During the past two decades, society has seen an evolution in the concept of depression. What was once known as depression the feeling, has become depression the illness. More specifically, depression became "medicalized" into a disorder. Depression, as well as other emotional and mental illnesses, bore the scrutiny of laboratory science. Behaviors became symptoms, and disturbances became known as disorders in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders . The study of depression as an illness paralleled enormous strides in the biological study of the brain. What was previously believed to be the result of learned helplessness or a harsh conscience became the possible result of a chemical imbalance in the brain.

The treatment of depression has increasingly emphasized the use of antidepressant medications. Although antidepressants initially were only used with depressed adults, they quickly found their way into the treatment of children. The use of antidepressants in children has become widespread by psychiatrists, pediatricians, and family practitioners alike. Their popularity has stirred unease with regard to their use, raising the question of not only possible potential over-use, but misuse . Confusion and uncertainty have developed in the "medicalized" maze of symptoms, medications, side effects, and alternative remedies involved in the identification and treatment of depression. What is the role of non-medical personnel in dealing with depressed children, their symptoms, their medications and the side effects that frequently accompany these medications? What is fueling the use of these medications? What is the logic behind their use? Who should and who should not receive them? Does the current emphasis on medication use for depressed children offer the hope of improved outcomes for these children, or harm? These are questions of the utmost importance that need to be dealt with as more children are identified with depressive illnesses and more medical expertise is required for their management.

The term depression describes emotional distress across a broad continuum, from simple sadness to medical illness. Depression can be a symptom of an illness or a syndrome itself. The use of the term depression varies among professionals, depending on their training and professional orientation. In the context of prescribing medications for childhood depression, the term depression refers to mental illness.

Mental illnesses are described as specific disorders in the Diagnostic and Statistical Manual of Mental Disorders (APA, 1994). They represent emotional and behavioral syndromes of sufficient severity that they are thought to be clearly abnormal. The identification and classification of a given mental disorder is the result of decades of literature review, statistical analysis, and ongoing research . The naming of a disorder facilitates consistent description and communication among mental health professionals, as well as the opportunity for the development of standards for treatment.

In the Diagnostic and Statistical Manual of Mental Disorders (APA, 1994), depression may represent a symptom in one disorder (as in bipolar disorder) or be classified by prominent qualities such as severity (as in major depressive disorder). There is terminology associated with mood disorders, such as a major depressive disorder, that requires an understanding in order to both appreciate how clinical communication occurs about depression as well as to grasp the implications of medication use. The following is a list of these terms and definitions:

• Acute -- Implies that the depression began over a short period;
• Chronic -- The depressive illness has been present for at least 6 months or longer;
• Episodic -- The illness has a beginning and end;
• Remission -- After the depressive illness subsides it is not thought that the patient is cured. This implies that the depression can return;
• Relapse -- The return of a depressive illness;
• Recurrent -- When the depressive illness has gone into remission and relapse has occurred more than once;
• Refractory -- The depressive illness does not respond to treatment. This can occur with prominent depressive symptoms present, or with only some symptoms present. The later is referred to as a partial remission; and,
• Co-morbidity -- When the depressive illness occurs in conjunction with other mental illnesses. The most common co-morbid illnesses in depressed children are attention deficit hyperactivity disorder (ADHD), anxiety, and oppositional defiant disorders.

Severe depressive disorders, such as those described by the term major depression, are increasingly believed to share important similarities in both biology and core symptoms across the lifespan . In all age groups, severely depressed individuals may describe feelings of helplessness and hopelessness, a loss of pleasure in usual interests, or apathy and sadness. They may be irritable, emotionally labile, or complain frequently of physical ailments. Certainly, a child’s stage of development will dictate how such symptoms will be expressed . Due to presumed maturational differences in the brain’s chemistry, depression can present at different stages with associated variations in each symptom’s quality, severity, or duration . Infants and toddlers might fail to thrive, school aged children might appear distractible and hyperactive or fail academically. A depressed teen’s irritability and sense of boredom (perhaps leading to excessive risk-taking or substance abuse) might mimic defiance and conduct problems. It is this consistency of symptoms across the lifespan that has made it easier for physicians to use antidepressants in children as well as adults.

A major depressive episode is defined in the Diagnostic and Statistical Manual of Mental Disorders (APA, 1994) in terms of core symptoms, duration of symptoms, and severity of symptoms. In addition to either depressed mood or loss of interest/pleasure, a diagnosis of major depressive episode would require the presence of at least five of the following daily, or nearly daily, for a minimum of two weeks:

• Depressed mood (or irritability in children)
• Diminished interest in usual activities
• Significant appetite change
• Sleep disturbance (insomnia or excessive sleep)
• Observable motor agitation or slowing
• Fatigue or low energy
• Feelings of worthlessness or guilt
• Poor concentration
• Preoccupation with death or suicidal thoughts

Major depression is not diagnosed if these symptoms are thought to be associated with the use of substances or medications, or associated with medical illness . Once the episode of symptoms has resolved, the occurrence of another episode at a later date would result in the diagnosis of major depressive disorder. If depressed mood persists daily for at least two years in adults, or one year in children, and at least two of the above symptoms are present continuously, the diagnosis of dysthymic disorder may be made. Such disorders are often described as chronic, mild depressions, but symptoms can be severe.

Major depressive disorder has been reported to occur in approximately 2% of children and in as many as 5% of adolescents. Other forms of depressive illnesses such as dysthymic disorder can affect an additional 2 to 9% of children and adolescents . Recovery from a depressive episode can take as long as 7 to 9 months from the time treatment is initiated, and 70% of those treated children will recover within a year, compared to 50% recovery during that period for the children without treatment. Furthermore, complete resolution of symptoms is rare. Three quarters of depressed children will experience another depressive episode, or even a lifetime course of intermittent depressive episodes . It is widely accepted that childhood depressive illnesses are the forerunners of chronic illnesses that will become life-long disorders.

What exactly is the medical problem in depression? What chemicals are involved in chemical imbalance? How do antidepressants work to relieve the symptoms of depression? These are questions of great medical and scientific interest. Many research scientists from the neurosciences, biochemistry, genetics and molecular biology spend their careers attempting to answer these questions. Pharmaceutical companies spend billions in the pursuit of new medications based on the resulting research.

The general assumption of a biological model of depression is that the illness involves a disturbance of a metabolic or chemical neurotransmitter system or systems. When all systems are operational, the mood maintains equilibrium. However, a problem in any one neurotransmission circuit resulting from the absence or excess of a substance required to make the neurotransmitter can cause an imbalance in mood. Overactivity or underactivity of the neurotransmitter itself, or the availability of a receptor can disrupt the activity or functioning of the entire system. Most biological models of psychiatric illnesses assume an imbalance is the cause of depression.

Historically, three neurotransmitter systems, or chemical mood systems, have been thought to be important in the development of depressive disorders. These are serotonin, norepinephrine, and dopamine. Current antidepressants have actions in all three chemical mood systems, but to varying degrees (table 1) . Usually, as in the case of the Selective Serotonin Reuptake Inhibitors (SSRI), medications are seen as influencing one system more than the others. In the case of SSRI, serotonin is the most influenced system.

It is important to know, however, that what constitutes chemical imbalance inside the central nervous system (brain), and outside the central nervous system, can be quite different. Thus, the amount of serotonin necessary to regulate the brain serotonin system, may be enough to exceed the optimal serotonin levels in other systems, such as the digestive system, creating what are known as side effects. Understanding each system facilitates an understanding of the chemical imbalance leading to a depression, the mechanism of action of an antidepressant, and the potential development of side effects.

Serotonin is of great current interest due to its association with the most frequently prescribed antidepressant medication, Prozac. Either a vulnerability to depression, or the actual depression itself is thought to result from low serotonin activity . Antidepressant medications formulated to re-regulate imbalances in the serotonin system make more seratonin available. If more is produced, or the system can somehow prevent its breakdown to keep it active, mood is observed to brighten, as sleep, energy, and concentration improve, while irritability lessens. Side effects can include nausea, diarrhea, heart palpitations, insomnia, headache, and jitters.

Norepinephrine belongs to a group of neurotransmitters responsible for the body’s "fight or flight" response to stress. This neurotransmitter in the nervous system is activated in response to such stresses as physical activity, psychological distress, or blood loss . Problems of chemical supply, production, or breakdown can result in an underactive or malfunctioning norepinephrine system, which results in the symptoms of depression. Side effects from antidepressants directed towards norepinephrine chemistry can include cardiac rhythm disturbances, constipation, or dry mouth.

Dopamine activity in the brain is tightly tied to such abstract behavioral functions as motivation and reward . Disturbances of dopamine regulation might result in mood disturbances and possibly disturbances of thought and perception, such as paranoia and hallucinations. The actions of antidepressants directed to dopamine chemistry might effectively bring relief of such depressive symptoms as low energy, emotional dulling, and poor appetite. Side effects can include a variety of movement, motivational, or weight-related problems.

Unfortunately, we do not understand enough about these systems or depressive illness in adults, much less in children, to be able to identify the specific role of each neurotransmitter in the presentation of the illness. It is likely that each system contributes specific symptom characteristics to an individual’s depression. This may explain the variability of individual responses to medications, why there is co-morbidity of certain mental illnesses, and why it often requires more than one medication to treat an illness. We know a great deal, but certainly not enough that all of our medical interventions are either always effective or always correct. At this time, the treatment of these disorders is art as much as science.

Based on strong data supporting SSRI effectiveness in adults, child psychiatrists have moved ahead with increased confidence in prescribing antidepressants for children. Until recently, tricyclic antidepressants were the only antidepressants extensively studied for use with children, and only one, imipramine, was approved by the FDA for use in children being treated for bed-wetting. The tricyclic class of antidepressant medication has not been found to be effective in the treatment of childhood depression. In addition, worrisome and disruptive side effects, as well as the tragic reports of several sudden deaths in children taking these medications, strongly influenced the heightened interest in using the less dangerous SSRI’s, such as Prozac, Zoloft, and Paxil.

The popularity of the SSRI has been driven primarily by safety and side effect considerations. The SSRI medications are safer in the event of overdose. Most of the research on antidepressant use in children to date has focused upon fluoxetine, or Prozac. When the as-yet unpublished studies of paroxetine (Paxil) and sertraline (Zoloft) are evaluated, the cumulative data will support the effectiveness of the SSRI’s for the short-term treatment of depression in children and adolescents . There is currently very little published data available on the use of the atypical antidepressant agents such as venlafaxine (Effexor) in children. The atypical medications have, like the SSRI’s, gained clinical reputations for use with specific symptoms, in spite of little published data in children. For instance, trazodone (Deseryl), an atypical antidepressant studied for adult use, has been prescribed in depressed children to aid sleep and treat aggressive symptoms .

As in adults, a child’s response to medication can be best judged if the child is known to have received an adequate dose for an adequate duration of time. Defining therapeutic dosage in children remains difficult. Children tend to require a higher relative dose than adults, due to their brisker metabolism. Furthermore, growth spurts or the beginning of puberty influence metabolic rates. These metabolic differences impact each drug’s effective dosage required for a therapeutic response.

The potential burden of depressive illness in children and their families has historically resulted in a comprehensive approach toward intervention. Children whose depressive illnesses are complicated by multiple areas of distress (economic adversity, social isolation and family conflict, and a lack of academic success) sustain the highest risk for a poor outcome without family-oriented or environmentally therapeutic intervention. Reasonable and achievable expectations must be set for a child during this time. These expectations should support the child’s successful continuing attainment of important developmental tasks and foster positive self-esteem.

Psychological interventions may include individual therapy, parent guidance, or group therapy. Interventions may occur in the environment of a therapist’s office, in school, at a day treatment program, or most intensively, in a hospital or residential treatment center. The day treatment, residential and hospital settings provide opportunities for special education, group therapy, or behavioral intervention to be coordinated among members of a multidisciplinary treatment team. Comprehensive treatment planning becomes essential in assuring the best fit between child and treatment setting . Most communities endeavor to coordinate diverse intervention needs in the child’s home setting. If necessary, arranging services in a "wrap-around" fashion is accomplished under the direction of a child’s case manager.

Medications are thought of as helpful in alleviating core depression symptoms sufficiently to facilitate the child’s ability to optimally benefit from non-medical interventions in the least restrictive setting possible. There is little empirical data to support the combined use of medications and treatments, or even the combined use of psychosocial treatments in the treatment of childhood depression. This remains an important area for further study.

There are children for whom antidepressant medication alone may be sufficient. Children with less severe symptoms, with strong families and good early social adjustment, or perhaps better school performance, require less intensive intervention than children thought to be at high environmental risk. Some children receive medication alone because they may not have access to comprehensive treatments for reasons related to family resistance, poverty, or managed care restrictions.

There is little doubt that the number of children receiving antidepressants continues to rise. Many of these children may receive more than one medication for severe, complex, or treatment resistant symptoms. Such use has gained momentum through the increased understanding of the biological basis for depression as an illness, and the directed use of medications to alleviate the symptoms of not only major depressive episodes, but co-morbid conditions as well. The ongoing development and availability of new medications with milder side effects, as well as health care financing restrictions limiting access to comprehensive treatments, appear to assure that prescription numbers will continue to grow. In short, children diagnosed with severe depressive disorder, who demonstrate recognizable target symptoms that markedly impair their daily ability to function and develop, such as pervasive sadness or irritability, will be likely candidates for a trial of antidepressant medication.

In 1991, child psychiatrists reportedly prescribed the vast majority of antidepressants to children. According to reports, prescription rates of SSRI’s to children have mushroomed since then. For instance, a four-fold increase in these prescriptions was reported between 1994 and 1996 alone . A child can currently receive an antidepressant prescription from a pediatrician, a family practitioner, or a specialist in neurology or child psychiatry. The combined growth of collaborative partnerships between mental health providers and primary care doctors that support depression screening and "front line" treatment of depression, coupled with the growing comfort with the use of the safer SSRI’s, suggests that antidepressants will be prescribed at high rates by a variety of doctors in the future.

Children on medications should be reassessed frequently for response to medication, reported side effects, and the need for continuing treatment. Children and adults are generally maintained on medication for a period of time after an optimal remission of symptoms is observed. Those who have experienced more than one episode of depression may receive a conservative dose of medication on an ongoing basis. Such decisions take into account the number of depressive episodes and other factors, such as whether severe or life-threatening symptoms, such as hallucinations or suicide attempts, accompany the depression. If a recurrent major depressive disorder can be life-long, it can be assumed that medications will be given on a life-long basis.

Concern about medication safety in children applies to all medications, not only those used for mood disorders. At this time, the vast majority of psychotropic medications (among the approximately 80% of all medications in use with children) are approved by the Food and Drug Administration for use in adults, not children .

Pre-marketing pharmaceutical trials have been criticized for their studies of too few patients for too brief a period of time. These studies have not dealt with long range side effects, rare and serious side effects, or side effects which might develop years after the child has been exposed to the medication studied. In spite of the growing numbers of children receiving multiple psychotropic medications, there are data gaps where the safety of combined medication treatment is concerned .

The research points to the need for the study of treatment combinations involving both medications and psychotherapies or other interventions . The risks of treatment and non-treatment must, however, always be considered in tandem. Would the risks of taking a medication outweigh the risk of not treating the child? Is taking antidepressant alone truly less helpful than combining it with therapy sessions?

The continued use of antidepressants with children demands that active roles are taken by treatment staff and teachers. The following is a list of recommendations for actions, which should be taken by those who have responsibility for children who are being treated for depressive illnesses.

1. Identify the professional prescribing the medications. Discuss with parents or guardians the potential benefit of obtaining a release of information to discuss coordination of care directly with the doctor. Cautious parents may seem initially reluctant; they will appropriately advocate for their child’s privacy. They need to trust that the obtained information will be treated with the utmost care. Collaboration enhances the likelihood of a best critical match of medication and environmental intervention for the depressed student. Astute teachers and staff have even conferenced with prescribing psychiatrists regarding continuing academic failure or clues to worsening signs of depression in children appearing to be non-responsive to their medication.
2. Know and learn more about the diagnosis for which the medication is being prescribed. Pursue information about the illness, its course (for instance, occurrence of seasonal variations in mood disorders), and the way in which it may present in your setting.
3. Learn about the target symptoms for which the medication is being prescribed. This can prove essential in understanding the course of the illness, if the medications are working, and whether there is a relapse occurring after the illness has been in remission.
4. Identify the most frequent side effects associated with the medication and whether they might occur in your setting. Medications may demonstrate distinct variations in effects or side effects in the presence of other medications or at specific intervals following a dose. Through collaboration, important opportunities for identification of side effects will exist.

The immediate, urgent and practical questions regarding the treatment of childhood depression will continue to surface, and will become as sophisticated as the growing medical information base of society at large. Educators and children’s services professionals are uniquely qualified to lend a strong voice to the questioning. They are capable of advocating not only equitable access to the best possible treatment strategies for children with depressive illness, but also scientific vigilance in the development of safe, effective medical interventions. The "front line" professionals can articulate the practical questions and offer reliable observations regarding both beneficial and harmful outcomes of the use of antidepressants in children, given the opportunity.

The increasing scientific appreciation for the biological basis of many childhood mental illnesses will result in the development of new and improved antidepressants, and the ongoing crises in health care financing in this country assures that the overall numbers of children receiving antidepressants will continue to increase . Antidepressants offer hope to many children who do not respond to the psychosocial interventions of the past, yet if not appropriately used they can be harmful. Hopefully, the development of care will increasingly focus not only on the right drug for the right disease in the right child, but on the needed attention to clinical monitoring that puts safety first. This will require medical sophistication and vigilant advocacy on the part of the physician and all helping professionals involved with the child. We should not only appreciate the hope that pharmaceutical advances offer to children; we must be prepared to collaborate in the prevention of harm.