from Brown University Child and Adolescent Psychopharmacology Update

E. Jane Garland, M.D., clinical associate professor of psychiatry and Elizabeth A. Baerg, M.D., clinical assistant professor of psychiatry at the University of British Columbia's Children's Hospital in Vancouver, Canada, report on five patients with dose-dependent, reversible frontal lobe (amotivational) syndrome characterized by delayed onset after treatment with fluoxetine and paroxetine, two selective serotonin reuptake inhibitors (SSRIs) commonly prescribed to treat adolescent depression.

A frontal lobe syndrome characterized by apathy, indifference, loss of initiative and/or disinhibition has developed in some adults during SSRI therapy but has not been previously reported in the pediatric population (Hoehn-Saric et al. 1990). In each case the patient had a significant change in behavior, which included becoming indifferent toward work performance, exhibiting impulsive and disinhibited behavior, or developing poor concentration and forgetful behavior (Hoehn-Saric et al. 1991).

Although a frontal lobe syndrome may be rare, it is important to consider, as its symptoms could be easily misinterpreted. Apathy and indifference could be mistakenly attributed to depressive symptoms or sedation; impaired judgment and disinhibition could be attributed to hypomania-induced behavior.

According to Garland, delayed onset is a consistent feature in both adult and child cases, although there is presently little understanding behind the late onset of symptoms.

"One hypothesis is that it only becomes evident as the primary condition remits and function returns. However, the common pattern is a period of 3-4 weeks or a month of good functioning before it is evident. Another hypothesis is that there is some neurochemical adaptation occurring, perhaps involving the dopaminergic system, or even the complex network of serotonin receptor subtypes," says Garland.

Case Report 1

The first case involves a 14-year-old male who sought treatment for major depression. The patient had one prior history of major depression a year earlier and a premorbid history of subclinical social anxiety and over-anxious traits. The first episode of depression was treated with St. John's Wort and symptoms resolved.

The patient was given imipramine but treatment was discontinued when depressive symptoms failed to resolve at 50 mg and anticholinergic side effects and tachycardia were present. The patient was then treated with 20 mg paroxetine and experienced full remission after six weeks of treatment.

At follow-up a month later, the patient was depression-free but had the mask-like flat affect attributed to parkinsonism. No muscular rigidity, tremors or other extrapyramidal side effects were present. The patient's apathy concerned his parents and the clinician, although he seemed unaware of any problems. Treatment was reduced to 10 mg paroxetine and some improvement in flat affect was noted and the patient's depressive symptoms did not reoccur. However, due to concerns about the patient's apathy and continued flat affect, treatment was reduced sooner than planned (after four months of remission) to 5 mg paroxetine and subsequently discontinued altogether a month later.

Case Report 2

The second case involves a 15-year-old male athlete with a mixed anxiety disorder that combined a specific performance anxiety with a history of inhibited temperament and trouble adjusting to change. The patient's family sought the help of a psychologist to help alleviate the patient's test anxiety. This failed to resolve the patient's anxiety, which was observed by the psychologist to be more consistent with "freezing up" rather than anticipatory worrying. The family agreed to pharmacotherapy if it did not interfere with sports performance.

The patient was given 10 mg fluoxetine daily. After four weeks of treatment he reported improvement in test anxiety and improved grades. His parents and coach also noted positive results on the sports field. However, 10 weeks after treatment initiation with fluoxetine, the parents, the coach and a teacher expressed concern over the patient's apathy toward schoolwork and major team losses. Other reports included increased "irresponsibility," including losing items of clothing and failure to do chores. The patient appeared calm and unconcerned when confronted about his behavior, as he did not recognize a problem.

Medication was stopped and within a month the patient returned to "his usual self." Two months later, however, the patient requested treatment with a lower dose of fluoxetine because his anxiety returned. Treatment with 2.5 mg fluoxetine was started and the positive benefits returned minus the amotivational features.

Case Report 3

The third case involves a 14-year-old male who was given 30 mg fluoxetine to treat obsessive-compulsive disorder (OCD). He experienced an over 50 percent reduction in symptoms and was able to manage residual symptoms successfully with cognitive behavioral strategies. However, a half-year later, the patient's symptoms became disabling.

The dose was titrated upward to 40 mg. During the next two months, a change in behavior was noted, as the boy became unconcerned about school and about helping his mother. At six-week follow-up, the patient had a flat affect and seemed emotionally removed and apathetic. The patient was not distressed about his situation despite a significant drop in his grades, and reported feeling good due to relief of his obsessive thoughts.

Over the next two months, the patient was closely monitored and more structure was implemented, with some success reported, although the patient's grades continued to be lower and he had noticeably decreased motivation during sports. Despite these symptoms, the mother and patient were reasonably satisfied with treatment, as the patient was relieved of the more worrisome obsessive thoughts. However, a future trial of dose reduction and increased cognitive-behavioral treatment were strongly encouraged by the clinician.

Case Report 4

The fourth case involves a 10-year-old female with acute OCD characterized by repeated thoughts about killing herself or family members. The patient had no prior history, although she had an inhibited temperament and was described as "sensitive."

The patient was given 10 mg paroxetine. The dose was increased to 20 mg and she experienced a 50 percent improvement in symptoms. The patient's dose was further increased to 40 mg two months later and she experienced full remission.

The patient's mother reported problems with disinhibition, which were present after dose increase to 30 mg and then worsened at 40 mg. The patient asked inappropriate questions and had problems with interpersonal boundaries. When describing inappropriate actions to the clinician, the patient seemed unconcerned and had a flat affect. The parents also reported diminished interest in schoolwork but wanted to continue treatment because the obsessive thoughts were more distressing.

The parents requested a dose reduction a few weeks later, however, when disinhibition became more problematic. The dose was decreased to 30 mg and symptoms related to disinhibition decreased at week 2 but returned a few weeks later. The dose was further decreased to 20 mg and disinhibition resolved but obsessive thoughts increased. Cognitive-behavioral therapy was recommended to manage the obsessive thoughts. When the dose was later reduced to 10 mg, the patient's affect became fully responsive, and the parents noted that their daughter appeared to have her "usual sparkling personality."

Case Report 5

The last case involves a 17-year-old female with "depressive disorder characterized by recurrent and chronic symptoms of mild major depression with irritability and affective instability." The patient had a (mild) prior history of attention-deficit disorder on parental report but not on teacher rating scales. The patient was an average student, played sports, worked part time and had a history of family conflict.

The patient was given 20 mg fluoxetine and depressive symptoms and irritability improved. When the patient was seen a few months later, she reported smoking marijuana daily but planned on scaling back her use because sports activities were about to begin. The patient's dose was increased to 30 mg. The patient reported improved mood and her parents reported that she was less irritable.

However, when compared with her previous lability, she was unmotivated and had a flat presentation. (During this time, the patient denied using marijuana and was deemed a reliable source.) The patient's dose was further increased to 40 mg to treat any residual depression; her mood appeared stable and her parents reported resolution of irritability. However, during the next month, the patient lost interest in sports and socializing, and was apathetic with a flat affect. The patient seemed unaware of any problem other than some "mental tiredness."

The parents were happy that her volatility had subsided but the psychiatrist expressed concern about the patient's clinical presentation, loss of goals and lack of motivation. Fluoxetine was subsequently decreased over the next two months to 20 mg and 150 mg bupropion was added to her regimen. The patient's affect normalized and her motivation and initiative improved.

Conclusions

"Clearly, it is important to weigh the risks and benefits [of treatment with SSRIs] carefully with children and families," Garland says. "A good measure is overall function in various dimensions of life. A young person who is apathetic may be easier to parent in some ways, but the negative effects on academic and social functioning with peers needs to be considered. This takes ongoing monitoring and negotiation, and input of various observers, including teachers."

Garland concludes, "These case reports remind us that intermediate term side effects, such as the more common sexual side effects and less common amotivational syndrome, require awareness on the part of the treating physician, and specific inquiry as patients may not bring them up spontaneously."

"These case reports also draw attention to the complex neurochemical effects of medications which overall have a relatively benign profile of side-effects.what this means for longer-term use, over several years, is less clear. While these medications clearly improve symptoms and quality of life tremendously, we need to keep an open mind and clinical awareness for new patterns of unexpected effects."