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C. is a 15-year-old Caucasian male who lives with his parents and 10-year-old sister. He was initially brought to the clinic for a psychiatric evaluation after expressing suicidal ideation to his parents. For the past two years, C. has been experiencing increasing depression and irritability.
C. first began to experience symptoms of depression at age 13. At that time, C. had become rejected by and isolated from his peers at school. He became increasingly sad, irritable, socially withdrawn, and discouraged with his schoolwork. A number of additional stressors occurred over the next two years, including a diagnosis of inflammatory bowel disease, the loss of his grandparents with whom he had a close relationship, a change of school, diagnoses of life-threatening illnesses in his father and uncle, confusion over his sexuality, and a break-up with his girlfriend. C.'s mood became increasingly unstable throughout this period. C. began individual psychotherapy for depressed mood in seventh grade, and continued with this treatment inconsistently until ninth grade. He was prescribed bupropion hydrochloride by his pediatrician during the eighth grade, after he changed schools and developed interpersonal struggles with his new teacher. The dosage was increased to 300mg within three weeks. However, C. and his parents decided to stop the medication after he began to date a girl and appeared to be feeling better.
Most recently, over the past several months, as reported by parents and the patient, C. has experienced depressed mood, hopelessness, worthlessness, guilt, low self-esteem, loss of interest in soccer and other sports, fatigue, impaired concentration, restlessness, and passive suicidal ideation. Bupropion was resumed approximately two months prior to C.'s initial evaluation due to worsening of mood. However, C. reported increased anxiety and lack of therapeutic response while he was taking the medication. One month prior to the evaluation, C. attempted to drown himself in the bathtub. He also acknowledged cutting his forearm a number of times in the past. C. denied that cutting himself was a suicidal act, but instead stated his intention was to “decrease emotional pain.”
C. reported drinking alcohol to “get drunk” and self-medicate in the several months prior to the evaluation. He had smoked marijuana occasionally in the past; however, he had not done so within the past six months.
C. denied suicidal intent or plan, and symptoms suggestive of mania or psychosis including racing thoughts, hearing voices, reduced need for sleep, grandiosity or delusional thinking.
Past history, as reported by his parents, was notable that, as a young child, C had difficulty sustaining attention, was disorganized, forgetful, easily distracted, hyperactive (as if “driven by a motor”), and forgetful. In second grade, C. was diagnosed with attention-deficit/hyperactivity disorder (ADHD), combined type, and was prescribed methylphenidate. He subsequently developed motor tics, and the medication was discontinued.
C. received individual psychotherapy between Grade 7 and 9, but inconsistently. C.'s most recent neuropsychological evaluation at age 14 years revealed a disorder of written language and a reading disorder, as well as confirmation of his diagnosis of ADHD, combined type.
C. was the product a full-term pregnancy complicated by preeclampsia. Delivery was vaginal with forceps. As an infant, C. was described as hyperactive; he cried excessively and was difficult to soothe. Furthermore, he had difficulty sleeping and feeding and was hypersensitive to sound. Most motor milestones were attained early, however language development was delayed. He received occupational and speech therapy beginning in the first grade.
C. was evaluated by the Board of Education in kindergarten and again in second grade. When C. changed schools in the middle of eighth grade, he was provided with special education services. C. is now a tenth grade student at a public high school. He was taken out of the special education program this year and is now in mainstream classes with resource room supports. C. reported that he does not like the school he currently attends and described feeling unmotivated and uninterested there.
C. experienced significant peer rejection toward the latter half of the seventh grade. Since then, he has struggled to feel like he “fits in” at school and denied having friends there. C. reported having friends from his neighborhood with whom he plays in a band. He reported that he is satisfied with these friends and was not interested in making additional friends at school.
C.'s mother, age 45, has a history of systemic lupus erythematosis. She also reports a history of depression, including a postpartum episode after the birth of her second child. She is currently treated with escitalopram. Maternal pedigree is significant for a history of anxiety and depression in other relatives.
C.'s father, age 48, has cirrhosis secondary to hepatitis C and also has a history of depression treated with escitalopram. He also has a history of learning difficulties, and possible ADHD. C.'s paternal grandfather is reported to have had a history of alcohol abuse and depression.
C.'s sister, age 10, was diagnosed with rheumatic fever in the past.
C. was diagnosed with inflammatory bowel disease at age 14; however, recent biopsy does not fully confirm the diagnosis. During a flare, he has stomachaches and diarrhea several times a week. Unfortunately, steroid treatment exacerbated the condition. He currently takes only lactose pills. C. has a history of leukopenia; hematological work up was within normal limits.
C. was treated with methylphenidate (immediate release,) 5mg po tid in Grade 2, which was associated with motor tics and it was discontinued. A trial of bupropion up to 300mg in Grade 8 was equivocal. Medication at the time of initial evaluation was bupropion 300mg.
C. is an attractive Caucasian male who appeared his stated age of 15 years old. He is of normal height. He is, however, quite thin and appeared underweight compared with other teenagers his age. He was dressed casually and age appropriately. C. was cooperative throughout the interview, and openly shared information about himself. He maintained adequate eye contact; mild, intermittent facial grimaces and eye blinking were noted. C.'s mood was depressed and affect was constricted. His speech was of normal rhythm, volume and rate, and his thought process was goal-directed. He spoke about his negative perception of life and was focused on his ex-girlfriend, who he stated he missed very much. He denied auditory and visual hallucinations, as well as delusions. C.'s recent and remote memory were intact. He demonstrated good insight and fair judgment. Although C. reported passive suicidal ideation, he denied active suicidal ideation, plan or intent and homicidal ideation.
On the Beck Depression Inventory, C.'s symptoms yielded a score in the severe range. On the Beck Suicidal Scale, C. reported that he did not wish to live and in fact, wanted to die.
In summary, C. is a 15-year-old mid-adolescent with a school-age history of ADHD, combined type, chronic motor tics, and disorders of written language and reading. He presents with at least a two-year history of adolescent-onset major depressive disorder, characterized by depressed mood, anhedonia, impaired concentration, and fatigue.
Family history contributes a strong diathesis for mood and anxiety disorders, given depression in both parents. Medical history contributes leukopenia of unknown origin and inflammatory bowel disease.
C. has several important strengths, including solid peer relations and musical interests, and appeared to be on a positive developmental trajectory for mid-adolescence prior to the onset of illness. He appears to have been significantly derailed at that time due to his symptomatology and at risk for serious complications of adolescent-onset affective illness including development of mania, substance abuse, and suicide.
Multi-modal treatment, including medication and biweekly cognitive behavioral therapy was recommended following C.'s initial evaluation. Fluoxetine 5mg was initiated and very slowly increased to 10mg with evidence of therapeutic benefit in terms of improved mood, energy, and concentration. Bupropion hydrochloride was gradually decreased from 300mg to 200mg. Approximately two months into treatment, C. impulsively took 16 ibuprofen pills and a “shot” of Nyquil. In addition, he reported cutting himself (two small cuts near wrist, no medical attention required), and shooting his forearm with a BB gun three times (three circular bruise marks, skin was not punctured) after unexpectedly being contacted by his ex-girlfriend. Although he denied suicidal intent during these actions, he was unable to contract for safety.
Notably, the suicide attempt occurred two days after fluoxetine was increased to 15mg. C. was subsequently admitted voluntarily for a psychiatric hospitalization. Fluoxetine was increased to 20mg and gradually to 25mg while bupropion hydrochloride was gradually tapered and discontinued during the hospitalization. Over the next two months of treatment C. experienced increased agitation, onset of panic symptoms, mood swings, and began to drink alcohol more regularly. Depression and suicidal ideation fluctuated in intensity on a weekly basis.
Brief trials of augmentation with low dose risperidone (0.125mg/QHS), aripiprazole (1mg/QHS) and lorazepam (0.25mg/QHS) resulted in severe drowsiness. Fluoxetine was decreased again to 20mg, and clonazepam 0.125mg QHS was initiated with good therapeutic response with respect to anxiety, sleep difficulties, and restlessness.
C. was initially motivated to engage in psychotherapy and expressed a desire to improve his mood and decrease his suicidal ideation and self-harm behavior. His treatment plan included the following goals: 1) learn and utilize emotion regulation skills to elevate mood and decrease irritability, 2) learn and utilize distress tolerance skills to decrease suicidal ideation and urges to engage in nonsuicidal self-harm behavior, 3) engage in exposure to decrease avoidance of negative and anxiety-provoking situations, and 4) improve peer and family relationships through the use of interpersonal effectiveness skills.
At present, while there has been improvement with respect to C.'s depressive symptoms, he has not been able to attend school regularly. He has been unable to actively engage in treatment; rather he reports that he is “not ready” to fight his depression and he would prefer to “wait it out.”
C. is a complex young man whose treatment course illustrates some of the challenges of treating adolescent depression. Depression is a serious illness in youth; up to 8% of adolescents meet criteria for major depressive disorder (Birmaher et al 1996) and the life-time rate may be even higher. Among the many interesting issues this case illustrates are 1) differential diagnosis of major depression in adolescents and risk for bipolar disorder, 2) complications of untreated adolescent depression, such as substance abuse and/or suicide, 3) treatment adherence in adolescents, which is often less than optimal, 4) role of family in treatment of depressed adolescents, and 5) development of suicidality in association with antidepressants in youth.
From the diagnostic standpoint, it is very important to recognize the depressed adolescent's potential risk for the development of bipolar disorder. Studies suggest that 10%–20% of youth with onset of depression in adolescence will go on to develop mania (Rao et al 1995). Adolescents with a family history of mood disorders, especially bipolar disorder, appear to be at higher risk for the development of mania (LaPalme 1997). Studies have also identified risk of switch into mania in association with antidepressant treatment in depressed youth. (Martin et al 2004)) Given C.'s recent development of mood swings, agitation, and increased use of alcohol while receiving antidepressants, and strong bilineal family history of affective illness, mania must be kept in mind as a significant possibility. It also appears that C.'s use of alcohol increased in association with the advent of mood swings and agitation, putting him at risk for ongoing substance use disorder, another complication of adolescent onset major depression.
Although most medication guidelines or algorithms for treatment of adolescent depression start with selective serotonin reuptake inhibitors (SSRIs) (TADS 2004; Brent 2008), there was a rationale for the choice of bupropion hydrochoride as the first antidepressant by C.'s pediatrician. Given C.'s childhood diagnosis of ADHD and mood and school difficulties, it was not an unreasonable choice. However, adherence to the treatment regimen was less than optimal, so it was unlikely that C. had an adequate trial. It is also notable that after several attempts at augmentation of fluoxetine with atypical neuroleptics, clonazepam was the only medication that was described as having therapeutic benefit. Positive response to the benzodiazepine would also raise the question of whether C. had developed a comorbid anxiety disorder, or at least significant anxiety symptoms, during the course of treatment.
A primary issue of interest illustrated by this case is the role of antidepressants in the development of suicidality in young people. Most antidepressant clinical trials in youth and adults with depression have excluded individuals with a history of suicidal behavior. The United Kingdom was the first to report an increased risk of suicidal behavior in depressed youth treated with antidepressants, specifically an SSRI, in June 2003. In December 2003, the United Kingdom's Committee on Safety of Medicines (CSM) stated that the risks outweighed the benefits for all SSRIs, except for fluoxetine, in the treatment of major depression in youth (CSM 2004). In October 2004, after public hearings and a meta-analysis of short-term placebo-controlled trials of nine antidepressant medications including tricyclics, bupropion and SSRIs, the U.S. Food and Drug Administration (FDA) issued a black box warning regarding increased risk of suicidal behavior associated with these medications, advising balance of need versus risk. (Hammad et al 2006). Following the FDA's black box warning, the use of antidepressants in youth declined.
Unfortunately, after a decade of declining adolescent suicide rates prior to 2004, the suicide rate climbed 18% after 2004 (Hamilton et al 2007). Wisely, the FDA recognized that classification of suicidal events in clinical trials had not been systematic, and subsequently commissioned Kelly Posner, Ph.D., and colleagues to develop a clinically meaningful and reliable classification system. The conundrum for investigators is to carefully sort out the risk for suicidal behavior associated with antidepressants versus the protective effects of antidepressants against suicidal behavior (March et al 2006; Brent 2007). Following the FDA-issued black box warning, Simon et al, in a large data base of outpatient claims from a prepaid health plan, compared the rate of suicide attempts in the 90 days before and 180 days after treatment (either antidepressants or psychotherapy) was initiated (Simon et al 2006). The authors reported that the peak period of attempts was in fact, in the month before treatment was initiated, suggesting that a suicide attempt was a common precipitant for treatment and not a result of treatment.
Unfortunately, observational studies and individual case reports cannot demonstrate causality (Jick et al 2004). However, in C.'s case, although there was a temporal correlation between the increase in fluoxetine dose and the advent of suicidal behavior, C. had demonstrated this behavior prior to treatment with fluoxetine; in addition, since he was not always compliant with bupropion alone, it is not clear if the association was the case with bupropion.
One way to address this issue of antidepressants as risk versus protective factors in treatment of depressed youth is to include patients with suicidal behavior in clinical trials; as an example, the National Institute of Mental Health (NIMH) funded Research Units in Pediatric Psychopharmacology (RUPP) Treatment of Adolescent Suicide Attempters Study (TASA) (2002–2007) is currently analyzing results of the first systematic study of youth, ages 12–18, with a history of nonbipolar depression and at least one suicide attempt. Results should be available later this year.
Given C.'s lack of full adherence to treatment, a more complete understanding of his resistance and development of a strong therapeutic alliance with the parents are essential next steps. Continuation of fluoxetine and cognitive behavior therapy are indicated, with periodic family meetings to improve compliance. Consideration of switch to escitalopram, given both parents' positive response is recommended. In addition, augmentation with lithium could be considered, both for its anti-suicidal effects and potential for leukocytosis.
Dr. Coffey has received research support from Eli Lilly Pharmaceutical, NIMH, NINDS, Tourette Syndrome Association, Bristol Myers Squibb, and Boehringer Ingelheim. She is on the Advisory Board for Novartis and for Jazz Pharmaceuticals. Dr. Gabbay has received research support from American Foundation for Suicide Prevention, Boehringer Ingelheim, National Institute of Mental Health, National Center for Complimentary and Alternative Medicine, and Tourette Syndrome Association. Dr. Spindel has no financial ties or conflicts of interest to report.