Abstract
Chief Complaint and Presenting Problem
History of Present Illness
B. was described by her mother as having been a quiet child since early childhood. When she was ∼ 5 years old after the World Trade Center attacks on September 11, B. reportedly experienced an episode of mutism. At age 13, 2 years prior to the current admission, she began to refuse to attend school and spent many hours, in the middle of the night, on the computer. Past psychiatric records indicated that she displayed paucity of speech and thought blocking, but no overt hallucinations. She was reported to lie in bed all day and refused to shower or eat regularly. At age 13 she was hospitalized for a suicide attempt after her parents attempted to set limits on her computer use. She was re-hospitalized the following year at age 14 for aggressive behavior in which she threatened her father with a knife for limiting her computer use, locked herself in her room, and scratched her sister. During hospitalization, B. was noted to be selectively mute, disorganized, and oppositional; she was treated with aripiprazole 10 mg and fluoxetine 30 mg and discharged home.
B. was admitted a third time several months later for social isolation, lack of school attendance, and refusal to eat. Aripiprazole was increased to 15 mg daily and fluoxetine to 40 mg daily, and she returned to school. B.'s family and psychiatrist reported that she was doing well 5 months prior to admission, when she was regularly attending school. However, there was doubt that she was fully adherent to her medications. Three months prior to the current admission, as a result of limited improvement and complaints of drowsiness, B. was switched to quetiapine 400 mg and escitalopram 10 mg daily.
One month prior to referral, B. once again stopped attending school, slept all day, played Internet games at night, stopped eating regular meals, lost weight, and stopped taking her medications. She became estranged from her school friends. B. denied any interest in classes, and her academic performance declined to failing grades. She preferred to stay in bed for most of the day rather than go outside, and complained of difficulty sleeping. She was reported to have blunted affect, paucity of thought, and deterioration in functioning.
There was no reported history of manic symptoms, auditory or visual hallucinations, or substance use.
Past Psychiatric History
B. began outpatient psychiatric treatment at age 13 after she was first hospitalized for a suicide attempt and diagnosed with depression. When she was 14, a second hospitalization occurred, this time for aggressive behavior, and a third hospitalization occurred several months later for social isolation and refusal to attend school. During the second hospitalization, records indicate that B.'s diagnosis was changed from depression to schizophrenia. However, the diagnosis was later changed to psychotic disorder, not otherwise specified, in the months prior to admission, because of prominent negative symptoms such as social withdrawal, apathy, lack of motivation to attend school, and minimal spontaneous speech.
Developmental History
B. had no perinatal exposures and was the product of a normal vaginal delivery. Her birth weight was not reported but thought to be average, and she had no postnatal complications. Mother reports that all developmental milestones were within normal limits.
Educational History
B. is currently enrolled in a regular junior high school classroom. However, her attendance was inconsistent in the 8 months prior to admission and had been sporadic for the previous 2 years. Prior to the past 3 years, she had passed all of her subjects and attended school regularly. B. scored in the average range of intelligence on all domains in her intelligence quotient (I.Q.) test within the past year.
Social History
B. was born in Asia and moved to the United States when she was an infant. English is her primary language; her parents speak a Chinese dialect and understand minimal English. B.'s younger sister, age 13, attended Chinese school and interprets for B. and her parents.
B. denies alcohol or illegal substance use, history of sexual/physical abuse, or exposure to violence.
Family History
B.'s parents are married. Her mother is a 45-year-old homemaker; her father is 47 years old and works in a warehouse, stocking products. Mother reports a history of postpartum depression after B. was born. Otherwise, there is no known psychiatric illness, including psychotic disorder, in the family.
Medical History
B. had no previous medical illnesses, surgery, or medical hospitalizations; she does not have any allergies. B. had menarche at age 13 and has had regular menstrual cycles. Current weight is 44 kg, and her height is 152 cm.
All laboratory studies were within normal limits, and there were no thyroid or metabolic abnormalities.
Medication History
B. denies taking any other medications, including vitamin supplements or herbal medicines, other than her psychiatric medications. As outlined in the History of Present Illness, B. had been treated with aripiprazole up to 15 mg, fluoxetine up to 40 mg, quetiapine up to 400 mg, and escitalopram up to 10 mg. She experienced excessive drowsiness on the combination of aripiprazole and fluoxetine.
Mental Status Examination
B. is a slender Asian girl who appeared to be her stated age, was wearing hospital pajamas, not showered, disheveled, and lying in bed throughout the interview. She was generally cooperative, with distant relatedness and intermittent eye contact. She had decreased psychomotor activity but no abnormal movements. When assessed, she had a normal gait. B.'s speech was slow, halting, and soft. She did not clearly articulate her words. She has a noticeable Chinese accent with an abnormal rhythm and intonation. She made few spontaneous comments. She reported her mood as: “I don't know,” and “sad.” B.'s affect was depressed and blunted, but not labile, with reduced intensity.
She displayed concrete thinking. She gave mostly one-word answers with few spontaneous comments and had a paucity of thought content. There was no evidence that she had delusions, paranoia, obsessions, or preoccupations. She denied current suicidal or homicidal thoughts, intent, or plans. She denied auditory, visual, tactile, olfactory, or gustatory hallucinations.
Sensorium examination revealed an alert adolescent who could state her name. She knew she was in a hospital on the 10th floor, but she could not describe what kind of unit she was on.
She was unwilling to perform serial sevens or serial fives. She was unable to focus attention on all questions and had difficulty following discussion. She frequently asked, “What you say?” Memory testing revealed adequate registration, but she was unable to recall three objects in 5 minutes. Distant memory was intact. Calculations, fund of knowledge, and capacity for abstraction were difficult to evaluate as she was uncooperative. Insight and judgment were poor.
Clinical Course
On the unit, B. was selectively mute, somnolent, and spent most of her time lying in bed. During interviews, answers were limited to “yes,” “no,” or “I don't know.” She was unable to report her mood or elaborate on her feelings. She had minimal interaction with peers or staff, refused to attend any unit activities, and ate minimally. She required significant prompting for self-care and activities of daily living. The treatment team assessed her symptoms as those of a severe, nonpsychotic depression with the primary affect of sadness and apathy, associated with poor self-care and poor speech production.
Upon admission, B. was maintained on escitalopram, which was increased to 20 mg daily, as it was felt that she had not had an adequate trial. Quetiapine was discontinued because of the lack of obvious benefit and the absence of a history of frank psychotic symptoms. To rule out catatonic symptoms, a brief trial of lorazepam 1mg p.o. twice daily was started with no significant effect. Two weeks after admission, despite some improvement with the increase in escitalopram, it was felt that adjunctive treatment was indicated. A stimulant medication was chosen to address, in particular, B.'s apathy, low energy, and disorganization. B. was started, with parental consent, on 5 mg extended release (XR) mixed amphetamine salts (MAS) and titrated up to 20 mg daily. Although other adjunctive medications were discussed, agents with sedating side effects were ruled out, as this type of medication had been problematic for B. in the past. In addition, given her notable history of nonadherence, agents such as lithium, which would require close monitoring, were not considered viable options for treatment.
B. subsequently displayed progressively improved mood, energy, appetite, concentration, and speech production. She attended more group activities and engaged more with staff. With increased activity and self-care, B. was more organized in her thoughts and was able to write and express her feelings (in English) to staff and to her parents via an interpreter. However, as she became more active and attended more unit activities, B. had some difficulty with social interactions and at times became disruptive with peers. The treatment team recommended the addition of psychotherapy with a focus on social and coping skills; B. responded well to this, acknowledging that she felt she needed help in understanding how to interact with others. Additional issues that became clear as B. verbalized her thoughts included her low self-esteem, feeling that her parents did not care for her, and frustration with the language barriers that interfered with her relationship with her parents. B. also revealed that she had difficulty with concentration and focus in school.
B. had no electrocardiogram (ECG) changes after initiation of stimulant medication. The only apparent significant adverse effect of escitalopram and MAS was mild insomnia, which was treated with lorazepam at bedtime. B. was discharged to her home with her parents after 8 weeks. Discharge medications included MAS XR 20 mg daily, escitalopram 20 mg daily, and lorazepam 1mg at bedtime. She was discharged with increased supportive services for her family and referral to an intensive day treatment program.
Brief Formulation
In summary, B. is a 15-year-old Asian-American girl with history of a suicide attempt, medication nonadherence, and evidence of major depressive disorder manifested by anhedonia, decreased appetite, decreased energy, sleep disturbance, poor concentration, and social withdrawal. B.'s family history of depression and experience of trauma after the September 11 attacks may be contributing factors to her clinical picture. From a psychological perspective, B. struggled in her relationship with her parents, in part as a result of lack of fluency in their primary language. Although B. was a mid-adolescent, she was socially isolated and demonstrated difficulty making age-appropriate social bonds with peers. From a cultural perspective, B.'s parents do not express a high degree of emotion, which likely contributed to her difficulty expressing her own emotional distress.
B.'s treatment course was characterized by hospitalization for suicidality, aggression, social withdrawal, and symptoms of depression. Differential diagnosis was challenging; an early onset psychotic disorder was initially considered, but a lack of positive symptoms and catatonia were significant factors in ruling it out. During this admission, adjunctive treatment with a stimulant medication was initiated to address B.'s negativism, low energy, and disorganization, and the treatment resulted in significant functional improvement.
Multi-Axial Diagnoses
Discussion
This is an interesting case of a difficult to treat severe mood disorder in an adolescent, for whom a stimulant served as a beneficial adjunct to treatment. B. had a robust response to hospitalization and the addition of MAS to escitalopram, which resulted in significantly improved energy, mood, self-care, and functioning. An important complexity in the presentation was the differential diagnosis of primary psychotic disorder with catatonia versus major mood disorder. As the clinical picture evolved over the course of B.'s admission, the mood features clearly predominated, and lack of response to acute lorazepam was helpful in ruling out acute catatonia.
B.'s depression was difficult to treat primarily in that her social withdrawal, nonattendance at school, lack of communication, and apathy were thought to represent negative symptoms of early onset schizophrenia. Negative symptoms in schizophrenia and major depression can often be confused or may overlap in the course of illness. Once B. was admitted for more in-depth evaluation, a working diagnosis of severe major depression was established, and treatment was begun accordingly. That said, it would be interesting to know whether she would have responded to higher doses of escitalopram alone, a switch to another selective serotonin reuptake inhibitor (SSRI), or an antidepressant from a different class, such as venlafaxine or bupropion. In addition, it would have been helpful to know whether psychotherapy had been attempted in the past and what her response might have been to the combination of antidepressant and psychotherapy.
To date, there is far less literature on treatment-resistant depression (TRD) in children and adolescents than in adults. Adult TRD has been defined in several ways, from failure to respond to one antidepressant or failure to respond to two or more trials of different antidepressant monotherapies, to failure to respond to four or more antidepressant trials, including augmentation, combination, and electroconvulsive therapy (ECT) (Souery et al. 2006). A classic definition for adults is that “depression may be considered resistant to treatment when at least two trials with antidepressants from different pharmacologic classes (adequate in dose, duration, and compliance) fail to produce a significant clinical improvement” (Shelton 2010). In adolescents, studies indicate that only ∼60% respond to a single antidepressant (Brent et al. 2008). In youth, an adequate antidepressant trial is typically at least 8–12 weeks on full dose. Whether B. might have experienced improvement in her symptoms with longer duration of treatment with escitalopram alone remains a question.
In addition, patients who have been misdiagnosed or inadequately treated may be described as “treatment resistant;” therefore, differential diagnosis and adequacy of treatment in terms of dosage and duration of trials are crucial. B.'s case is notable for an evolution of the diagnostic picture over time, which is typical in youth; hence, in her case, it was not so much a misdiagnosis as an unfolding of the diagnosis. Furthermore, patients with comorbidity are more likely to be treatment resistant; perhaps a comorbid diagnosis of attention-deficit/hyperactivity disorder or an anxiety disorder may have rendered B. less likely to fully respond to antidepressants.
According to a recent review by Maalouf et al. (2011), ∼ 40% of depressed adolescents can have treatment-resistant depression. Treatment options include switch to another antidepressant and/or augmentation with another medication (Al-Harbi 2012; Keitner et al. 2012). Brent and colleagues (2008) studied adolescents who had failed to respond to an adequate trial of at least one SSRI in a controlled trial of switch to a second SSRI, switch to venlafaxine, or switch to either plus cognitive behavioral therapy (CBT). Results indicated that the combination of CBT and a switch to another antidepressant resulted in a higher rate of response than a medication switch alone. They also reported that switch to another SSRI was just as efficacious as switch to venlafaxine, and resulted in fewer adverse effects.
As B. had been tried on two antidepressants in the past, the team reviewed several options for adjunctive treatment. A stimulant medication was ultimately chosen to address B.'s clinical picture of apathy, low energy, and disorganization once an active psychotic process was ruled out. Although other adjunctive medications were considered, medication that was likely to be associated with drowsiness or sedation was ruled out, as this had been a problem for B. in the past. Additionally, given B.'s history of nonadherence, addition of medications such as lithium, which would require close monitoring, was also not considered a viable option.
Few studies have focused on treating treatment-resistant depression in adolescents using therapies other than SSRIs, serotonin–norepinephrine reuptake inhibitors (SNRIs), and CBT. The use of stimulants in treatment-resistant depression is not common and has been criticized by many authors (Stotz et al. 1999). However, stimulant use, especially in the presence of prominent fatigue and apathy, is becoming more well established as an adjunct therapy in adults (Howland 2012). Stimulants are already well established in the treatment of severe psychomotor retardation in severely medically ill patients (Walling and Pfefferbaum 1990; Huffman and Stern 2004; Kerr et al. 2012). It is thought by some authors that these beneficial effects could also be observed in medically healthy, depressed patients (Patkar et al. 2006).
Cases of depressive disorders that are refractory to treatment despite intensive antidepressant therapy may benefit from adjunct treatment with stimulants (Patkar 2006; Abolfazil et al. 2011). As stimulants produce a more rapid onset of action than antidepressants (Hare et al. 1962), they have the theoretical advantage of providing benefit in the antidepressant therapeutic latency period and potentiating their effect (Wharton et al. 1971; Feighner et al. 1985). In the practice parameters of the American Academy of Child and Adolescent Psychiatry, stimulants are now indicated in treatment-refractory depression (Greenhill et al. 2002).
Depression in adolescents, unfortunately, has a high rate of recurrence; some studies report recurrence rates >50% (Dunn and Goodyer 2006). Severity of depression and suicidality appear to be robust predictors of persistent depression after 28 weeks of follow-up (Wilkinson et al. 2009). B. had severe symptoms of depression but did not express suicidality during the initial evaluation or throughout her hospital course. She did, however, have a history of previous suicide attempt. Although her past history and clinical phenomenology suggest a high risk of recurrence of symptoms, her outlook will improve if she can maintain adherence to her medication and regular, frequent follow-up with her clinicians.
Disclosures
Dr. Coffey has received research support from Eli Lilly Pharmaceutical, National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS), Tourette Syndrome Association, Otsuka, Shire, Bristol-Myers Squibb, Pfizer, and Boehringer Ingelheim. Dr. Gibbs, Dr. Weis, and Ms. Tan have no disclosures to report.
Footnotes
Acknowledgments
We thank Resham Gellatly, Lindsay Farmer, and Laura Ibanez-Gomez for their assistance in review and preparation of the manuscript.