg	0.125-0.375 mg/kg
Fluvoxamine	Luvox	C: 25 mg A 25-50 mg	25-200 mg	1.5-4.5 mg/kg
SNRI
Venlafaxine, XR	Effexor XR	C: 12.5 mg A: 25-37.5 mg	C: 12.5-37.5 mg A: 25-75+ 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 mg	A: 10-60 mg	A: 1 mg/kg
NRI
Atomoxetine	Strattera	C: 10 mg A: 40 mg	C: 10-60 mg A: 40-100 mg	C: 1.2-1.8 mg/kg
NDRI
Bupropion SR	Wellbutrin, SR	C: 100 mg	C: 50-150 mg	C: 3-6 mg/kg
Atypical
Mirtazapine	Remeron	C: 7.5 mg A: 15 mg	C: 15-30 mg A: 15-45 mg	not determined
Trazodone (1)	Desyrel	C: 25 mg A: 50 mg	C: 25-75 mg A: 25-100 mg	C: 1-3 mg/kg
(1)Trazodone is technically an antidepressant but has limited efficacy in treating depression. However, it is often used as a non-habit-forming medication for the treatment of initial insomnia.

 

Figure 2-E. Common Side Effects of Antidepressants
Medication	Activation (1)	Sedation	Nausea	Sex. Dysfunction (2)	Weight Gain
SSRI
Fluoxetine	+++	+/-	+	++	(3)
Sertraline	++	+/-	++	++	(3)
Paroxetine	+	++	+	++	(3)
Citalopram	+	+/-	+	++	(3)
Escitalopram	+	+/-	+	++	(3)
Fluvoxamine	+/-	++	++	++	(3)
SNRI
Venlafaxine	+	+	+	++	(3)
Desvenlafaxine	+	+	+	++	(3)
Duloxetine	+	+	+	+	(4)
NRI
Atomoxetine	+	++	+/-	0	0
NDRI
Bupropion	++	0	+	0	0
Atypical
Mirtazapine	+/-	++	0	++	+++
Trazodone (5)	0	+++	0	0	0
(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 thereafter it often subsides. (2) Primarily inorgasmia (3) Acute weight gain is rare. A small percent (possibly 10%) may experience weight gain after being on the medication for 12+ months. (4) Not yet determined (5) The low incidence of side effects (except sedation) assumes the use of low doses (see Figure 2-D).

In addition to prescription antidepressants, there are two over-the-counter products that 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 children 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 special 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.

Treatment Guidelines

Treatment is started with low doses for the first week (see Figure 2-D), and then if tolerated, gradually increased. The reason for a low starting does is that approximately 5% of children have a condition referred to as 2D6 hypometabolism. 2D6 is a liver enzyme that is responsible for metabolizing a number of antidepressant (and other) drugs. In these children, there is inadequate first-pass metabolism resulting 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-dose strategy.

One of the most common problems in initiating treatment is activation. This is an acute onset side-effect that may occur within a few hours after taking the first dose of a drug or when dosages are increased. It presents with 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 if it does, to contact the doctor right away. 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 (by the end of one month of treatment, tranquilizers usually are no longer necessary).

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). There are no well-established guidelines regarding how long to wait between dosage adjustments, although 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 children, and there is some positive yield by continuing to treat for a number of weeks until clinical improvement is noted.

If there is a positive clinical response, then how long does continuation treatment last? This also has not been clearly determined in efficacy studies. It is well known that, in adults and older adolescents, it is very important to continue treatment at the same dose of antidepressant for a minimum of six months following symptomatic improvement, followed by gradual discontinuation. This guideline also has often been adopted in the treatment of children, despite the absence of empirical support for this strategy.

The clinician should be alert to the possible development of two late-onset side effects that can be seen in some patients treated with antidepressants (this is the case for all antidepressants with the exception of bupropion). The adverse effects are 1. apathy and emotional blunting, 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).

Side Bar

Antidepressants and suicidality There has been a good deal of media attention regarding potential risks of antidepressants and increased suicidality (especially in children and adolescents). The initial fear came from studies in England that raised concerns about increased suicidality in young patients treated with the antidepressant Paxil. In this study, which included 1300 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 youngsters and a number of so-called suicidal “events” occurred in the Paxil group when the children stopped taking the medication. In trying to understand and address this issue, one significant problem is that the concept of “suicidality” has been very loosely defined in this and other studies. Most times it includes reports of increased thoughts about suicide, suicide gestures, non-lethal-intent self mutilation (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. Currently, the United Kingdom Committee on Safety of Medications has banned the use of all antidepressants for use in patients under the age of 18, with the exception of fluoxetine (Prozac). In the United States, the FDA has also responded to concerns about increased suicidality by requiring drug companies to issue warnings about the use of these drugs with younger clients. They also initiated a study to investigate the data; they are currently evaluating a database of 4,400 teenagers treated with antidepressants and final conclusions are pending. It is interesting to note that in this large group of adolescents treated with SSRIs, there have been no suicides. It has also been documented that in geographic areas where antidepressants are in widespread use, suicide rates have dropped among adolescents (Mahler, 2004). Ever since the negative media attention regarding antidepressants and suicidality began, the number of antidepressant prescriptions for youngsters has significantly declined. At the same time, the suicide rate for adolescents increased by 8%. Although correlation does not imply causality, these data do 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 that suffer from major depression. It is certainly possible that, in some cases, the drug can contribute to this problem. The following may account for increased suicidality seen in some individuals treated with antidepressants: Activation and increased restlessness may add to a general sense of emotional discomfort. Antidepressants can provoke dysphoric mania in some youngsters who, in fact, have bipolar disorder. Increased energy may occur before a decrease in dysphoric mood (the person then has the energy to carry out a suicide attempt). Noncompliance Patient-initiated discontinuation: there are two common, problematic results that might account for increased suicidality — antidepressant withdrawal symptoms (see below), and/or the loss of what had been a positive antidepressant effect, plunging the patient back into depression. What is clear is that untreated major depression carries significant risks of potential suicide, antidepressants take several weeks of treatment before the first signs of clinical improvement, and depression can worsen during this startup period of treatment. In evaluating these kinds of concerns, it is always important to differentiate between media hype and scientific data.

Side Bar

Treatment of Depressive Subtypes

There are several non-blinded studies showing effectiveness of antidepressants in the treatment of dysthymia in children (Nobile, et al. 2003). Treating dysthymia is important since without treatment it generally lasts for 3-4 years with substantial negative effects on psychosocial functioning and development. Additionally, many if not most children with dysthymia eventually develop major depression. It is unclear if early treatment can prevent later more serious, major depression, although there is speculation that it can. Obviously, 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 and NDRIs are not effective in treating PMDD). Unlike the treatment of 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 that period of time 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 opposed to those seen in schizophrenia or drug-induced psychosis. Many very depressed youngsters harbor delusional thinking (e.g. somatic 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 very important 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 electro convulsive 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 Chapter 3).

Medication Discontinuation

Discontinuation withdrawal symptoms have been well documented. These occur if there is abrupt discontinuation and generally present with: nausea, body aches, 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 and venlafaxine. It can occur in most other antidepressants as well, with the exception of fluoxetine (where it occurs very rarely, due to its long half-life). Withdrawal symptoms can generally be completely avoided if the medication is gradually discontinued over a period of from 4-8 weeks.

Relapse Prevention

Adults experiencing a third episode of major depression are best treated by ongoing, chronic antidepressant therapy to reduce the likelihood of recurrence. As noted earlier, many if not most children experiencing a major depression will have recurrences. However, there is inadequate data to recommend chronic use of antidepressants with youngsters. Until more research is available to address this issue, it is probably prudent to discontinue medications after the six months 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).

Critical Issues to Consider

a) Start doses low and gradually titrate up

b) Be watchful for:

• Activation (within first few hours)
• Switching (within two weeks or more)
• Apathy and emotional blunting (late-onset side effect)
• Emotional disinhibition (late-onset side effect)
• Weight gain (late-onset side effect)

c) Educate parents regarding the sometimes long period of time before onset of actions

d) Be especially watchful for the emergence of suicidal thoughts or behaviors, especially during the early phases of treatment or during drug withdrawal

e) Continue to treat for six months after symptomatic remission at same dose

f) Always discontinue medications gradually

Chapter 3: Bipolar Disorder

The average of onset of bipolar disorder is 21-22 years (Hirschfeld, APA, 2002, p. 386). However, it is becoming clear that there are cases of childhood-onset. This is an area of investigation where the jury is still out. A good deal of controversy exists about the prevalence of very early-onset bipolar disorder, but it may be that up to 20-25% of cases first emerge in late childhood or early adolescence. 35% or more now have their onset in late adolescence.

Diagnostic Issues

As mentioned above, 70% of cases of early onset bipolar illness 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. Signs and Symptoms of Early-Onset Bipolar Disorder (Papolos, 2005)

Non-episodic (more continuous) Mixed mania is most typical with marked dysphoria and irritability Intense rage episodes (the most common and highly diagnostic sign of bipolar mania, seen in 92% of cases) Severe oppositional behavior Ultra-rapid cycling

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 a considerable amount of symptom overlap (see Figure 3-B).

Figure 3-B. Symptomatic Similarities: ADHD and Childhood Onset Mania

Irritability Inattention Hyperactivity Impulsivity High level of energy Pressured speech Chronic and non-episodic

Possible diagnoses of co-morbities may exist, including:

• ADHD and bipolar disorder are two separate diagnoses that are co-morbid in some children.
• In some presumably ADHD children, the ADHD may be a prodrome of bipolar disorder (i.e., may be an early manifestation of the disorder). Note: Most ADHD children do not go on to develop bipolar illness. Thus, there may be a subtype of bipolar illness that simply presents with early signs that mimic ADHD.
• Childhood-onset bipolar disorder may be related to other bipolar spectrum conditions, but represent a particular subtype of mood disorder (i.e., it is, in some ways, different from adult onset bipolar conditions).

An accurate diagnosis matters since inappropriate medical treatment may worsen the clinical condition (e.g. stimulants or 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. Differentiating Bipolar Disorder from ADHD

Symptoms common to bipolar but very rare with ADHD (1) Decreased need for sleep without daytime fatigue Intense, prolonged rage attacks (lasting 2-4 hours) Hyper sexuality Flight of Ideas Psychotic symptoms Family History of clear-cut bipolar disorder or one or more of the following in blood relatives: Suicide History of psychiatric hospitalizations Severe alcohol/drug abuse Multiple marriages Starting numerous businesses Hyperthymia (a form of chronic hypomania characterized by high energy and productivity, gregariousness, impulsive behavior, and decreased need for sleep)

(1) Geller, G. and DelBello (2003)

In addition, many children that present with severe emotional lability may not have true bipolar disorder. One such group has been recently referred to as Temper Dysregulation Disorder with Dysphoria (DSM V first draft: 2010…www.dsm5.org). This disorder is characterized by the following: severe temper outbursts that are significantly out of proportion in terms of intensity and duration, three or more such episodes per week, onset between 6-10 years of age, nearly every day  angry, irritable and sad, non-episodic: has been continuous for at least 12 months, no history of grandiosity,  no decreased need for sleep and an absence of pressured speech. Unfortunately, this group of youngsters typically do not respond well to mood stabilizers. Other diagnoses that need to be considered and ruled out Are: reactive attachment disorder, agitated unipolar depressions, PTSD, post-head injury, conduct or oppositional disorder, pre-schizophrenic, substance abuse disorders and a history of fetal alcohol or other drug exposure.

Psychopharmacology

The choice of treatment will depend on the current clinical presentation:

• Major depression where bipolar disorder is suspected
  • Since antidepressants may provoke switching or cycle acceleration, they should be avoided as a monotherapy.
  • Medications that have some bipolar antidepressant actions should be used first (e.g. lithium, Symbyax, or Seroquel). Note: Lamotrigine is an effective treatment for bipolar depression but, owing to an increased risk of severe rashes, it may not be a first-time medication for children. Lamictal appears to be safe to use in adolescents if the drug is started at low doses and gradually increased during the first 4-6 weeks of treatment.
  • Combinations of medications (e.g. lithium and Seroquel).
• Mania
  • If there is a very severe agitation, benzodiazepines (minor tranquilizers, with the exception of Xanax which can aggravate mania) or atypical antipsychotics may be administered. Lithium and anticonvulsant mood stabilizers often take 7-14 days to begin reducing symptoms. Benzodiazepines and atypical antipsychotics may begin to work in several hours.
  • Head-to-head comparisons of mood stabilizers fail to show that any one mood stabilizer is superior (at least in group studies). Thus, the choice of treatment often is based on the side effect profile of the medication. Ultimately, the majority of children with mania must be treated with two or more mood stabilizers in combination (e.g., Depakote and lithium) to achieve a good outcome (Kowatch, 2000; Emslie and Mayes, 2001; Geller and DelBello, 2003).
  • Atypical antipsychotics (e.g. Seroquel) may be used as a mono therapy or added to mood stabilizers. All antipsychotics have antimanic effects.
  • Although widely used, gabapentin is an ineffective monotherapy for mania. As an add-on drug, it may, however, be useful especially in reducing anxiety.
• CO-morbid ADHD and Bipolar Disorder
  • Initiate treatment with mood stabilizers
  • Once stability has been achieved, stimulants may be gradually added.

Details regarding side effects and drug interactions for what is often very complex polypharmacy are beyond the scope of this course. However, I would like to highlight some side effects and drug interactions that can be especially problematic for children and teenagers.

• Lithium
  • Increased thirst, urination, and bedwetting
  • Weight gain (seen in 30-40% of patients)
  • Aggravation of acne
  • Tremor
  • Cognitive impairment
  • Sedation
  • Frequent blood tests are required which may be very hard for young children to tolerate
• Mood Stabilizing Anticonvulsants
  • Weight gain (especially with carbamazepine and divalproex)
  • Menstrual irregularities
  • Polycystic ovaries (with divalproex): be watchful for irregular menses and/or abnormal growth of hair on the face or chest.
  • Tremor
  • Sedation
• Be especially alert to the likelihood that carbamazepine, oxazepine, and topiramate can reduce levels of birth control pills rendering them ineffective.
• Symbyax (combination of Prozac and Zyprexa) may cause weight gain and other manifestations of metabolic syndromes: increased blood glucose, increases in cholesterol and triglycerides, and  type II diabetes. Children may be prone to these metabolic symptoms than adults.

Childhood-onset bipolar disorder may be a more severe version of the disorder. Early recognition, accurate diagnosis, appropriate acute treatment, and ongoing maintenance treatment are necessary, not only for reducing the intense suffering, but also to prevent kindling and suicide (which is an all too common outcome of untreated or poorly-treated bipolar disorder in young people).

Suggested Readings

Bezchlibnyk-Butler, K.Z. and Virani, A.S. (2008) Clinical Handbook of Psychotropic Drugs for Children and Adolescents. Hogrefe and Huber: Toronto.

Geller, B. and DelBello, M.P. (Eds.) (2003) Bipolar Disorder in Childhood and Early Adolescence. The Guilford Press: New York.

Preston, J.D., O’Neal, J. and Talaga, M. (2010) Handbook of Clinical Psychopharmacology for Therapists: 6^th Edition. New Harbinger: Oakland.

Preston, J.D., O'Neal, J. and Talaga, M. (2010) Child and Adolescent Clinical Psychopharmacology Made Simple. Second Edition. New Harbinger: Oakland.

Preston, J.D, O’Neal, J.H., and Talaga, M. (2009) Consumer’s Guide to Psychiatric Drugs; Second Edition. Simon and Schuster: New York.

References

Barnhart, W.J., Makela, E.H., And Latocha, M.J. (2004) SSRI-induced apathy syndrome: A clinical review. Journal of Psychiatric Practice, 10(3): 196-199.

Biederman, J. et al. (1999) Pharmacotherapy for ADD reduces risk for substance abuse disorder. Pediatrics. 104(2): e20.

Brotman, A. (1992) Practical Reviews in Psychiatry. Birmingham, Alabama: Educational Reviews.

Brown University (2004) Experts, parents weigh in at FDA’s public hearing on SSRI safety. Child and Adolescent Psychopharmacology Update, 6(3): 1-3.

Emslie, G.J., And Mayes, T.C. (2001) Mood disorders in children and adolescents: Psychopharmacological Treatment. Biological Psychiatry. 49: 1082-1090.

Geller, B. and DelBello, M.P. (Eds.) (2003) Bipolar Disorder in Childhood and Early Adolescence. The Guilford Press: New York.

Geller, B. et al. (2002) Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype. American Journal of Psychiatry. 159: 927-933.

Glass, R.M. (2004) Treatment of adolescents with major depression: Contributions of a major trial. JAMA, 292 (7): 861-863.

Hirschfeld, R.M.A., et al. (2002) Practice guidelines for patients with Bipolar Disorder. Washington, D.C. American J. Psychiatry, 159, 1-50.

Jureidini, J., Doecke, C.J., et al. (2004) Efficacy and safety of antidepressants for children and adolescents. British Medical Journal, 328: 879-883.

Kowatch, R.A., et al. (2000) Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. J. Amer. Acad. Child and Adol. Psychiatry. 39: 713-720.

Kuczenski, R., et al. (2002) Exposure of adolescent rats to oral methylphenidate. Journal of Neuroscience 22:264-271.

Luby, J.L., et al. (2002) Preschool major depressive disorder: Preliminary validation for developmentally modified DSM-IV criteria. Journal of the American Academy of Child and Adolescent Psychiatry. 41(8): 928-937.

Mahler, J. (2004) The antidepressant dilemma. The New York Times. 11-21-04, page 1.

March, J., Silva, J., Petrycki, S., Curry, J., et al. (2004) Fluoxetine, cognitive-behavioral therapy and their combination for adolescents with depression. JAMA, 292: 807-820.

Nobile, M., Cataldo, G.M., Marino, C., & Molteni, M. (2003) Diagnosis and treatment of dysthymia in children and adolescents. CNS Drugs, 17(13): 927-946.

Papolos, D. and Papolos, J. (2005) The Bi-Polar Child, Broadway Books: New York.

Safer, D.J. and Krager, J.M. (1992) Effect of a media blitz and a threatened lawsuit on stimulant treatment. JAMA, 268: 1004-1007

Wagner, K.D., Ambrosini, P., et al. (2003) Efficacy of sertraline in the treatment of children and adolescents with major depression disorder: Two randomized, controlled trials. JAMA, 290: 1033-1041.

Walkup, J. (2004) Child and adolescent psychopharmacology: What’s new. US Psychiatric and Mental Health Congress, San Diego, CA.

Whittington, C.J., Kendall, T., et al. (2004) SSRIs in childhood depression: Systematic review of published versus unpublished data. Lancet, 363 (9418): 1341-1345.

 

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