Depression Pharmacotherapy in an Adolescent with Hodgkin's Lymphoma

Chief Complaint and Presenting Problem

K . is a 16-year-old Caucasian girl in the eleventh grade, diagnosed with Hodgkin's lymphoma (HL) type 4b 4 months prior to referral by the oncology service for depressed mood, anxiety, and passive suicidal ideation.

History of Present Illness

K. had taken four of six doses of chemotherapy when the psychiatry and psychology services were consulted by the oncology service to evaluate her ongoing depression and anxiety. She had a history of depression, attention-deficit/hyperactivity disorder (ADHD), and anxiety, and was being treated by an outpatient child and adolescent psychiatrist. K. had previously been taking escitalopram 20 mg and methylphenidate OROS 36 mg. The oncology service made the recommendation to discontinue the escitalopram and methylphenidate OROS when K. was diagnosed with HL so as to begin chemotherapy, as these medications could interact with the regimen proposed for chemotherapy of HL. K. was started on methotrexate, vincristine, prednisolone, and procarbazine (MOPP) after a 2-week washout period. Her symptoms of depression, anxiety, and poor concentration returned ∼2 weeks after discontinuation of her psychotropic medications, hence the referral.

Upon initial evaluation, K. reported feeling overwhelmed with depressed mood, crying for no apparent reason, sleeping for ∼16 hours per day, decreased interest in her hobbies, isolation from family and friends, decreased energy, increased guilt, poor concentration, and passive suicidal thoughts. She also described anxiety characterized by worrying constantly about making everyone happy; anxiety attacks characterized by intense fear, shortness of breath, palpitations, sweaty palms, with subsequent fear of recurrent attacks. These attacks were usually precipitated by a stressful event; episodes occurred once a month or less. She denied symptoms of agoraphobia, or manic or psychotic symptoms.

During chemotherapy, K. had become nauseated, a common side effect of this regimen, and was started on olanzapine 2.5–5 mg, which is frequently used as an antiemetic by the oncology service. Both the patient and her mother reported that the olanzapine worsened her depression and anxiety ∼1 week after starting it.

Psychosocial stressors that contributed to K.'s mood and anxiety symptoms included social isolation as a result of homeschooling to prevent infection during her immunocompromised state; changes in peer support; and self-image issues including hair loss, significant weight gain due to chemotherapy and steroid use. In addition, changes in family support also contributed; her brother, with whom she was close, had left home for college, and her father became anxious and estranged from her because of her diagnosis. K. restrained herself from talking about her illness for fear of upsetting her parents, and had concerns about failing her classes because she was unable to do the work.

Past Psychiatric History

K. was evaluated by a psychiatrist in the sixth grade and diagnosed with anxiety. She subsequently was treated with psychotherapy for 1 year to address her anxiety, with some improvement. She was diagnosed with dysthymia, generalized anxiety disorder, and ADHD in the ninth grade, when these symptoms recurred. She had been prescribed escitalopram 20 mg and methylphenidate OROS 36 mg at that time, with good symptom resolution.

Developmental History

K. was the product of an uncomplicated pregnancy born at term by normal delivery. Developmental milestones were met within normal ranges.

Educational History

K. was a junior in high school and did well academically until she was diagnosed with HL; at that point she was homeschooled while on chemotherapy. She had not failed any grades, but she had persistent concerns about failing and needing to repeat the grade.

Social History

At the time of evaluation, K. was living with her biological parents who were divorced but living under the same roof for financial reasons. Her older brother, with whom she was quite close, was a freshman in college and lived at school. She had a boyfriend who was supportive. K.'s hobbies included cheerleading, arts and crafts, and visiting friends. She had become withdrawn from peers and friends at school since being diagnosed with HL. K. also described difficulties in her relationship with her boyfriend because she did not want to see him as often.

Family History

Family history is significant for depressive illness in the mother and anxiety disorder in both parents.

Medical History

K. had been healthy prior to her present illness. She had been diagnosed with HL, nodular sclerosing extranodal type, 4 months prior to psychiatric consultation, and had undergone the following procedures: lymph node biopsy, peripherally inserted central catheter (PICC or PIC line) insertion, bone marrow biopsy, and fluoroscopy. Laboratory studies showed pancytopenia with marked derangements in white blood cell morphology, elevated erythrocyte sedimentation rate (ESR) and liver function tests (LFTs), pericardial effusion on echocardiogram, a mediastinal mass, and enlarged lymph nodes.

Medication History

In addition to the MOPP regimen, K. was administered dexamethasone, promethazine, polyethelylene glycol, gabapentin, esomeprazole, ondansetron, and intravenous fluids. Prior to starting chemotherapy, she had been taking escitalopram for anxiety and dysthymia, and methylphenidate OROS for inattention.

Mental Status Examination

Upon evaluation, K. was well groomed and dressed, wearing a wig, pale, fatigued, and moderately overweight. Her affect was constricted, and she appeared sad. Her speech was soft and she reported passive death wishes. K. denied suicidal and homicidal ideation. She also reported low self-esteem, feeling helpless and decreased interest, but normal concentration. Her thought processes were normal.

Clinical Course

Because antidepressants were contraindicated, it was decided that K.'s depression should first be treated with cognitive behavioral therapy (CBT). Escitalopram and methylphenidate had been discontinued for 1 month prior to this time. However, within 1 week of being treated with CBT, her suicidal thoughts became more frequent and distressing, which necessitated starting pharmacotherapy. Multiple medications for depression were considered. All commonly used antidepressants were contraindicated because of concomitant use of procarbazine, which was determined necessary by the oncology team and pharmacist as part of her regimen for her advanced illness.

The following drugs have a warning with concomitant procarbazine use: clonazepam or lamotrigine combined with olanzapine, gabapentin, and quetiapine, as they would increase central nervous system (CNS) depression. We discussed the possibility of using another chemotherapy regimen that did not have a drug that interacted with antidepressants, but because of the late stage of K's disease, her oncologist said that chemotherapy with MOPP or therapies with procabazine would be more potent than those without (i.e., adriamycin, bleomycin, vincristine, and dexamethasone [ABVD]).

K. was subsequently started on quetiapine, as this medication has been shown to be effective in alleviating depression in several clinical trials of adults with bipolar depression, as well as in a trial of adolescents with bipolar depression. Unlike antidepressant medications, quetiapine is not contraindicated for use with the chemotherapeutic regimen. It was titrated up to a total daily dose of 62.5 mg. K's depression showed some response, but she complained of excessive somnolence, fatigue, and low motivation. The dose was then decreased to 50 mg/day. K. continued to complain of significant anxiety symptoms. A routine electrocardiogram (ECG) showed a QT prolongation and sinus tachycardia 1 month after K had started quetiapine. The plan had been to resume K.'s selective serotonin reuptake inhibitor (SSRI) after her chemotherapy. She continued quetiapine use at 50 mg daily, and no new medication was added to her regimen. Her ECG was monitored during weekly visits for chemotherapy. She also continued to receive weekly individual psychotherapy.

During the last week of chemotherapy, K. was examined by her oncologist and found to have new lymph nodes that required biopsy in her left lung and cervical and inguinal regions, consistent with relapsed HL 4 months after beginning psychotropic medication; the decision was subsequently made to prepare her for autologous stem cell transplant. Quetiapine was discontinued and she resumed escitalopram 20 mg after a 2 week washout of procarbazine. Her depression and anxiety improved and she continues to attend psychotherapy sessions. However, she continues to struggle with bouts of depressed mood because of the relapse/treatment failure of HL.

Brief Formulation

In summary, K. is a16-year-old adolescent with a previous history of depression, anxiety, and ADHD, currently diagnosed with stage 4b HL. She presented with a recurrence of depression and anxiety in the context of starting chemotherapy and discontinuation of escitalopram and methylphenidate extended release because of potential drug interactions. Multiple stressors contributed to her clinical picture, including the HL and understandable, developmentally based anxiety about the impact of the illness on her life. In addition, there was a strained relationship between her parents prior to her illness, and her brother, with whom she was close, had left home for college. There was a diathesis for mood disorder, anxiety, and ADHD based on a family history significant for depression, anxiety, and ADHD. In terms of strengths and coping, K. had developed a closer bond with her mother after her lymphoma diagnosis, and her boyfriend and mother accompanied her for chemotherapy appointments, thus providing her some support. Although she was anxious and conflicted, she was hopeful about achieving remission.

Multi-Axial Diagnoses

Discussion

Differential diagnosis of depression and anxiety can be difficult in adolescents with concurrent medical illness, which may be a result of the illness itself, or adverse effects of the medical treatment regimen. In this adolescent, her mood and anxiety symptoms could not be explained by the lymphoma alone. Notably, K. had a previous history of depression and anxiety, and significant genetic loading.

The treatment of depression in HL is quite difficult, and is a pharmacologic challenge. HL is a cancer of lymphoid tissue in lymph nodes and spreads quickly to multiple lymphoid organs. Peak periods of occurrence are in the young (15–35 years) and the aged (≥55 years.) There is a high prevalence of psychological disorders in patients diagnosed with cancer. These include anxiety and posttraumatic stress (25–48%), major depressive disorder (5–42%) schizophrenia (0.5–1.5%), and bipolar disorder (0.4–1.6%) (Zabora et al. 2001; Akizuki et al. 2003; Miovic and Block 2007; Yap et al. 2011). The prevalence of depression and anxiety in children with cancer is 7–32% (Kersun and Elia 2007). Major depressive disorder can be treated successfully with a wide variety of antidepressant medications. But often, contraindications in the presence of cancer medications make treatment of psychiatric illness difficult, given the long treatment course of cancer. There is often the risk of drug–drug interaction when chemotherapeutic agents are given with psychotropic medications; these interactions are thought to cause ∼ 20–30% of all adverse drug reactions (Yap et al. 2008). The risk of drug–drug interactions increases as the number of concomitant medications administered to patients increases (Yap et al. 2011). K's case presented a therapeutic challenge because of these drug interactions.

Procarbazine is an alkylating antineoplastic chemotherapy agent, in the class of monoamine oxidase inhibitors (MAOIs) (Massoud et al. 2004) and, therefore, concomitant use with a typical antidepressant is contraindicated because of drug–drug interactions. Procarbazine metabolism yields azo-procarbazine and hydrogen peroxide, resulting in the breakdown of DNA strands. It also inhibits cytochrome p450, leading to increased effects of drugs metabolized by this enzyme. Concomitant use of the SSRI antidepressants is contraindicated because they can raise blood pressure or cause potentially fatal serotonin syndrome by 5-HT reuptake inhibitory actions. MAOI interactions with antidepressants have been documented in numerous studies. Concomitant use of an alkylating agent and tricyclic antidepressants (TCAs) (Neuvonen et al. 1993), SSRIs, (Graber et al. 1994; Clark et al. 2006), serotonin/norepinephrine reuptake inhibitors, (Hodgman et al. 1997) atomoxetine, mirtazapine (Physicians' Desk Reference 2010, pp. 1957, 3215), could lead to increased risk of CNS toxicity, also known as serotonin syndrome. This is characterized by hyperthermia, rigidity, myoclonus, autonomic instability, and mental state changes including delirium and coma. The causative mechanism is excessive serotonergic activity at synapses and additive MAOI inhibitory activity, in the case of moclobemide.

There are currently no studies on alternatives to antidepressant treatment in youth with malignancies undergoing chemotherapy. Options for use of psychotropic drugs that have minimal interaction with procarbazine include clonazepam, lamotrigine, and second generation antipsychotics. This case presented a therapeutic dilemma as initial treatment with CBT was not sufficient to alleviate the patient's depression.

Our strategies were as follows: CBT was started for K. to alleviate her depression and anxiety with the hope that pharmacotherapy would not be necessary if this worked. Her depression worsened over the week and it was decided that an antidepressant medication would be needed.

Quetiapine was combined with CBT. Quetiapine monotherapy has been shown to be effective in five trials of adults with bipolar depression (Sanford and Keating 2012), as well as in one trial of adolescents with bipolar depression (DelBello et al. 2009). Quetiapine has also been shown to decrease depression relapse, although it was associated with poorer tolerability and side effects than placebo or antidepressants in adult patients with major depressive disorder (Liebowitz et al. 2010). Quetiapine extended release seems to have been more efficacious than short-acting quetiapine, according to the adult studies. Other atypical antipsychotics have limited evidence of benefit as adjuncts to antidepressants (Komossa et al. 2010). For example, aripiprazole monotherapy had little or a deleterious effect with a 5.15% difference in remission rate than placebo on depression (Arbaizer et al. 2009). Lamotrigine was more effective than placebo in one trial of adult bipolar depression, but four other trials were negative. Whereas open studies of lamotrigine in adolescents with bipolar depression have shown promise, there are currently no published placebo-controlled trials of lamotrigine in youth. Of note, all of the trials of non-antidepressants have been in patients with bipolar depression, and there are currently no studies of the efficacy of atypical antipsychotics or other novel medications to treat major depressive disorder. Given that there are a number of pediatric medical illnesses in which antidepressants are contraindicated because of drug–drug interactions (e.g., HL and procarbazine, osteomyelitis and linezolid), it is important for clinicians to identify potential alternatives for treatment for these patients.

Conclusion

There is very little research on treatment of pediatric cancer and comorbid depression with antineoplastic medications in which concomitant use of antidepressants is contraindicated. MAOIs and the antibiotic linezolid are examples of medications that are contraindicated for antidepressant use. There have been no studies of children being treated for HL with procarbazine with comorbid mood problems. Further studies and clinical guidelines for treatment of children with depression, when conventional antidepressants are contraindicated, are necessary.

Disclosures

Dr. Isa and Dr. Miles have no disclosures or conflicts of interest. Dr. Emslie has received research support from Eli Lilly, Forest, GlaxoSmithKline, and Somerset, and has served as a consultant for Biobehavioral Diagnostic Inc., Eli Lilly, Forest, GlaxoSmithKline, INC Research Inc., Lundbeck, Pfizer, Seaside Therapeutics, Shire, and Wyeth Pharmaceuticals, and has been on the Speakers Bureau for Forest.

Dr. Coffey has received research support from Eli Lilly Pharmaceutical, the National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke (NINDS), Tourette Syndrome Association, Otsuka, Shire, Bristol-Myers Squibb, Pfizer, and Boehringer Ingelheim.