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USE AND IMPACT OF ANTIDEPRESSANTS IN THE SCHOOL SETTING

CHAD A. NOGGLE

Southern Illinois University, School of Medicine

RAYMOND S. DEAN

Ball State University

Depression-based presentations constitute some of the most commonly seen psychiatric manifes- tations within the school-age population. In conjunction with increased numbers of children and adolescents being diagnosed with depressive symptomology over the past 2 – 3 decades, there has been seen a concurrent increase in the amount of antidepressant agents being prescribed within this group. This increase is largely related to the development of the newer class antidepressants, the selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, which have demonstrated preferred efficacy and adverse effect profiles over the older monoamine oxi- dase inhibitors and tricyclics. This article discusses the primary differences between the various forms of antidepressants, including their utility and efficacy. Positive and negative impacts are also reviewed, including potential impact on schooling. C© 2009 Wiley Periodicals, Inc.

It has been reported that major depressive disorder (MDD) and variants of depressive syndromes effect up to 10% – 15% of children and are associated with substantial short- and long-term morbidity and mortality (Fleming, Offord, & Boyle, 1989; Pataki & Carlson, 1995). Functional impairments oftentimes correspond with deficits in school and work performance (Rao, Ryan, & Birmaher, 1995; Rohde, Lewinsohn, & Seeley, 1994) related to aspects of cognitive dysfunction (Noggle, Neal, Hall, Hiller, & Dean, 2006; Ravnkilde et al., 2002) as well as lack of motivation and vigilance (Easau, Petermann, & Reynolds, 1999) among other factors. Although children and adolescents demonstrate some overlap in functional outcomes associated with depression in adults, behavioral differences tend to exist (Poznanski & Mokros, 1994), which has in the past distorted the clinical picture. In the past 35 years, information has been gathered regarding the presentation, course, epidemiology, and family factors of depression in childhood and adolescence that has begun to clarify the clinical picture. As this information has been synthesized, in addition to refining knowledge about the presentation of depression in children and adolescents, there has been a concurrent advancement of intervention and treatment strategies for depression within this age group. Although behavioral and psychotherapeutic techniques have demonstrated substantial utility in this population, the efficacy of pharmacological intervention continues to be debated. In fact, antidepressants are frequently prescribed in children and adolescents (Safer, 1997), and the use of these agents within this age group, especially the selective serotonin reuptake inhibitors (SSRIs; Ma, Lee, & Stafford, 2005; Murray, de Vries, & Wong, 2004), has increased significantly over the past decade (Zito, Safer, Dosreis, 2000, 2002). Given this prevalence, professionals working with children and adolescents in the schools would likely benefit from a general understanding of these agents. As such, this article provides an overview of the different forms of antidepressants, differences and similarities between them, including clinical indications for them, their impact on children and adolescents, both positive and negative, and how they correspond with outcomes in the school.

PREVALENCE OF DEPRESSION IN CHILDREN AND ADOLESCENTS

Epidemiological research has estimated the point prevalence of depression in children and adolescents (4 – 17 years of age) to be between 0.92% and 4.6% (Angold, Erkanli, Farmer, Fairbank,

Correspondence to: Chad A. Noggle, Southern Illinois University, School of Medicine, Department of Psychiatry, 901 W. Jefferson Street, P.O. Box 19642, Springfield, IL 62794. E-mail: [email protected]

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Burns, et al., 2002; Canino, Shrout, Rubio-Stipec, Bird-Hector, Bravo, et al., 2004; Ford, Goddman, & Meltzer, 2003). However, research has also demonstrated a trend in which point prevalence rates climb the older the pediatric population. For example, in adolescents older than 13 years, point prevalence is between 4% and 8% (Birmaher, Ryan, & Williamson, 1996). Overall, the lifetime prevalence rates of depression in adolescents range from 15% to 20% (Birmaher et al., 1996). However, in past years it has been suggested, and it likely holds true today, that numbers rendered through epidemiological investigation, in the case of depression in children and adolescents, are likely an underestimation (Lewisohn et al., 1994) as one may assume the percentage of children and adolescents experiencing soft depressive symptoms or “mild depression” are even higher. Furthermore, increases in rates as well as earlier symptom onset in children and adolescents have also been outlined by research (e.g., Murphy, Laird, Monson, Sobol, & Leighton, 2000), thus numbers are always changing. Regardless, what is clear is that there is a fair amount of children and adolescents who present with depressive manifestations in the schools, and thus continued refinement of our understanding and treatment of these presentations is warranted, especially given the relatively broad, negativistic impact that depression may have on day-to-day functioning in children and adolescents.

FUNCTIONAL IMPACT AND PRESENTATION OF DEPRESSION IN PEDIATRIC POPULATIONS

It has long been noted that although children and adolescents do exhibit symptoms of depres- sion, the signs and symptoms present differently in this population than in adults (Cytryn & McKnew, 1974; Malmquist, 1977). For example, whereas adults may exhibit the traditional depressed mood and tearfulness, children may instead become more irritable, angry, or aggressive. Compared to adults, depressed adolescents are more likely to report feelings of worthlessness and/or guilt and less likely to report weight/appetite changes and thoughts of death or suicide (Lewinsohn, Rohde, & Seeley, 1998). Depressed children, in contrast, are less likely to display extensive motor retarda- tion, hypersomnia, cognitive disorientation, and chronically disrupted appetite than are depressed adolescents, adults, and elderly patients (Lewinsohn et al., 1998). This has even been cited in the text revision of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text Revision (American Psychiatric Association [APA], 2000), in which it is stated that “In children and adolescents, an irritable or cranky mood may develop rather than a sad or rejected mood.” In prepubertal children, depression is less common, equally distributed among boys and girls, and less likely to evolve into adult depression (Harrington, 2002) whereas somatic complaints, psychomo- tor agitation, hallucinations, and comorbidities are more common (Ryan, Puig-Antich, Ambrosini, 1987). Adolescents are more likely to experience hopelessness and vegetative symptoms, and have a higher incidence of substance use and suicidal behavior than do prepubertal children (Ryan et al., 1987).

In addition to the mood symptoms, most commonly thought of when discussing depression, decreased energy, tiredness, fatigue, diminished ability to think and concentrate, decreased vigilance and interest in activities, and social withdrawal may all manifest secondary to depression (APA, 2000). The ramifications of these symptoms are broad in terms of functional compromise. For the child or adolescent, mood disturbance may be just the tip of the iceberg as he or she is at substantial risk for cognitive disturbance and diminished school performance as well as disruptions of relationships with peers, family, and school personnel, which, in turn, increases risk of victimization, truancy, and delinquency (Kovacs, Feinberg, Crouse-Novak, 1984a,b; Rao et al., 1995). Oftentimes we may fail to appreciate the true scope of impairment that may manifest secondary to presentations in children and adolescents, and depression is no different. In response, there is substantial utility in continually educating psychological professionals who work with this age group about advances in research that have developed our understanding of the presentations with which they work, but also, and possibly even more importantly, provide updated reviews of the advances in addressing

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those issues in clinical practice. With regard to depression, one area in which empirical knowledge is constantly growing, which, in turn, corresponds with an ever-changing landscape of treatment, is in the utilization and efficacy of pharmacological intervention and practices. The fact that the vast majority of psychological professionals do not have prescription privileges does not suggest an acceptability of a lack of understanding of the practice, the agents commonly used, and the functional outcomes. In fact, psychological professionals within the school may be in a position to have some of the most dramatic impacts on pharmacological practice by serving as primary consultants monitoring the clinical efficacy in the children and adolescents being treated. For further discussion along this line, see the last article of this special issue entitled “Future Trends in the Application and Impact of Psychopharmacology within the School Setting.”

USE OF ANTIDEPRESSANTS BY CHILDREN AND ADOLESCENTS

Based on reported prescription rates by child psychiatrists, as well as other medical professionals who see children and adolescents, it is clear that antidepressant medications have become central to management of depression within this age group (Wong, Besag, Santosh, & Murray, 2004). However, literature still suggests that the decision to use this method of treatment comes only after a period of careful observation and after nonpharmacological therapy options have been exhausted (Garland, 2004). Regardless, there has never been a time when antidepressants have been more frequently prescribed in children and adolescents than is presently the case (Zito, Safer, dosReis, 2000, 2002). While this reflects the prevalence of antidepressant use overall, this involves the summation of different classes of agents. The term “antidepressant” reflects a general description of the agents that fall under this umbrella. Medications termed antidepressants are generally classified into one of four groups: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), SSRIs, and selective norepinephrine reuptake inhibitors (SNRIs). Although each of these classes includes individual agents that are termed antidepressants due to their resulting impact, they differ substantially in their chemical makeup, which corresponds with discrepancies in clinical indications, efficacy, and adverse effects. Together this speaks to their general utility and appropriateness for use in children and adolescents. In the following section we discuss key features of each class of antidepressant individually.

CLASSES OF ANTIDEPRESSANTS AND THEIR IMPACT

MAOIs

Although the MAOIs fall under the umbrella of antidepressant agents, they are used consider- ably less than other classes due to their prominent adverse effect profiles, especially in children and adolescents. Although significant discrepancies between the rate at which MAOIs are prescribed in comparison to other groups (i.e., TCAs, SSRIs, SNRIs) are quite prominent, this is not necessarily due to significant differences in efficacy, but rather related to significant adverse effects commonly associated with MAOIs (Riederer, Lachenmayer, & Laux, 2004). In fact, whereas early studies sug- gested that MAOIs were less effective than other antidepressants, more recent studies have demon- strated that, when prescribed in adequate dosages, some of the MAOIs (e.g., phenelzine [Nardil] and tranylcypromine [Parnate]) demonstrate efficacies comparable to select TCAs and SSRIs. How- ever, again, the side effects can be severe. The most frequent adverse effects of irreversible MAOIs are orthostatic hypotension, sleep disturbances, and nervousness/agitation (Riederer et al., 2004). Furthermore, the chemical makeup of MAOIs creates for dangerous interactions with tyramine-rich foods and sympathomimetic and serotonergic substances (Ballenger, Wheadon, Steiner, Bushnell, & Gergel, 1998). To avoid such interactions, patients must remain strongly compliant with dietary restrictions, which can be variable, and thus dangerous in children and adolescents.

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Given the aforementioned risk for adverse effects and concerns of negative interactions, utiliza- tion of MAOIs, as suggested, is limited. The main indications for the classical irreversible MAOIs are subgroups of depression such as atypical depression and/or dysthymia or for patients who do not respond to reuptake inhibitors. For example, high doses of tranylcypromine, an MAOI, has been shown to be effective in the treatment of therapy-resistant depressions (Riederer et al, 2004). However, these studies have been of adults only, and have been strictly on an inpatient basis so to assure dietary compliance and monitor possible adverse reactions.

Although nonselective, irreversible MAOIs, including those noted earlier in text, carry signif- icant adverse effects that correspond with the prominent infrequency of their use, moclobemide (Aurorix), a newer MAOI, has little effect on the cardiovascular system and does not demonstrate as great a risk for interaction due to tyramine sensitivity (Riederer et al., 2004). In addition to a more favorable adverse effect profile, some research has shown moclobemide to be equivalent to TCAs in efficacy and tolerated just as well, if not better. Furthermore, long-term follow-up studies demonstrated continued effectiveness of moclobemide over the treatment period of 1 year, with more than 60% of patients having continued response (Riederer et al., 2004). Of concern is research suggesting that adequate efficacy of moclobemide is dependent upon higher dosages, especially in cases of moderate to severe cases of depression, which may negate some of its previously noted superiority in tolerability over other MAOIs.

Although additional research on newer variants of the MAOIs (e.g., moclobemide) may demon- strate advanced efficacy in their treatment of depression, in comparison to other antidepressants there remain substantial concerns about the degree of adverse effects associated with their use. This latter point has and will likely continue to prominently limit the amount of MAOIs used in children and adolescents.

TCAs

TCAs represent a second class of antidepressants that, in comparison, are used far more of- ten than MAOIs, especially within the pediatric population. Although TCAs are widely used in the clinical management of depressed children and adolescents, published studies have failed to produce a repeatable pattern of efficacy (Emslie & Judge, 2000). In fact, Geller, Cooper, Mc- Combs, Graham, and Wells (1989) found that, when compared to placebo, nortriptyline, a TCA, did not demonstrate significant improvement in depressive symptomatology in a sample of patients 5-12 years old. In a follow-up study, they found similar results in a sample of patients 12 – 17 years old (Geller, Cooper, Graham, Marsteller, & Bryant, 1990). Although these studies focused on the efficacy of nortriptyline (Aventyl), additional investigations have called into question the efficacy of imipramine (Tofranil; Puig-Antich, Perel, & Lupatkin, 1987; Ryan, Puig-Antich, Cooper, 1986) and desipramine (Norpramin; Kutcher, Boulos, & Ward, 1994) in the pediatric population. These studies, in addition to others like them, have contributed to meta-analyses that have concluded that TCAs appear no more effective than placebo in the treatment of depression in children and adolescents (Hazell, O’Connell, Heathcote, Robertson, & Henry, 1995). In addition to questionable efficacy, empirical research has documented the prominent adverse effects of TCAs when used in children and adolescents. These negative effects include dry mouth, constipation, urinary retention, blurred vision, sinus tachycardia, sedation, impaired motor functioning, weight gain, hypotension, imbal- ance, impaired coordination, orthostatic hypotension, and cognitive dysfunction (Kasper, Hoflich, Scholl, & Moller, 1994; Kuzel, DeWester, & Richardson, 1996; Nemeroff, 1994). In compari- son, the SSRIs have a milder side-effect profile and are better tolerated than the TCAs (Edwards, 1992; Edwards, Inman, Wilton, & Pearce, 1994; Grimsley & Jann, 1992; Murdoch & McTavish, 1992).

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Although failure to demonstrate adequate effectiveness beyond that seen in placebo may in and of itself question the utility of TCAs in the treatment of depression in children and adolescents, when compared to that for SSRIs, the outlook for TCAs diminishes further. In head-to-head comparisons, SSRIs have largely demonstrated superior efficacy in the remediation of depressive symptomatology in children and adolescents in comparison to TCAs (e.g., Colle, Belair, DiFeo, Weiss, & La Roche, 1994; Emslie, Rush, & Weinberg, 1997) while also demonstrating lower rates of discontinuation compared to the TCAs (Beasley, Bosomworth, & Wernicke, 1990). Furthermore, SSRIs present with a more preferential adverse event profile compared to TCAs (Jain, Birmaher, Garcia, Al-Shabbout, & Ryan, 1992). The specifics of SSRIs, including their utility and possible adverse reactions, are discussed later in this chapter. Although the potential for aforementioned adverse effects is troubling, risk for cardiovascular events and cognitive dysfunction are particularly concerning. To date, the TCAs have been associated with a number of sudden cardiac deaths in children and adolescents (Nemeroff, 1994). In terms of cognitive performance, the TCAs have been more prominently linked to cognitive skill impairments as well as degradation of psychomotor ability than have the SSRIs (Peretti, Judge, & Hindmarch, 2000). Much of this impact has been related to the effects of TCAs on cholinergic, histaminergic, and adrenergic receptors. A number of studies have demonstrated the negative impact TCAs have had on cognition in comparison to placebos and/or SSRIs (e.g., Fairweather et al., 1996; Hindmarch, 1997). When seen in children and adolescents, the secondary detriment this may create in school performance may be substantial. As a result, any student taking a TCA, likely because there has been poor response to SSRIs, should be monitored closely to detect any possible degradation along these lines as soon as they begin to present.

SSRIs and SNRIs

By far, the SSRIs and SNRIs are the most commonly used antidepressants in children and adolescents. The basis for this is twofold. First, SSRIs and SNRIs have demonstrated a general efficacy in the management of depression in children and adolescents, in comparison to placebo (Emslie, Walkup, Pliszka, & Ernst, 1999). This positive finding is seen in conjunction with findings that have demonstrated a lack of benefit of TCAs and MAOIs within this same population (Hazell, O’Connell, & Heathcote, 2002). Second, in comparison to both the TCAs and the MAOIs, the SSRIs and SNRIs have presented with a far better safety record (van Laar, van Willigenburg, & Volkerts, 2002). Although evidence appears largely in support of the use of SSRIs and SNRIs in the treatment of depression in children and adolescents (Emslie et al., 1999), there are findings in opposition to this suggestion.

When discussing the efficacy of the SSRIs one may offer a generalized coverage as there has been some report that there is little evidence to suggest differentiation among these agents (SSRIs) in the overall efficacy of treating depression (e.g., Hansen, Gartlehner, Lohr, Gaynes, & Carey, 2005; Kroenke et al., 2001; Papakostas, Thase, Fava, Nelson, & Shelton, 2007). Furthermore, when comparing SSRIs and SNRIs, although a few individual studies have reported differences between these agents, no study has shown convincing improvements of efficacy or a preferential adverse effect profile of one over the other (Olver, Burrows, & Norman, 2001). Nevertheless, there are some who would disagree with this suggestion (e.g., Mallinckrodt et al., 2007; Papakostas, Petersen, Sklarsky, et al., 2007). For example, there are some studies that have suggested increased efficacy of the SNRIs, due to their dualistic impact on serotonin as well as norepinephrine, as opposed to the SSRIs, which inhibit only one monoamine (Stahl, Entsuah, & Rudolph, 2002; Thase, Entsuah, & Rudolph, 2001). However, other findings have failed to support this difference (APA, 2000; Hansen et al, 2005). In terms of supporting this claim, investigations into the treatment of mild depression have appeared to demonstrate slightly greater efficacy of duloxetine (Cymbalta), an SNRI, in comparison

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to SSRIs (Mallinckrodt et al., 2007). This finding does not suggest that the SSRIs were not beneficial, rather, that in this grouping, duloxetine may be slightly better. As depression was more moderate to severe, this discrepancy dissipated to some extent. Across groupings, there was found a general efficacy of the SSRIs in comparison to placebo. A second part of this study (Mallinckrodt et al., 2007), demonstrated that duloxetine may not be as effective as the SSRIs when there is prominent comorbid anxiety, which can be a common manifestation in depression. The overall findings of this study suggest that differences between SSRIs and duloxetine, a prominent SNRI, exist, although minimally, and likely correspond to differences between agents in their responsiveness to symptom type and severity and that these differences do not play out in such a way as to demonstrate favorability of one agent over the others (Mallinckrodt et al., 2007). This point has been reiterated by others as well. Specifically, Fava and Rush (2006) report that mindfulness of subtle differences of the responsiveness of certain depressive subtypes to different agents is essential in increasing chances for symptom relief and possible remission. Nevertheless, the overall clinical picture suggests utility of SSRIs and SNRIs in the treatment of depression in children and adolescents, although differences exist between these classes, not consistently favoring one over the other.

Although the efficacy of the SSRIs and SNRIs appears relatively positive, and, in comparison to MAOIs and TCAs, these groups demonstrate a preferred adverse risk profile (van Laar et al., 2002), they are not without possible negative effects. Truly, they are associated with fewer adverse effects than are other classes (Nutt, 2003; Peretti et al., 2000), and are relatively free from cognitive and psychomotor impairment (Peretti et al., 2000). Most studies also suggest that SSRIs produce fewer cardiotoxic, anticholinergic, and antihistaminergic side effects than do TCAs (Pacher & Ungvari, 2001). However, other studies have called some of these claims into question. SSRIs and SNRIs have been linked to increased fatigue (Papakostas, Thase, et al., 2007), and some have suggested a link between their use and cognitive impairment. However, the suggestion of “cognitive” impairment suggests too broad of an impact. In reality, positive findings along this front have merely suggested memory problems associated with SSRIs and SRNIs (Joss, Burton, & Keller, 2003). In terms of this link with specific SSRIs and/or SNRIs, fluoxetine (Prozac; Joss et al., 2003) and paroxetine (Paxil; Furlan et al., 2001) represent those previously associated with memory impairments, yet they have also been linked with memory improvement (Schmitt, Jorissen, & Sobczak, 2001). Without question, studies have shown that depression itself can impair cognitive functioning (Alvarez-Rueda, Guiterrez-Aguilar, Rosales, Martinez, & Lablache, 2001), including memory (Landro, Stiles, & Sletvold, 1997). In fact, within the geriatric population, cognitive deficits associated with depression may manifest in such a way that, clinically, they appear similar to those impairments associated with neurodegenerative courses (Noggle, 2006). Such manifestations tend to reflect impaired retrieval skills as well as slowed cognitive processing, impaired attention, and higher-order/abstract reasoning (Noggle, 2006). It has also been proposed that, as depressive symptoms are relieved, concurrent improvements in cognition may be seen as well (Harmer, Shelley, Cowen, & Goodwin, 2004; Zobel, Schulse-Rauschenbach, & von Widdern, 2004). This has led to the cognitive impairment associated with depression being viewed as one form of reversible dementia. In fact, some researchers have suggested that the link between SSRIs and/or SNRIs and cognitive disturbances are more an artifact of (as yet) ineffectively treated anxiety or depression (Hemmeter, Heimberg, Naber, Hobi, & Holsboer-Trachsler, 2000). Kent, Coplan, and Gorman (1988) reiterated this suggestion by noting that changes in cognitive processing associated with SSRIs may occur earlier in treatment than the therapeutic effect can occur, suggesting that changes in psychological function precede the improvement in psychopathology (Harmer et al., 2004). This suggestion is similar to that of Wadsworth, Moss, Simpson, and Smith (2005) in which they state that recall may be impaired among those taking SSRIs whose symptoms have not (yet) resolved, leading to fewer words correctly recalled, and more false alarms made. However, among those taking SSRIs whose

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symptoms are controlled, fewer words may be recalled correctly, but fewer false alarms are also made. In other words, there is improvement following SSRIs and/or SNRIs, but it may not be of such a degree to alleviate all noted impairment. Further investigation along these lines is likely warranted, but at the present time, although there may be some studies that oppose this suggestion, far more studies appear to suggest no detrimental effect on cognition by SSRIs or SNRIs than those that do. This includes, but is not limited to, the SSRIs/SNRIs having no detrimental effect on psychomotor speed, momentary inefficiency, speed of focus of attention, speed of encoding of new information, organization of response, mood, or perceived work performance (Peretti et al., 2000). In terms of this subject matter in children and adolescents, the best advice is to remain vigilant in follow-up with them during pharmacological intervention, so as to identify any negative impact as soon as it begins to appear.

While raised concerns of the impact that SSRIs and SNRIs may have on cognitive functioning may be unsupported to a certain degree, adverse behavioral effects may represent the negative outcomes of greatest concern. Agitation, irritability and behavioral disinhibition, emotional lability, increased conduct problems, and hostility as well as aggressiveness have all been linked to the use of SSRIs and/or SNRIs (Garland, 2004). However, some researchers have questioned whether this is a manifestation of the medications or merely secondary to unresolved symptomology. Of additional concern are suggestions of increased suicidal ideation and gesturing in the use of SSRIs and/or SNRIs. Following a review of research along these lines, the Medicine and Healthcare products Regulatory Agency of the British Department of Health (MHRA) has warned against the use of paroxetine as well as venlafaxine (Effexor)or any SSRI or SNRI other than fluoxetine in pediatric MDD patients, due to data suggesting some possible increase in suicidal behavior and thoughts. However, in a more thorough evaluation done on the various SSRIs and SNRIs, it was revealed that venlafaxine was the only individual drug with a statistically significant increased risk of suicidality (Hammad, Laughren, & Racoosin, 2006). In fact, when used in the depressive states of bipolar disorder, venlafaxine has been linked to the induction of mixed states. In this situation, there may be a substantial increase in energy and grandiosity while mood remains depressed, and there possibly remains a degree of hopelessness as well. Within such a psychological/behavioral constellation as this, an individual may not only have the will to commit suicide, but then also have the energy and disinhibition/impulsivity that will carry it through. Although this may represent one link between the use of specific SSRIs and/or SNRIs, there is also a link between suicidal ideation and a lack of pharmacological intervention (Cheung, Emslie, & Mayes, 2006). For further review of issues surrounding suicidal ideation and pharmacological intervention, see the article by Pierson (in this issue) (2009). What appears to be the most effective is concurrent utilization of pharmacological and psychotherapeutic techniques. In fact, the American Academy of Child and Adolescent Psychiatry (AACAP) recommends psychosocial and pharmacologic intervention for depression. However, it also recommends psychotherapy as the preferred initial treatment for most adolescent patients, with the induction of pharmacological efforts only coming after there is seen a lack of responsiveness to therapeutic endeavors (Kane, Fagan, & Wolf, 2007). It is within this situation (i.e., lack of response to nonpharmacological interventions) that physicians could choose an SSRI that has been approved for use in children and adolescents, such as fluoxetine (Garland, 2004) and then, upon doing so, continue to offer psychotherapeutic interventions. Research along this line has supported this clinical suggestion. In an investigation of the effectiveness of flouxetine and cognitive behavioral therapy (CBT) together as well as in comparison to each other singularly, the combination of pharmacological and psychotherapeutic treatment was found to be statistically superior to unipolar techniques (Kane et al., 2007), although fluoxetine alone outperformed CBT alone.

The only other drawback of SSRIs is their failure to demonstrate desired levels of effectiveness in more severe forms of depression. Findings from meta-analyses have suggested that SSRIs are

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significantly less effective than TCAs in more severe depression (Anderson, 1998). Parker, Roy, Wilhelm, and Mitchell (2001) further support this finding in suggesting that, in the treatment of severe depression of the melancholic subtype, electroconvulsive therapy (ECT), TCAs, and MAOIs are the most effective treatments and that SSRIs are less effective (Gillman, 2007). Of note, this was determined in an adult sample; thus, MAOIs and definitely ECT are substantially less viable options. It has also been suggested that venlafaxine may be more effective than SSRIs in such cases as well (Smith, Dempster, Glanville, Freemantle, & Anderson, 2002); however, as previously noted, venlafaxine has also been associated with increased risk of suicidal ideation. Given the fact that suicidal thoughts and gestures are most commonly seen in severe depressive forms, questions may be raised about whether this proposed use may be contraindicated. Further empirical investigation is likely warranted along these lines. For example, expansions of research incorporating other agents such as sertraline (Zoloft), escitalopram (Lexapro), and citalopram (Celexa), to name a few, continue to be needed as these too have shown some efficacy in early trials, yet the number of studies remains too few in comparison to those previously noted.

IMPACT ON SCHOOLING

Antidepressants’ impact on schooling may be grouped into two categories, either positive or negative. Determination of these reactions is related to outcome assessment, which psychological professionals within the school or those who work with this age population are likely most capable of performing. Specifically, following administration of an antidepressant agent, an essential role of psychological professionals is to assess responsiveness and outcome. This outcome may be positive, negative, or a mixture of the two. With regard to positive outcome, this involves assessment of the emotional and behavioral changes that appear to manifest secondary to the usage of the medication. Although we use the term “positive,” not all medicinal responses will necessarily be of such a nature. Notation of behavioral/emotional depletion may be seen as well. Of particular concern is an increase in suicidal ideation. As previously noted, venlafaxine (Effexor) was the only individual drug with a statistically significant increased risk of suicidality in a larger scale investigation of the links between antidepressants, particularly SSRIs and SNRIs, and suicidal thoughts and gestures (Hammad et al., 2006). This finding does not suggest that such manifestations are not possible when using other medications, merely additional agents assessed were not related to significantly increased suicidal risk. Continued evaluation of suicidal ideation is recommended in all cases of depression, with particularly close attention paid to changes in presentation along these lines in the acute stages of medicinal use.

In addition to assessing the responsiveness of behavioral and emotional symptoms to antide- pressants, attention may be paid to the evaluation of the remediation of secondary symptoms as well. This may include, but is not necessarily limited to, improved attention and concentration, increased energy (make note of induced mania if seen), decreased irritability and agitation, increased social interaction, improved sleeping and eating habits, and improved academic achievement. Although improvements may be seen across these aforementioned domains, it may not be of such a level that it is deemed adequate. Clinical determination of these shortcomings may assist in medicinal management while also indicating areas in which psychotherapeutic or behavioral services may be focused. As previously discussed, in comparison, combined treatment that incorporates pharmaco- logical treatment and psychotherapeutic services has been found to be superior to the singular forms (Kane et al., 2007), leading the AACAP to support such an approach.

In terms of negative outcome, this involves recording/documenting the adverse reactions to pharmacological interventions. Determination of utility can vary from person to person and is usually seen as a numbers game. Specifically, how much do the positive outcomes outweigh the negative? It may be the case that behaviorally there is clinical improvement, but if it is viewed as

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minimal to low-moderate (yet there are seen significant disruptions of sleep, decreased appetite and weight, increased anxiety, etc.), then the positive responsiveness may be dwarfed by the negative reactions. Just as positive outcomes may be used to determine medicinal management, so too can the negative reactions. Data may suggest a need to change the medication altogether, alter dosage, or supplement with other agents to remediate secondary symptoms. The article by Roberts, Floress, and Ellis (2009) within this issue delves further into the issue of school impact.

SUMMARY

It is undeniable that MDD and variants of depressive syndromes are seen in children and adolescents. Furthermore, it is evident that the primary, secondary, and tertiary manifestations of these presentations correspond with substantial impairment as well as increased morbidity and mortality over both the short and long term (Pataki & Carlson, 1995; Rao et al., 1995; Rohde et al, 1994). As a means of fighting back against this psychiatric opponent, utilization of antidepressant medication has become a major player in the management of depression in children and adolescents (Wong et al., 2004). There are four primary classes of antidepressants including MAOI, TCAs, SSRIs, and SNRIs, and research investigating efficacy and adverse effect profiles have led to the most prominent support for use of the latter two groups (i.e., SSRIs and SNRIs) in pediatric populations. Although superior to placebos in terms of efficacy, the SSRIs and SNRIs are not without flaws. They have shown diminished effectiveness in the remediation of severe depression and have been, at times, associated with adverse effects that can include increased fatigue as well as behavioral changes including irritability, aggression, and externalizing behaviors. There have been suggestions of these agents being linked to increases in suicidal ideation, but this has been more prominently linked to venlafaxine, an SNRI, and even in this instance, situational factors play prominent roles (i.e., depressive state in bipolar compared to severe MDD). Still yet, lack of pharmacological intervention has been related to far greater suicidal ideation in severe depressive cases, thus the argument may be somewhat moot. Finally, although efficacy is seen in the use of these agents, research demonstrates that a combined utilization of pharmacology and psychotherapy still remains superior. These findings are of clinical importance as they demonstrate the need for psychological professionals working with these children and adolescents to remain vigilant in their therapeutic and behavioral offerings. It is essential to continue to maintain a supportive dialogue with the child, parents, and teachers even after the start of antidepressant treatment, to not only continue to offer therapeutic services, to alleviate the many common behavioral manifestations associated with depression that may not be remedied medicinally, but also to assist in tracking the effects of the antidepressant agent, both positive and negative. Although medical professionals have superior training in the prescription of such agents, the work of psychological professionals, especially in the schools, provides them with the opportunity to be essential consultative resources for medical personnel in managing chosen pharmacological interventions. In the treatment of depression in children and adolescents, this is a role that psychological professionals in the schools should strive to perform.

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